Nutritional Management of Hepatic patients Presented by Faten farid elsayed

Points will be covered Background on Liver Dysfunction Review of liver physiology Diseases of the liver Acute hepatic failure Chronic liver disease Historical Treatment Theories/Practice Protein Restriction & BCAA Supplementation Goals of MNT

Let’s Take It From The Top A Physiology Review

Functions of the Liver: A Brief Overview Largest organ in body, integral to most metabolic functions of body, performing over 500 tasks Only 10-20% of functioning liver is required to sustain life Removal of liver will result in death within 24 hours

Functions of the Liver Main functions include: Metabolism of CHO, protein, fat Storage/activation vitamins and minerals Formation/excretion of bile Steroid metabolism, detoxifier of drugs/alcohol Action as (bacteria) filter and fluid chamber Conversion of ammonia to urea Gastrointestinal tract significant source of ammonia Generated from ingested protein substances that are deaminated by colonic bacteria Ammonia enters circulation via portal vein Converted to urea by liver for excretion CHO metabolism: glycogenesis, glycogenolysis, gluconeogenesis Protein metabolism: deamination and transamination, synthesis of serum protein, blood clotting protein, lipoprotein Fat: converts fatty acids from diet and adipose tissue Acetyl-CoA, also synthesis of cholesterol and phospholipids Storage: fat soluble vitamins, B12, and other minerals Conversion of Vit. D to active form, carotenes to vit. A, vit. K to prothrombin

Aspartate Transaminase(AST) The Urea Cycle Alanine Transaminase (ALT)

Liver Diseases Classifications Viral hepatitis A, B, C, D, E (and G) Duration Acute vs Chronic Pathophysiology Hepatocellular vs Cholestasic Etiology Viral Alcohol Toxin Autoimmune Stage/Severity ESLD Cirrhosis Viral hepatitis A, B, C, D, E (and G) Fulminant hepatitis Alcoholic liver disease Non-alcoholic liver disease Cholestatic liver disease Hepatocellular carcinoma Inherited disorders

Progression of Liver Diseases

Metabolic change in acute liver failure These patients with hepatic failure have metabolic response= Failing liver +stress response of critical ill patient Nutritional support may aid in regeneration or wait for transplantation These patients with hepatic failure have metabolic response= Failing liver +stress response of critical ill patient Nutritional support may aid in regeneration or wait for transplantation

Metabolic change………..continued Increased resting energy expenditure by 20 -30% Energy expenditure 1- decrese insulin sensitivity as glucagon secretion increased 2- glucagon not suppressed by glucose infusion Glucose metabolism Decreased hepatic ketogenesis -- -- -- low conc of free fatty acids and ketone bodies However they tolerate intravenous lipid emlusion contain (MCT/LCT) Lipid metabolism Increased its level 3 to 4 folds Decreased( BCCA) and increased (Tryptophan, AAA and sulphur containing AA No elemination of AA in splanchnic area Increased rate of conversion of glutamine to ammonia +alanine More glutamine production in brain and skeletal muscle No urea formation Plasma amino acids

Treatment of ALF Various measures in current treatment of ALF Strategies to lower ammonia production/absorption Nutritional management Protein restriction BCAA supplementation Medical management Medications to counteract ammonia’s effect on brain cell function Lactulose Antibiotics Devices to compensate for liver dysfunction Liver transplantation

Proposed Complex Feedback Mechanisms In Treatment Of HE

Nutrition requirement in ALF

Nutrition requirement in ALF Patient with ALF have glucose intolerance Hyperammonia Increased REE Malnourished patients: begin nutrition at reduced calorie levels Caloric requirement Potien requirement-----discussed below Carbohdrate and lipid to supply calories Minerals and vitamines should be supplied Substrate requirements -oral feeding -if patient not tolerate oral; entral is recommended to ensure adequate intake of calories Route of nutrition feeding

Nutritional Management of ALF Historical treatment theories Protein Restriction BCAA supplementation

Historical Treatment Theories:Protein Restriction Studies in early 1950’s showed cirrhotic pts given “nitrogenous substances” developed hepatic “precoma” Led to introduction of protein restriction Began with 20-40g protein/day regardless body weight Increased by 10g increments q3-5 days as tolerated with clinical recovery Upper limit of 0.8-1.0 g/kg Was thought sufficient to achieve positive nitrogen balance Lack of Valid Evidence Efficacy of restriction never proven within controlled trial

Normal Protein Diet for Episodic Hepatic Encephalopathy Protein restriction?? Normal Protein Diet for Episodic Hepatic Encephalopathy Cordoba et al. J Hepatol 2004; 41: 38-43 Objective: To test safety of normal-protein diets Randomized, controlled trial in 20 cirrhotic patients with HE 10 patients subjected to protein restriction, followed by progressive increments No protein first 3 days, increasing q3days until 1.2g/kg daily for last 2 days 10 patients followed normal protein diet (1.2g/kg) Both groups received equal calories

Protein restriction?? Results Conclusion On days 2 and 14: Similar protein synthesis among both groups Protein breakdown higher in low-protein group Conclusion No significant differences in course of hepatic encephalopathy Greater protein breakdown in protein-restricted subjects

Protein and HE Considerations No valid clinical evidence supporting protein restriction in pts with acute ALF Protein intake < 40g/day contributes to malnutrition and worsening ALF Increased endogenous protein breakdown NH3 Susceptibiliy to infection increases under such catabolic conditions

BCAA Supplementation Effective or Not?

