Nutritional Management of Hepatic Encephalopathy

1. Nutritional Management of Hepatic Encephalopathy Presented by Chris Theberge & Sara Murkowski

2. 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

3. Let’s Take It From The Top • A Physiology Review

4. 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

5. 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

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

7. Liver Diseases Classifications • 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 • Duration • Acute vs Chronic • Pathophysiology • Hepatocellular vs Cholestasic • Etiology • Viral • Alcohol • Toxin • Autoimmune • Stage/Severity • ESLD • Cirrhosis

8. 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

9. 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)

10. InheritedLiver 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

11. 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

12. Progression of Liver Diseases

13. Normal Liver

14. Alcoholic Fatty Liver

15. Cirrhotic Liver

16. 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

17. 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

18. 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

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20. 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

21. 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

22. 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

23. 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

24. Precipitants of Hepatic Encephalopathy • Portosystemic Shunting • Radiographic or surgically placed shunts • Spontaneous shunts • Vascular Occlusion • Portal or Hepatic Vein Thrombosis • Drugs • Benzodiazepines • Narcotics • Alcohol • Dehydration • Vomiting • Diarrhea • Hemorrhage • Diuretics • Large volume paracentesis • Increased Ammonia Production, • Absorption or Entry Into the Brain • Excess Dietary Intake of Protein • GI Bleeding • Infection • Electrolyte Disturbances (ie., hypokalemia) • Constipation • Metabolic alkalosis Primary Hepatocellular Carcinoma

25. 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

26. Stages of Hepatic Encephalophay

27. 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 • Zinc defficiency • Manganese deposits

28. 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%

29. 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

30. Abnormal plasma amino acids:chronic liver disease 400 Glu 350 Phe Asp Meth 300 250 Tyr % of Normal 200 Try 150 Gly 100 Orn Thr Ser Lys Tau His Val 50 Leu Arg Pro Ala Ileu Essential Non-Essential Cerra, et al; JPEN, 1985 J. Y. Pang

31. Pathogenesis Theories: False Neurotransmitter Hypothesis • AAA are precursors to neurotransmitters and elevated levels result in shunting to secondary pathways

32. Gamma-Aminobutyric Acid (GABA) BCAA-Ammonia Connection Pathogenesis Theories:Change In Neurotransmitters and Receptors

33. 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

34. Changes in mental state, consciousness Confusion, disorientation Delirium Dementia (loss of memory, intellect) Mood swings Decreased altertness, responsiveness Coma Course muscle tremors Muscle stiffness or rigidity Loss of small hand movements (handwriting) Seizures (rare) Decreased self-care ability Speech impairment Symptoms of HE

35. 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)

36. 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 Diagnostic Criteria

37. Table 3. Differential diagnostic considerations in hepatic encephalopathy Metabolic encephalopathiesDiabetes (hypoglycemia, ketoacidosis)HypoxiaCarbon dioxide narcosis Toxic encephalopathiesAlcohol (acute alcohol intoxication, delirium tremens, Wernicke-Korsakoff syndrome)Drugs Intracranial eventsIntracerebral bleeding or infarctionTumorInfections (abscess, meningitis)Encephalitis Differential Diagnosis

38. 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

39. Proposed Complex Feedback Mechanisms In Treatment Of HE

40. Nutritional Management of HE • Historical treatment theories • Protein Restriction • BCAA supplementation • Goals of MNT • Treatment of PCM associated with ESLD

41. 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

42. 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

43. 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

44. 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

45. 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?

46. 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

47. Nutritional Supplementation with Branched-Chain Amino Acids in Advanced Cirrhosis: A Double-Blind, Randomized Trial Marchesini et al.,(2004). Gastroenterology, 124, 1792-1801

48. 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

49. 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 • Nutritional parameters and liver function tests (Child-Pugh scores) • Anorexia and health-related quality of life • Therapy needs

50. * Significantly different 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.