A 43-year-old female with a history of paranoid schizophrenia and multiple episodes of selfharm, presented to the Emergency Department with decreased conscious state. She had been seen three days earlier for possible worsening of her psychosis and discharged home.

Her haematology and biochemistry results at both presentations are as follows:

Parameter Patient Value Normal Adult Range
1st Presentation 2nd Presentation
Haemoglobin  134 g/L 135 g/L 115 – 160
White cell count  12.6 x 109 /L* 7.5 x 109/L 4.0 – 11.0
Platelet count  250 x 1012/L 76 x 1012/L* 150 – 400
Prothrombin time    40.0 seconds* 12.3 – 16.6
International Normalised Ratio (INR)   4.1* 0.9 – 1.3
Activated partial thromboplastin time (APTT)    35.0 seconds 27.0 – 38.5
Fibrinogen    1.8 g/L* 2.0 – 4.0
 
Sodium  139 mmol/L 136 mmol/L 134 – 146
Potassium  3.6 mmol/L 4.6 mmol/L 3.4 – 5.0
Bicarbonate 18 mmol/L* 21 mmol/L* 22 – 32
Urea 5.0 mmol/L 18.9 mmol/L* 3.0 – 8.0
Creatinine  56 µmol/L 448 µmol/L* 45 – 90
Bilirubin total  6.0 µmol/L 81 µmol/L* < 20
Alanine aminotransferase (ALT)  31 U/L 11700 U/L* < 35
Alkaline phosphatase (ALP)  88 U/L 245 U/L* 35 – 135
Gamma glutamyl transferase (GGT)  13 U/L 104 U/L* < 40
Lactate    4 mmol/L < 1.5
 
Paracetamol    < 10 mg/L 10 mg/L
Urine Ethanol    Not detected  
Urine Amphetamines    Not detected  
Urine Benzodiazepines    Detected  
Urine Cannabinoids    Not detected  
Urine Opiates   Not detected  

a) What is the underlying diagnosis?

b) List the possible causes in this patient.

c) Outline your immediate management.

[Click here to toggle visibility of the answers]

College Answer

a) What is the underlying diagnosis?

Hyperacute (fulminant) hepatic failure

b) List the possible causes in this patient.

Paracetamol
Idiosyncratic drug reaction
Other toxin e.g. Amanita phalloides
Viral (hepatitis A and E as hyperacute consider B, CMV, Epstein Barr)
Ischaemic hepatitis
Budd-Chiari

c) Outline your immediate management.

Concurrent resuscitation and institution of supportive care and monitoring with focussed assessment
to identify underlying cause and definitive management as indicated.

Airway management and oxygen – likely to need intubation and mechanical ventilation with
ARDSNet targets and PCO2 32-38 mmHg

Haemodynamic support for adequate MAP and CPP >60 and appropriate monitoring (A-line,
PAC/PiCCO, bedside echo etc.). Avoid fluid overload

Strategies to offset cerebral oedema (head-up, neutral position, sedation, PCO2 targets, Na 145-155
etc.) 

ICP monitoring controversial

Consider renal replacement therapy
Extracorporeal albumin dialysis therapies (SPAD, MARS and Prometheus) have limited evidence to
support use

Monitoring of coagulopathy using TEG/ROTEM to guide correction. Correction to cover invasive
procedures or if bleeding otherwise not.

Monitor blood glucose

Screening for infection and antibiotics as indicated +/- empiric broad spectrum cover including antifungal

Stress ulcer prophylaxis

Nutrition

Specific 
NAC
Lactulose / Neomycin / Rifaximin controversial and use varies from unit to unit

Investigations including liver USS, viral screen

Discussion with liver transplant team / transfer to ICU with liver unit (does not currently meet
transplantation criteria)

Discussion

The diagnosis is clearly liver failure. The college further qualify their description as "fulminant". That term is very 1990s. What makes a liver failure fulminate? Well, apparently that just means it is acute (see Sass et al, 2005). The term was originally applied to patients in whom encephalopathy developed within two weeks of the development of jaundice. These days, the terminology we use is hyparcute (0-7 days), acute (8-28 days) and subacute  (29 days to 8 weeks). The disorders were redefined by Williams et al in 1993, on the basis of the fact that they correlate better with survival statistics (paradoxically, the hyperacute ones do much better).

Possible categories of the causes:

Vascular:

  • Right heart failure
  • Hepatic arterial ischaemia (eg. due to either global ischaemia, or due to an embolic event)
  • Hepatic venous insufficiency (Budd-Chiari syndrome)
  • Veno-occlusive disease (eg. post bone marrow transplant)

Infectious:

  • Hepatitis A, B and C
  • Hepres simlex
  • Cytomegalovirus
  • Varicella

Neoplastic:

  • Colonic carcinoma metastases
  • Hepatocellular carcinoma
  • Lymphoma

Drug-induced:

  • Paracetamol
  • Alcohol
  • Kava-kava
  • Tuberculosis antibiotics
  • Amanita phalloides mushroom
  • Cocaine (by ischaemia)
  • Solvents: xylene, chloroform, trichloroethylene, carbon tetrachloride
  • MDMA

Idiopathic: idiosyncratic drug reactions:

  • Anticonvulsants
  • NSAIDs
  • Aspirin in children (Reye's syndrome)

Congenital:

  • Wilson's disease

Autoimmune:

  • Haemophagocytic syndrome
  • Vasculitic hepatitis

Traumatic:

  • Crush injury to the liver
  • Capsular hematoma
  • Disruption of hepatic vessels
  • Hyperthermia-induced liver injury

Endocrine/metabolic:

  • Acute fatty liver of pregnancy
  • HELLP syndrome
  • Pregnancy-associated liver rupture

Of these, the following short list is relevant. However, it must be added that the college did not specify how many differentials they wanted. You could have brought up your various azathiprine-induced hepatitis and Amanita phalloides mushrooms.

