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Nutritional Management of Hepatic Encephalopathy Presented by Chris Theberge & Sara Murkowski Presentation At A Glance Background on Liver Dysfunction Review of liver physiology Diseases of the liver Development of Hepatic Encephalopathy Pathogenesis Theories Incidence, Prognosis, Diagnostic Criteria Clinical manifestations, Nutritional manifestations Treatment: Medical Management Case Study Nutritional Management 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 The Urea Cycle Aspartate Transaminase(AST) Alanine Transaminase (ALT) Liver Diseases Classifications Duration Viral hepatitis A, B, C, D, E (and G) Acute vs Chronic Fulminant hepatitis Pathophysiology Hepatocellular vs Alcoholic liver disease Cholestasic Non-alcoholic liver disease Etiology Viral Cholestatic liver disease Alcohol Hepatocellular carcinoma Toxin Inherited disorders Autoimmune Stage/Severity ESLD Cirrhosis Liver Diseases Fulminant Hepatic Failure (“Shocked Liver”) Rapid, severe acute liver injury with impaired function and encephalopathy in someone with a previously normal liver or with well-compensated liver disease Encephalopathy within 8 weeks of symptom onset or within 2 wks of developing jaundice Multiple causes (ie, drug toxicity, hepatitis) Malnutrition often not major issue Chronic Hepatic Failure (“Subfulminant" Hepatic Failure) At least 6-month course of hepatitis or biochemical and clinical evidence of liver disease with confirmatory biopsy findings of unresolving hepatic inflammation Multiple causes: autoimmune, viral, metabolic, toxic Liver Diseases Cholestatic Liver Diseases Primary biliary cirrhosis (PBC) Immune-mediated chronic cirrhosis of the liver due to obstruction or infection of the small and intermediate-sized intrahepatic bile ducts 90% of patients are women Nutritional complications Osteopenia, hypercholesterolemia, fat-soluble vitamin deficiencies Sclerosing cholangitis Fibrosing inflammation of segments of extrahepatic bile ducts, with or without involvement of intrahepatic ducts Nutritional complications Inflammatory bowel disease, fat soluble vitamin deficiencies, hepatic osteodystrophy (steatorrhea) Inherited Liver Disorders Hemochromatosis Inherited disease of iron overload Wilson’s disease Autosomal recessive disorder associated with impaired biliary copper excretion α1-antitrypsin deficiency Causes cholestasis or cirrhosis and can cause liver and lung cancer Liver Diseases Alcoholic Liver Disease, Alcoholic hepatitis, and Cirrhosis Diseases resulting from excessive alcohol ingestion characterized by fatty liver (hepatic steatosis), hepatitis, or cirrhosis (fibrous tissue) Prognosis depends on degree of abstinence and degree of complications Malnutrition often an issue in these patients Most common liver disease in US Progression of Liver Diseases Normal Liver Alcoholic Fatty Liver Cirrhotic Liver Prognosis of Cirrhosis Child-Pugh and MELD Score Both used to determine prognosis of Cirrhosis (mortality and survival) Determine Need For Transplantation Used in studies to determine effect of treatment on liver function Malnutrition In Liver Disease Malnutrition is an early and typical aspect of hepatic cirrhosis Contributes to poor prognosis and complications Degree of malnutrition related to severity of liver dysfunction and disease etiology (higher in alcoholics) Mortality doubled in cirrhotic patients with malnutrition (35% vs 16%) Complications more frequent than in well-nourished (44% vs 24%) Usually more of a clinical problem than hepatic encephalopathy itself Cirrhosis is common end result of many chronic liver disorders 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 And Now Our Featured Presentation… What is Hepatic Encephalopathy? Broadly defined All neurological and psychological symptoms in patients with liver disease that cannot be explained by presence of other pathologies Brain and nervous system damage secondary to severe liver dysfunction (most often chronic disease) resulting from failure of liver to remove toxins Multifactorial