LECTURE HEPATIC ENCEPHALOPATHY for study.ppt

Lectures on hepatic encephalopathy

1. HEPATIC HEPATIC
ENCEPHALOPATHYENCEPHALOPATHY
Dr E.A. ODEGHE,Dr E.A. ODEGHE,
Consultant Physician/Gastroenterologist,Consultant Physician/Gastroenterologist,
Gastroenterology Unit,Gastroenterology Unit,
LUTHLUTH

2. Introduction
•A complex neuropsychiatric syndrome that
occurs with significant liver dysfunction. It is
characterized by disturbances in consciousness
and behaviour, personality changes, fluctuating
neurological signs, asterixis and distinctive
EEG changes.
•It is classified as
•Type A: HE associated with acute liver failure
•Type B: HE associated with portal-systemic
bypass with no intrinsic liver disease
•Type C: HE associated with cirrhosis and portal
hypertension or portal-systemic shunts.

3. Porto-systemic
encephalopathy
•More commonly, HE occurs in the
setting of chronic liver disease,
severe liver dysfunction and porto-
systemic shunting caused by portal
hypertension

4. Mechanism of HE
•The causative toxins most likely originate
from the gut
•They are not metabolized by the liver so
they bypass the liver via porto-systemic
shunts
•Enter the systemic circulation, cross the
BBB and exert direct/indirect effects in
CNS
•Neuropathology changes: astrocytes
mainly affected. Alzheimers type 11
astrocytosis

5. Ammonia
•Described to be crucial to HE over 100
years ago
•Found in portal vein, produced from the
breakdown of protein by urease producing
colonic bacteria (hence has been the
primary treatment target)
•Gain access to the systemic circulation as a
result of decreased hepatic function and/or
porto-systemic shunts.
•Neurotoxic in CNS (astrocytes, enzymes,
neurotransmission)

6. Ammonia detoxification
cycle
Ammonia
Urea
Glutamine
Acts as a temporary buffer
that can regenerate
ammonia (enterocyte) or
excrete it (Kidneys)
Severe liver dysfunction
reduces this path
Combines with
GLUTAMATE and
depletes it

7. Alterations in the BBB
•Decreased ratio of BCAA and AAA
•Interfere with physiologic
neurotransmission
(competitive inhibition of dopamine, nor-
adrenaline)
•Favour formation of false
neurotransmitters (octopamine, tyramine
and beta-phenylethanolamines )
•Enhance GABA-ergic neurotransmission
(inhibitory)

8. Others
  
•Decreased cerebral blood flow
•Decreased glucose and oxygen
consumption
•Other gut derived factors:
neurotoxic short and medium chain
fatty acids, phenols, mercaptans
•Zinc deficiency
•Manganese deposition

9. Clinical features
•2 distinct forms of HE can be identified
in patients with cirrhosis
Subclinical form
•Consciousness is not disturbed.
•Occurs in 30% to 84% of cirrhotics
•Causes reduced ability to drive and poorer
quality of life
•Identified by abnormalities in
electrophysiological and psychometric
tests

10. Clinical/Overt form
•General features include nausea, vomiting,
weakness, jaundice
•Fetor hepaticus (a sweet smell to the breath),
•Asterixis: a coarse flapping tremor seen when the
hands are outstretched
•Constructional apraxia: with the patient being
unable to write or draw e.g. a five pointed star
•Decreased mental function which can be assessed
by using the serial-sevens test or a trail-making
test
•Features of chronic liver disease such as ascites,
splenomegaly may be present
•Neurological examination shows spasticity and
extension of the arms and legs. Plantar responses
are flexor

11. Clinical stages of HE
Stage Mental status Asterixis EEG changes
I Euphoria or depressed,
mild confusion, slurred
speech, disordered sleep

+ or - Usually
normal
II Lethargy, moderate
confusion
+ Abnormal
III Marked confusion,
incoherent speech, semi-
stupor
+ Abnormal
IV Coma; initially responsive
to noxious stimuli, later
unresponsive
- Abnormal

13. Common precipitants of
hepatic encephalopathy
•Increased nitrogen load: GIT bleeding, excess
dietary protein, azotemia, constipation.
•Electrolyte imbalance: hypokalemia, alkalosis,
hypoxia, hypovolaemia
•Drugs: narcotics, tranquilizers, sedatives,
overtreatment with diuretics
•Miscellaneous: Infections, including
spontaneous bacterial peritonitis, surgery,
exacerbation of underlying disease,
development of HCC

