hepatic encephalopathy
DESCRIPTION
hepatich encephalopathy in children & its management with referrence from standard text booksTRANSCRIPT
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Hepatic Encephalopathy Hepatic Encephalopathy
Dr Bikash Ranjan PraharajPost Graduate, Dept of Pediatrics
MKCG Medical College, Berhampur
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• Definition• Etiology & classification• Pathogenesis• Precipitating factors• Clinical manifestation• Management • Outcome
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Definition
Hepatic encephalopathy (HE) is a complex metabolic mental state disorder with a spectrum of potentially reversible neuropsychiatric abnormalities seen in patients with severe acute or chronic liver dysfunction after exclusion of other brain diseases
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Characterized by
Disturbances in consciousness & behaviour
Personality changes
Fluctuating neurologic signs, asterixis or
flapping tremor
Distinctive EEG changes
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Epidemiology Exact data regarding incidence and prevalence is lacking 60-70% of patients with liver cirrhosis, while clinically unremarkable have pathologic changes on EEG and psychometric tests.(MHE) Prevalence of minimal HE is about 53% in patients with extra hepatic portal vein obstruction Approximately 50% of patients with liver cirrhosis develop HE after surgical portosystemic bypass procedures
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Type Description Subcategory Subdivision
A
Encephalopathy associated with acute liver failure, typically associated with cerebral edema
_____ ______
B
Encephalopathy with Porto-systemic bypass and nointrinsic hepatocellular disease
_____ ______
C
Encephalopathy associated with cirrhosis or portalhypertension ⁄ Porto-systemic shunts
Episodic
Persistent
Minimal
•Percipated •Spontaneous •Recurrent •Mild •Severe•Treatment dependent
Classification
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Pathogenesis Theories
– Ammonia hypothesis– False neurotransmitters & AA imbalance– Increase permeability of BBB– GABA hypothesis– Others
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Alanine Transaminase (ALT)
Aspartate Transaminase(AST) The Urea Cycle
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Neurotoxic Action of Ammonia• Readily crosses blood-brain barrier
• Ammonia reacts with α-ketoglutatrate to produce glutamate and glutamine
• Consumption of α-ketoglutatrate, NADH and ATP, inhibition of pyruvate decarboxylase decrease TCA cycle activity which is vital for brain metabolism
• Increased glutamine formation depletes glutamate stores which are needed by neural tissue l/t Irrepairable cell damage and neural cell death ensue.
• Directly depress the cerebral blood flow & glucose metabolism
• Direct toxic effect on the neuronal membrane
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False neurotransmitters & Aminoacid imbalance
• BCAA/AAA (N= 3-3.5, In hepatic coma=0.6-1.2)
• BCAA : hyperinsulinemia increased uptake & utilization by muscle & adipocytes
• AAA :- insulin/glucagon --> catabolism of liver
proteins & muscle --> AAA - Decrease hepatic deamination- Decrease gluconeogenesis
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Which ultimately l/t
Increase FNTsDecrease normal neurotransmittersIncrease inhibitory neurotransmitters
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False Neurotransmitter Hypothesis
AAA are precursors to neurotransmitters and elevated levels result in shunting to secondary pathways
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Increase Permeability of Blood-Brain Barrier
• Astrocyte (glial cell) volume is controlled by intracellular organic osmolyte which is glutamine
• Increase glutamine levels in the brain result in increase volume of fluid within astrocytes resulting in cerebral edema (enlarged glial cells)
• Neurological impairment
“Alzheimer type II astrocytosis”– Pale, enlarged nuclei – characterisic of HE
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• Major inhibitory neurotransmitter.• Evidence: increased GABAergic tone &
Flumazenil improves clinical outcome• Cause- Decrease hepatic metabolism- Increase gut wall permeability
GABA hypothesis
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Some other theories
• Dysregulation of serotonergic system (inversion of sleep rhythm)
• Depletion of zinc & accumulation of Mn in globus pallidus.
• Action of cytokines and bacterial LPS on astrocytes which are formed d/t inflmm. elsewhere in the body.
• Neuronal NO synthase may increase c/t the altered cerebral perfusion.
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Other neurotoxins
• Mercaptans: Inhibit Na+-K+ ATPase• Short & medium chain fatty acids:
inhibit Na+-K+ ATPase & Urea synthase• Phenol: a neurotoxin
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Precipitating factors
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CLINICAL MANIFESTATIONS
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• Variable & fluctuating• Mild disturbance of consciousness &
altered behavior to deep coma• Psychiatric changes of varying degrees• F/o liver cell failure like flapping tremor
& fetor hepaticus
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In MHE : • children have normal abilities of
memory, language, construction & pure motor skills.