Branched Chain Amino Acids (BCAA) Valine Leucine Isoleucine Important fuel sources for skeletal muscle during periods of metabolic stress Metabolized in muscle & brain, not liver -promote protein synthesis -suppress protein catabolism -substrates for gluconeogenesis Catabolized to L-alanine and L-glutamine in skeletal muscle

Branched-Chain Amino Acids For Hepatic Encephalopathy Als-Nielsen B, Koretz RI, Kjaergard LL, Gluud C. The Cochrane Database of Systematic Reviews, 2003, 1-55

Branched-Chain Amino Acids For Hepatic Encephalopathy Meta-Analysis of randomized-controlled trials on the treatment of HE with IV or oral BCAA Objective To evaluate the beneficial and harmful effects of BCAA or BCAA-enriched interventions for patients with hepatic encepalopathy Review Criteria All randomized trials included, irrespective of blinding, publication status, or language Data from first period of crossover trials and unpublished trials included if methodology and data accessible Participants Patients with HE in connection with acute or chronic liver disease or FHF Patients of either gender, any age and ethnicity included irrespective of etiology of liver disease or precipitating factors of HE

Branched-Chain Amino Acids For Hepatic Encephalopathy Types of Interventions Experimental Group BCAA or BCAA-enriched solutions given in any mode, dose, or duration with or without other nutritive sources Control Group No nutritional support, placebo support, isocaloric support, isonitrogenous support, or other interventions with a potential effect on HE (ie., lactulose) Outcome Measures Primary Improvement of HE (number of patients improving from HE using definitions of individual trials) Secondary Time to improvement of HE (number of hours/days with HE from the time of randomization to improvement) Survival (number of patients surviving at end of treatment and at max f/up according to trial) Adverse events (number and types of events defined as any untoward medical occurrence in a patient, not necessarily causal with treatment)

Branched-Chain Amino Acids For Hepatic Encephalopathy Data Collection and Analysis Trial inclusion and data extraction made independently by two reviewers Statistical heterogeneity tested using random effects and fixed effect models Binary outcomes reported as risk ratios (RR) based on random effects model

Branched-Chain Amino Acids For Hepatic Encephalopathy: Results Eleven randomized trials (556 patients) Trial types: BCAA versus carbohydrates, neomycin/lactulose, or isonitrogenous controls Median number of patients in each trial: 55 (range 22 to 75) Follow-up after treatment reported in 4 trials Median 17 days (range 6 to 30 days) Compared to control regimens, BCAA significantly increased the number of patients improving from HE at end of treatment RR 1.31, 95% CI 1.04 to 1.66, 9 trials No evidence of an effect of BCAA on survival RR 1.06, 95% CI 0.98 to 1.14, 8 trials No adverse events (RR 0.97, 95% CI 0.41 to 2.31, 3 trials)

Authors' conclusions:  No convincing evidence that BCAA had a significant beneficial effect on improvement of HE or survival in patients with HE Small trials with short and most of poor quality Primary analysis showed a significant benefit of BCAA on HE, but significant statistical heterogeneity was present Low methodological quality source of heterogeneity (=bias) Benefits of BCAA on HE only observed when lower quality studies included Effect size and “small study bias” No significant association between dose or duration and the effect of BCAA

How Much Protein: That is the Question?? Grade III to IV hepatic encephalopathy Usually no oral nutrition Upon improvement, individual protein tolerance can be titrated by gradually increasing oral protein intake every three to five days from a baseline of 40 g/day Oral protein not to exceed 70 g/day if pt has hx of hepatic encephalopathy Below 70 g/day rarely necessary, minimum intake should not be lower than 40 g/day to avoid negative nitrogen balance. 1.0g/kg/day protein, depending on degree of muscle wasting BCAA-enriched solutions may benefit protein intolerant (<1g/kg)

How Much Protein: That is the Question?? Up to 1.6g/kg/day protein as tolerated Low-grade HE (minimal, I, II) should not be contraindication to adequate protein supply In patients intolerant of a daily intake of 1 g protein/kg, oral BCAA up to 0.25 g/kg may be beneficial to create best possible nitrogen balance BCAA’s do not exacerbate encephalopathy It should consider in patients with transjagular intrahepatic port systemic shunt( high incidence for HE)

L-ornithine L-asprtate(LOLA) in ALF L-Ornithine L-asprtate(LOLA) acts to stimulate the urea cycle and glutamine synthesis which are important mechanisms in ammonia detoxification, and by that it is considered an ammonia lowering treatment. Many clinical trials found that LOLA improved hepatic encephalopathy better than placebo.