pathogenesis with exact cause unknown Symptoms vary from nearly undetectable, to coma with decerebration Characterized by various neurologic symptoms Cognitive impairment Neuromuscular disturbance Altered consciousness Reversible syndrome Incidence & Prognosis Incidence 10-50% of cirrhotic pts and portal-systemic shunts (TIPS) experience episode of overt hepatic encephalopathy True incidence/prevalence of HE unknown Lack of definitive diagnosis Wide spectrum of disease severity Prognosis 40% survival rate 1 year following first episode 15% survival rate 3 years following first episode Clinical Manifestations of HE Cerebral edema Brain herniation Progressive, irreversible coma Permanent neurologic losses (movement, sensation, or mental state) Increased risk of: Sepsis Respiratory failure Cardiovascular collapse Kidney Failure Variants of Hepatic Encephalopathy Acute HE Associated with marked cerebral edema seen in patients with the acute onset of hepatic failure (FHF) Hormonal disarray, hypokalemia, vasodilation (ie, vasopressin release) Quick progression: coma, seizures, and decerebrate rigidity Altered mental function attributed to increased permeability of the blood-brain barrier and impaired brain osmoregulation Results in brain cell swelling and brain edema Can occur in cirrhosis, but usually triggered by precipitating factor Precipitating factors usually determine outcome Precipitants of Hepatic Encephalopathy Drugs Portosystemic Shunting •Radiographic or surgically placed shunts •Benzodiazepines •Spontaneous shunts •Narcotics •Vascular Occlusion •Alcohol •Portal or Hepatic Vein Thrombosis Dehydration Increased Ammonia Production, •Vomiting Absorption or Entry Into the Brain •Diarrhea •Excess Dietary Intake of Protein •Hemorrhage •GI Bleeding •Diuretics •Infection •Large volume paracentesis •Electrolyte Disturbances (ie., hypokalemia) Primary Hepatocellular •Constipation Carcinoma •Metabolic alkalosis Variants of Hepatic Encephalopathy Chronic HE Occurs in subjects with chronic liver disease such as cirrhosis and portosystemic shunting of blood (Portal Systemic Encepalopathy [PSA]) Characterized by persistence of neuropsychiatric symptoms despite adequate medical therapy. Brain edema is rarely reported Refractory HE Recurrent episodes of an altered mental state in absence of precipitating factors Persistent HE Progressive, irreversible neurologic findings: dementia, extrapyramidal manifestations, cerebellar degeneration, transverse cordal myelopathy, and peripheral neuropathy Subclinical or “Minimal HE” Most frequent neurological disturbance Not associated with overt neuropsychiatric symptoms Subtle changes detected by special psychomotor tests Stages of Hepatic Encephalophay Stage Symptoms I Mild Confusion, agitation, irritability, sleep disturbance, decreased attention II Lethargy, disorientation, inappropriate behavior, drowsiness III Somnolent but arousable, slurred speech, confused, aggressive IV Coma Pathogenesis Theories Endogenous Neurotoxins Ammonia Mercaptans Phenols Short-medium fatty acids Increased Permeability of Blood-Brain Barrier Change in Neurotransmitters and Receptors GABA Altered BCAA/AAA ratio Other defficiency Zinc Manganese deposits Neurotoxic Action of Ammonia Readily crosses blood-brain barrier Increased NH3 = increased glutamate α-ketoglutarate+NH3+NADH→glutamate+NAD glutamate+NH3+ATP→glutamine+ADP+Pi As a-ketoglutarate is depleted TCA cycle activity halted Increased glutamine formation depletes glutamate stores which are needed by neural tissue Irrepairable cell damage and neural cell death ensue. In liver disease, conversion of ammonia to urea and glutamine can be reduced up to 80% Pathogenesis Theories: False Neurotransmitter Hypothesis Liver cirrhosis characterized by altered amino acid metabolism Increased Aromatic Amino Acids in plasma and influx in brain Decrease in plasma Branched Chain Amino Acids Share a common carrier at blood-brain barrier BCAAs in blood may result in AAA transport to brain Abnormal plasma amino acids: chronic liver disease 400 Glu 350 Phe