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[2015] hepatic encephalopathy


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Review of hepatic encephalopathy

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[2015] hepatic encephalopathy

  1. 1. Hepatic Encephalopathy Ayman Alsebaey, MD. Lecturer of Hepatology, National Liver Institute. 1 FROM BASICS TO UPDATES
  2. 2. History • Hippocrates (460–371 B.C.) described the association between jaundice and acute behavioral disturbances. • GB. Morgagni (1682–1771) reported the history of a noble from Venice who was an alcohol misuser in the past. This man developed ascites and some episodes of agitation, and then he developed prolonged episodes of somnolence and delirium and finally died. His autopsy revealed the existence of liver cirrhosis (the Morgagni-Laennec cirrhosis). • Hann et al, 1893; who showed that dogs undergoing experimental portal- caval shunt develop behavioral changes within 10–40 days after surgery [meat intoxication syndrome]. 2
  3. 3. History • van Coulert et al 1932; reported the capacity of ammonia to induce coma or stupor in patients with cirrhosis. • S. Sherlock et al., 1954; defined hepatic encephalopathy and coined it as portal-systemic encephalopathy. • Fazekas, et al 1957; coined new term ‘hepatic encephalopathy’ (HE). • Rikkers et al 1978; first identification of latent HE. • H. Schomerus, W. Hamster, 1998: coined MHE. 3
  4. 4. Definition • HE It is a reversible impairment of neuropsychiatric function. • It is reversible neuropsychiatric state (brain dysfunction) varying from subtly altered mental status to deep coma complicating acute or chronic liver disease. • CONDITIONS OF HE OCCURRENCE: • Hepatocellular failure: so patients with pure Schistosomiasis and collaterals don’t develop HE owing to functioning hepatocytes. • Shunts  the toxic substances bypass the liver : • FHF: the liver itself is the shunt as nonfunctioning cells. • Cirrhosis: the blood bypasses the liver through a) external shunts: collaterals b) internal shunts: seen around the cirrhosis nodules. • Portocaval anastomoses and TIPS. 4
  5. 5. Prevalence  Overall: 30%–40% of those with cirrhosis at some time during their clinical course.  The prevalence of OHE at the time of diagnosis of cirrhosis is 10%–14% in general.  In decompensated cirrhosis is 16–21%.  After TIPS: 10-50%.  CHE: 20-80%.  The risk for the first bout of OHE is 5%–25% within 5 years after cirrhosis diagnosis.  Recurrence:  40% within 1st year after index OHE.  Subjects with recurrent OHE have a 40% cumulative risk of another recurrence within 6 months, despite lactulose treatment. 5
  6. 6. 6 OVERT [OHE] Neurological and neuropsychiatric abnormalities 20% annual risk in cirrhosis pts Prevalence 30-45% Detected by bedside clinical tests. COVERT [CHE] (Minimal HE) Normal mental and neurological status Prevalence 60-80% High risk of traffic violations and accidents. Abnormal psychometric tests
  7. 7. Updated Nomenclature Of HE Types 7
  8. 8. 8
  9. 9. Clinical diagnostic criteria West-Haven criteria for HE Stage Consciousness Intellect and behaviour Neurological findings 0 Normal  Normal  Normal examination; if impaired psychomotor testing, then MHE 1 Mild lack of awareness  Shortened attention span; impaired addition or subtraction  Mild asterixis or tremor 2 Lethargic  Disoriented; inappropriate behaviour  Obvious asterixis; slurred speech 3 Somnolent but arousable  Gross disorientation; bizarre behaviour  Muscular rigidity and clonus; Hyperreflexia 4 Coma  Coma  Decerebrate posturing 9
  10. 10. 10 Newly Designed One
  11. 11. 11 According to the new American Association for the Study of Liver Diseases/European Association for the Study of Liver guidelines
  12. 12. 12
  13. 13. Pathogenesis “the labyrinth” 13
  14. 14. 14 THEORIES
  15. 15. Intestinal Bacteria • Patients with cirrhosis have bacterial overgrowth that secretes intoxicants that contribute to HE. • Bacteria flora contribute to the production of ammonia • So HE may improve with oral antibiotics. 15
  16. 16. Ammonia Theory 16 Since Pavlov and Nencki in Russia in the 1890's.
  17. 17. 17 H pylori
  18. 18. Ammonia Sinks 18
  19. 19. Ammonia And The Brain  Astrocytes are the only cells in the brain that can metabolize ammonia.  α keto-glutaric acid 𝑁𝐻3 glutamic acid 𝑁𝐻3 glutamine  synapsis.  Glutamine accumulation  astrocyte swelling  brain edema.  In FHF [type A HE]:  Marked elevation of the ammonia   glutamate  excitatory changes  agitation, confusion, seizures and coma.  Glutamine is osmolyte so that it causes cerebral edema and increased intracranial tension. 19
  20. 20. In Patients With Liver Cirrhosis [Type C HE]:  There mild brain edema and neuro-inhibition status. • Chronic Exposure To Ammonia Has Another Effects: A. Release of the osmolytes “myoinositol and taurine” from inside the cell to counteract the glutamine effect. B. Downregulated glutamate receptors in the postsynaptic plate. C. Inactivated glutamate transporters on the astrocyte cell membrane. D. Over time, some of these cells change in shape and form and become 'Alzheimer type II' astrocytes. 20
  21. 21. Astrocytes • Astrocytes are the most abundant cells of the central nervous system (CNS) • Functions: • The provision of nutrients and mechanical support to surrounding neurones. • Regulation of ion transport and neurotransmitter uptake in the brain. • Key components of the blood–brain barrier (BBB). • Whilst astrocytes are sensitive to the effects of ammonia, neurons are almost completely unaffected by exposure to this neurotoxin 21
  22. 22. Ammonia Theory Debate Pros GIT bleeding and meet ingestion HE HE patients have increased NH3 levels CSF glutamine α HE degree Cons Injection of ammonia does not cause HE Serum ammonia does not correlated with HE degree or Brain levels of NH3 Hyperammonemia in certain enzyme deficiencies (e.g. Krebs–Henseleit urogenesis cycle) is never associated with coma. 22
  23. 23. Inflammation theory Systemic inflammatory response syndrome (SIRS) and Sepsis effect: 1) Hyperammonemia induction by amino acid solution  deterioration of the psychometric test results. 2) After SIRS treatment; hyperammonemia induction by amino acid solution  no effect on the psychometric test results. 23
  24. 24. 1) SIRS is associated with increased degranulation of the neutrophils and release of inflammatory mediators esp. TNF, IL-1, IL-6. 2) MHE have higher inflammatory markers but is not related to levels of ammonia and the severity of liver disease. 3) Inflammation   TNF  disturb blood–brain barrier   diffusion of ammonia into astrocytes. 4) Inflammation   neuro-steroids. 5) In animal model: NSAIDS improved HE. 24
  25. 25. 25
  26. 26. Neuro-steroids Theory • NSs are synthesized in the central and peripheral nervous system, either from cholesterol or from steroid precursors. • 8-kDa translocator protein (TPSO) NSs formation and endogenous benzodiazepines. • Inflammation Ammonia NSs formation. • Ammonia tricarboxylic acid cycle activity [Krebs cycle]  GABA synthesis • Action of NSs: • Affect mainly the GABAA receptor. • It  GABAergic tone. • Pros: • Autopsy  increased density of expression of translocator proteins that regulate neuro- steroid synthesis. 26
  27. 27. Oxidative And Nitrosative Stress • HE is related to  production of reactive nitrogen species (RNS) and reactive oxygen species (ROS) through the N-methyl-D-aspartate receptor pathways. • There is interplay between astrocyte swelling and ROS. • Both causes astrocyte senescence, senescence genes stimulation, inhibition of astrocyte proliferation • So cognitive impairment may not resolve after an attack of overt HE. • Patients following clinical resolution of overt HE have shown persistent and cumulative deficits in working memory, response inhibition, and learning capacity. 27
