HEPATIC DISEASES

1. Dr. Parag Moon
Senior resident,
Dept. of Neurology,
GMC, Kota

2.  Hepatic encephalopathy
 Hepatocerebral degeneration
 Hepatic myelopathy
 Cirrhosis-related parkinsonism
 Cerebral infections
 Cerebral Hemorrhage
 Osmotic demyelination.

3.  In addition, neurologic complications can be
exclusive to certain disorders, for example,
Wilson disease, alcoholism (Wernicke
encephalopathy, alcoholic cerebellar
degeneration, Marchiafava-Bignami disease,
etc), hemocromatosis etc

4.  Syndrome of neuropsychiatric,
neuropsychological and neurological
disturbances that may arise as a complication
of liver disease.
 Reversible complete or incomplete.
 10-50% of liver disease- overt hepatic
encephalopathy in lifetime.

5. Ferenci P et al ;Hepatology :2002.

6.  Multifactorial pathogenesis
 Combination of chronic low-grade glial
oedema and potentiation of effects of gamma
amino butyric acid (GABA) on CNS by
ammonia.
 Increase in GABA release
 Enhanced activation of GABA-A receptor
complex.
 Increased concentrations of endogenous
benzodiazepines-found in brain in liver
failure

7.  Ammonia- neurotoxic, but at higher levels
than those found in liver failure
 It tends to cause neuronal excitation.
 At lower concentrations, potentiates actions
of GABA, possibly by enhancing ligand
binding to GABA-A receptor complex.
 It reduces glutamate synthesis and down-
regulates glutamate receptor in vitro-reduced
excitatory transmission in brain.

8.  Fulminant hepatic failure-levels of ammonia
tend to be higher
 May contribute to neuroexcitatory symptoms
seen-agitation, seizures and multifocal
muscle twitching via direct toxicity.
 Ammonia-adverse effect on osmoregulation
via its reaction with glutamate to form
glutamine-exacerbating cerebral oedema
 Dopaminergic, serotonergic and opioid
neurotransmitter systems-pathogenesis of
HE.

9.  Mechanisms for cerebral edema
 Breakdown of blood-brain barrier (vasogenic
oedema)
 Impaired cellular osmoregulation (cellular or
cytotoxic oedema)
 In later stages there is loss of cerebral
autoregulation.

10.  In fulminant hepatic failure autopsy reveals brain
oedema and astrocyte swelling.
 In cirrhosis and portal-systemic shunts-
Alzheimer type II astrocyte-pathological hallmark
of HE.
 Found in cortex and lenticular, lateral thalamic,
dentate and red nuclei.
 Abnormal astrocytes-shown to be produced by
ammonia.
 Increased levels of manganese in basal ganglia
and to a lesser extent other areas of brain.

11.  Sleep disturbance most common early signs-
50% of cases.
 Derangement of consciousness accompanied
by decreased (or occasionally increased)
psychomotor activity through increasing
drowsiness, stupor and coma.
 Asterexis- common but nonspecific
 Signs of pyramidal tract dysfunction initially
eventually being replaced by hypotonia
 Seizures- rare.

12.  HE differ from other metabolic
encephalopathies in early stages-striking
Parkinsonian syndrome
 Correlate with degree of T1 hyperintensity in
basal ganglia, changes in choline/creatine
ratios.
 Focal neurological deficits rare.
 Visual disturbances-result of cortical and
retinal dysfunction.
 Hepatic retinopathy-damage to retinal glia or
Muller cells.

13. Jones EA et al; JNNP; 1997

14.  Routine investigation
 Arterial blood ammonia-usually raised, level
bears little relation to severity of HE.
 EEG- triphasic waves, non specific
 Visual (VEP), sensory (SEP) and brainstem
auditory (BAEP) evoked potentials- delayed
latencies (a slower response) which become
more prolonged in relation to degree of HE.
 Lumbar puncture- not indicated.
 Neuroimaging-if doubt.

15.  Supportive.
 Precipitating factors-treated or removed
 Reduction of absorption of nitrogenous
substances from intestinal tract-evacuation
of bowel by purgation, enemas, elimination of
dietary protein
 Oral Lactulose
 Mannitol
 Gut sterilization- Rifaximin, neosporin
 Hepatic transplantation.

16.  Nursed supine with head and upper body
raised 20°-30° above horizontal
 Psychomotor agitation- small dose of BZD
(oxazepam) or small dose of morphine
 Measurement of ICP- Epidural catheters if
coagulopathy other wise intraventricular
device in fulminant hepatic failure.
 ICP be maintained below 20 mm Hg

17.  Oral protein load
 Upper
gastrointestinal bleed
 Constipation
 Diarrhoea and
vomiting
 Dehydration
 Electrolyte and
acid/base imbalance
 Diuretic therapy
 Abdominal
paracentesis
 Hypoxia
 Hypotension
 Anaemia
 Hypoglycaemia
 Sedative/hypnotic
drugs
 Azotaemia
 Infection
 Induction of medical
or surgical portal-
systemic shunt
 General surgery

18.  Flumazenil
 Central BDZ antagonist with weak partial agonist
action
(1) Often reproducible in individual patient;
(2) occur in only about 60%
(3) Occur rapidly, within four minutes of drug
administration;
(4) substantial ameliorations occur after low doses—0.3-
0.5 mg
(5) short duration
(6) usually partial (for example, one or
two clinical stages).
(7)improve cognitive component in subclinical hepatic
encephalopathy.

