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Hepatic encephalopathy

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hepatic encephalopathy presentation

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Hepatic encephalopathy

  1. 1. HEPATIC ENCEPHALOPATHY Presentor – Dr. Nikhil Bhangale General Medicine
  2. 2. Hepatic encephalopathy  Definition – Hepatic encephalopathy is a brain dysfunction caused by liver insufficiency and/or Portosystemic shunt(PSS); it manifests as a wide spectrum of neurological or psychiatric abnormalities ranging from subclinical alterations to coma. (AASLD guidelines 2014)
  3. 3. Pathophysiology 1) Hepatocellular failure 2) Portosystemic shunt Gut derived neurotoxins Brain water homeostasis Oxidative nitrosative stress Astrocyte dysfunction Neurotransmitter dysfunction
  4. 4. Gut derived neurotoxins  Ammonia(mainly)  Mercaptans (from Methionine)  Short & medium-chain fatty acids  Gamma-amino butyric acid(GABA)  Octopamine  False neurotransmitter substances  Alterations in plasma levels of ↑ aromatic & ↓branched chain amino acids  Indoles (from tryptophan)
  5. 5. Brain water homeostasis  ↑ NH3 + Glutamate Glutamine ↑ Efflux of Myoinositol Astrocyte swelling (Alzeimer type 2 Astrocytosis)
  6. 6. 8
  7. 7. Oxidative nitrosative stress  Ammonia , hypo-osmotic swelling,inflammatory cytokines, BZD induce oxidative and nitrosative stress response in astrocytes.  Response mediated by NMDA receptors
  8. 8. Astrocyte dysfunction  Oxidative / nitrosative stress can promote covalent modification of tyrosine residues in astrocyte proteins.  This protein tyrosine nitration ,interfere with protein function and intracellular signal transduction.
  9. 9. Neurotransmitter dysfunction  Shift of balance between inhibitiry and excitatory neurotransmission towards inhibitory.  Increase in GABAergic tone(due to excess GABA,endogenous BZD in brain & upregulation of GABA receptors)  Increased NMDA receptor activation.  Dopamine depletion due to ↑ action of MAO- A  Acetyl choline(Ach) levels decresed
  10. 10. Precipitating Factors  GI bleeding  Infections(sepsis)  Excess protein in diet  Electrolyte disorder- Hyponatremia,hypokalemia  Constipation  Dehydration- Fluid restriction Excessive diuresis Paracentesis abdominis(large volume >3-5 Lt ) Diarrhoea/vomitting  Alcohol misuse/bout  TIPS insertion  Surgery
  11. 11.  Types of HE according to underlying disease A – with Acute liver failure (has distinct features like its associated with Increased ICT & risk of cerebral herniation) B – with portosystemic Bypass or shunts C – with Cirrhosis of liver Classification of Hepatic Encephalopathy
  12. 12.  According to time course – 1) Episodic HE 2) Recurrent HE denotes bouts of HE that occur with a time interval of 6 months or less. 3) Persistent HE denotes a pattern of behavioral alterations that are always present and interspersed with relapses of overt HE.
  13. 13. West haven criteria
  14. 14. Clinical features  Minimal HE  Affection of 1) Attention span 2) Working memory(WM) 3) psychomotor speed 4) visuospatial ability
  15. 15. Asterixis/Flapping tremors  often present in the early to middle stages of HE that precede stupor or coma  It is easily elicited by actions that require postural tone  Rapid flexion-extension movements at MCP(metacarpohalangeal) and wrist joints with lateral movements of fingers  Absent at rest, less marked on movement and maximum on sustained posture  actuality, not a tremor, but a negative myoclonus consisting of loss of postural tone(impaired inflow of joint and afferent sensations to brainstem reticular formation → arryhtmic lapses in posture)  Asterixis is not pathognomonic of HE because it can be observed in other diseases
  16. 16. CoAsterixis is also seen in  uraemia  ventilatory failure (CO2 narcosis)  drug intoxication-barbiturates, phenytoin alcoholism  Electrolyte imbalance-hypokalaemia hypomagnesaemia hypoglycemia 19
  17. 17. Asterixis (Flap Test))
  18. 18. Fetor hepaticus  It is a sour , musty, feculent smell detected on breath of some patients  Due to presence of mercaptans(byproduct of methionine metabolism)  Its presence does not correlate with degree or duration of encephalopathy and its absence does not exclude hepatic encephalopathy.
