BCAAs and Decompensated Liver

BCAAs in liver transplantation

The detrimental effect of malnutrition on the outcome of patients undergoing liver transplantation has recently been confirmed (46). These patients constitute a specific group in which to test the efficacy of nutritional supplementation with BCAAs, both before transplantation, to prevent progressive malnutrition, and after surgery, to increase the rate of recovery. The altered amino acid turnover of cirrhosis seems to normalize after liver transplantation (47), but BCAA levels fail to normalize >6 mo after transplantation (48). In children awaiting liver transplantation, a BCAA-enriched formula (BCAA, 31% of total protein intake) improved growth and the overall nutritional status, but the incidence of postoperative complications was not different (44).

In adults, 7-d postoperative total parenteral nutrition with either a standard or a BCAA-enriched formula (1.5 g protein · kg body weight^–1 · d^–1; BCAAs, 0.60 g/kg) was better than nutrition with glucose alone (45). The rapid achievement of nitrogen balance was accompanied by improved respiratory muscle function and more rapid recovery, with a shorter period of intensive care treatment. No specific effects of BCAA supplementation were demonstrated, but the limited sample size carries a high risk of type 2 error.

In summary, cirrhotic patients undergoing liver transplantation remain a select group who might take great advantage of the theoretical beneficial effects of BCAA supplementation, and new studies are needed.

Mechanism for BCAA effectiveness in advanced cirrhosis

The beneficial effects of BCAAs in a variety of liver diseases raise questions as to the mechanism of improved liver function. In experimental animals and humans, liver resection stimulates a regenerative response, mediated by circulating factors, including HGF, a pleiotropic substance with mitogenic activity (13), which also prevents hepatotoxin-mediated liver damage. HGF is secreted by hepatic stellate cells, and BCAAs, specifically leucine, are potent stimulators of HGF production (14). Accordingly, BCAAs not only provide substrates for protein synthesis but also accelerate the biochemical machinery, which facilitates liver regeneration, compensating for progressive liver-cell death. The simultaneous activation of mammalian target of rapamycin signaling in the liver, a well-demonstrated effect of BCAAs, promotes albumin synthesis in the liver (49) and protein and glycogen synthesis in the muscle tissue. All these effects will ultimately be beneficial in poor-risk patients with advanced cirrhosis.

Dietary management of hepatic encephalopathy in cirrhotic patients

Hepatic encephalopathy is a syndrome of impaired mental status and abnormal neuromuscular function which results from major failure of liver function. Important factors contributing to it are the degree of hepatocellular failure, portosystemic shunting, and exogenous factors such as sepsis and variceal bleeding.³ The pathogenesis of the syndrome is still uncertain, although current hypotheses include impaired hepatic detoxification of ammonia absorbed from the gut⁴ and an increase in aromatic amines, which are precursors for false transmitters in the brain.

Protein restriction in symptomatic patients with hepatic encephalopathy has been the cornerstone of treatment since the 1950s,² yet there is no evidence that it has any clinical benefit. 

This practice continues despite evidence showing that patients with stable cirrhosis have a higher protein requirement than normal, around 1.2 g/kg dry body weight to remain in positive balance.⁷

Protein energy malnutrition, defined by anthropometric criteria, may occur in 20-60% of patients with cirrhosis depending on the severity of the liver disease.⁸ It is a common finding, with causative factors which include anorexia, nausea, malabsorption, and a hypermetabolic state. Intake may be further reduced by use of unpalatable low protein diets, already restricted in sodium and fluid.

