Acute Liver Failure

Topics
 Definitions of failure and classification
 Aetiology- Acute versus acute on chronic
 Basic diagnostic workup
 Liver biopsy in the context
 ACLF-Ethical dilemma- HDU admission
 Treatment of complication
 Hepatic encephalopathy
 Renal failure
 GI bleed
 Infection
 Coagulopathy
 Aetiology specific treatment
 Organ support
 Liaison with Transplant centre
The mortality rate for acute liver failure
ranges between 56% and 80%
Abnormal LFT is NOT ALF

 Dear Doctor
 Patient’s bilirubin is 600 and has liver
failure- kindly urgently see
 Family was told transplant may be
necessary
Formal diagnosis of acute liver failure

 An increase in PT by 4-6 seconds

(INR>1.5)

 And the development of hepatic

encephalopathy (HE).

 In a patient without pre-existing cirrhosis

and with an illness of less than six months
duration.
 UK incidence of cirrhosis 17 per 100,000
 Prevalence of cirrhosis is 76 per 100,000
 ALF incidence is 1-6 per million per year
aCLF
 This entity is quite common- background
of cirrhosis. Innocent precipitating event
culminates in MOF
 Events
 Toxins (alcohol!)
 Vascular (hypotension- GI bleed,
dehydration, Portal vein thrombosis)
 Infection (SBP)
 HCC
ACLF-Ethical dilemma- HDU admission
For patients with aCLF

 Young age
 First presentation
 Reversible pathology- sepsis, GI
bleeding or severe hepatitis
 A trip to ITU is a life changing
experience to some ‘alcoholics’
Few definitions

 Hyperacute- <7days

 Acute - >7days <21days

 Subacute- >21days <6months

 FHF- not used

Diagnostics:

 Good history- difficult

if HE
Initial Laboratory Analysis- general
 Prothrombin Time/INR

 Blood Chemistry
Sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphate,
AST, ALT, alkaline phosphatase, GGT, total bilirubin, albumin,
Creatinine, urea
Glucose

 Arterial blood gas

 Arterial lactate
 Full blood count
 Blood type and screen
 Ammonia (arterial if possible)
 HIV status
 Amylase and lipase
Diagnostics- specific
 Paracetamol (acetaminophen)
level
 Toxicology screen
 Viral hepatitis serologies
Anti-HAV IgM,
HBSAg, anti-HBc IgM,
anti-HEV,
anti-HCV
CMV
EBV
VZ/HZ
 Ceruloplasmin level
 Pregnancy test
 Autoimmune markers- ANA,
ASMA, Immunoglobulin levels
 Doppler US- ischaemic vs
thrombosis
Liver biopsy

 Importance of early biopsy- severity and

aetiology
 Particularly useful in Hep B, AIH,
Alcoholic hepatitis, differentiate between
ALF and aCLF
 Transjugular route
www.gastrotraining.com
 Urgent OLT is the only life saving
therapy
 The main role of intensive care therapy
is multi-organ support
All Liver transplants

 CLD – 60%
 Malignancy- 10%
 ALF- 10% ( Paracetamol)
 Cholestasis - 10-20%
 Phase I – 0-24h
 Anorexia, nausea and vomiting, malaise
 LFT derrangement at 12h
 Phase II – 18-72h
 RUQ pain
 LFT derrangment
 Phase III – 72-96h
 Centrilobar necrosis
 Liver failure
 Phase IV – 4d-3wk
 Recovery, transplant or death
 No chronic state
When to pick up the phone
 D2-
 pH <7.3
 INR>3
 Cr >200
 Hypoglycaemia
 D3-
 HE
 Cr>200
 INR >4.5
 D4-
 Any rise in INR
 Cr >250
 HE
Definition:
HRS
 ARF in a patient
 CLD, severe alcoholic hepatitis or ALF
from any cause
 End-stage of reduction in renal perfusion
induced by increasingly severe hepatic
injury.
1. Sinusoidal portal hypertension, in
the presence of severe hepatic
decompensation

2. Leads to splanchnic and systemic

vasodilatation-role of NO

3. Decreased effective arterial blood

volume

4. Activation of RAS, and vasopressin

aimed at restoring arterial filling
pressure.

5. Renal vasoconstriction increases

counterbalanced by the intrarenal
prostaglandins.

6. When this balance is lost renal

hemodynamics worsens, and
hepatorenal syndrome develops
 Terlipressin
 NSBB
HRS
 Major criteria
 Chronic or acute hepatic disease and liver failure with portal
hypertension
 Serum creatinine level >133 micromoles/L
 Absence of shock, ongoing bacterial infection, recent use of
nephrotoxic drugs, excessive fluid or blood loss
 No sustained improvement in renal function after volume
expansion with 1.5 L isotonic saline solution
 No Proteinuria (Protein<500 mg/day) and no ultrasonographic
evidence of renal tract or parenchymal disease
 Minor criteria
 Urine volume <500 mL/day
 Urine sodium <10 mEq/L
 Urine osmolality greater than plasma osmolality
 Urine red blood cell count <50 per high-power field
 Serum sodium <130 mEq/L
Classification of HRS

 Type I is defined by a rise in creatinine

level to over 221 micromoles/L in less
than 2 weeks
 Median survival of 2 weeks

 Type II is defined as less severe renal

insufficiency; it is principally
characterized by ascites that is resistant
to diuretics.
 Median survival of 3-6 months.
Vasoactive Medical treatment

 Terlipressin bolus(0.5mg/4h)-increase
every 3 days if no response to 1-2mg/4h
 Given until creatinine normalizes or for 15 days

 Albumin 1g/kg on day1( one bag of HAS

contains 20grams)
 20-60g/d thereafter
Step by step guide :
PRERENA HRS ATN
L

 Normal renal us
 Normal urine dipsix – Spot Na <10 <10 >30
no RBC cast
 No nephrotoxic drugs
 Fluid challenge Urine Nil Nil Positive
sediment
 Spot Na and serum
Na
 Serum and urine Fluid Responds Nil Nil
osmolality challenge

 Urine output
The stages of HE- West Haven
criteria:
Stage 0. Lack of detectable changes in personality or behaviour.
Asterixis absent.

