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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
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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%

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

 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

 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

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

 Hyperacute- <7days
 Acute - >7days <21days
 Subacute- >21days <6months
 FHF- not used

 Good history- difficult if HE

 Prothrombin Time/ INR
 Blood Chemistry
Sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphate,
AST, ALT, alkaline phosphatase, GGT, total bilirubin, albumin,
Creatinine , urea
Glucose
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Arterial blood gas
Arterial lactate
Full blood count
Blood type and screen
Ammonia (arterial if possible)
HIV status
Amylase and lipase

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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

 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

 CLD – 60%
 Malignancy- 10%
 ALF- 10% ( Paracetamol )
 Cholestasis - 10-20%

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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
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Recovery, transplant or death
No chronic state

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D2-
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D3pH <7.3
INR>3
Cr >200
Hypoglycaemia
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HE
Cr>200
INR >4.5
D4-
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Any rise in INR
Cr >250
HE

 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
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Leads to splanchnic and systemic vasodilatation-role of NO
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Decreased effective arterial blood volume
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Activation of RAS, and vasopressin aimed at restoring arterial filling pressure.
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Renal vasoconstriction increases counterbalanced by the intrarenal prostaglandins.
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When this balance is lost renal hemodynamics worsens, and hepatorenal syndrome develops

 Terlipressin
 NSBB

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Major criteria
Chronic or acute hepatic disease and liver failure with portal hypertension
Serum creatinine level >133 micromoles/L
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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
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Minor criteria
Urine volume <500 mL/day
Urine sodium <10 mEq/L
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Urine osmolality greater than plasma osmolality
Urine red blood cell count <50 per high-power field
Serum sodium <130 mEq/L

 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.
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 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 

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

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.

 Cerebral vasomotor dysfunction
 Oedema secondary to ammonia toxicity
 Inflammation due to SIRS
 putative benzodiazepine-like molecules

 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.

 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 – 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.

 For acute encephalopathy, lactulose (ingested or via nasogastric tube ), 45 ml p.o.,
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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.

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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 coexists.
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

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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.

 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.

 Choice of antibiotic should be guided by local microbiological surveillance.
 The high incidence of mycoses - low threshold for antifungal .
 Regular microbiological surveillance

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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??

 Hepatocyte bioreactor- hepatoma cells cultivated on the exterior surface of semipermeable hollow fibres
 MARS (molecular adsorbent recirculating system)

 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

• 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.