Hepatic encephalopathy

Hepatic Encephalopathy Hepatic Encephalopathy

Dr Bikash Ranjan PraharajPost Graduate, Dept of Pediatrics

MKCG Medical College, Berhampur

• Definition• Etiology & classification• Pathogenesis• Precipitating factors• Clinical manifestation• Management • Outcome

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

Characterized by

Disturbances in consciousness & behaviour

Personality changes

Fluctuating neurologic signs, asterixis or

flapping tremor

Distinctive EEG changes

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

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

Pathogenesis Theories

– Ammonia hypothesis– False neurotransmitters & AA imbalance– Increase permeability of BBB– GABA hypothesis– Others

Alanine Transaminase (ALT)

Aspartate Transaminase(AST) The Urea Cycle

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

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

Which ultimately l/t

Increase FNTsDecrease normal neurotransmittersIncrease inhibitory neurotransmitters

False Neurotransmitter Hypothesis

AAA are precursors to neurotransmitters and elevated levels result in shunting to secondary pathways

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

• Major inhibitory neurotransmitter.• Evidence: increased GABAergic tone &

Flumazenil improves clinical outcome• Cause- Decrease hepatic metabolism- Increase gut wall permeability

GABA hypothesis

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.

Other neurotoxins

• Mercaptans: Inhibit Na+-K+ ATPase• Short & medium chain fatty acids:

inhibit Na+-K+ ATPase & Urea synthase• Phenol: a neurotoxin

Precipitating factors

CLINICAL MANIFESTATIONS

• 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

In MHE : • children have normal abilities of

memory, language, construction & pure motor skills.

• have normal standard mental status testing & abnormal psychometric testing.

Mild to moderate HE:• Decreased short term memory or

forgetfulness• Loss of concentration & irritability• Asterixis, hyperventilation &

hypothermia• Relative bradycardia (if ass. with increase

ICP)

Clinical grading

• West Haven classification system• Prognostic significance• Better in grade I & worse in grade IV

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.

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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Number Connection Test (NCT)Number Connection Test (NCT)

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Manifestations & Diagnosis :MHE

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

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

Investigations

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

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

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

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

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

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

ProposedComplexFeedback Mechanisms In TreatmentOf HE

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

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

Actions Of Lactulose

Bowel sterilization

• Neomycin : orally through NGT dose: 50-100mg/kg

• Ampicillin• Rifaximin • metronidazole

Other measures

• NGT aspiration• High colonic wash• Zn • L-Ornithine-L-Aspartate : oral/iv• Sodium Benzoate: 5g PO BD• H.Pylori eradication

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

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

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

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

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

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

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

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

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

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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