  28. 28. Trojan Horse Hypothesis • It is used to explain the toxic effect of glutamine in astrocytes. • Glutamine formed in the cytoplasm  enters the mitochondrial matrix  cleaved to release ammonia while still inside the mitochondria  the released ammonia mediates release of ROS and RNS through calcium-dependent pathways. • ROS  nitration of tyrosine residues in intracellular proteins  affection of the tans- astrocytic substrate transport and selective degradation of the permeability of the blood–brain barrier  ultimately promotes astrocyte swelling and cerebral edema. 28
  29. 29. Manganese Theory • MRI of patients with cirrhosis especially after portocaval shunt showed accumulation of Mg in the basal ganglia. • It is associated with Alzheimer type II astrocytes. • So it is responsible for the Parkinsonian symptoms such as tremors. • It increases NSs level and GABAergic tone. • HYPONATREMIA: • is a predictor of the development of OHE in patients with cirrhosis. 29
  30. 30. Genetics Theory About 40% of cirrhotic patients with minimal HE do not develop overt HE despite follow up > 7 years. Cirrhotic patients showing the same degree of liver dysfunction and suffering from the same precipitant factor (i.e., variceal bleeding) may, or may not, develop overt HE. Polymorphisms in the promoter region of K-glutaminase gene that could influence protein activity in either direction (an increase or a decrease) in glutaminase activity. 30
  31. 31. Old Theories • GABAergic theory: • Bacterial over growth  GABA  escapes metabolism by the liver through collaterals  brain  neuro-inhibition. • Cons: • no increase in cerebral GABA levels can be detected. • Benzodiazepine theory: • BZs receptors are related to GABA receptors  neuro-inhibition. • False neurotransmitter theory: • There is increases arromatic aa and decreased branched chain aa. • Aromatic aa form false neurtotransmitors  neuro-inhibition. • Cons: • IV octopamine   cerebral catecholamine levels, but does not lead to alteration of consciousness. • Norepinephrine and dopamine concentrations in the brains of deceased cirrhotics who had HE are normal. • Imbalances in plasma amino acid levels are also observed in cirrhotics without HE. • Treatment of HE by bromocriptine is ineffective. 31
  32. 32. Clinical Examination • HE is not the only reason of altered mental status in cirrhotic patients. • So it is a diagnosis of exclusion: • intra-cranial events, electrolyte abnormalities and sepsis. • Findings: • Global motor deficit, hyperreflexia, positive Babinski’s sign. • Compensatory hyperventilation. • Fetor hepaticus [dimethyl sulfide; breath of the dead]. • Asterixis • Persistent encephalopathy: • Parkinsonian symptoms • Spastic paraparesis from hepatic myelopathy [post-portocaval shunt]. • Hepatic dementia with attention deficit, dysarthria and apraxia (neuronal loss). 32
  33. 33. Asterixis • Is a flapping tremor. • Cause: • Imbalance between the agonist and antagonist muscle due to disturbed diencephalic motor centers • Detection areas: • tongue, and the upper and lower extremities. • Not specific to the liver: • Carbon dioxide intoxication, uremia, organ failure and stroke of basal ganglia. • Not seen in advanced cases and coma. 33
  34. 34. Symptom Cause Comments Altered mental status, memory loss, disorientation, personality changes, memory impairment, shortened attention span, slurred speech, confusion, coma  Cerebral edema (varying degrees) with astrocyte swelling  GABA toxic effects  Systemic inflammation  Alterations in the cerebral blood flux and in the oxidative metabolism  Altered communication between the astrocyte and the neuron  Trojan horse theory: oxidative stress caused by mitochondrial ammonia accumulation (glutamate transport) Transient focal neurologic deficits or seizures  Cerebral edema (varying degrees) with astrocyte swelling  GABA toxic effects  Alterations in the cerebral blood flux and in the oxidative metabolism  Rarely occurs Asterixis (flapping tremors)  Abnormal function of diencephalic motor centers that regulate the tone of agonist and antagonist muscles, normally involved in maintaining posture  Adams and Foley first described asterixis in 1949 in patients with severe liver failure and encephalopathy  Present in early to middle stages of HE  Not pathognomonic; it occurs with renal failure, hypercapnia, and stroke affecting basal ganglia  Asterixis does not occur in advanced HE  Never seen in coma  Testing for asterixis 34
  35. 35. Symptom Cause Comments Hyperreflexia, hypertonia, or extensor plantar responses  Pyramidal involvement  Never seen in coma Parkinsonian symptoms: bradykinesia, tremors  Deposition of manganese in the basal ganglia (globus pallidus and substantia nigra)  Manganese induces changes in astrocytes of the basal ganglia that promote the formation of Alzheimer type II astrocytes  Manganese acts as a neurotoxin to stimulate translocator proteins on astrocytes  Tics or chorea are rare  Severe Parkinson seen only in chronic HE Sleep latency, sleep fragmentation, inversion of sleep-wake pattern  Impaired hydroxylation and sulfation to 6- sulfatoxymelatonin in the liver  Ammonia levels  — Fetor hepaticus  Attributed to dimethyl sulfide, a volatile sulfur compound that can be identified in the breath and serum of patients with cirrhosis  Found in cirrhotics with or without HE 35
  36. 36. Symptom Cause Comments Hyperventilation  Associated with acidotic pH  Compensatory mechanism that decreases the entrance of ammonia into the brain  It has also been related to increased levels of estrogens and progesterone Hepatic dementia  Pathogenetic mechanism is obscure  Associated neuronal loss  In chronic HE  Fluctuating symptoms with periods of improvement and a subcortical pattern  The initial manifestations are attention deficits, visuopractic abnormalities, dysarthria, and apraxia  Seen rarely; is reversible after LT/TIPS Hepatic parkinsonism  Pathogenetic mechanism is obscure  Associated demyelination along the pyramidal tract  In chronic HE  Resembles Parkinson disease, except for a symmetric presentation and lack of significant tremor Hepatic myelopathy  Pathogenetic mechanism is obscure  In chronic HE  Usually motor abnormalities exceed mental deterioration  Is characterized by a progressive spastic paraparesis accompanied by hyperreflexia and extensor plantar responses  Only a few patients have sensory symptoms or incontinence  Does not respond to standard therapy 36
  37. 37. Where is the predator or beast in the image?? 37
  38. 38. Where is the enemy in the image?? 38
  39. 39. Minimal Hepatic Encephalopathy [MHE] ----------------------------------- The Hidden Unknown Enemy 39
  40. 40. Definition of Covert MHE • The presence of measurable cognitive defects in patients with liver disease and/ or porto-systemic shunting that are not identified by detailed clinical history and complete neurological examination, including interview of close family members. • Is detected by abnormalities in neuro-psychometric or neurophysiological tests that can be performed at the bedside and in the outpatient setting, in the absence of other known causes of abnormal cognitive tests. • AASLD/EASL • CHE is the preclinical stage of OHE • It consists of MHE and West Haven grade 1 HE due to poor reliability of the grade I stage. • OHE starts with grade 2 or with evidence of asterixis and disorientation. 40
  41. 41. Prevalence • High prevalence of CHE (30-80%) among patients with cirrhosis without overt HE. • Overt HE develops in >50% of MHE patients within three years. • Prevalence of CHE increases with increasing severity of liver disease. • MHE is present in a significant proportion of patients with portal hypertension without intrinsic liver disease. • All patients with cirrhosis of the liver should be tested for the presence of MHE. • RISK FACTORS: • Alcohol as etiology of cirrhosis, have history of overt HE in the past. • Advanced liver disease; CTP C, esophageal and gastric varices. 41