Asp 300 Meth % of Normal 250 Tyr 200 Try 150 Gly 100 Thr Ser Orn Lys Tau His 50 Val Leu Pro Ala Arg Ileu Essential Non-Essential Cerra, et al; JPEN, 1985 J. Y. Pang Pathogenesis Theories: False Neurotransmitter Hypothesis AAA are precursors to neurotransmitters and elevated levels result in shunting to secondary pathways Pathogenesis Theories: Change In Neurotransmitters and Receptors Gamma-Aminobutyric BCAA-Ammonia Acid (GABA) Connection Increase Permeability of Blood- Brain Barrier Astrocyte (glial cell) volume is controlled by intracellular organic osmolyte Organic osmolyte is glutamine. glutamine levels in the brain result in volume of fluid within astrocytes resulting in cerebral edema (enlarged glial cells) Neurological impairment N=Normal Astrocytes A=Alzheimer type II astrocytes Pale, enlarged nuclei characterisic of HE Symptoms of HE Changes in mental Course muscle state, consciousness tremors Confusion, Muscle stiffness or disorientation rigidity Delirium Loss of small hand Dementia (loss of memory, intellect) movements (handwriting) Mood swings Decreased altertness, Seizures (rare) responsiveness Decreased self-care Coma ability Speech impairment Diagnosing HE No single laboratory test is sufficient to establish the diagnosis No Gold Standard Pt brains cannot be studied with neurochemical/neurophysiologic methods Data on cerebral function in HE usually derived from animal studies Underlying cause of liver disease itself may be associated with neurologic manifestations Alcoholic liver disease (Wernicke’s) Diagnostic Criteria Asterixis (“flapping tremor”) Hx liver disease Impaired performance on neuropsychological tests Visual, sensory, brainstem auditory evoked potentials Sleep disturbances Fetor Hepaticus Slowing of brain waves on EEG PET scan Changes of neurotransmission, astrocyte function Elevated serum NH3 Stored blood contains ~30ug/L ammonia Elevated levels seen in 90% pts with HE Not needed for diagnosis Table 3. Differential diagnostic considerations in hepatic Differential Diagnosis encephalopathy Metabolic encephalopathies Intracranial events Diabetes (hypoglycemia, Intracerebral bleeding or ketoacidosis) infarction Hypoxia Tumor Carbon dioxide narcosis Infections (abscess, Toxic encephalopathies Alcohol (acute alcohol meningitis) intoxication, delirium tremens, Encephalitis Wernicke-Korsakoff syndrome) Drugs Treatment of Hepatic Encephalopathy Various measures in current treatment of HE 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 Nutritional Management of HE Historical treatment theories Restriction Protein BCAA supplementation Goals of MNT Treatment of PCM associated with ESLD 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 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 Dispelling the Myth 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 Dispelling the Myth Results 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 Presence of malnutrition in pts with cirrhosis and ESLD clearly established No valid clinical evidence supporting protein restriction in pts with acute HE Higher protein intake required in CHE to maintain positive nitrogen balance Protein intake < 40g/day contributes to malnutrition and worsening HE Increased endogenous protein breakdown NH3 Susceptibiliy to infection increases under such catabolic conditions Other Considerations Vegetable Protein Beneficial in patients with protein intolerance <1g/kg Considered to improve nitrogen balance without worsening HE Beneficial effect d/t high fiber content Also elevated calorie-to-nitrogen ratio 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 Nutritional Supplementation with Branched- Chain Amino Acids in Advanced Cirrhosis: A Double-Blind, Randomized Trial Marchesini et al.,(2004). Gastroenterology, 124, 1792-1801 Nutritional Supplementation with Branched-Chain Amino Acids in Advanced Cirrhosis: A Double-Blind, Randomized Trial Multi-Center, randomized, controlled study involving 15 centers with interest in patients with liver disease Inclusion Criteria A diagnosis of liver cirrhosis