14. Precipitating factors of HE
Possible mechanism Precipitating factors
Increased blood ammonia
levels
Renal azotemia
Volume depletion
Diuretics
Sepsis,GI bleeding
Constipation, Large protein
meal, Hypokalemia
Impairment of liver
function
Acute hepatitis,Sepsis
Hepatocellular carcinoma
Enhancement of effect on
CNS
Sedatives, Narcotics
Hypoxaemia, Surgery

16. Differential diagnoses
•Metabolic encephalopathies (diabetes
–hypoglycaemia, ketoacidosis, hypoxia,
carbon dioxide narcosis)
•Toxic encephalopathies (alcohol,
drugs)
•CNS infections (abscess, meningitis)
•Intracranial vascular events (stroke)
•Space occupying lesions (tumours)

17. Diagnosis
•Usually based on the presence of
typical clinical features in the right
clinical context.
•It is important initially to rule out
other possible causes in a patient with
advanced liver disease e.g. metabolic
abnormalities, sepsis, stroke, brain
tumour, Wernicke-Korsakoff
encephalopathy, and seizures.

18. Investigations
•Routine liver biochemistry,
Hyperbilirubinaemia, high amino
transferases, low coagulation factors.
•Amino transferases may not be useful
indicators of the course of the disease as
they tend to fall along with the albumin
with progressive liver damage
•Electrolytes, urea, Arterial blood ammonia
•Ultrasound will show liver size and
underlying liver disease.
•Additional tests may include EEG, Visual
evoked potentials

19. •Blood tests to identifying precipitating
factors (hypoglycaemia, azotaemia, electrolyte
imbalance and infection.)
•Elevated serum ammonia is often observed but
correlates poorly with the degree of HE and
may be normal in up to 10% of cases.
•Lumbar puncture and brain imaging studies such
as CT scan or MRI (to rule out other CNS
pathology)
•The CSF is usually normal and may show
increased protein with increased GABA levels.
•The EEG shows slow, triphasic wave activity
(mainly over frontal areas), highly sensitive and
characteristic of HE, but not specific.

20. Principles of management
•Provision of supportive care
•Identification and treatment of
precipitating causes (Correct electrolyte
imbalance, stop diuretics, treat any
infection, upper GI bleeding)
•Reduction of nitrogenous load from the
gut
•Management of the underlying liver
disease (orthotopic liver transplantation)

21. Evaluation of the patient
with suspected HE
•History
•Clinical and neurological examination
•Investigations
•Treatment

22. Reduction in nitrogen load
•Enemas (containing non-absorbable disaccharides eg
mannitol/lactulose)
•Lactulose 10-30mls 3x daily- an osmotic purgative
that reduces colonic pH and limits ammonia
absorption. Lactilol can also be used.
•Antibiotics: Neomycin is useful in modifying the
bacterial flora, but has serious ototoxic and
nephrotoxic side effects. Metronidazole may also
be used.
•Newer agents such as sodium benzoate and
ornithine are aimed at metabolic removal of
ammonia.

23. Nutritional management
•Diet: Traditional protein-free diet with adequate
calories (IV dextrose, fine-bore nasogastric tube).
•Protein restriction is effective but should only be
used in the short term to avoid the harmful
nutritional consequences.
–Recommended protein intake of 1-1.2g protein/kg/day
–Vegetable/dairy sources preferred
–Provide higher calorie:nitrogen ratio
–Provide non-absorbable fibre
–Enhance colonic acidification (bacterial breakdown of
fibre)
•Zinc supplementation
•Oral/parenteral formulations of BCAA

24.  Other therapies
•Cerebral neurotransmitters
Flumazenil, a benzodiazepine antagonist can induce a
transient improvement especially in patients who had
received benzodiazepines
•Other approaches such as supplementation with
branched chain amino acids, drugs aimed at
serotonin, opiate, melatonin and zinc metabolism

25. Fulminant hepatic
failure.
•Usually presents acutely, with rapidly
progressive liver failure within 8 weeks
of onset of symptoms in patients
without previous history of liver
disease
•Can occur occasionally in some patients
with previous liver damage e.g. HDV
superinfection in patients with previous
HBV liver damage).

26. Commonest causes
•Acute viral hepatitis
•Drug induced hepatotoxicity
•Autoimmune liver disease
•Shock, hypoperfusion
•Less common causes include Wilson’s
disease, acute fatty liver of pregnancy,
malignant infiltration of the liver,
hyperthermia.