  42. 42. Natural history of CHE  Course:  Unchanged.  Improve.  Deteriorate.  Develop overt HE.  CHE α degree of liver dysfunction.  CHE is associated with:  worsened survival, increased risk of hospitalization and overt HE development 42
  43. 43. CHE Impaired HRQOL High risk of OHE High risk of mortality  Ability to operate complex machinery High risk of falls High risk of accidents Driving problems Higher prevalence of sleep disorders Burden on health care resources Cognitive dysfunction 43 Catastrophic effects of CHE
  44. 44. • Health related quality of life (HRQOL): • HRQOL is all aspects of human well being, encompassing physical and cognitive capabilities, functional behavior, emotional status and psychosocial adjustment • It is measured by different scores e.g. NHP, SIP, SF-36, CLDQ, NIDDK-QA. • CHE adversely affects HRQOL: • Complex activities: e.g. driving, planning a trip • Impaired social interaction, alertness, emotional behavior, sleep, work, home management, and recreation and pastimes. • MHE is associated with decreases appetite  malnutrition HRQOL. • MHE is associated with depression, anxiety-trait and alexithymic symptoms HRQOL. • It may reverses with lactulose, rifaximin or probiotic therapy. 44
  45. 45. • Sleep Disturbances: • Patients with MHE have more sleep troubles than those without. • Unsatisfactory night sleep due to delayed sleep onset and multiple night awakenings resulting in reduced sleep time and excessive daytime sleepiness. • Circadian rhythm abnormalities due to toxic effect on suprachiasmatic nucleus and impaired melatonin clearance. • Memory and Learning Difficulties: • Short memory affection. • Attention deficits  encoding defect and learning impairment. • Hyperammonemia cGMP  learning impairment. 45
  46. 46. • Driving: • there is impaired driving performance both by using real road driving tests or a driving simulator. • More traffic violations and motor vehicle accidents or collisions. • Fatigue that develops with work worsens this condition. • Navigational Skills: • Navigation is a complex process for safe driving. • Difficulties in following a map. • There is more number of illegal turns and accidents. • There is poor insight of the driving skills, prolonged reaction time, impaired navigational skills and worsening fatigue. • Driving simulation is beneficial. 46
  47. 47. • Falls in CHE • 40% of CHE patients had falls  need for hospitalization. • impaired attention and visuomotor coordination and slowed reaction time and psychomotor speed. • Falling  fractures and associated surgery  morbidity, decompensation, mortality, disturbances of the patient family and high economic burden. • Employment and Socioeconomic Burden : • 50% of CHE have not regular employment • slowing of psychomotor function and reduced work performance. • 60% of blue-collar workers are unfit to work compared to only 20% of white collar workers. • Diminished work performance and lost wages 47
  48. 48. Diagnosis of MHE Psychome- tric tests Stroop application Ammonia Brain imaging Lumbar puncture EEG MRI spectrosc- opy Single PET 48
  49. 49. Test Domain Tested Comments Paper-and-pencil psychometric tests  Number connection test, part A Psychomotor speed Poor specificity  Number connection test, part B Psychomotor speed More specific  Digital symbol test Psychomotor speed/attention Very sensitive  Serial dotting test Psychomotor speed Psychomotor speed only  Block design test Psychomotor speed Lasts 20 min  Line tracing test Psychomotor speed Speed and accuracy  Repeatable battery for the assessment of neuropsychological status Psychomotor speed Used in dementia and brain injury Computerized psychometric tests  Inhibitory control test Attention, vigilance, working memory Requires highly functional patient, computer skilled  Cognitive drug research Attention + episodic + working memory Requires highly functional patient, computer skilled  Stern paradigm Working memory, vigilance, attention –– Neuropsychological tests  EEG mean dominant frequency Generalized brain activity Can be performed in comatose patients  Visual evoked potentials Interval between visual stimulus and activity Highly variable, poor results  Brainstem auditory evoked potentials Response in the cortex after auditory click stimuli Inconsistent response  Critical flicker frequency Visual discrimination and general arousal Requires highly functional patients 49
  50. 50. 50 Test (domains examined) Advantages Disadvantages Diagnoses Outcome prediction Paper-Pencil PHES: NCT-A and B, digit symbol test, line-tracing test, and serial-dotting test (attention, processing speed, response inhibition, and visuospatial awareness) Validated, gold standard Lack of reference normative data in the United States Score of < -4 Score < -6 predicted poor survival RBANS (visuospatial, attention, language, immediate and delayed memory) Has US reference data Copyrighted, needs interpretation by a psychologist Dependent on a psychologist’s interpretation Not studied in HE; 2 domains not impaired in CHE Computerized ICT (working memory, response inhibition, psychomotor speed) Validated and does not require a psychologist’s interpretation Requires high-functioning patients with working knowledge of a computer High lures or weighted lures Significant impairment leads to increased motor vehicle crashes and violations, and predicting OHE CDR (attention, continuity of attention, speed of memory, and quality of episodic and working memory) Not validated in the United States Requires high-functioning patients with working knowledge of a computer Score of -5 to 15 Able to predict resolution of cognitive dysfunction after transplant and TIPS Continuous reaction time (sustained cerebral processing time, reaction time and response inhibition, and nerve inhibition) Not validated in the United States Requires adequate hearing, no reference data for United States CFT index of <1.9 -- EncephalApp Stroop Application (psychomotor speed, cognitive flexibility) Free, and can be used on a mobile platform. Has US reference data Cannot be performed in red-green color- blind subjects >190 seconds (on and off time) Longer times can predict OHE episodes Neurophysiological EEG (brain activity, mean dominant frequency) Can be used on all stages of HE without learning Highly variable, requires a neurologist’s interpretation Dependent on a neurologist’s interpretation EEG plus MELD increases accuracy in predicting prognosis CFF (visual processing and discrimination, general arousal) Test can be administered at bedside Requires high-functioning patients and expensive equipment, needs binocular vision CFF < 39 Hz Can predict OHE Evoked potentials (visual, auditory, and somatosensory) Sensitive without learning effects High variable results, requires a neurologist’s interpretation Variable, dependent on a neurologist’s interpretation Can predict the development of OHE
  51. 51. Paper-and-pencil Psychometric Tests  Psychometric Hepatic Encephalopathy Score (PHES):  Validated for MHE diagnosis in Germany, Italy and Spain not USA.  Number connection test:  part A [NCT-A]  part B [NCT-B]  Digital symbol test [DST]  Serial dotting test [SDT]  Block design test [BDT]  Line “trail” tracing test [LTT]  96% sensitivity and 100% specificity. If <-4 is diagnostic, <-6 is of poor prognosis.  If not available then abnormalities in 2 of the tests (at least 2 standard deviations from age- and education-matched controls) would identify CHE [NCT-A, NCT-B, BDT, DST]  Easy but time consuming, difficult to interpret, patient must be literate with fine motor activities [pencil and paper]. 51
  52. 52. 52