Chronic Liver Disease Algorithm content developed by John Anderson, PhD, and Sanford C. Garner, PhD, 2000. Updated by Jeanette M. Hasse and Laura E. Matarese, 2002.

Clinical manifestation of cirrhosis Severe damage to structure & function of normal cells Inhibits normal blood flow Decrease in # functional hepatocytes Results in portal hypertension & ascites Portal systemic shunting Blood bypasses the liver via shunt, thus bypassing detoxification Toxins remain in circulating blood Neurtoxic substances can precipitate hepatic encephalopathy

Chronic liver disease —malnourished?? Decreased Absorption • Inadequate bile flow • Bacterial overgrowth • Pancreatic insufficiency Iatrogenic Factors • unecessary dietary restrictions • Frequent Paracentesis • Diuresis (micronutrient losses) • Lactulose therapy Decreased Intake • Anorexia(altered tast sensation) • Early sensation of fullness (ascites) • Ascites • Altered mental status/encephalopathy • Frequent hospitalizations Metabolic Alterations Elevated leptin Increased cholecystokinin Elevated TNF-a

Metabolic change in chronic liver disease Hypermetabolic state energy Glucose intolerance in nearly 2/3 of patients with cirrhosis (10-37% develop diabetes) - Occurs because of insulin resistance in peripheral tissues and decreased in insuline like growth factor. - Hyperinsulinemia, possibly because insulin production increased, hepatic clearance decreased - Fasting hypoglycemia occur after 12 hours fasting due decreased glycogen stores; patients may need small, frequent meals - diminished hepatic and muscle glycogen stores carbohydrate metabolism In fasting state: Plasma level of free fatty acids, glycerol and ketone body Increased Increased lipolysis and mobilization of lipid deposits After meal: Lipid oxidation n’t uniformly impaired and plsma clearance not decrease so the patients can utilize fat Essential and polysaturated FA decreased in cirrhotic patients Fat metabolism

Metabolic change in chronic liver disease - Increase breakdown and decrease synthesis - Depleted glycogen stores utilize increased fat and muscle protein for fuel even during short-term fasting lead to muscle wasting - Protein catabolism may lead to hyper ammonia Stable cirrhotic patient: Keep positive nitrogenous balance and preserve their lean body mass from protein intake during oral feeding protein - Zinc deficiency is common with cirrhosis. Decreased dietary intake of meats, increased urinary excretion of zinc due to diuretic use, and increased zinc needs have been suggested as causes . Zinc is essential for the function of over 300 enzymes, including those of the urea cycle. - Fat soluble deficiency in patient with cholestatic jaundice - Water soluble vitamine deficiency in alcoholic cirrohosis Mineral and vitamines

MNT in chronic Liver Disease Poor Dietary Intake Due to poor appetite, early satiety with ascites Small frequent meals- Aggressive oral supplementation Zinc supplementation Nutrient Malabsorption Due to bile, failure to convert to active forms ADEK supplementation Calcium + D supplementation Folic Acid Supplementation early supplement of thiamine before glucose in alcoholic hepatitis

MNT in chronic Liver Disease Calories Most patients are malnourished so supplementing full calories refeeding syndrome Caloric requirement/kg of estimated euvolmic weight Begin with reduced caloric level for the first 2 -3 day Malnourished patients We calculate calories according to euvolemic weight to prevent overestimated energy Patients with ascites 15 to 20 kcl/kg Refeeding risk 25 to 30 kcl /kg Maintainance 30 to 35 cal /kg anabolism

MNT in in chronic Liver Disease Abnormal Fuel Metabolism Increased perioxidation, gluconeogenesis Bedtime meal to decrease it Protein Deficiency protein catabolism, repeat paracentesis High protein snacks/supplements 1.2-1.5 gms/day

MNT in in chronic Liver Disease Standard Guidelines IV with minerals 2gm Na restriction in presence of ascites Do not restrict fluid unless serum Na <120mmol NGT used in pts awaiting transplant TPN should be considered only if contraindication for enteral feeding

Treatment of assosciated steatorrhea Fat restricted when steatorrhea is present Medium-chain triglycerides (MCT) can replace some of the fats. They contain only 8-12 carbons:changes their physical characteristics. They are much more water soluble; can be absorbed across the small intestine wall into the blood stream. Mainly, they are transported direct to the liver via the portal vein. They do not bind to fatty acid-binding proteins, are not reesterified to triglycerides, and are not packaged in chylomicrons

Nutrition in liver transplanted patients - initiate entral or oral within 12 to 24 hours post operatively In early postoperative phase suffer from hyperglycemia: ----Diabetogenic potential of tacrolimus ----Disturbed glucose metabolism and presence of insulin resistance These patients have negative nitrogen balance up to 28 days post op so they need increase supplementation of protien and amino acids upto 1 to 1.5 g/kg/day with no need for branched chain AA. Postoperative magnesium should be monitored.

conclusion Medical nutrition therapy is cornerstone in manging hepatic patients besides other medical treatments

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