19.  Disadvantages of flumazenil-
◦ Partial agonistic action, mechanism other than
increase GABAnergic tone
 Levodopa, bromocriptine and infusions of
branched chain amino acids-false
neurotransmitter hypothesis
 Results unconvincing

20.  Mortality high at around 70–80% in fulminant
hepatic failure
 Following first episode of overt hepatic
encephalopathy-1-year survival 40%
 15% after 3 years.

21.  Replaced old terms of latent or sub-clinical
hepatic encephalopathy.
 Affect between about 20% and 70% of
patients
 Impairment of visuospatial functioning,
attention and psychomotor speed
 Critical flicker frequency
 Constructional apraxia
 Neuroimaging
 Evoked potential

22.  Acquired (non-Wilsonian) hepatocerebral
degeneration (AHCD)
 Originally characterised by Victor et al. in 1965.
 Chronic and irreversible.
 Typical clinical features-dementia, dysarthria,
ataxia of gait, intention tremor and
choreoathetosis.
 Diffuse but patchy cortical necrosis, diffuse
proliferation of Alzheimer type II glial cells and
uneven neuronal loss in cerebral cortex, basal
ganglia and cerebellum

23.  Hepatic or portal-systemic myelopathy (HM)
 Described Zieve et al. in 1960
 Spastic paraparesis with minimal sensory
involvement.
 Symmetrical demyelination, predominantly of
lateral pyramidal tracts, sometimes
associated with axonal loss, generally going
no higher than cervical cord level

24.  Pathogenesis poorly understood
 Nitrogenous products bypassing liver through
porto-caval shunt play an important role.
 AHCD -represents damage accumulated from
multiple episodes of hepatic encephalopathy.
 Chronic exposure to toxic substances
bypassing liver-causes both AHCD and HM.

25.  Treatment difficult.
 Case reports of transplantation being used
with varying degrees of success.
 In early stages, demyelination seems to
predominate
 As disease progresses axonal loss occurs,
and is likely to be irreversible.
 Case reports suggest- transplantation done
within 10 months-good clinical outcome.
 TIPSS- may increase AHCD

26.  Unique, consistent, and common subset of
acquired hepatocerebral degeneration
 Abnormal manganese (Mn) deposition in BG
 Increased dopamine metabolism with
decreased D2 dopamine receptor density,
 Altered glutamate- or γ-aminobutyric acid–
mediated neurotransmission,
 Reduced glucose consumption in BG.

27.  Rapidly evolving and symmetric akinetic-rigid
syndrome
 Early gait and postural impairment
 Focal dystonia in 50%
 Resting tremor notably minimal or absent
 Postural tremor prominent.
 Oculomotor, cerebellar, pyramidal, or sensory
abnormalities lacking.

28.  Cognitive functions globally preserved except
for some degree of frontal lobe dysfunction
 No prominent psychiatric features except
mild depression.
 Insidious onset and rapid progression over
months until parkinsonism reaches a plateau,
followed by chronic and more stable course
over years.
 Parkinsonism develops independently and
separately from HE episodes

29.  Appearance of parkinsonism- more related to
degree of liver failure rather than to specific
cause.
 Trials show good response to levodopa
suggestive presynaptic defect.

30.  Central pontine myelinolysis and extrapontine
myelinolysis-osmotic demyelination
disorders.
 Not exclusive to liver disease
 More common in association with liver
disease, particularly alcoholic liver disease.

31.  Central pontine myelinolysis-rapidly evolving
paraparesis or quadraparesis, pseudobulbar
palsy and impaired responsiveness.
 Pathologically-loss of myelin in basis pontis,
often in strikingly symmetrical fashion
 Neurological impairment range from minimal
symptoms to full ‘locked in’ syndrome
 Most cases involve a change in osmolality,
often rapid and often involving correction of
hyponatraemia but not all cases.

32.  Pruritus of cholestasis may at least in part
have its origins in CNS.
 Several mechanisms :
1. opioid agonists induce pruritus by a central
mechanism,
2. central opioidergic tone is increased in cholestasis
3. opioid antagonists can improve symptom.

33.  Peripheral neuropathy
 More common with alcohol, hepatitis C,
porphyria
 Worse liver disease, worse neuropathy,
independent of aetiology
 Suggests-liver disease itself is causing, or at
least contributing to neuropathy.

34.  MRI- abnormally high signal on T1-weighted
imaging in basal ganglia, particularly globus
pallidus
 Believed to be due to manganese deposition
 Chronic manganese poisoning produces
syndrome very similar to AHCD
 AHCD-more extensive high signal in white
matter on T2-W.
 Hepatic myelopathy-usually no MRI
abnormalities

36. THANK You

37.  Neurologic Presentations of Hepatic Disease;
Harris, Meghan K. et al.;Neurologic Clinics; 2010;
Volume 28 , Issue 1 , 89 - 105
 Burkhard PR, Delavelle J, Du Pasquier R, Spahr L.
Chronic Parkinsonism Associated With Cirrhosis:
A Distinct Subset of Acquired Hepatocerebral
Degeneration. Arch Neurol.2003;60(4):521-528.
 The neurology of liver failure; M. LEWIS and P.D.
HOWDLE; Q J Med 2003; 96:623–633
 Neurology and the liver; E A Jones, K
Weissenborn;Journal of Neurology, Neurosurgery,
and Psychiatry 1997;63:279–293
 Sherlock diseases of liver and biliary system.