  53. 53. Repeated battery for the assessment of neuropsychological status (RBANS) • RBANS has been used for the evaluation of Alzheimer’s disease, schizophrenia, traumatic brain injury in 20-25m. • Was tested in a selected population of patients with cirrhosis awaiting liver transplantation. • It has not been specifically validated in HE. • The test has 2 domains, cortical and subcortical. • HE patients predominantly perform worse in the sub-cortical component. • The applicability of RBANS in practice is limited because it must be administered and scored by a psychologist. 53
  54. 54. Neuropsychological Tests • They are offered under the supervision of a neurologist and require specialized equipment, personnel and time. • EEG and Visual evoked potentials: • have not been shown to provide diagnostic information critical for the diagnosis of CHE • Brainstem auditory evoked potentials • Critical flicker frequency 54
  55. 55. Critical Flicker Frequency (CFF) • Flicker light is going on and off repeating. • No need for a psychologist, short period of time & minimal costs. • Principle: • In HE the retinal cells like astrocytes undergoes edema “hepatic retinopathy” • Light from 60Hz and gradually decreasing till flickering. • The subject has to press a button as soon as the impression of fused light switches to flickering light. • CFF threshold of 38–39 Hz • After patient training, done 8 times and the mean value is calculated as CFF. • Drawbacks: • Not validated in USA. • It requires intact binocular vision and absence of red-green blindness. • Fogging of glasses. Age, medications. • Moderated sensitivity and specificity so should be used for follow up. 55 Pulsating light emitting diode The HEPAtonorm™ Analyzer consists of a) hand held control unit b) headset c) patient stop button
  56. 56. Computerized Psychometric Tests • Inhibitory Control Test • Cognitive Drug Research • Scan Test 56
  57. 57. Inhibitory Control Test (ICT) • It is a computerized that assesses inhibition, attention span, vigilance, and working memory. • ICT is the most currently available computerized tests for HE. • It has been used in the description of traumatic brain injury, schizophrenia and attention deficit disorder. • Principle: • ICT consists of 1728 stimuli, 40 lures and 212 targets that are presented within 13 min after a training run: • The principle of this test is based on 'targets' and 'lures'. • Patients are shown a series of different alphabet sequences that flash on the computer screen one after another, and are expected to respond when 'X' is followed by 'Y' and vice versa—a so-called 'target'. • Patients are told not to respond to a 'lure'—when 'X' followed by 'X' or 'Y' is followed by 'Y'. • A lure response greater than five (out of 40 attempts) detects MHE with high sensitivity. • Clinic personnel were able to administer ICT with minimal training and it was found to be cheaper than psychometric test administration. • CHE is diagnosed when patients have longer reaction times, a lower rate of target responses, and a higher rate of lure responses with a sensitivity and specificity of 87% and 77%, respectively. 57
  58. 58. The Cognitive Drug Research (CDR) • The CDR consists of five psychometric subsets that test attention power, attention continuity, speed of memory and quality of episodic and working memory. • These tests have 50 parallel forms and have population norms for the UK. • This test has shown good correlation with the gold-standard PHES test and is popular in the UK. 58
  59. 59. Scan Test • Scan Test is also a computerized test that measures reaction time to visual stimuli, reaction time to choice, and scan reaction time based on the Sternberg paradigm. • It is not available in the USA, but has been validated in Europe as a good psychometric test that prognosticates cirrhosis. • It has also been endorsed as a test that is clinically useful in CHE diagnosis 59
  60. 60. The Stroop Smartphone Application • It is developed by Bajaj et al., 2013. • It is a short and recently validated test, simple, easy, no need for psychologist. • EncephalApp—Stroop Test is available as a free download on iTunes. • It measures psychomotor speed and cognitive flexibility and have been validated for the diagnosis of CHE. • It consists of identifying the color of symbols presented, delineating the correct color of a color word that is a different color than the word itself (e.g., red in a green-colored font), and reaction times. • It assesses time to correctly identify a series of symbols with different colors (off-time) and printed words with different colors (on-time). • A cut-off time of more than 190 seconds identified CHE with excellent accuracy. • OHE patients do worse than those without OHE. • It correlated with accidents and illegal turns in driving simulation tests. 60
  61. 61. 61
  62. 62. Serum Ammonia Levels • Levels of arterial and venous ammonia may correlate positively with the severity of HE. • Elevated ammonia level is not diagnostic of HE. • Routine measurement of ammonia levels in the blood is not recommended. • Difficult precautions: • Blood sample should be collected from a stasis-free vein (that is, without using a tourniquet or clenching and taking care not to cause turbulence or hemolysis or release of ammonia from the muscles) and must be immediately transported on ice to the laboratory to be analyzed within 20 min in lithium heparin– or sodium heparin– containing (green top) Vacutainer because heparin inhibits the release of ammonia from red blood cells.. • Artifactual increase in ammonia levels can be seen in patients with mild exertion prior to sampling and spontaneous release of ammonia from red blood cells in blood samples left at room temperature. 62
  63. 63. Lumbar puncture • CSF shows increase of glutamine and aromatic amino acids. • You may do to exclude meningitis, encephalitis or subarachnoid hemorrhage. • Do not do • LC patients have coagulopathy, LP is associated with bleeding. • In FHF, LP increases brain herniation. 63
  64. 64. SINGLE-PHOTON EMISSION COMPUTED TOMOGRAPHY [SPET] • SPECT studies the spatial distribution of radioactive tracer technetium Tc 99 and its local metabolism in the brain. • CHE patients have increased blood flow in the basal ganglia. • SPET is more available and less expensive than PET. • Small studies are done till now, so still of limited use. 64
  65. 65. Thanks to Apple store • For Free • Stoop Test • Inhibitory Control Test • Trail Marking Test • Line Drawing Test 65
  66. 66. 66 MRI technique Imaging abnormality Clinical correlate T1-weighted imaging  Bilateral, symmetrical, high- intensity signal in the basal ganglia (globus pallidus and substantia nigra)  Attributed to preferential deposition of manganese in the basal ganglia  Found in patients with cirrhosis who have substantial portosystemic shunts  No quantitative relation to severity of HE  Reverses after liver transplantation Proton spectroscopy (1H MRS)  Increase in glutamate and glutamine signals  Decrease in myoinositol and choline signals  Homeostatic compensatory metabolic changes occur in the astrocytes of patients with chronic liver failure that prevent massive cerebral edema  Changes seen on MRS imaging usually correlate with the severity of HE  Changes resolve after liver transplantation Magnetic transfer ratio  Mild, diffuse reduction in magnetic transfer ratio in the white matter  Reflects mild cerebral edema  Reverses after liver transplantation T2-weighted FLAIR sequence and diffusion weighted imaging  Diffuse increase in white matter signal intensity in the cerebral hemispheres and the corticospinal tract  Observed changes because of cerebral edema  Could explain neurologic abnormalities in patients with cirrhosis  Reverses after liver transplantation Abbreviations: FLAIR, fluid attenuation inversion recovery; HE, hepatic encephalopathy; MRS, magnetic resonance spectroscopy.
