Hepatic Encephalopathy

at a Glance

Syifa Mustika

A Patient Case

History

a 62 years old male admitted to ER with complaint of confusion since this

morning, disorientation, lethargy, abdominal pain, constipation.

Past medical history: DM ( on OHG agent), CLD (LC, Hematemesis), HCV

Home medications: Glimepiride 3 mg PO OD, Metformin 500 mg PO BID,

Furosemide 40 mg PO OD, Lactulose 30 mL PO TID

Examination:

o General condition: Disorientation & Confusion, flapping tremors

o Vital signs within normal limit

o Chest: Bilateral basal crepitation

o Abdomen: Distended, soft, lax, liver span 6cm , mild ascites

Definition

Epidemiology & Classification

Pathogenesis

Precipitating factors

Clinical manifestation

Diagnosis Approach

Treatment

Outcome

OUTLINE

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 & behavior, Personality changes,

Fluctuating neurologic signs, asterixis or flapping tremor,

Distinctive EEG changes

o Exact data regarding incidence and prevalence is

lacking

o 60-70% of patients with liver cirrhosis, while clinically

unremarkable have pathologic changes on EEG and

psychometric tests.(MHE)

o Prevalence of minimal HE is about 53% in patients with

extra hepatic portal vein obstruction

o In Indonesia, the incidens are 30-88% range from

subclinical to overt HE

Epidemiology

Type Description Subcategory Subdivision

A

Encephalopathy associated with acute

liver failure, typically associated with

cerebral edema

_____ ______

B

Encephalopathy with Porto-systemic

bypass and no

intrinsic hepatocellular disease

_____ ______

C

Encephalopathy associated with cirrhosis

or portal

hypertension 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

Neurotoxic Action of Ammonia

Readily crosses blood-brain barrier

Ammonia reacts with -ketoglutatrate to produce glutamate and glutamine

Consumption of -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 results in 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

Decrease Rasio BCAA/AAA (N= 3-3.5, In hepatic coma=0.6-1.2)

Decreased BCAA : hyperinsulinemia increased uptake & utilization by muscle & adipocytes

Increased AAA :

- Decreased Rasio insulin/glucagon --> increased catabolism of liver proteins & muscle -->

increased AAA

- Decrease hepatic deamination

- Decrease gluconeogenesis

Which results in

Increase FNTs

Decrease normal neurotransmitters

Increase 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

GABA hypothesis

Major inhibitory neurotransmitter.

Evidence: increased GABAergic tone &

Flumazenil improves clinical outcome

Cause

- Decrease hepatic metabolism

- Increase gut wall permeability

PRECIPITATING FACTORS

CLINICAL MANIFESTATIONS

Variable & fluctuating Mild disturbance of consciousness & altered

behavior to deep coma

Psychiatric changes of varying degrees Signs of liver cell failure like flapping tremor &

fetor hepaticus

Stages of Hepatic Encephalopathy

Signs of CLD

In MHE :

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 MANIFESTATIONS

CLINICAL MANIFESTATIONS

Clinical Grading

West Haven Classification system

ISHEN Criteria

Prognostic significance

Better in grade I & worse in grade IV

Diagnosis Approach

No single laboratory test is sufficient to establish the diagnosis

No Gold Standard

Diagnosis is mainly clinical on basis of history, clinical exam (including mental status) & raised blood ammonia level

Recommendation on Diagnosis HE

The diagnosis of HE is through exclusion of other causes of brain dysfunction

HE should be divided into various stages of severity

Overt hepatic encephalopathy is diagnosed by clinical criteria and can be

graded according the WHC and the GCS

The diagnosis and grading of MHE and CHE can be made using several

neurophysiological and psychometric tests that should be performed by

experienced examiners

Increased blood ammonia alone does not add any diagnostic, staging, or

prognostic value for HE in patients with CLD. A normal value calls for diagnostic

reevaluation

Diagnostic Criteria

Asterixis (flapping tremor)