In 1997 the European Society for Parenteral and Enteral Nutrition published consensus guidelines recommending that the daily protein intake in patients with liver disease should, if possible, bearound 1.0- 1.5 g/kg depending on the degree of hepatic decompensation.⁷ The guidelines also recommended that in patients who were intolerant of dietary protein 0.5 g protein/kg should be used transiently and that the remainder of theirrequirements should be achieved by giving branched chain amino acids.⁹  Furthermore, aggressive enteral nutritional support of patients with alcoholic liver disease accelerates improvement without exacerbating hepatic encephalopathy.¹¹ Taking smaller meals more often and eating a late evening meal also improve nitrogen balance without exacerbating hepatic encephalopathy.¹² This may also be achieved with vegetable protein as opposed to animal proteins.¹³ 

Hepatic encephalopathy and liver cirrhosis

Hepatic Encephalopathy

Hepatic encephalopathy is potentially reversible abnormal brain function that occurs in liver failure. It can occur as a complication of cirrhosis or if the liver fails or in acute (sudden onset) liver failure. Hepatic encephalopathy occurs as the liver fails to remove certain toxic substances generated in the gut from the bloodstream. A normally functioning liver removes these toxins from the blood before they reach the brain. In cirrhosis, some blood leaving the gut bypasses the liver as blood flow through the liver is decreased. Metabolism of the substances is also decreased as liver cell function deteriorates. Ammonia, which is one of the potentially substances toxic to the brain, accumulates in the blood as the liver fails and can be measured by routine blood testing.
The signs of hepatic encephalopathy can range from subtle to dramatic. In its early stages, hepatic encephalopathy is characterized by subtle mental changes such as poor concentration, confusion and difficulty sleeping can occur. Some patients sleep during the day and stay awake at night. The inability to do simple constructive tasks, such as make a six-point star or do a child’s “connect the dots” picture is also an early subtle sign. In some cases, a flapping tremor known as asterixis, usually best observed in the hands, occurs. In severe cases, hepatic encephalopathy can lead to stupor, coma, brain swelling and death.
Signs and symptoms of hepatic encephalopathy can be aggravated by concurrent metabolic problems that occur with liver failure. Infection and bleeding into the gastrointestinal tract are common aggravating factors. Drugs such as narcotics, benzodiazepines, diuretics and alcohol also make signs and symptoms worse. High dietary protein intake can also worsen hepatic encephalopathy.
Several interventions can reverse hepatic encephalopathy. Improvement of even subtle signs and symptoms, such as sleep problems or mild concentration problem, will greatly benefit a patient. Commonly used treatments include reduced protein intake, lactulose and the antibiotic neomycin. However, there are major drawbacks with these treatments, including protein malnutrition and significant diarrhea.

Malnutrition in Liver Disease

The liver is responsible for the metabolism of many hormones that have discordant effects on protein, carbohydrate, and lipid metabolism, including insulin, the sex hormones, insulin-like growth factors, and glucagon. It is thus not surprising that chronic and acute liver disease can profoundly alter nutritional status and amino acid metabolism.

The prevalence of malnutrition in patients with liver disease varies from 10% to 100%, depending largely on the method of nutritional assessment performed and the population studied. Protein-calorie malnutrition (PCM)⁵ can be observed in all clinical stages but is more frequently seen in advanced stages of liver disease (1). Alcoholic liver disease is the form of liver disease most frequently associated with PCM. Reported prevalences of PCM are between 20% for patients with compensated alcoholic liver disease in the community and 100% in hospitalized patients with acute alcoholic hepatitis (2). Reliable data based on a detailed nutritional assessment of the prevalence of PCM in patients with nonalcoholic liver disease are relatively scant. In a study by Morgan et al. (3), 40% of patients with primarybiliary cirrhosis were found to have evidence of PCM vs. 12% of patients with chronic hepatitis.

The pathophysiology of malnutrition in liver disease is complex and multifactorial. Contributing factors include diminished intake, increased requirements (e.g., due to ascites formation and maldigestion), altered substrate utilization (characterized by lowered respiratory quotients), and altered protein and amino acid metabolism.