  67. 67. 67 Diagnostic test Advantages Disadvantages Serum levels of ammonia Positively correlated with the severity of HE Does not change approach to diagnose and manage HE Can be challenging to take appropriate blood samples in the clinic Clinical scales for OHE West Haven criteria Well-established classification criteria (in use for ≈30 years) Used in multiple studies of OHE Interobserver variation influences test results (especially for low grades of HE) HE Scoring Algorithm Minimal variability in results between different test sites Characterizes low grades of HE Time consuming (which may be a limiting factor in the outpatient setting) Neuropsychometric tests ('paper and pencil' tests) for MHE Psychometric HE score Specifically designed to diagnose subtle cognitive changes in patients with MHE Endorsed as the 'gold standard' by the Working Party at the 1998 World Congress of Gastroenterology, Vienna, Austria Poor test of memory Difficult to interpret and score Excessive reliance on measuring fine motor skills Unpopular in USA (lack of US-specific normative data and availability) Repeatable Battery for the Assessment of Neurological Status Tests can be completed rapidly (within 25 min) Difficult to interpret and score Excessive reliance on measuring fine motor skills Computerized psychometric tests for MHE Inhibitory control test Detects MHE with high sensitivity Validated against existing psychometric tests Studies using this test have mostly been conducted in a single institution located in either Wisconsin or Virginia, USA CDR system Correlates well with neuropsychometric tests Time consuming, which could be a limiting factor Trial run needed before formal testing Neurophysiologic tests Critical flicker frequency High sensitivity and specifity Correlates well with neuropsychometric tests Widely used in clinical trials Lack of widespread availability in the USA to permit use in ambulatory patients Electroencephalography HE associated with slow frequency of electrical activity Variable sensitivity for the diagnosis of HE (43–100%) Brain imaging MRI Multiple techniques available Identifies several brain abnormalities associated with HE (e.g. levels of glutamate) Can be expensive (especially the newer techniques that show low grades of cerebral edema) CT Useful for excluding other causes of encephalopathy Identifies conditions that worsen HE (subdural hematoma or a cerebrovascular event) Poor detection of low grades of cerebral edema in most patients with HE Risk associated with radiation exposure Abbreviations: CDR, Cognitive Drug Research computerized assessment; HE, hepatic encephalopathy; MHE, minimal hepatic encephalopathy; OHE, overt hepatic encephalopathy.
  68. 68. 68 End of Part I Thanks a lot
  69. 69. Treatment of Hepatic Encephalopathy 69
  70. 70. HE TREATMENT Overt HE [OHE] Special cases [FHF, TIPS] Covert HE [CHE] 70
  71. 71. Overt Hepatic Encephalopathy [OHE] Treatment 71
  72. 72. OvertHepatic encephalopathytreatment Exclusion of other causes of encephalopathy Identification of precipitating factor Empiric treatment launch Reassessment after 72 hr. 72
  73. 73. 1st step is to exclude other causes e.g. meningitis, encephalitis. Identification of the precipitating factor e.g. GIT bleeding. 90% of patients can be treated with just correction of the precipitating factor Start empiric therapy. A rapid response means right diagnosis. ICU admission for comatosed one. If no response after 48-72hr: Wrong diagnosis so MRI of the brain should be done to exclude CNS causes. Missed so untreated precipitating factor. Missed a synchronous causes of encephalopathy. Inadequate treatment. 73
  74. 74. 74
  75. 75. Treatment Precipitating factor ttt Enema ?? Nutrition & BCAS Medical therapy Non- absorbable disaccharides Lactulose Lactilol Antibiotics Rifaximin Neomycin, paromomycin Ammonia lowering agent Ammonia scavengers Lola Ornithine phenylacetate Na benzoate Na & glycerol phenylbutrate Spherical carbon adsorbent Polyethylene glycol Experimental Zinc Probiotics Combination therapy Embolization of portosystemic shunt Secondary prophylaxis Artificial liver support Liver transplantation 75
  76. 76. 76
  77. 77. Treatment Of The Precipitating Factor GI bleeding Octreotide, IV PPI, endoscopic or angiographic therapy Blood transfusions, correction of coagulopathy NG lavage to remove blood from stomach Infection Antibiotic therapy Sedating medications Discontinue benzodiazepines, narcotics, consider flumazenil or naloxone Electrolyte abnormalities Discontinue diuretics, perform serial paracentesis if needed Correct hypokalemia or hyperkalemia, hyponatremia Constipation Provide laxatives and enemas Renal failure Discontinue diuretics Albumin administration Discontinue nephrotoxic medications 77
  78. 78. Enema??? Cons to enema:  Difficult for nursing staff.  Variable efficacy due to variation in the indwelling and drug exposure time.  It should be done by placing the pt in Trendelenburg left lateral decubitus position, right decubitus position, then a position in which the upper part of the body is elevated to maximize the exposure of the entire colon. Pros:  Is a safe and effective method for obtunded patients if oral administration is not possible least aspiration e.g HE III.  Lactulose also can be given rectally (300 mL in 700 mL of saline) 78
  79. 79. Nutrition Old concept:  Protein restriction is useful as decreasing the nitrogenous load, NH3. New concept:  Patients with cirrhosis must eat at least 1.2 – 1.5 g/kg of protein daily.  divided between at least 4 meals every day, and patients should take a late evening snack to reduce protein breakdown during the overnight fast  Branched-chain amino acids (BCAAs) and vegetable protein or dairy products should be added when HE develops.  Muscles are alternative pathway for NH3 metabolism in patients with cirrhosis “ammonia sink”.  Lack of protein diet causes muscle wasting (sarcopenia), cachexia with increased episodes of encephalopathy. 79
  80. 80. Vegetable-based protein  Less ammoniogenic so better tolerated by cirrhotic patients.  It may causes bloating and flatulence in some patients.  It has 2 actions:  High fiber content that increases colonic motility and purgation.  It decreases the colonic pH reducing ammonia absorption. 80
  81. 81. Branched-chain Amino Acids Valine, Leucine, and Isoleucine  Pros:  Action:  BCAAs  glutamate formation +NH3  glutamine in the muscle, so cirrhotic patients have low serum BCAAs levels.  Leucine promote protein synthesis by the liver  ammonia formation.  Recent studies and meta-analysis: BCAAs augments rapid recovery from HE without survival effect.  Apart from encephalopathy; BCAAs improve levels of serum albumin, increase progression- free survival and reduce both the number of hospitalizations and the length of hospital stays in patients with cirrhosis.  Dose: 0.25 g/kg body weight.  Cons:  Expensive with poor availability.  IV preparation are not effective so use only oral formulas. 81
  82. 82. Non-absorbable Disaccharides  They are the 1st line therapy [Cochrane review found insufficient evidence to either support or refute the use of lactulose].  Members: Lactulose and Lactilol [more palatable and less GIT upsets].  Action:  Laxative effect  ammonia elimination.  Reduced NH3 synthesis and absorption:  Lactulose  intestinal bacteria  acetic and lactic acid  pH [acidic media]   the synthesis and absorption of ammonia.  It increases movement of NH3 from blood to the GIT.  Lactulose  colonic lactate and H ions NH3 NH4 non absorbable form.  Promote the growth of beneficial acid resistant, non–urease-producing bacteria [difficult to prove]. 82 Medical Therapy