Stage 1. Trivial lack of awareness. Shortened attention span.

Impaired addition or subtraction. Hypersomnia, insomnia, or
inversion of sleep pattern. Euphoria or
depression. Asterixis can be detected.

Stage 2. Lethargy or apathy. Disorientation. Inappropriate behaviour.

Slurred speech. Obvious asterixis.

Stage 3. Gross disorientation. Bizarre behaviour. Semistupor to

stupor. Asterixis generally absent.

Stage 4. Coma.
HE- Four compatible theories

 Cerebral vasomotor dysfunction

 Oedema secondary to ammonia toxicity
 Inflammation due to SIRS
 putative benzodiazepine-like molecules
The pathophysiology of HE
 A large body of work points at ammonia as a
key factor in the pathogenesis of HE.
 Portal ammonia is derived from both the
urease activity of colonic bacteria and the
deamidation of glutamine in the small bowel.
 The intact liver clears almost all of the portal
vein ammonia, converting it into glutamine and
preventing entry into the systemic circulation.
 Ammonia- astrocyte swelling in brain
 Patients with grade II HE should be managed
in a HDU environment.
 Grades III and IV HE requires definitive airway
protection and appropriate monitoring.
 Grade IV HE is strongly associated with
elevated levels of serum ammonia, a high
incidence of raised intracranial pressure and
the development of uncal herniation.
GCS –HE correlation

 Grade1- GCS 14-15

 Grade2- GCS 11-13- HDU

 Grade3- GCS 8-11 (Stupor or precoma)

 Grade4- GCS<8 (Coma)
 In acute and chronic liver disease,
increased arterial levels of ammonia are
commonly seen.
 However, correlation of blood levels with
mental state in cirrhosis is inaccurate.
Lactulose is a first-line
pharmacological treatment of HE.

 Lactulose – reaches colon, where bacteria will

metabolize the lactulose to acetic acid and
lactic acid.
 This lowers the colonic pH
 formation of the non-absorbable NH4+ from
NH3,
 Other effects like catharsis also contribute to
the clinical effectiveness of lactulose.
Lactulose

 For acute encephalopathy, lactulose (ingested

or via nasogastric tube), 45 ml p.o.,

 Is followed by dosing every hour until

evacuation occurs.
 Target -three soft bowel movements per day

 If response to disachharide is poor- add

antibiotic (metronidazole or rifaximine after
48Hrs) to reduce enteric bacterial mass.
If patient is refusing oral lactulose prescribe
phosphate enemas TDS!

An excessively sweet taste, flatulence, and

abdominal cramping are the most frequent
subjective complaints with this drug.
The coagulopathy of liver disease

 Failure to produce clotting factors II, V, VII and IX

 Failure of the diseased liver to clear activated clotting
factors.
 Degree of hypersplenism and thrombocytopaenia
often adds to the coagulopathy, especially if
disseminated intravascular coagulation (dic) also co-
exists.
 The degree of coagulopathy is a measure of severity
of liver disease and of patient prognosis.
 Routine correction of coaguloapthy is therefore NOT
indicated unless active bleeding or planned
interventions require it
Sepsis

 Infection may be the initiating event of liver

failure,
 Intercurrent sepsis is also a common problem .
 Impaired immune function, in part secondary
to reduced complement factor production and
 Impaired neutrophil, leukocyte and monocyte
function, can result in delayed presentation of
clinical signs of infection.
 The interventions required for diagnosis and
management of liver disease also increase
patient vulnerability to invasive infection.
Role of prophylactic antibiotic

 Only patients who have an episode of

gastrointestinal bleeding
 or an episode of spontaneous bacterial
peritonitis (SBP) have been shown to
have a significant outcome benefit from
prophylactic antibiotics.
In presence of sepsis

 Choice of antibiotic should be guided by

local microbiological surveillance.
 The high incidence of mycoses - low
threshold for antifungal.
 Regular microbiological surveillance
Role of NAC
 Efficacy of NAC is well established in PCM
induced ALF
 Non PCM ALF – role of NAC is controversial
 175 patients of non PCM ALF received NAC
 Transplant free survival at 3 weeks was 52% in
NAC group compared to 30% in placebo arm ( only
with coma grade of 1-2)
 United States ALF study group- overall was 70% vs
66%
Artificial liver??
Extracorporeal Liver Assist Device
(ELAD)
 Hepatocyte bioreactor- hepatoma cells
cultivated on the exterior surface of
semipermeable hollow fibres

 MARS (molecular adsorbent

recirculating system)
ELAD

 Both reduce the level of bilirubin, bile salt

ammonia etc
 However no of patients dying or
requiring liver transplant did not improve

Devices remain experimental and large-scale phase two

and three trials are awaited
Summary
• The mortality rate for acute liver failure ranges between 56% and
80%
• The main role of intensive care therapy is multi-organ support
• The commonest cause of acute liver failure in the western world
is paracetamol toxicity
• Hepatic encephalopathy is no longer the main cause of death but
it’s detection and management requires sophisticated
cardiovascular and cerebral monitoring
• Hepatorenal failure is due to the complex interplay between
splanchnic, renal and systemic circulatory responses to liver
failure. Terlipressin has been shown to be of use in its treatment
• Novel hepatic replacement therapies are under development but
definitive studies as to their efficacy are, as yet, unpublished.