Acute liver failure

By
PROF: Abdel Rahman A. Mokhtar
Professor of internal Medicine
( hepatogastroenterology )
Mansoura University
2013
 Definition
 ALF is a dramatic clinical syndrome in which
a previously normal liver fails within days to
weeks.
 Terms and Classifications
 ALF: syndrome is defined by
o Encephalopathy.
o Coagulopathy.
o Jaundice.
o Individual with previously normal liver.
 Fulminant Hepatic Failure

o Potentially reversible condition

o Consequence of severe liver injury
o Encephalopathy appears within 8 wks. of
initial Symptom.
o Absence of pre-existing liver disease.

( Trey & Davidson ,1970 )

 Revised definition and terms
 Modified in 1993 Considering the interval
between the onset of jaundice and the
development of encephalopathy in recognition
of the fact that the jaundice to encephalopathy
time is an important prognostic index
 King’s classification:

o Hyperacute: encephalopathy within <7 days

o Acute: 8-28 days

o Subacute: 5-26 weeks

Causes
 Causes
Cause Agent Responsible
Viral Hepatitis Hep. A, B, D, E, CMV, HSV, seronegative
hepatitis (14-25% in UK)
Drug-related Dose-related, e.g.paracetamol; idiosyncratic
reactions, e.g. anti-TB, statins, recreational
drugs, anticonvulsants, NSAIDs, many others
Toxins Carbon tetrachloride, amanita phalloides

Vascular events Iscahemic hepatitis, veno-occlusive disease,

Budd-Chiari, heatstroke
Other Pregnancy-related liver disease, Wilson’s
disease, lymphoma, carcinoma, trauma
 The initiating events and their clinical implications .

 Drug induced ALF ( esp. acetaminophen toxicity ) has surpassed viral

hepatitis as the most common etiology in the states & UK .
The initiating events and their clinical implications :

Unlike other causes of ALF drug induced LF

arises more often in older than younger
patients , especialy 60 yrs old or more.
 Acetaminophen toxicity
 The most popular analgesic antipyretic.
 Recommended < or = 4 gm / day.
 Sustained consumption of 4 gm/ day for > 4days may cause asymptomatic
increase of serum liver enzymes with no evidence of serious liver injury.
 Enhanced liver injury has been described with consumption of therapeutic
doses for symptom relief at the onset of acute liver disease due to other
causes.
 Preexisting conditions as alcohol abuse may influence the liver
susceptibility to lower doses of acetaminophen.
 Compared with all other causes of ALF , patients who had ingested
acetaminophen , had higher rates of spontaneous recovery and better
outcomes.
 Viral infections :
 HEV:
 The most common cause of ALF in India , Pakistan , China & south east Asia.
 Mortality can exceed 50% if no emergency liver transplant available.

Highest mortality in pregnant females .
 HBV:
 The main cause of ALF in Asia , Sub-saharan Afica and the Amazon basin.

Follow 4% of acute HBV & markedly decrease after vaccination programs .

 Other viral causes :

 Herpes simplex types 1 & 2 , VZs , EBV , CMV and Parvovirus 19.


HCV is a rare cause .
 Histopathology in ALF :
 Hepatic failure with in 1-26 weeks.
 Massive necrosis, shrinkage, wrinkled
 Collapsed reticulin network
 Only portal tracts visible
 Massive necrosis .
 More than a week – regenerative activity
 Complete recovery – or - death.

14
PATHOPHYSIOLOGY :
 PATHOPHYSIOLOGY :

 Normal liver function.

 The spectrum of functional derangement.
 Factors determining the severity.
Normal liver function.

 Largest organ in body, integral to most metabolic

functions of body, performing over 500 tasks.
 Only 10-20% of functioning liver is required to
sustain life
 Removal of liver will result in death within 24 hours
 Produces over 160 different proteins
 Makes clotting factors for the blood
 Metabolizes, detoxifies, synthesizes
liver functions ?
Main liver function.
 Metabolism of CHO, protein, fat
 Storage/activation vitamins and minerals
 Formation/excretion of bile
 Steroid metabolism, detoxifier of drugs/alcohol
 Action as (bacteria) filter and fluid chamber
 Conversion of ammonia to urea
 Gastrointestinal tract significant source of ammonia
 Generated from ingested protein substances that are deaminated by
colonic bacteria
 Ammonia enters circulation via portal vein
 Converted to urea by liver for excretion
The spectrum of functional derangement in ALF:

CEREBRAL OEDEMA

HAEMODYNAMIC INSTABILITY

RENAL FAILURE

COAGULOPATHY

PROFOUND METABOLIC DERANGEMENT

IMMUNE DERANGEMENT : BACTERIAL & FUNGAL SEPSIS

 Factors determining the severity & prognosis:

INJURIOUS
LOAD Degree of
metabolic derangement,
Endotoxin scavenging activity.
Oxidant stress

ALF is still responsible for 6% of mortality from liver

disease.
In earlier reports mortality was around 85% , however in
the era of transplant the one year survival became 60 –
80 % in higher centers. Regegenerative
capacity
Clinical presentation.
 The clinical expression:
 ALF leads to
A unique
combination of
often rapidly
progressive
severe multi
organ failure
with
unpredictable
complications .
 Clinical Features
Early presentation Failure of Impact on other
of acute injury systems
liver function
 ± prodromal  microcirculatory
 hepatobiliary
illness
excretion  respiratory
 non-specific
 metabolize toxic  hematologic
epigastric and
substances  GI
upper
abdominal  intermediary  neurologic
distress metabolism
 renal failure
 liver size  biosynthetic
function
 infection
normal-small
 electrolyte
 marked AST
and ALT
Failure of liver function:

Disturbed function Result

Hepatobiliary excretion hyperbilirubinemia
Metabolize toxic substances • G Ammonia  HE, intracranial HT
•alter drug level

Intermediary metabolism  CHO

◦ hypoglycemia
◦ hyperglycemia
 Lipid
◦ G plasma FFA, altered arterial ketone body
ratio
 Protein
◦ G protein breakdown, G plasma amino
acid, relative HBCAA

biosynthetic function HF II, V, VII, IX, X

Impact on other systems
Microcirculatory
Dysfunction
Circulatory Respiratory
Dysfunction Dysfunction

Renal
Failure ALF Infection

HematologicDisturba
Electrolyte nce
Disturbance

GI Consequences Neurologic
Consequences
 Microcirculatory Dysfunction

 Impaired pulmonary oxygenation of blood.