  19. 19. Personality changes  Apathy  Irritability  Euphoria  Disinhibition  Childishness  Loss of concern for family and friends
  20. 20. Intellectual deterioration-  Slight impairment of mental function to gross confusion  Constuctional apraxia (inability to make designs from match or blocks)  Changes in handwriting
  21. 21. Disturbed consciousness Day time sleepiness - Early sign  Disturbed night sleep Speech slow slurred voice – monotonus
  22. 22. Motor system  Hypertonia  Hyper-reflexia  Positive Babinski sign  Transient focal symptoms
  23. 23. Extrapyramidal dysfunction  Hypomimia (masked facies, masking of facies)  muscular rigidity  bradykinesia, hypokinesia  monotony and slowness of speech  parkinsonian-like tremor  dyskinesia with diminished voluntary movements
  24. 24.  Hepatic myelopathy (HM) Mainly with surgically created long-standing portocaval shunts. Demyelination of pyramidal tracts → 1) paraplegia with progressive spasticity 2) hyper-reflexia 3) weakness of lower limbs 4) relatively mild persistent or recurrent mental alterations, 5) without sensory or sphincter involvement. It does not respond to standard therapy, including ammonia lowering, but may reverse with liver transplantation (LT).
  25. 25. Prevalence (AASLD guidelines 2014)  Minimal HE (MHE) or covert HE (CHE) occurs in 20%-80% of patients with cirrhosis  The prevalence of OHE is 10%-14% at the time of diagnosis of cirrhosis in general & 16%-21% in those with decompensated cirrhosis. 10%-50% in patients with transjugular intrahepatic portosystemic shunt (TIPS)
  26. 26. Diagnosis  Diagnosis is very easy in setting of known cirrhosis,precipitating factors and asterixis.  But diagnosis becomes a challenge in absence of above factors as there is no gold standard test for diagnosis.  According to AASLD guidelines – The diagnosis of HE is through exclusion of other causes of brain dysfunction.
  27. 27. Differential diagnosis Metabolic CNS Toxins Infection Hypo-natremia stroke CNS depressants sepsis Hypokalemia subdural hematoma alcohol (abuse/withdrawal) Meningitis Hypoxia / Hypercapnea Intracranial bleed Wernicke-Korsakoff syndrome Encephalitis Hypoglycemia / Ketoacidosis abscess Uremia CNS neoplasm Seizure / Postictal
  28. 28.  But following tests may aid in diagnosis- 1) Thorough Neurological examination- changes in mental state,memory 2) Serum ammonia level –  But serum levels of NH3 are neither sensitive nor specific for its presence in blood,as affected by site or method of collection.  Blood ammonia levels may be a useful indicator of HE in the absence of cirrhosis and portal hypertension, as in patients with metabolic disorders that influence ammonia generation or metabolism, such as urea cycle disorders.
  29. 29. Special tests for MHE 1) Portosystemic encephalopathy (PSE) syndrome test – PHES(Psychometric Hepatic Encephalopathy Score) five paper-pencil tests 2) The Critical Flicker Frequency (CFF) test - fused light (presented from 60 Hz downward) appears to be flickering to the observer 3) The Continuous ReactionTime (CRT) test - repeated registration of the motor reaction time (pressing a button) to auditory stimuli (through headphones)
  30. 30. 4) The Inhibitory ControlTest (ICT) - computerized test of response inhibition and working memory X →Y orY→ X press button X→ X orY→Y Don’t press button 5) The Stroop test - evaluates psychomotor speed and cognitive flexibility by the interference between recognition reaction time to a colored field and a written color name. 6) The SCANTest - computerized test that measures speed and accuracy to perform a digit recognition memory task of increasing complexity. 7) Electroencephalography examination
  31. 31. Portosystemic encephalopathy (PSE) syndrome test five paper-pencil tests
  32. 32. EEG findings-  Progressive slowing of normal alpha(8-13Hz) frequency  Burst of slow activity in theta range(4-8Hz)  Triphasic waves or arrythmic delta activity, seen in more severe grade of encephalopathy  Coma – slow , low voltage delta activity with sequences of electric silences.  Triphasic waves – not pathognomonic,since also observed in other metabolic encephalopathies (like uremia,hypercapnia,hyponatremia) & with drug induced (lithium,valproate,baclofen).