27. Drug induced
hepatotoxicity
•Dose-related (Paracetamol)
•Idiosyncratic (isoniazid, phenytoin,
halothane, some herbs etc)

28. Acetaminophen (PCM)
hepatotoxicity
•Supra-therapeutic quantities (inadvertent, suicidal)
•>10g/day
•Very high AST and ALT >3,500 iu/l
•Activated charcoal useful for GI decontamination
(within 1-4hrs)
•N-acetyl cyteine (NAC) antidote effective and safe
(within 48 hrs)
•140mg/kg oral or via NG tube
•May cause allergic reactions ( eg bronchospasm)
which can be managed with antihistamines,
epinephrine

29. What is Activated charcoal?
•Activated charcoal is type of carbon made
from wood, vegetables and other materials.
It looks like a fine black powder.
•Activated charcoal is believed to have a large
adsorptive capacity, making it able to bind
with unwanted substances and toxins in the
gut.
•Activated charcoal may help to lower
cholesterol by interfering with enterohepatic
circulation of bile acids. It has been found to
lower total cholesterol and LDL cholesterol

30. Drug induced hepatotoxicity
•Drugs other than acetaminophen can rarely cause
dose-related toxicity.
•Most examples of idiosyncratic drug hepatotoxicity
occur within the first 6 months after drug initiation.
•Classes of drugs commonly implicated include
antibiotics, non-steroidal anti-inflammatory agents
and anti-convulsants
Drug combination agents with enhanced toxicity:
•Trimethoprim-sulfamethoxazole
•Rifampin-isoniazid
•Amoxicillin-clavulanate

31. Other causes of ALF
•Acute Fatty Liver of Pregnancy/HELLP (Haemolysis,
Elevated Liver Enzymes, Low Platelets) Syndrome.
A small number of women near the end of pregnancy
will develop rapidly progressive hepatocyte failure
that has been well characterized and associated with
increased foetal or maternal mortality.
•Malignant infiltration of the liver may cause ALF.
Such malignancies as breast cancer, small cell lung
cancers, lymphomas and melanoma.

32. .
•Cerebral oedema is found in 80% of
patients, and its consequences of
intracranial hypertension and brain
herniation are the most common causes
of death.
•The clinical signs of elevated ICP
(hypertension, bradycardia and
irregular respiration i.e Cushing’s triad)
may not be uniformly present

33. Complications
•Commonest complications are
increased intracranial pressure,
infections or multiorgan failure.
•Others include coagulopathy, renal
failure, lactic acidosis,
hypoglycaemia, hypoxaemia and
hypotension

34. Encephalopathy vs septicaemia
•Encephalopathy is a hall mark of FHF and may
also be a manifestation of sepsis syndrome
•If the hepatic manifestation of sepsis
(jaundice, abnormal LFT) are prominent, it can
be mistaken for FHF
•The differential diagnosis has practical
importance in patient management
•Measurement of F8 which is not synthesized
in the liver may be helpful in the
differentiation (F8 low in sepsis, normal in
FHF)

35. Management
•Supportive therapy in ICU is essential
•20% mannitol (1g/kg body weight) for cerebral
oedema.
•Treat associated complications. IV glucose, IV
vitamin K, fresh frozen plasma for coagulopathy.
H2 receptor antagonists to prevent GI bleeding,
blood transfusion for UGI bleeding, antibiotics
for infections.
•Liver transplant has been a major advance for
patients with FHF
•Overall mortality for grade III and IV
encephalopathy is 70%

36. Future directions
•Volume expansion in cirrhotic patients produce
significant increases in renal ammonia excretion
•Use of probiotic therapy: may alter the gut flora
and modulate the gut permeability
(Lactobacillus acidophillus, Enterococcus
faecium)
•Liver support system such as MARS may play an
important role (Molecular adsorbent recirculating
system). The MARS system can remove a number
of toxins, including ammonia, bile acids, bilirubin,
copper, iron and phenols.

37. Liver dialysis
•The removal of lipophilic, albumin-bound
substances such as bilirubin, bile acids,
metabolites of aromatic amino acids, medium-
chain fatty acids and cytokines should be
beneficial to the clinical course of a patient in
liver failure. This led to the development of
artificial filtration and adsorption devices.
•Haemodialysis is used for renal failure and
primarily removes water soluble toxins, however it
does not remove toxins bound to albumin that
accumulate in liver failure.
•Liver dialysis is considered to be a bridge to liver
transplantation or liver regeneration (in the case
of acute liver failure)

38. Thank you

39. MARS
(Molecular adsorbent recirculating system)
•Albumin is a plasma expander and binds numerous
substances such as bile acids, nitrous oxide and
cytokines
•MARS combines albumin bound molecule clearance and
novel dialysis membrane compatibility and thus has
opened up the word of haemodialysis to hepatology
•Removes albumin-bound (water insoluble) and water
soluble substances in ALF and CLF
•Effective in treatment of hepatic encephalopathy
•Randomized controlled trials currently being
performed.