  83. 83. Dose: 15–30 ml given twice a day to induce 2–3 soft bowel movements daily. Added to enema: 1-3 L of 20% lactulose is more effective than tap water in comatosed patients to avoid aspiration [lack evidence]. Adverse effects: sweet taste, bloating, over treatment [dehydration] and hypokalemia. Risk factors for failure of lactulose therapy: High MELD, high total leukocyte count, Low serum sodium, low MAP, HCC 83 Medical Therapy
  84. 84. Cons: Studies were small and underpowered. Variable efficacy. Insufficient evidence showing that lactulose is efficacious for OHE Meta-analysis by Als-Nielsen et al 2004:  when compared to placebo or no intervention, nonabsorbable disaccharides had no statistically significant effect on mortality, but did show to reduce the risk of no improvement of OHE. Pros: clinical anecdotal experience and comfort with the use of lactulose, which accounts for the lack of placebo RCTs for HE. 84 Medical Therapy
  85. 85. Comparison of Non-absorbable Disaccharides and Placebo or No Treatment for Hepatic Encephalopathy. Trial Study design Patients No Treatment Assessment Efficacy Simmons et al Parallel AHE + CHE 26 Lactulose/g lucose Clinical grading, ammonia, stool production Lactulose = glucose Uribe et al Parallel AHE 15 Lactulose enema Mortality, clinical grading Lactulose > placebo Lanthier et al Crossover CHE 5 6 months Clinical examination, psychometric tests, ammonia levels, EEG, cerebral blood flow Lactulose = lactitol Heredia et al Parallel AHE 40 5 days Mortality, clinical grading, PSE grade, adverse events Lactulose = lactitol Riggio et al Parallel CHE + MHE 31 6 months PSE index, new episodes of HE, adverse events Lactulose = lactitol 85
  86. 86. Antibiotics  Neomycin:  It was the first antibiotic that was used.  It inhibits the intestinal glutaminase plus reduced ammonia production by bacteria.  Dose: 3-4g/day.  Side effects: Ototoxicity, nephrotoxic [??].  Metronidazole:  Though effective but associated with resistance and peripheral neuropathy.  Paromomycin and vancomycin  Is associated with bacterial resistance.  Vancomycin-resistant enterococcus 86 Medical Therapy
  87. 87. Rifaximin  Is minimally absorbed drug with very low systemic absorption and a high barrier to resistance.  Recent meta-analysis: is equal or superior to lactulose with less abdominal pain.  It is equal to neomycin but more NH3 lowering action with less side effects.  Rifaximin monotherapy is unproven so usually combined with lactulose.  Action:  Broad spectrum drug with low risk of resistance.  It acts against Gram-positive and Gram-negative organisms, both aerobes and anaerobes.  Acts mainly in the small intestine with marked lowering bacterial effect.  Dose:  550mg /12hr.  AE: flatulence, abdominal pain, headaches, and constipation. 87 Medical Therapy
  88. 88. Rifaximin for Hepatic Encephalopathy. Trial Study design No of patients Duration of treatment Assessment Efficacy Festi et al Lactulose (open- label) 21 21 Neurological signs of HE, asterixis score, HRNB, EEG, ammonia levels Rifaximin = lactulose Massa et al Lactulose (double-blind) 40 15 HE index severity, mental status, cancellation tasks, HRNB, EEG Rifaximin > lactulose Mas et al Lactitol (double- blind) 103 5–10 days Mental status, asterixis score, EEG, ammonia levels, PSE index, psychometric tests Rifaximin = lactitol Paik et al Lactulose (open- label) 54 7 days Ammonia levels, flapping tremor, mental status, HE index, psychometric tests Rifaximin = lactitol Jiang et al Meta-analysis 264 – – Rifaximin = disaccha rides Eltawil et al Meta-analysis 565 – – Rifaximin = disaccha rides 88
  89. 89. Ammonia Lowering Agent Ammonia Scavengers: LOLA  L-Ornithine-L-Aspartate (LOLA) supplies substrates for urea cycle and glutamine synthesis.  Not available in USA.  Actions:   urea production by increasing carbamyl phosphate synthetase in periportal hepatocyte.   liver and muscle glutamine by increasing GLN synthetase  It is a promising drug though most studies used I.V. form on HE I-II patients.  Oral route needs more evaluation.  IV preparations are better than oral ones. 89 Medical Therapy
  90. 90. Ammonia Lowering Agent Ammonia Scavengers: Na Benzoate  It combines with glycine so decreasing serum ammonia.  Approved in urea cycle defects and hyperammonemia.  Usually used in combination with sodium phenylacetate (Ammonul®) or sodium phenylbutyrate (Buphenyl®).  High sodium content (1-2g/day):  Salty taste so not palatable.  Fluid retention with ascites  Hypernatremia with altered mental status so not useful in HE patients. 90 Medical Therapy
  91. 91. 91
  92. 92. Ammonia Lowering Agent Ammonia Scavengers: Na & Glycerol Phenylbutrate  Sodium phenylbutyrate (SPB):  SPB  phenylbutyric acid  phenylacetate + glutamine  phenylacetylglutamine  urine.  High sodium content  ascites.  Glycerol phenylbutyrate (GPB); Ravicti®:  is an oral prodrug of Na phenylbutyrate that is safe in cirrhotic patients.  nearly tasteless, odorless, sodium-free liquid compound.  Approved in urea cycle defects and hyperammonemia.  Still phase III in HE (, NCT00999167).  6 mL twice a day for 16 weeks .  improved outcomes, decreased ammonia levels.  Useful in treatment and prevention of recurrent HE. 92 Medical Therapy
  93. 93. Ammonia Lowering Agent Ammonia Scavengers: Ornithine Phenylacetate  L-Ornithine-phenylacetate [LOPA]:  Is similar to LOLA  OP (OCR-002) combines ornithine and PAA.  It supplies urea cycle with ornithine.  Phenylacetate + glutamine  phenylacetylglutamine [easily excreted].  Still phase IIb decompensated cirrhosis for overt HE. 93 Medical Therapy
  94. 94. Ammonia Lowering Agent Ammonia Scavengers: Spherical Carbon Adsorbent AST-120:  It is a spherical carbon adsorbent (0.2-0.4 mm microspheres).  It was approved in Japan in 1991 to improve uremia and delay the initiation of dialysis in patients with chronic renal insufficiency.  It is safe for prolonged use as being or degraded or adsorbed from  It has minimal interference with digestive enzymes or drug absorption.  It binds very small molecules in the gut e.g. TNF-α, lipopolysaccharide, or endotoxin, and block their absorption.  It has also ammonia lowering properties. Still phase II study. 94 Medical Therapy
  95. 95. Ammonia Lowering Agent Ammonia Scavengers: Polyethylene Glycol  PEG is used for bowel preparation before colonoscopy  Idea is rapid clearance of gut bacteria (4-L dose of PEG). , NCT01283152.  More effective than lactulose as treatment for OHE with less hospital stay.  Less ammonia lowering effect than lactulose [? Dehydration related effect].  There were no significant changes in serum sodium, creatinine, or BUN after either PEG or lactulose treatment.  The data are promising as a treatment for acute OHE. 95 Medical Therapy
  96. 96. Ammonia Scavengers Appearance Mechanism of Action/Byproduct Dosage Approved Use Sodium benzoate  White or colorless crystalline powder • 1 mol of Nitrogen removed/mole of benzoate after conjugated with glycine • 5.5 g/m2 IV over 90–120 min, repeat daily • Urea cycle disorders Food preservative Sodium phenylacetate  White to off-white crystalline powder • 2 mol of Nitrogen removed/mole of PAA after conjugated with glutamine • Urea cycle disorders GPB  Colorless to pale yellow liquid • Nitrogen removal in the form of urinary PAGN • 5–12.4 g/m2 daily • Urea cycle disorders OP  Crystalline salt • Nitrogen removal in the form of urinary PAGN • 10 g IV daily • Possibly future approval for overt HE AST-120  Charcoal powder • Binding of neuroactive substances (including ammonia) in the GI tract • 6–12 g IV daily • Delaying dialysis in chronic kidney disease; uremic symptoms 96