  33. 33. Radiological tests  CT,MRI of brain –  To rule out other causes of cerebral dysfuncion  may show Manganese deposition in globus pallidus in cirrhosis, responsible for upregulation of BZD receptors ,resulting in HE.  MRS(magnetic resonance spectrometry)  PET(positron emission tomography),SPET(single photon emission tomography) with radiotracer imaging– both provide mainly biochemical information of metabolic processes,neuronal activity.
  34. 34.  SPEM (smooth pursuit eye movements) – conjugate gaze movements used to track or pursue smooth trajectory of small targets. Shows clear disruption in MHE & more pronounced disruption with OHE.  Evoked potentials (P300 latency ) – for MSE,it has a diagnostic potential.
  35. 35. TREATMENT  A) elimination or correction of precipitating causes  B)Decrease ammonia levels – I. Nonabsorbable Disaccharides II. antibiotics, such as rifaximin III. oral branched-chain amino acids (BCAAs) IV. intravenous (IV) L-ornithine L-aspartate (LOLA) V. probiotics VI. other antibiotics.  C) Nutrition  D)LiverTransplantation
  36. 36. Non-absorbable Disaccharides  Like lactulose / lactitol -is the first choice for treatment of episodic OHE  Mechanism of action-  Synthetic disaccharide monosaccharide +VFA(volatile fatty acids) + Hydrogen ions + methane . VFA substrate for bacterial growth, which forms bulk H+ ions decreases pH , acidic gut environment  Decreases pH causes 1) Leeching of NH3 from circulation into colon , which are then used by bacteria for protein synthesis 2) Decrease proliferation of harmful bacteria in gut, so decreasing ammonia production. 3) NH3 converted to NH4 ions , which are less readily absorbed
  37. 37.  Acts as probiotic – helps in growth of good bacteria like bifidobacterium,lactobacillus and supresses NH3 forming bacteria (bacteroids)  Reduction of intestinal NH3 production – through inhibition of glutaminase activity
  38. 38.  Dosage – 15-30 ml ,two – four times/day, Dose needs to be titrated ,so as to pass 2-3 bowel movements/day.  Can be given as rectal enema  Overuse has its risks like Aspiration, dehydration, hypernatremia, and severe perianal skin irritation. overuse can even precipitate HE.
  39. 39. Antibiotics - Rifaximin  aim of modifying the intestinal flora (selectively eliminate urease producing bacteria).  Rifaximin is an effective add-on therapy to lactulose for prevention of OHE recurrence  Other antibiotics – metronidazole, Neomycin (also a known glutaminase inhibitor)
  40. 40. oral branched-chain amino acids (BCAAs)  oral BCAA-enriched formulations improve the manifestations of episodic HE whether OHE or MHE  There is no effect of IV BCAA on the episodic bout of HE.  Leucine → potent stimulator of production of hepatocyte growth factor by stellate cells, so might stimulate liver regeration.  Improve albumin synthesis, decrease insulin resistance,decrease HCC occurance, improve immune function
  41. 41. L-ornithine L-aspartate (LOLA)  Can be given Intravenously (preferred) or Oral use  salt of the amino acids ornithine and aspartic acid and provides key substrates to & promotes metabolic pathway,urea cycle,resulting in detoxification of ammonia.