• have normal standard mental status testing & abnormal psychometric testing.
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Mild to moderate HE:• Decreased short term memory or
forgetfulness• Loss of concentration & irritability• Asterixis, hyperventilation &
hypothermia• Relative bradycardia (if ass. with increase
ICP)
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Clinical grading
• West Haven classification system• Prognostic significance• Better in grade I & worse in grade IV
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Minimal encephalopathy
• Defined as encephalopathy that does not lead to clinically overt cognitive dysfunction but can be demonstrated with neuropsychological studies.
• May account for 60% of patients with portosystemic shunts.
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Clinical Manifestations & Diagnosis :MHE • Clinically normal• No mental deficit • Normal verbal ability • Deficit in attention ,visual perception, memory function, and learning • Impaired daily activities / driving• Only sophisticated tests such as EEG,CFF,ICT,NCT,DST, RBANS & PSE Syndrome test.• Neuroimaging : SPECT ,MRI,MRS.DWI
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BeginBegin
EndEnd
Time to complete____________________Time to complete____________________
Number Connection Test (NCT)Number Connection Test (NCT)
SAMPLE HANDWRITINGSAMPLE HANDWRITING
Draw a starDraw a star
Manifestations & Diagnosis :MHE
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Diagnosis of HE
• No single laboratory test is sufficient to establish the diagnosis– No Gold Standard
• Dx is mainly clinical on basis of history, clinical exam (includ mental status) & raised blood ammonia level
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Diagnostic Criteria• Asterixis (“flapping tremor”)• Hx liver disease• Impaired performance on neuropsychological tests
– Visual, sensory, brainstem auditory evoked potentials• Sleep disturbances• Fetor Hepaticus• 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
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Investigations
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Confirmation of liver disease/portosystemic shunt
1. LFT: increase in the following - Sr bilirubin/AST/ALT/ALP/GGT - PT(INR) > 1.5 with encephalopathy or >2
without encephalopathy - Sr protein, A:G ratio2. Sr ammonia level is increased in most cases3. USG
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Detection of causative factors• Viral serologic markers: HBs Ag, HBe Ag, anti-HBc,
HBV DNA increased in Hepatitis• TORCH screening• Autoimmune ab: ANA, ASMA, LKM1• Sr Cu, ceruloplasmin, urinary Cu : wilson’s disease• Urine for metabolic disorders• Sweat chloride & cystic fibrosis mutation studies• Alfa 1 antitrypsin levels : Alfa 1 antitrypsin def • Alfa feto protein : tyrosinemia type 1• Sr lactate & pyruvate : GSD & resp chain defects• Liver biopsy: cirrhosis
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R/o other diseases with similar presentation
• CT Scan: to r/o cerebral hemorrhage• EEG: r/o seizure disorder• CSF study: meningitis or encephalitis• Blood tests: metabolic causes of
encephalopathy including hypoglycemia & uremia
• Serum urea, Cr & electrolytes: renal failure
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Detection of complications• ABG- hypoxia is common• CBC: to r/o infection• Hb,PCV,CPS• PT, aPTT• Pt count decreased in advanced cases &
coagulopathy• Blood glucose: hypoglycemia• Sr ammonia• RFT
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Differential Diagnosis
Metabolic encephalopathies- Diabetes (hypoglycemia, ketoacidosis)- Hypoxia- Carbon dioxide narcosis
Toxic encephalopathies- Alcohol (acute alcohol intoxication, delirium tremens, Wernicke-Korsakoff syndrome)- Drugs
Intracranial events- Intracerebral bleeding or infarction-Tumor- Infections (abscess, meningitis)- Encephalitis
Psychiatric diseases
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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
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ProposedComplexFeedback Mechanisms In TreatmentOf HE
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Diet
• Decreased protein intake with high carbohydrates
• Calorie in the form of 10%D infusion• Protein restricted to 0.5-1 g/kg/day• Veg protein preferred as they are less
amminogenic , contain less amount of methionine & AAA and more fibres
• Dietary supplementation of BAA• 50% of non-protein calories should come from