  97. 97. Experimental Agents Zinc: Is a cofactor of urea cycle. Zinc replacement is not harmful, but it does not seem to have a place in the management of HE. Can be used only with zinc deficient patients or resistant to usual treatment/ 97 Medical Therapy
  98. 98. Experimental Agents  Probiotics:  Probiotics are live microbiologic dietary supplements that alter the intestinal balance of microflora in the gut e.g. Lactobacilli and Bifidobacteria  They reduce bacterial translocation and subsequent endotoxemia .  Useful in patients with CHH not OHE.  Its use in management of high grade HE is lacking and different strains may have different effects on HE should be kept in mind.  In a Cochrane meta-analysis of 7 CHE/OHE trials there were no reported differences of probiotics compared with lactulose with respect to a reduction in ammonia levels and improvement in mental status.  The analysis did show an advantage of probiotics compared with no treatment in all-cause mortality, number of adverse events, and HRQOL.  Regular use of probiotics in the management of HE still need more data. 98 Medical Therapy
  99. 99. Combination Therapy  The evidence evaluating the use of combination therapy for the treatment of HE does not support its widespread use.  The combination of rifaximin and lactulose may be considered in the treatment of HE and in patients refractory to monotherapy.  RECENT STUDY:  Sharma et al., 2013 should combined rifaximin and lactulose are better than lactulose monotherapy. 99 Medical Therapy
  100. 100. Embolization of portosystemic shunt  Patients with persistent or chronic encephalopathy usually have porto- systemic shunt especially spleno-renal shunt.  It can be embolized by angiography [balloon-occluded retrograde transvenous Obliteration] using coils. 100 Medical Therapy
  101. 101. Post-TIPS HE  Lactulose and rifaximin are of no benefit in preventing post-TIPS HE.  The only effective therapy is to decrease the the diameter of the stent. 101 Medical Therapy
  102. 102. Secondary Prophylaxis  There is no primary prophylaxis ???.  No drug was shown to prevent 1st HE episode after TIPS [Riggio et al., 2005].  ??? Prevention of CHC to OHE.  Secondary prophylaxis.  It is the prevention of second HE episode after index episode.  Lactulose can be used.  46% recurrence of OHE due to lactulose misuse.  Combined lactulose and rifaximin have a decreasing risk of both breakthrough HE episodes as well as hospitalizations when compared with lactulose alone.  Probiotics [VSL#3] in a recent study is equal to lactulose [Agrawal et al., 2012]. 102 Medical Therapy
  103. 103. Secondary Prophylaxis When to stop secondary prophylaxis:  Usually it is used indefinitely.  Exception: Controlled precipitating factor as variceal bleeding HE. Improving liver condition as treated AIH, antiviral for HCV, HBV etc. 103 Medical Therapy
  104. 104. 104 Secondary Prophylaxis of Hepatic Encephalopathy. Secondary Prophylaxis of Hepatic Encephalopathy. Trial Type of prophylaxis Study design No of patient (n) Duration of treatment Assessment Efficacy Riggio et al Primary Lactulose and lactitol in portosystemic shunt 31 6 months PSE index Lactulose = lactitol Sharma BC et al Secondary Lactulose (open-label) in cirrhosis with previous HE 140 14 months Psychometry and CFF Lactulose > no treatment Bass et al Secondary Rifaximin + lactulose (randomized, double- blind, placebo- controlled) in cirrhosis with previous HE 299 6 months HE clinical Rifaximin > placebo Agrawal et al Secondary Lactulose, probiotics (open-label trial) in cirrhosis with previous HE 235 12 months Psychometry and CFF Lactulose = probiotic s
  105. 105. Artificial Liver Support • Not studied well • In a small trial of 56 patients: • MARS with albumin infusion did not show faster recovery from HE. • Only a mortality benefit in albumin treated group. • May be used for refractory cases without survival benefit. 105 Medical Therapy
  106. 106. Liver Transplantation  Liver transplantation resolves both hepatic dysfunction and portal hypertension  It usually results in complete resolution of HE.  Indication:  recurrent or treatment resistant cases.  MELD obstacle:  HE does not necessarily correlate with MELD score.  Patients with HE may be disadvantaged in the era of MELD-based organ allocation despite a serious impact of HE on productivity, health, and survival. 106
  108. 108. •Most studies in CHE have not measured outcomes data such as •hospitalizations, •OHE prevention, •death, •but rather had end points such as improvement in HRQOL and cognitive testing. 108
  109. 109. Non-absorbable dissacharides Lactulose therapy:  resulted in improved abnormal psychometric tests , HRQOL and decreased the progression to overt HE [primary prophylaxis]. The laxative effect [30-60 mL/day] and titration to 2–3 soft bowel movements per day make adherence to lactulose classically low. Poor tolerance:  Diarrhea, abdominal pain/cramping, nausea, and flatulence.  Overuse resulted in dehydration and hyponatremia with worsening of HE. 109
  110. 110. Rifaximin  Dose: 550 mg bid. Recent study half dose is equal.  Actions:  it does not seem to alter the normal fecal flora and, thus, is not associated with Clostridium difficile colitis.  It reduced Veillonellaceae and an increased in Eubacteriaceae.  Clinical Benefits in CHE patients:  It is associated with improved cognitive function, reduced endotoxemia, abnormal psychometric tests, HRQOL.  reduced total driving related errors, specifically speeding tickets and navigation of illegal turns  decreased the progression to OHE.  Pros:  Patients adhere to it better than lactulose.  Cons:  Expensive drug but weight against progression to OHE and hospitalization costs. 110
  111. 111. Probiotics  Probiotics:  They are live microorganisms that alter the balance of intestinal microflora,.  Synbiotics:  They are probiotics with the addition of fermentable fiber.  Clinical benefits:  30 days synbiotic treatment resulted in a decrease in intestinal pH, blood ammonia levels, and reversal of MHE.  Probiotic yogurt treatment reversed CHE and prevented progression to OHE.  VSL # 3 (3 capsules daily—108 CFU)  50% reduction in progression to OHE.  Phase I; Lactobacillus had reduced levels of endotoxemia, tumor necrosis factor-a, and dysbiosis  Larger studies with a longer duration of follow-up are required with standardization of probiotic formulations. 111
  112. 112. LOLA  Clinical benefits:  It resulted in improved abnormal psychometric tests , HRQOL and decreased the progression to overt HE.  Side effects:  Nausea, cough, muscle cramps, and less frequently diarrhea  Cons:  Few studies with small sample size.  A recent study [Alvares-da-Silva et al., 2013] there was no difference in the whole psychometric battery evaluation between patients treated with LOLA and placebo. 112
  113. 113. 113 Published Egyptian Studies
