Acute Liver Failure

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Acute Liver Failure
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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

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• The mortality rate for acute liver failure ranges
  between 56 and 80

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Abnormal LFT is NOT ALF

• Dear Doctor
• Patients bilirubin is 600 and has liver failure-
  kindly urgently see
• Family was told transplant may be necessary

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Formal diagnosis of acute liver failure

• An increase in PT by 4-6 seconds (INRgt1.5)
• And the development of hepatic encephalopathy
  (HE).
• In a patient without pre-existing cirrhosis and
  with an illness of less than six months duration.

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• 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

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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

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• ACLF-Ethical dilemma- HDU admission

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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

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Few definitions

• Hyperacute- lt7days
• Acute - gt7days lt21days
• Subacute- gt21days lt6months
• FHF- not used

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Diagnostics

• Good history- difficult if HE

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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

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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

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Liver biopsy

• Importance of early biopsy- severity and
  aetiology
• Particularly useful in Hep B, AIH, Alcoholic
  hepatitis, differentiate between ALF and aCLF
• Transjugular route

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www.gastrotraining.com
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• Urgent OLT is the only life saving therapy
• The main role of intensive care therapy is
  multi-organ support

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All Liver transplants

• CLD 60
• Malignancy- 10
• ALF- 10 ( Paracetamol)
• Cholestasis - 10-20

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Paracetamol Overdose

• 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

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When to pick up the phone

• D2-
• pH lt7.3
• INRgt3
• Cr gt200
• Hypoglycaemia
• D3-
• HE
• Crgt200
• INR gt4.5
• D4-
• Any rise in INR
• Cr gt250
• HE

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DefinitionHRS

• 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.

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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

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• Terlipressin
• NSBB

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HRS

• Major criteria
• Chronic or acute hepatic disease and liver
  failure with portal hypertension
• Serum creatinine level gt133 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 (Proteinlt500 mg/day) and no
  ultrasonographic evidence of renal tract or
  parenchymal disease
• Minor criteria
• Urine volume lt500 mL/day
• Urine sodium lt10 mEq/L
• Urine osmolality greater than plasma osmolality
• Urine red blood cell count lt50 per high-power
  field
• Serum sodium lt130 mEq/L

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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.

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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

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Step by step guide

• 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

PRERENAL HRS ATN
Spot Na lt10 lt10 gt30
Urine sediment Nil Nil Positive
Fluid challenge Responds Nil Nil
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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 ordepression. 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.

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HE- Four compatible theories

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

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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

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• 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.

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GCS HE correlation

• Grade1- GCS 14-15
• Grade2- GCS 11-13- HDU
• Grade3- GCS 8-11 (Stupor or precoma)
• Grade4- GCSlt8 (Coma)

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• 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.

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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.

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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.

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• 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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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

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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.

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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.

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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

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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

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• Artificial liver??

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Extracorporeal Liver Assist Device (ELAD)

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

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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

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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 its 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.