MCT
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Lactulose/lactitol• Non absorbable synthetic diasachharide• Degraded by colonic bacteria to form lactic acid & acetic
acid
• Fecal acidity increase l/t decrease absorption of NH3• Favours growth of lactose fermenting bacteria &
diminished growth of ammo producing bacteria like bacteroides
• Detoxify short chain FAs produced in presence of blood & proteins
Dose: 1-2 ml/kg per orally or as enema in higher dosesN:B:- Alternatively, phosphate enema can be used
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Actions Of Lactulose
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Bowel sterilization
• Neomycin : orally through NGT dose: 50-100mg/kg
• Ampicillin• Rifaximin • metronidazole
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Other measures
• NGT aspiration• High colonic wash• Zn • L-Ornithine-L-Aspartate : oral/iv• Sodium Benzoate: 5g PO BD• H.Pylori eradication
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Supportive care• Fluid & electrolyte balance: - Should contain 1meq/kg/d of glucose- Met acidosis: NaHco3- Hypokalemia: pot. Chloride• Early identification & T/t of GI bleeding,
septicemia & hypoxia• Avoidance of ppt factors: drugs/paracentesis• Drugs: To improve sensorium e.g Flumazenil, l-
dopa, bromocriptine
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T/t in Resistant cases
• Plasmapheresis/hemodialysis• exchange transfusion• Surgical shunt occlusion • Temporary hepatic support:- ELAD (Extracorporeal Liver Assist Devices)- MARS (Molecular Adsorbent Recirculating
System)• Liver transplantation
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T/t of complications
1. CNS complications:• Cerebral edema:- Elevation of bed by 30 “,mannitol,
hyperventilation & fluid restriction- Hypothermia & phenobarbitone• Seizures: phenytoin & gabapentin• Cerebral hypoxia: O2, N-acetylcysteine2. Hypotension: colloids/albumin infusion3. Bleeding: Inj Vit-k/ FFP/ Inj Ranitidine
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4. Respiratory failure: - In Stage III & IV- Endotracheal Intubation 5. Renal Failure: - Furosemide in a dose of 1-2 mg/kg in early
stages if CVP > 8-10 cm of H2O- Hemodialysis in established cases- Urine output should be maintained- Dopamine: Improve renal perfusion6. Ascites: 5% albumin, bile acid binders
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Monitoring Protocol
Daily Once in 3 days Weekly
•Blood glucose (2 hrly)•Sr electrolytes: Na, K, HCO3-•Hb, PCV, CPS
-Renal function tests-PT-NEC
-Sr amino acids-EEG
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Minimal HE
1.No established indication for treatment 2.Consider changes in daily activities (avoid
driving)3.In selected patients • Lactulose /lactitol• Dietary intervention vegetable based diet• Probiotics
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1.Control of precipitating factors2.Nutritional support 3.Adequate protein intake with dairy and
vegetable based diets 4.Vitamins 5.Zinc supplementation 6.Lactulose /lactitol as needed 7. OLT evaluation
Prophylaxis Of New Episodes
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Course And Prognosis
•Develops rapidly few hours – 1-2 days•Mortality in grade IV is 80% •Death usually due to brain herniation / edema ICH•Type C develops slowly – undulating course / recurrence •Neuropsychiatric manifestations are reversible•Can lead to permanent damage with dementia, extra pyramidal signs, cerebellar degeneration,myelopathy with spastic paraplegia, peripheral polyneuropthy•Liver TX can reverse all changes
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Prognostic indicatorsFEATURES GOOD PROGNOSIS BAD PROGNOSIS
AGE CHILDREN ADOLESCENTS
ETIOLOGY PCM POISONING, HEP A HEP C
DURATION OF ENCEPHALOPATHY < 7 DAYS > 7 DAYS
COMA GRADE I & II III & IV
LIVER SIZE ENLARGED SHRINKING/NON PALPABLE
BLEEDING TENDENCY ABSENT PRESENT
FLUID RETENTION ---- +++
SR ALBUMIN N
PT N PROLONGED
LIVER ENZYMES: AST/ALT N
AFP
ASS. COMPLICATIONS ABSENT PRESENT
IMPROVEMENT OF SENSORIUM WITH T/t RAPID NO IMPROVEMENT AFTER
48 HRS OF T/t
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Take home points• Ammonia is the main culprit• Dx mainly by clinical exclusion• Bad prognostic indicators: - Liver span - Bilirubin level - Liver enzyme levels - Prothrombin time• T/t of precipitating causes & supportive care is
the mainstay of t/t• Prognosis bad in type A & better in other types
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