  114. 114. Advantages and disadvantages of the therapeutic agents most studied for the management of covert hepatic encephalopathy Drug Advantages Disadvantages Evidence Probiotics Excellent tolerability Palatable food product Inexpensive No adverse events No prescription required Decreases CHE Prevents OHE Multiple cultures Unregulated medical food Optimal dose and duration unknown  Liu et al  50% vs 13% reversal of CHE (P<.05). Decreased ammonia and endotoxin levels (P = .05). Improved Child-Pugh scores (P = .04)  Bajaj et al  70% vs 0% with placebo in reversal of CHE (P = .03). 0% developed CHE vs 25% in placebo  Lunia et al  50% decrease in development of OHE (P<.05)  Vlachogiannakos et al  57% decrease in CHE vs placebo (P<.01). >80% compliance with therapy Lactulose Inexpensive Cost-effective Improves quality of life Decreases CHE Diarrhea Abdominal pain Bloating Compliance (ADR) Poor palatability  Dhiman et al  57% resolution of CHE. Improvement in psychometric testing (P = .04)  Prasad et al  HRQOL (Sickness Index Profile) improved (P = .002)  Sharma and Sharma  53% improved CHE during treatment Rifaximin Excellent tolerability Decreases CHE Improves quality of life Expensive Not cost-effective  Bajaj et al  91% vs 61% with placebo improved psychometric testing (P<.05). Psychosocial HRQOL improved (P = .04). Decreased driving errors on simulators (76% vs 31%; P = .13)  Sidhu et al  75% vs 20% placebo cleared CHE (P<.0001). Total HRQOL improved with 8 wk of therapy  Bajaj et al  Not cost-effective at current pricing LOLA, oral Decreases rates of OHE 6 mo after discontinuation MELD/Child-Pugh scores improved 6 mo after discontinuation Not shown to decrease CHE No improvement in QOL or depression/anxiety scores Limited experience  Alvares-da-Silva et al  No statistically significant change in CHE, QOL, or depression/anxiety scores. OHE developed in 5% of LOLA vs 37.9% in placebo group 6 mo after discontinuation of therapy (P = .016). MELD/Child-Pugh scores improved 6 mo after discontinuation (P<.001) 114
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  116. 116. 116
  117. 117. 117 Trial Treatment Total patients Study design Assessment Efficacy Covert hepatic encephalopathy Horsmans et al Lactulose vs placebo 14 RCT Psychometric tests, ammonia levels Lactulose > placebo for psychometric tests Watanabe et al Lactulose vs no treatment 36 RCT Psychometric tests, ammonia levels Lactulose > no treatment for psychometric tests Dhiman et al Lactulose vs no treatment 26 RCT Psychometric tests Lactulose > placebo Prasad et al Lactulose vs no treatment 61 NB- RCT Psychometric tests, HRQOL Lactulose > placebo for psychometric tests and HRQOL Sharma et al Lactulose vs lactulose + probiotics vs probiotics alone 105 NB- RCT 3 psychometric tests, ammonia levels Lactulose + probiotics > lactulose > probiotics for all parameters Bajaj et al Rifaximin vs placebo 42 DB- RCT Total driving errors, cognitive performance, SIP, ammonia levels, inflammatory cytokines Rifaximin > placebo for total driving errors, cognitive performance, SIP, and anti-inflammatory markers Sidhu et al Rifaximin vs placebo 94 DB- RCT 2 psychometric tests, SIP Rifaximin > placebo for all parameters
  118. 118. 118 Trial Treatment Total patients Study design Assessment Efficacy Covert hepatic encephalopathy Lunia et al Probiotics vs placebo 160 OL-RCT Psychometric tests, CFF, glucose and lactulose hydrogen breath test, ammonia levels Probiotics > placebo for all parameters Bajaj et al Probiotic (Lactobacillus GG) vs placebo 30 RCT Endotoxemia, TNF-α levels, dysbiosis Lactobacillus > placebo for all parameters Pratap Mouli et al Probiotic (VSL#3) vs lactulose120 OL-RCT Psychometric tests, ammonia levels VSL #3 = lactulose (noninferior) for all parameters Stauch et al LOLA vs placebo 66 RCT CHE (psychometric tests), ammonia levels, PEI, WHC grade LOLA > placebo for all parameters Kircheis et al LOLA vs placebo 114 DB-RCT CHE (psychometric tests), ammonia levels, PEI, WHC grade LOLA > placebo for all parameters Mittal et al LOLA vs lactulose vs no treatment vs probiotics 160 OL-RCT Psychometric tests, ammonia levels, HRQOL LOLA = lactulose = probiotics for all parameters Poo et al LOLA vs lactulose 20 OL-RCT Psychometric tests, WHC grade, asterixis, EEG LOLA = lactulose for ammonia levels LOLA > lactulose for WHC grade, asterixis, psychometric tests, EEG Sharma et al LOLA vs rifaximin vs probiotics vs placebo 124 RCT Psychometric tests, CFF LOLA = rifaximin = probiotics > placebo for all parameters Alvares-da- Silva et al LOLA vs placebo 64 DB-RCT Psychometric tests, CFF, EEG, ammonia levels, Beck’s anxiety-depression, HRQOL, prevention of OHE LOLA > placebo for prevention of OHE
  119. 119. 119 Trial Treatment Total patients Study design Assessment Efficacy Acute episode of overt hepatic encephalopathy Simmons et al Lactulose vs glucose 26 RCT WHC grade, ammonia levels, stool production Lactulose = glucose for all parameters Rodgers et al Lactulose vs sorbitol 6 Cross-over RCT WHC grade, EEG, ammonia levels Lactulose = sorbitol for all parameters Uribe et al Lactulose or lactitol (enema) vs placebo 15 DB-RCT Mortality, WHC grade Lactulose > placebo for all parameters Elkington et al Lactulose vs sorbitol 7 DB cross- over RCT Stool pH, ammonia levels, EEG Lactulose vs sorbitol for all parameters Festi et al Rifaximin vs lactulose 21 DB, DD- RCT Neurologic signs of HE, asterixis score, EEG, HNRB, ammonia levels Rifaximin = lactulose for all parameters Buci et al Rifaximin vs lactulose 58 DB, DD- RCT Neurologic status, asterixis score, cancellation tasks, HRNB EEG, ammonia levels Rifaximin > lactulose
  120. 120. 120 Trial Treatment Total patien ts Study design Assessment Efficacy Acute episode of overt hepatic encephalopathy Massa et al Rifaximin vs lactulose 40 DB, DD-RCT HE index severity, mental status, cancellation tasks, HRNB, EEG Rifaximin > lactulose for all parameters Fera et al Rifamixin vs lactulose 40 DB, DD-RCT Mental status, asterixis score, cancellation tasks, HRNB, EEG, ammonia level, PSI Rifaximin > lactulose for all parameters Mas et al Rifaximin vs lactitol 103 DB, DD-RCT Mental status, asterixis score, EEG, PSI, psychometric tests Rifaximin = lactitol for mental status and asterixis score; Rifxamin > lactitol for PSI, psychometric tests, and EEG Leevy et al Rifaximin vs lactulose 145 Cross-over WHC grade, asterixis score, hospitalizations Rifaximin > lactulose for all parameters Paik et al Rifaximin vs lactulose 54 OL-RCT Ammonia levels, flapping tremor, mental status, HE index, psychometric tests Rifaximin = lactulose for all parameters Sharma et al Rifaximin + lactulose vs lactulose 120 DB-RCT Reversal of HE, mortality, hospital stay Rifaximin + lactulose > lactulose for all parameters
  121. 121. 121 Trial Treatment Total patient s Study design Assessment Efficacy Secondary prevention of OHE Sharma et al Lactulose vs placebo 140 OL-RCT Psychometric tests, CFF, ammonia levels, re- admission for HE, mortality Lactulose > placebo for readmission for HE Bass et al Rifaximin vs placebo (>90% patients on lactulose) 299 DB-RCT Time to first breakthrough HE, time to first HE-related hospitalization Rifaximin > placebo for all parameters Agrawal et al Lactulose vs probiotics vs no therapy 235 RCT Psychometric tests, CFF, ammonia levels, secondary prevention of OHE, mortality Lactulose = probiotics > no therapy for secondary prevention of OHE Dhiman et al Probiotic (VSL#3) vs placebo 130 DB-RCT Secondary prevention of OHE, all-cause hospitalizations, CTP and MELD scores Probiotics > placebo for all parameters
  122. 122. Thanks a lot 122