HE Pit Ipd2014

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

OUTLINE  Definition  Epidemiology

& Classification

 Pathogenesis  Precipitating

factors  Clinical manifestation  Diagnosis Approach  Treatment  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 & behavior, Personality changes, Fluctuating neurologic signs, asterixis or flapping tremor, Distinctive EEG changes

Epidemiology 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

Classification Type

A

Description

Subcategory

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

Subdivision

______

_____

______

Episodic

•Percipated •Spontaneous •Recurrent •Mild •Severe •Treatment dependent

Persistent Minimal

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 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 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



Increased AAA

-

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

-

Decrease hepatic deamination

-

Decrease gluconeogenesis

: hyperinsulinemia  increased uptake & utilization by muscle & adipocytes :

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

CLINICAL MANIFESTATIONS 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 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 

Psychometric test Number Connection Test (NCT)

Draw a star

Time to complete____________________ End

10

6

4 7 5

25

9 Begin

1

11

14 3

23

8

24

2 13 17 16

15 19

18

SAMPLE HANDWRITING

12 22

20

21

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 : wilson’s 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  BCAA  Medical 

restriction

supplementation

management

Medications to counteract ammonia’s 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: 50100mg/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

Treatment of complications 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

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

Prophylaxis Of New Episodes

1. Control

of precipitating factors

2. Nutritional

3. Adequate

support

protein intake with dairy and vegetable based diets

4. Lactulose

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 Trasplantation can reverse all changes

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

LIVER ENZYMES: AST/ALT

N

PROLONGED

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