 Altered O2 carriage and delivery capacity of blood.
 Altered ability to deliver oxygenated blood to tissues.
• Impaired O2 utilization by tissues.
 Circulatory Consequences
 Early
 hyperdynamic state
 CO: tachycardia, SV
 SVR: NO  peripheral arteriolar dilatation, capillary recruitment
in peripheral tissues, AV shunting
 CVP
Late
 profound peripheral vasodilation, failing heart , hemodynamic
collapse
 relative adrenal insufficiency
 subclinical myocardial injury
 Pulmonary Consequences

 Initial
 central hyperventilation with respiratory alkalosis
 Airway problems
◦ mucus plugs, aspiration, ET tube cuff leak
 Pulmonary alveolar and parenchymal processes
◦ pneumonia, pulmonary hemorrhage, atelectasis,
pneumothorax
 Pulmonary vascular processes
◦ volume overload, heart failure, ARDS
 Renal failure in ALF
 Prerenal azotemia  Sepsis-related
 GI losses ◦ renal perfusion
 inadequate volume ◦ cortical necrosis
replacement ◦ UTI
 ATN  HRS
 volume depletion
 iatrogenic

poor prognosis
 Hematologic Disturbances
 altered production of coagulation factors
 activity of F II, V, VII, IX, X
 activity of F VIII
 consumption of coagulation factors
DIC, fibrinolysis
 thrombocytopenia
production VS. Sequestration DIC
bone marrow dysfunction medication
 qualitative Plt dysfunction
 de novo, renal failure
 fibrinolysis, fibrinogen, dysfibrogenemia, DIC
 GI consequences
 Early- nausea and vomiting
late-ileus (electrolyte, acid-base disturbances, sepsis,
narcotic)
 1/3 elevated pancreatic enzyme, infrequent clinically
significant pancreatitis
 GI bleeding: acute portal hypertension, increased ICP,
coagulopathy
 varices, rare bleeding
 ascites
 Infection

 Infection usually within 1st few days after onset

(Candida-2nd-3rd weeks)
 most common-pneumonia,bacteremia, UTI
 S. aureus, E. coli, Candida spp.
 fungal infection
 risk: renal failure, prolonged antibiotic Rx, invasive
monitoring
 high fever unresponsive to antibiotics, profound
leukocytosis, ARF
 Electrolytes Disturbances

 hypoNa
 free water excretion, diuretics, mannitol
 hypoK alkalosis (early), hyperK acidosis (late)
 hypoK
 GI losses, aggressive diuresis, alkalosis
 hypoP
 shift due to glucose infusions, use in regenerating
hepatocytes, respiratory alkalosis
 worsening mental status, respiratory failure
 hyperK, hyperP, hypoCa in oliguric renal failure
 Neurologic consequences

ALF Cirrhosis

Seizures and Agitation yes, frequent no

Cerebral edema and yes very rare
Intracranial hypertension
 Vasogenic origin
 systemic NO
 elevated bacterial
endotoxin, TNF-alpha,
and IL-1 and IL-6
Cytotoxic edema
• impaired cellular
osmoregulation in brain
• accumulation of
glutamine in astrocyte

disruption of astrocyte edema

cerebral autoregulation

intracranial hypertension
most serious complication

cerebral hypoperfusion, hypoxia, uncal herniation, brain death

 Hepatic Encephalopathy
 Ammonia
 circulating concentrations correlate only weakly with
degree of neurologic dysfunction
 Endogenously derived BDZ receptor agonist
 GABA and glutamatergic system
 circulating endogenous ligands for GABA receptor
 ammonia increases affinity of ligands to receptor
 turnover of GABA
 tone of inhibitory GABA
 glutamate
Management
 History taking
 Symptoms..GI upset , Gen malaise up to confusion.
 Detailed history looking for the cause.

 Physical & Mental examination:

To differentiate acute
from acute on top of CLD.

To identify a possible
cause
Monitoring mental status.
Monitoring mental status.
Laboratory evaluation :
 Evidence of ALF
 Possible cause,
 Evidence of
complications.
 Liver biopsy :

 To confirm the
etiology if lab
results are
inconclusive.

 Transjugular
approach is
preferred.
TREATMENT
Treatment Principles : 1

 Dealing with the possible

cause :
May limit the severity.

Potentially prevent
progression from
isolated hepatic failure to
multi
organ damage,
Treatment Principles : 2

 Supportive care in ICU

To maintain body
systems & combat
multi organ failure
 3
Treatment Principles :
 Liver transplant when indicated

This is the only definitive

treatment for patients
who failed to have spontaneous
regeneration.

Early identification of those who

will not recover is of utmost
importance.

Different selection criteria are

used at different centers
 Future directions :
 Artificial liver support system now is the most potential.

Bioartificial support systems utilizing hepatocytes …pose a

lot of challenges.

Hepatocyte transplant ..under investigation.

 Fruitful directions :
Public health measures to :

 Minimize drug – induced ALF.

 Vaccination a against A, B and E viruses.

Thank
You