documented by histology and confirmed lab data Child-Pugh score ≥ 7 (Class B or C) Sonographic and endoscopic evidence of portal hypertension Exclusion Criteria Active alcohol consumption, overt HE, refractory ascites, reduced renal function (Cre ≥ 1.5 mg/dL), Child-Pugh score ≥ 12, suspected hepatocellular carcinoma, previous poor compliance to pharmacological treatment of nutrition counseling Nutritional Supplementation with Branched-Chain Amino Acids in Advanced Cirrhosis: A Double-Blind, Randomized Trial Primary Outcomes Combined survival and maintenance of liver function, as assessed by death (any reason), deterioration to exclusion criteria, or transplant Number of hospital admissions Duration of hospital stay Secondary Outcomes parameters and liver function tests (Child- Nutritional Pugh scores) Anorexia and health-related quality of life Therapy needs Study Profile of BCAA Trial BCAA Lactoalbumin Maltodextrin Total number 59 56 59 Lost to follow-up 1 — — Intention-to-treat analysis 58 56 59 Events (death, any cause, or progression of liver 9 (15.5%)* 18 (32.1%) 16 (27.1%) failure to exclusion criteria) Removed from systematic follow-up1 7 4 4 Development of HCC2 1 1 2 Noncompliance to treatment3 5 (1) 2 (1) 0 Side effects3 44 (1) 2 (1) 2 Treatment-unrelated diseases — 1 — Regular 3-mo follow-up 42 (71.2%)* 34 (60.7%) 39 (66.1%) Admission to hospital 15 (35.7%)* 27 (79.4%) 28 (71.8) Admission rate (patients/y) 0.6 ± 0.2* 2.1 ± 0.5 1.9 ± 0.4 Total no. d in hospital 195* 327 520 * Significantlydifferent from both lactoalbumin and maltodextrin. 1 Some individuals were removed based on more than 1 criterion. 2 Cases with HCC were censored at the time of HCC diagnosis. 3 The number of withdrawn patients who died or progressed to exclusion criteria within 12 mo from entry into the study is reported in parentheses. 4 Including the patient lost to follow-up. Primary Outcome Results Based on ITT, time course of events was not different between groups (p=0.101) A benefit of BCAA only found when non- liver disease-related events excluded from analyses compared to L-ALB BCAA significantly reduced the combined event rates compared with L-ALB, but not with M-DXT L-ALB-OR, 0.43; 95% CI (0.19-0.96); p=0.039 M-DXT-OR, 0.51; 95% CI (0.23-1.17); p=0.108 Less frequent hospital admissions with BCAA vs two control arms (p = 0.021) Secondary Outcomes Nutritional Parameters Albumin Concentration •No change in serum albumin among ANOVA, P=0.670 groups Serum Albumin (g/dL) •Significant interaction between BCAA and 4 M-DXT 3.6 BCAA 3.2 •Significant reduction in prevalence and 2.8 L-ALB severity of ascites in BCAA vs controls 2.4 M-DXT •No significant improvement in HE based 2 nd on Reitan Test) o o o e in M M M E el 3- 6- 9- •Trend for superiority of BCAA over M-DXT as B (p=0.108) Child-Pugh Score Total Bilirubin (g/dL) ANOVA, P=0.025 Repeated Measures ANOVA time x treatment; P=0.0012 Child-Pugh Score 10 Total Bilirubin 9 BCAA 3.5 (g/dL) 8 3 L-ALB 2.5 7 2 1.5 BCAA 6 M-DXT 1 0.5 0 5 L-ALB d o o o e M-DXT d o o o e lin En M M M lin En M M M 3- 6- 9- 3- 6- 9- se se Ba Ba Anorexia and Health-Related Quality of Life Increased hunger/satiety in BCAA (p=0.019), while no change in L-ALB and M-DXT (p=0.026) Prevalence of anorexia significantly (p=0.0014) decreased in BCAA, while unchanged in controls Significant improvement in physical functioning in BCAA, while no change in controls Trend (p=0.069) towards better scoring of health in subjects with BCAA only After 1 year, the percentage of subjects who felt their health improved increased (29% to 52%) and who felt it had worsened decreased (43% to 18%) (p=0.001) Conclusions Long-term BCAA supplementation showed an advantage compared to equicaloric, equinitrogenous supplemenation Prevention of combined death Progressive liver failure Hospital rates Secondary Outcomes The Mother of All BCAA Trials? Randomized Study Limitations Poor subject compliance and adverse reactions 3 times more common in BCAA (15%) arm compared to controls (5% combined) resulting in greater withdrawal Ascertainment