History of 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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Begin

End

Time to complete____________________

Number Connection Test (NCT)

SAMPLE HANDWRITING

Draw a star

Psychometric test

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 ratio

2. Sr ammonia level is increased in most cases

3. 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 : wilsons disease

Urine for metabolic disorders

Alfa 1 antitrypsin levels : Alfa 1 antitrypsin def

Alfa feto protein : tyrosinemia type 1

Sr lactate & pyruvate : GSD & resp chain defects

Liver biopsy: cirrhosis

Rule Out 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

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

Guidelines and Recommendation

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 ammonias effect on brain cell function

Lactulose

Antibiotics

Liver transplantation

Proposed

Complex

Feedback

Mechanisms

In Treatment

Of HE

Diet

Decreased protein intake with high carbohydrates

Calorie in the form of 10% Dextrose 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 BCAA

Lactulose

Non absorbable synthetic diasachharide

Degraded by colonic bacteria to form lactic acid & acetic acid

Fecal acidity increase so there will be 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 doses

Actions Of Lactulose

Bowel sterilization

Rifaximin :550mg twice daily

Neomycin : orally through NGT dose: 50-

100mg/kg QID

Metronidazole 250mg orally TID

Other treatment options

Oral BCAA

IV LOLA

Metabolic Ammonia Scavenger: Gliceryl Phenyl Buthirate

Probiotics

Glutaminase Inhibitors

Laxative

Flumazenil

Supportive care

Fluid & electrolyte balance:

- Should contain 1meq/kg/d of glucose

- Met acidosis: NaHco3

- Hypokalemia: pot. Chloride

Early identification & treatmen of GI bleeding, septicemia &

hypoxia

Avoidance of precipitating factors: drugs/paracentesis

Drugs: To improve sensorium e.g Flumazenil, l-dopa,

bromocriptine

Treatment 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-acetylcysteine

2. Hypotension: colloids/albumin infusion

3. Bleeding: Inj Vit-K/ FFP

4. Respiratory failure:

- In Stage III & IV

- Endotracheal Intubation and Mechanical Ventilation

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 perfusion

6. Ascites: 5% albumin, bile acid binders

Treatment of complications

Minimal HE: Special Considerations

1. No established indication for treatment

2. Consider changes in daily activities (avoid driving)

3. In selected patients

Lactulose

Dietary intervention vegetable based diet

Probiotics

1. Control of precipitating factors

2. Nutritional support

3. Adequate protein intake with dairy and vegetable

based diets

4. Lactulose

Prophylaxis Of New Episodes

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 Trasplantation can reverse all changes

Course and Prognosis

Prognostic indicators

FEATURES 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 Messages

Ammonia is the main culprit

Diagnosis mainly by clinical exclusion

Bad prognostic indicators:

- decreased Liver span

- increased Bilirubin level

- alteration Liver enzyme levels

- prolonged Prothrombin time

Managing of precipitating causes & supportive care is the

mainstay of treatment

Comprehensive Approach in Hepatic Encephalopathy

Rule Out Other Cause Identify Precipitating Factor Initiate Empiric Treatment

Hypoxia Sepsis Lactulose od 15-30 ml 2-3 times daily

Hypercapnea GI Bleeding Rifaximin od 550mg twice daily

Acidosis Constipation Neomycin od 500mg four times daily

Uremia Dietary protein overload Metronidazol od 250mg four times

CNS drugs Dehydration Flumazenil iv 1-3mg

Electrolyte changes CNS active drugs BCAA oral

Prior seizure or stroke Hypokalemia LOLA iv

Delirium ttremenz Poor compliance

Wernicke-korsakoff

syndrome

Prior anesthesia

Intracerebral

hemorrhage

Bowel obstruction

CNS sepsis Uremia

Cerebral edema Development of HCC

Hypoglycemia

Minimal Hepatic Encephalopathy

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 perhaps normal