Thus:

  • Hepatic ischaemia
  • Acute viral hepatitis or liver abscess
  • Acute right heart failure due to PE
  • Drug-induced hepatitis eg. paracetamol overdose (or Amanita)
  • Autummune hepatitis, eg. cryptogenic cirrhosis or idiopathic autoimmune hepatitis (IAIH)
  • Traumatic hepatic injury due to fall

Management

As with most things, management falls into the category of specific management and supportive management. Specific management may be viewed as a series of antidotes or proven solutions tailored to specific causes of the liver failure.

Paracetamol overdose

N-acetylcystine

Wilson's disease (chronic)

Copper chelating agents

Hepatic vein thrombosis

Thrombolysis / clot retrieval;

TIPS procedure

Hepatitis viruses

Antiviral drugs

Autoimmune hepatitis

Steroids may be helpful... or may be harmful.

Alcoholic hepatitis

Steroids are probably helpful

Valproate overdose

L-carnitine, and probably also dialysis to extract the excess ammonia

Amanita phalloides

Haemopherfusion may remove the phallotoxins

A discussion of supportive management might take the following shape:

  1.  Intubate the patient for airway protection, as they will be obtunded (and to control the CO2)
  2. Hyperventilation to low-normal PaCO2 (35 mmHg)
  3. Maintain haemodynamic stability using noradrenaline preferentially.
  4. Use propofol instead of benzodiazepines, and avoid long-acting opiates.
    Consider an ICP monitor
  5. Hypothermia to a temperature of 32-33°
    Hypernatremia (to control ICP, with hypertonic saline) to achieve a sodium of 145-155 mmol/L
  6. Haemodiafiltration - continuously - to remove ammonia
  7. Anticipate hypoglycaemia.
  8. Anticipate coagulopathy.
    Administer Vitamin K empirically.
    Consider blood products, but view complete correction as unobtainable.
  9. Vigilant surveillance for sepsis: they are prone to it, and it makes the encephalopathy worse

References

References

​Sass, David A., and A. Obaid Shakil. "Fulminant hepatic failure." Liver Transplantation 11.6 (2005): 594-605.

Williams, R., S. W. Schalm, and J. G. O'Grady. "Acute liver failure: redefining the syndromes." The Lancet 342.8866 (1993): 273-275.

Chapter 44   (pp. 501) Liver  failure by Christopher  Willars  and  Julia  Wendon

Daly, Frank FS, et al. "Guidelines for the management of paracetamol poisoning in Australia and New Zealand-explanation and elaboration." Medical journal of Australia 188.5 (2008): 296.

Bailey, Benoit, René Blais, and Anne Letarte. "Status epilepticus after a massive intravenous N-acetylcysteine overdose leading to intracranial hypertension and death." Annals of emergency medicine 44.4 (2004): 401-406.

Parsons-Smith, B. G., et al. "The electroencephalograph in liver disease." The Lancet 270.7001 (1957): 867-871.

Ramos, Juan Francisco Rivera, and Celina Rodríguez Leal. "Review of the final report of the 1998 Working Party on definition, nomenclature and diagnosis of hepatic encephalopathy." Ann Hepatol 10 (2011): S36-S39.

Walsh, Timothy S., et al. "Energy expenditure in acetaminophen-induced fulminant hepatic failure." Critical care medicine 28.3 (2000): 649-654.

Ichai, Philippe, et al. "Usefulness of corticosteroids for the treatment of severe and fulminant forms of autoimmune hepatitis." Liver transplantation 13.7 (2007): 996-1003.

O’Grady, John G., et al. "Early indicators of prognosis in fulminant hepatic failure." Gastroenterology 97.2 (1989): 439-445.

Dhiman, Radha K., et al. "Early indicators of prognosis in fulminant hepatic failure: An assessment of the Model for End‐Stage Liver Disease (MELD) and King's College Hospital Criteria." Liver transplantation 13.6 (2007): 814-821.

Yantorno, Silvina E., et al. "MELD is superior to King's college and Clichy's criteria to assess prognosis in fulminant hepatic failure." Liver transplantation13.6 (2007): 822-828.

Wiesner, Russell, et al. "Model for end-stage liver disease (MELD) and allocation of donor livers." Gastroenterology 124.1 (2003): 91-96.

Gleisner, Ana L., et al. "Survival benefit of liver transplantation and the effect of underlying liver disease." Surgery 147.3 (2010): 392-404.

Ding, G. K. A., and N. A. Buckley. "Evidence and consequences of spectrum bias in studies of criteria for liver transplant in paracetamol hepatotoxicity." QJM101.9 (2008): 723-729.

Lee, William M., R. Todd Stravitz, and Anne M. Larson. "Introduction to the revised American Association for the Study of Liver Diseases Position Paper on acute liver failure 2011." Hepatology 55.3 (2012): 965-967.

McPhail, Mark JW, Julia A. Wendon, and William Bernal. "Meta-analysis of performance of Kings’s College Hospital Criteria in prediction of outcome in non-paracetamol-induced acute liver failure." Journal of hepatology 53.3 (2010): 492-499.

Stravitz, R. Todd, et al. "Intensive care of patients with acute liver failure: recommendations of the US Acute Liver Failure Study Group." Critical care medicine 35.11 (2007): 2498-2508.

Warrillow, S. J., and R. Bellomo. "Preventing cerebral oedema in acute liver failure: the case for quadruple-H therapy." Anaesthesia and intensive care 42.1 (2014): 78.