bias for event rates Only 115 of 174 subjects had regular f/u at end of study, reducing power May explain lack no difference in time course of events A benefit of BCAA supplementation only found when non-liver-related deaths were excluded from analysis Mortality was lower, but BCAA group had similar number of deaths compared to the other groups Mean admission rate lower in BCAA compared to controls No cost-effectiveness analysis done Reasons for hospital admission? The Mother of All BCAA Trials? Further Study Limitations No differences in encephalopathy test scores, including Reitan testing seen among treatment groups, but significant improvement in nutritional status in BCAA compared to others Most likely this attributed to reduced admission rates 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 Excluded trials in which patients allocated by quasi-random method 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) Significant Not significant Combining survival data regardless of window of f/u showed no significant Difference in survival between BCAA and controls Branched-Chain Amino Acids For Hepatic Encephalopathy: Results Sensitivity Analyses Methodological quality had a significant impact on results Higher quality vs lower quality In trials with adequate generation of allocation sequence, allocation concealment, and adequate double-blinding, BCAA had no significant effect on improvement or survival In trials with unclear generation of allocation sequence, allocation concealment, and inadequate double-blinding a significant effect of BCAA on HE was found BCAA had no significant effect on survival when given parenterally to acute HE or enterally to chronic HE Discrepancy between each applied model (fixed vs random) Trend towards beneficial effect of BCAA using best-case analysis with fixed model only [p=0.03 vs p=0.13 with random] No significant effect of BCAA with worst-case analysis 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 f/u and most of poor quality Primary analysis showed a significant benefit of BCAA on HE, but significant statistical heterogeneity was present and result not robust to sensitivity analysis 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 Conclusions In general, BCAAs were more effective when given enterally to subjects with chronic encephalopathy, then when given IV to patients with acute encephalopathy Most likely through improved nutrition Limitations Significant heterogeneity among studies (ie., patient populations, settings, routine care) making a meta-analysis decipherable Division of HE into categories is arbitrary and precipitating factors not always identified The definition of “improvement” different among studies Scales and items used for defining and assessing HE are arbitrary and not tested for reliability or validity Implications For Future Research The absence of evidence for an effect of BCAA does not mean there is evidence of lack of effect Future randomized trials warranted Trials could randomize according various types of HE to BCAA versus placebo All trials should use parallel group design Spontaneously fluctuating nature of HE Need for assessing outcomes (improvement, recovery, mortality, and adverse events) after end of treatment There is substantial need for clear diagnostic criteria of HE, as well as reassessment and validation of scales and items used for measuring its course Implications For Future Research New studies are awaited to identify patients at higher risk where BCAA is probably the only way to prevent catabolic losses and improve prognosis Dose-finding studies are needed to detect optimum dosage, safe limits of administration, and whether higher doses will show more benefit Studies needed to define whether all 3 BCAA’s need to be supplied Effects of leucine on protein turnover and HGF secretion Leucine alone might achieve similar beneficial results at lower total doses BCAA Enteral Formulations NutriHep Enteral Hepatic-Aid II Nutrition (Nestle) (Hormel Health Labs) 1.5 kcal/mL 1.2 kcal/mL Fat (12%) MCT Fat (28%) No MCT (66%) Protein: 46% BCAA, Protein: 50% low AAA BCAA, low MET CHO: 58% CHO: 77% Vitamin and RDI: 100% Electrolyte-free Gluten-free, lactose-free The Child-Turcotte-Pugh Classification Goals of MNT for HE Treatment of PCM associated with Underlying Liver Disease Suppression of endogenous protein breakdown to reduce stress placed on de-compensated liver Achieve positive nitrogen balance without exacerbating neurological symptoms PCM associated with morbidity and mortality in cirrhosis (65- 90% with PCM) Severity of pcm positively correlated with mortality Nutritional Implications: PCM associated Liver Dz Malnutrition reported in Nutrient malabsorption/ 65%-90% cirrhotic pts maldigestion Cholestatic & non-cholestatic Poor Dietary Intake liver disease Anorexia Excessive protein losses Dietary Restrictions Pancreatic insufficiency Ascites Gastroparesis Abnormal Metabolism Hypermetabolism Zinc Deficiency Hyperglucogonemia Increased proinflammatory cytokines Increased protein metabolism Increased lipid oxidation Osteopenia MNT in Advanced 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 MNT in Advanced Liver Disease Abnormal Fuel Metabolism Increased perioxidation, gluconeogenesis Bedtime meal to decrease Protein Deficiency protein catabolism, repeat paracentesis High protein snacks/supplements 1.2-1.5 gms/day MNT in Advanced Liver Disease Standard Guidelines MVI with minerals 2gm Na restriction in presence of ascites Do not restrict fluid unless serum Na <120mmol Low threshold for NGT in pts awaiting transplant TPN should be considered only if contraindication for enteral feeding 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 if hepatic encephalopathy Below 70 g/day rarely necessary, minimum intake should not be lower than 40 g/day to avoid negative nitrogen balance MNT Specifically in HE Non-protein energy: 35-45 kcal/kg/day Up to 1.6g/kg/day protein as tolerated Low-grade HE (minimal, I, II) should not be contraindication to adequate protein supply 40g temporary restriction if considered protein intolerant, but gradual increase q3-5 days 30-40g Vegetable protein/day for these pts 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 MNT Specifically in HE HE coma (grade III-IV) 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 Enteral and parenteral regimens providing 25-30 kcal/kg/day non-protein energy 1.0g/kg/day protein, depending on degree of muscle wasting BCAA-enriched solutions may benefit protein intolerant (<1g/kg) Conclusions in HE Management Intervention directed against the precipitating cause(s) will lead to improvement or disappearance of acute hepatic encephalopathy Our understanding of pathogenesis is improving, but much work remains Link between liver and brain still only partially understood No evidence supporting standard use of BCAA formulations, but may benefit small subgroup Cost analysis not conducted in trials Cost outweigh benefits for standard protocol Thank You! Special Thanks to Nicole Varady Comments? Questions? References Müller, M. J., Selberg, O. & Böker, K. (1994) Are patients with liver cirrhosis hypermetabolic?. Clin. Nutr. 13:131 -144. The ESPEN Consensus GroupPlauth, M., Merli, M., Kondrup, J., Weimann, A., Ferenci, P. & Muller, M. J. (1997) ESPEN guidelines for nutrition in liver disease and transplantation. Clin. Nutr. 16:43-55. Falck-Ytter, Y., Younossi, Z. M., Marchesini, G. & McCullough, A. J. (2001) Clinical features and natural history of nonalcoholic steatosis syndromes. Semin. Liver Dis. 21:17-26. Italian Multicentre Cooperative Project on nutrition in liver cirrhosis (1994) Nutritional status in cirrhosis. J. Hepatol. 