  42. 42. L-ornithine phenylacetate - would participate in the clearance of ammonia in muscles and the liver through glutamine synthesis ammonia  L-ornithine Glutamine  Glutamine + phenylacetate phenylacetylglutamine Excreted by kidney
  43. 43. Acarbose  intestinal α-glucosidase inhibitor used to treat type 2 diabetes mellitus  inhibits the intestinal absorption of carbohydrates and glucose and results in their enhanced delivery to the colon  the ratio of saccharolytic to proteolytic bacterial flora is increased, and blood ammonia levels are decreased.
  44. 44. Drugs which increase ammonia clearance  Sodium benzoate,sodium phenylbutyrate,sodium phenylacetate, GPB(Glyceryl phenylbutyrate)  Conjugate with glycine, excess nitrogen excreted in urine as hippurate  high sodium load,so cautious use is advised.  Efficacy is not clearly established yet.
  45. 45. Zinc supplementation  zinc deficiency is common in patients with cirrhosis.  Poor zinc levels → impaired activity of urea cycle enzymes in liver & glutamine synthetase  zinc increases the activity of ornithine transcarbamylase, an enzyme in the urea cycle, may also improve HE
  46. 46. Probiotics  promote nonammoniagenic(non-urease producing) bacteria in the gut  Like Lactobacillus acidophilus,bifidobacterium
  47. 47.  Flumazenil- selective BZD antagonist not frequently used. It transiently improves mental status in OHE without improvement on recovery or survival.  Laxatives - Simple laxatives alone do not have the prebiotic properties of disaccharides,so not useful.  Albumin - daily IV albumin showed no effect on resolution of HE,but was related to better postdischarge survival.
  48. 48.  Bromocriptine - (2.5 mg OD to max 5 mg BD) for Deficits in dopaminergic neurotransmission in HE  Hypertonic saline(23.4%) – some studies shown reduction in brain volume due to resolution of edema.  Shunt occlusion – vascular embolisation,baloon occlusion,vascular plugging
  49. 49.  Nasogastric intubation – for patients unable to take orally & also for those who are at risk of aspiration due to depressed sensorium.
  50. 50. Liver transplantation  only treatment option for HE that does not improve on any other treatment.  Artificial liver support system (MARS, molecular adsorption recirculating system) Purifies blood by removal of albumin bound and water soluble molecules. It removes NH3,endotoxin, inflammatory mediators.
  51. 51. Nutrition  Malnutrition is often underdiagnosed, and approximately 75% of patients with HE suffer from moderate-to-severe protein-calorie malnutrition with loss of muscle mass and energy depots.  Chronic protein restriction is detrimental because patients’ protein requirements are relatively greater than that of healthy patients and they are at risk of accelerated fasting metabolism. Malnutrition and loss of muscle bulk,sarcopenia, is a risk factor for development of HE.
  52. 52.  Daily energy intakes should be 35-40 kcal/kg ideal body weight  Daily protein intake should be 1.2-1.5 g/kg/day  Small meals or liquid nutritional supplements evenly distributed throughout the day and a late- night snack should be offered.  Vegetable protein is better tolerated than animal protein, benefits related to dietary fibre on colonic function, decrease transit time , decrease in intraluminal pH, increase in fecal ammonia excretion
  53. 53. Other experimental drugs  Metabolic Ammonia Scavengers – 1) Ornithine phenylacetate, 2) Glyceryl phenylbutyrate (GPB) Such drugs have been used for treatment of inborn errors of the urea cycle.
  54. 54. Other drugs  Rivastigmine – Ach levels are decreased , so rivastigmine improves psychometric performance  Sildenafil - ↓ function of NO-cGMP pathway, so , ↓ extracellular cGMP levels. Sildenafil improves cGMP levels & restore learning ability & intellectual function.
  55. 55. AST-120 (cremezin) –  oral adsorbent used in Japan to delay initiation of dialysis in patients with ESRD. Binds ammonia, bile acids, inflammatory mediators.  NMDA-receptor antagonists ammonia leads to overstimulation of NMDA receptors

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