When the liver fails acutely, it is the loss of hepatic regulation of protein metabolism that results rapidly in death. The alterations in amino acid metabolism associated with liver disease are characterized by low levels of circulating BCAAs (leucine, isoleucine and valine), elevated levels of circulating aromatic amino acids(phenylalanine, tryptophan and tyrosine), and methionine (4). It is widely believed that the changes in amino acid metabolism play a role in the pathogenesis of many of the complications of cirrhosis, such as portosystemic encephalopathy. Cirrhosis is often associated with a) increased endogenous leucine flux, an indicator of protein breakdown and leucine oxidation; and b) decreased protein synthesis response to a meal.

The presence of malnutrition has been variably associated with increased short- and long-term mortality in patients with acute and chronic liver diseases (5,6). Preoperative malnutrition has also been reported to be associated with increased operative blood loss, longer lengths of stay in intensive care units, increased mortality, and higher total hospital charges after liver transplantation (7). Furthermore, malnutrition is associated with its own morbidity in patients with acute and chronic liver disease, for example, cognitive dysfunction and dermatological manifestations of zinc deficiency. In this setting, nutritional therapy, particularly BCAA supplementation, is an attractive concept in the prevention and treatment of complications.

 

Hepatic Encephalopathy

What Is Hepatic Encephalopathy?

Hepatic encephalopathy refers to the changes in the brain that occur in patients with advanced acute or chronic liver disease. If liver cells are damaged, certain substances that are normally cleansed from the blood by the healthy liver are not removed (ammonia mainly, and other toxins). A patient with chronic hepatic encephalopathy may develop progressive loss of memory, disorientation, untidiness, and muscular tremors, leading to a form of chronic dementia. The ingestion of protein invariably aggravates these symptoms.

The treatment of hepatic encephalopathy involves, first, the removal of all drugs that require detoxification in the liver and, second, the reduction of the intake of protein. Restricting the amount of protein in the diet will generally lower the levels of amino acids and ammonia in the bloodstream and brain. Most physicians advise their patients with this condition to eat only about 40 grams of protein a day, and will prescribe lactulose or neomycin to lower amino acid production. Non-meat proteins, such as those found in vegetables and milk, are preferred. Certain amino acids are used in treatment, since they are considered less likely to cause mental impairment. A dietary supplement rich in these amino acids is used at many liver treatment centers.

http://hepatitis-central.com/hcv/whatis/encephalopathy.html

Hepamin and Your Liver

Liver is an interesting organ with high regenerative capacity and complex functions (Michalopoulos and DeFrances, 1997; Taub, 2004; Michalopoulos and Khan, 2005c;Fausto et al., 2006). Liver receives all exiting circulation from the small and most of the large intestine, as well as spleen and pancreas, through the portal vein. Its “strategic” location in relation to the food supply via the portal vein, and the unique gene-and protein-expression patterns of hepatocytes (the main functional cells of the liver) allow it to function as a biochemical defense against toxic chemicals entering through the food and as a re-processor of absorbed food ingredients. Nutrients entering the liver are transformed into secreted proteins (albumin, most coagulation factors, several plasma carrier proteins etc. in the peripheral blood), lipids sent as lipoproteins into the other tissues, carbohydrates stored in the liver as glycogen (the main glucose reserve used for stabilization of glucose levels in the blood). Synthesis of bile is essential for absorption of fat and lipophilic nutrients. As a major regulator of plasma glucose and ammonia levels, liver is essential for optimal function of the brain. Loss of liver function leads to chronic “hepatic encephalopathy” and eventually coma. The wide array of functions performed by liver towards the rest of the body has been safeguarded by evolutionary events which imparted to liver a phenomenal capacity to regenerate. This process allows liver to recover lost mass without jeopardizing viability of the entire organism. The phenomenon of liver regeneration following loss of liver mass is seen in all vertebrate organisms, from humans to fish. It is also triggered when livers from small animals (e.g., dogs) are transplanted to large recipients of the same species. It has been recorded and mythologized in ancient times from the myth of Prometheus and libraries of clay tables picturing scarred livers of sacrificial animals, used to foretell the future in ancient Babylon and Rome (Michalopoulos and DeFrances, 1997).