2 1:317-325. Marchesini, G., Bianchi, G., Amodio, P., Salerno, F., Merli, M., Panella, C., Loguercio, C., Apolone, G., Niero, M. & Abbiati, R. (2001) Factors associated with poor health-related quality of life of patients with cirrhosis. Gastroenterology 120:170-178. Selberg, O., Bottcher, J., Tusch, G., Pichlmayr, R., Henkel, E. & Muller, M. J. (1997) Identification of high- and low-risk patients before liver transplantation: a prospective cohort study of nutritional and metabolic parameters in 150 patients. Hepatology 25:652 - 657. James, J. H., Ziparo, V., Jeppsson, B. & Fischer, J. E. (1979) Hyperammonaemia, plasma amino acid imbalance, and blood-brain amino acid transport: a unified theory of portal-systemic encephalopathy. Lancet 2:772-775. Naylor, C. D., O’Rourke, K., Detsky, A. S. & Baker, J. P. (1989) Parenteral nutrition with branched-chain amino acids in hepatic encephalopathy. A meta-analysis. Gastroenterology 97:1033-1042. Fabbri, A., Magrini, N., Bianchi, G., Zoli, M. & Marchesini, G. (1996) Overview of randomized clinical trials of oral branche d-chain amino acid treatment in chronic hepatic encephalopathy. J. Parenter. Enteral Nutr. 20:159-164. Als-Nielsen, B., Koretz, R. L., Kjaergard, L. L. & Gluud, C. (2004) Branched-chain amino acids for hepatic encephalopathy (Cochrane review). The Cochrane Library, Issue 2 2004 John Wiley and Sons Chichester, UK . Ishiki, Y., Ohnishi, H., Muto, Y., Matsumoto, K. & Nakamura, T. (1992) Direct evidence that hepatocyte growth factor is a hepatotrophic factor for liver regeneration and has a potent antihepatitis effect in vivo. Hepatology 16:1227-1235. Tomiya, T., Inoue, Y., Yanase, M., Arai, M., Ikeda, H., Tejima, K., Nagashima, K., Nishikawa, T. & Fujiwara, K. (2002) Leucine stimulates the secretion of hepatocyte growth factor by hepatic stellate cells. Biochem. Biophys. Res. Commun. 297:1108-1111. Fenton, J. C., Knight, E. J. & Humpherson, P. L. (1966) Milk-and-cheese diet in portal-systemic encephalopathy. Lancet 1:164-166. Bianchi, G. P., Marchesini, G., Fabbri, A., Rondelli, A., Bugianesi, E., Zoli, M. & Pisi, E. (1993) Vegetable versus animal protein diet in cirrhotic patients with chronic encephalopathy. A randomized cross-over comparison. J. Intern. Med. 233:385-392. Rossi-Fanelli, F., Riggio, O., Cangiano, C., Cascino, A., De Conciliis, D., Merli, M., Stortoni, M., Giunchi, G. & Capocaccia, L. (1982) Branched-chain amino acids vs. lactulose in the treatment of hepatic coma. A controlled study. Dig. Dis. Sci. 27:929-935. References Wahren, J., Denis, J., Desurmont, P., Eriksson, L. S., Escoffier, J. M., Gauthier, A. P., Hagenfeldt, L., Michel, H. & Opolon, P., et al (1983) Is intravenous administration of branched chain amino acids effective in the treatment of hepatic encephalopathy?. A multicenter study. Hepatology 3:475-480. Michel, H., Bories, P., Aubin, J. P., Pomier-Layrargues, G., Bauret, P. & Bellet-Herman, H. (1985) Treatment of acute hepatic encephalopathy in cirrhotics with a branched-chain amino acids enriched versus a conventional amino acids mixture. A controlled study of 70 patients. Liver 5:282-289. Cerra, F. B., Chung, N. K., Fischer, J. E., Kaplowitz, N., Schiff, E. R., Dienstag, J. L., Bower, R. H., Mabry, C. D., Leevy, C. M. & Kiernan, T. (1985) Disease-specific amino acid infusion (F080) in hepatic encephalopathy: a prospective, randomized, double-blind controlled trial. J. Parenter. Enteral Nutr. 9:288-295. Fiaccadori, F., Ghinelli, F., Pedretti, G., Pelosi, G., Sacchini, D., Zeneroli, M. L., Rocchi, E., Gibertini, P. & Ventura, E. (1985) Branched-chain enriched amino acid solutions in the treatment of hepatic encephalopathy: a controlled trial. Ital. J. Gastroenterol. 17:5-10. Strauss, E., dos Santos, W. R., da Silva, E. C., Lacet, C. M., Capacci, M.L.L. & Bernardini, A. P. (1986) Treatment of hepatic encephalopathy: a randomized clinical trial comparing branched chain enriched amino acid solution to oral neomycin. Nutr. Supp. Services 6:18 -21. Vilstrup, H., Gluud, C., Hardt, F., Kristensen, M., Køler, O., Melgaard, B., Dejgaard, A., Hansen, B. E. & Krintel, J. J., et al (1990) Branched chain enriched amino acids versus glucose treatment of hepatic encephalopathy. A double-blind study of 65 patients with cirrhosis. J. Hepatol. 10:291-296. Eriksson, L. S., Persson, A. & Wahren, J. (1982) Branched-chain amino acids in the treatment of chronic hepatic encephalopathy. Gut 23:801- 806. Sieg, A., Walker, S., Czygan, P., Gärtner, U., Lanzinger-Rossnagel, G., A., S. & Kommerell, B. (1983) Branched-chain amino acid-enriched elemental diet in patients with cirrhosis of the liver. Z. Gastroenterol. 21:644-650. Simko, V. (1983) Long-term tolerance of a special amino acid oral formula in patients with advanced liver disease. Nutr. Rep. Int. 27:765-773. Horst, D., Grace, N. D., Conn, H. O., Schiff, E., Schencker, S., Viteri, A., Law, D. & Atterbury, C. E. (1984) Comparison of dietary protein with an oral, branched chain-enriched amino acid supplement in chronic portal-systemic encephalopathy. Hepatology 4:279-287. Christie, M. L., Sack, D. M., Pomposelli, J. & Horst, H. (1985) Enriched branched-chain amino acid formula vs. a casein-based supplement in the treatment of cirrhosis. J. Parenter. Enteral Nutr. 9:671-678. Egberts, E. H., Schomerus, H., Hamster, W. & Jürgens, P. (1985) Branched chain amino acids in the treatment of latent portosystemic encephalopathy. A double-blind placebo-controlled cross-over study. Gastroenterology 88:887-895. Fiaccadori, F., Elia, G. F., Lehndorff, H., Merli, M., Pedretti, G., Riggio, O. & Capocaccia, L. (1988) The effect of dietary supplementation with branched-chain amino acids vs. casein in patients with chronic recurrent portal systemic encephalopathy: a controlled trial. Soeters, P. B. Wilson, J.H.P. Meijer, A. J. Holm, E. eds. Advances in Ammonia Metabolism and Hepatic Encephalopathy 1988:489-497 Excerpta Medica Amsterdam, The Netherlands. . Swart, G. R., van den Berg, W. O., van Vuure, J. K., Rietveld, D., Wattimena, D. L. & Frenkel, M. (1989) Minimum protein requ irements in liver cirrhosis determined by nitrogen balance measurements at three levels of protein intake. Clin. Nutr. 8:329-336. References Marchesini, G., Dioguardi, F. S., Bianchi, G. P., Zoli, M., Bellati, G., Roffi, L., Martines, D. & Abbiati, R. & the Italian Multicenter Study Group (1990) Long-term oral branched-chain amino acid treatment in chronic hepatic encephalopathy. A randomized double-blind casein- controlled trial. J. Hepatol. 11:92-101. Marchesini, G., Bianchi, G., Merli, M., Amodio, P., Panella, C., Loguercio, C., Rossi Fanelli, F. & Abbiati, R. (2003) Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Gastroenterology 124:1792-1801. Lieber, C. S. (2000) Alcoholic liver disease: new insights in pathogenesis lead to new treatments. J. Hepatol. 32:113-128. Marsano, L. & McClain, C. J. (1991) Nutrition and alcoholic liver disease. J. Parenter. Enteral Nutr. 15:337-344. Merli, M., Nicolini, G., Angeloni, S. & Riggio, O. (2002) Malnutrition is a risk factor in cirrhotic patients undergoing surg ery. Nutrition 18:978-986. Fan, S. T., Lo, C. M., Lai, E. C., Chu, K. M., Liu, C. L. & Wong, J. (1994) Perioperative nutritional support in patients und ergoing hepatectomy for hepatocellular carcinoma. N. Engl. J. Med. 331:1547-1552. The San-in Group of Liver Surgery (1997) Long-term oral administration of branched chain amino acids after curative resection of hepatocellular carcinoma: a prospective randomized trial. Br. J. Surg. 84:1525-1531. Poon, R. T., Yu, W. C., Fan, S. T. & Wong, J. (2004) Long-term oral branched chain amino acids in patients undergoing chemoembolization for hepatocellular carcinoma: a randomized trial. Aliment. Pharmacol. Ther. 19:779-788. Reilly, J., Mehta, R., Teperman, L., Cemaj, S., Tzakis, A., Yanaga, K., Ritter, P., Rezak, A. & Makowka, L. (1990) Nutritional support after liver transplantation: a randomized prospective study. J. Parenter. Enter Nutr. 14:386-391. Bilbao, I., Armadans, L., Lazaro, J. L., Hidalgo, E., Castells, L. & Margarit, C. (2003) Predictive factors for early mortality following liver transplantation. Clin. Transplant. 17:401-411. Tietge, U. J., Bahr, M. J., Manns, M. P. & Boker, K. H. (2003) Hepatic amino-acid metabolism in liver cirrhosis and in the long-term course after liver transplantation. Transpl. Int. 16:1-8. Charlton, M. (2003) Branched-chain amino acid-enriched supplements as therapy for liver disease: Rasputin lives. Gastroenterology 124:1980- 1982.
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