Hepatic Encephalopathy in Acute Liver Failure

Management of Hepatic Encephalopathy in Acute Liver Failure

A 30 year old woman with a background of substance abuse and deliberate self harm was found collapsed and semi-conscious following an overdose of co-codamol and was presenting late. It was possible that she had taken around 100g paracetamol. Her GCS was 11, and she had grade II/III hepatic encephalopathy. Her bilirubin was 60 and she had significant transaminitis with a lactic acidosis. . She was commenced on N-acetylcysteine despite undetectable paracetamol levels. Liver US was normal. Early repeat bloods showed worsening jaundice, transaminitis and rising INR. She was transferred to the regional liver unit initially for monitoring, but was subsequently admitted to the liver HDU. She did not require a liver transplant and recovered with conservative management.

What is the optimum management of hepatic encephalopathy in acute liver failure?

Prad Shanmugasundaram
Acute liver failure (ALF) is classically a triad of coagulopathy, encephalopathy and jaundice. Trey et al defined acute liver failure as evidence of coagulation abnormality (INR >1.5), any degree of mental alteration (encephalopathy) in a patient without pre-existing cirrhosis and with an illness of less than 26 weeks’ duration.(1) The development of encephalopathy with acutely deranged liver function is very specific for acute liver failure, and indicates the development of cerebral oedema.

Hepatic encephalopathy is classified according to the West Haven system, where grade I encephalopathy indicates subtle neurocognitive deficits, grade II represents mild disorientation, lethargy and apathy, grade III indicates more severe brain oedema and may manifest with drowsiness, confusion and gross disorientation and grade IV encephalopathy is coma.

High quality critical care is essential for these patients, and even low grade encephalopathy warrants admission to a critical care unit and possible transfer to a specialist centre as they may deteriorate rapidly from multi-system derangements and have a high risk of developing complications such as sepsis.

Measuring ammonia levels have proven predictive as an independent risk factor for the development of high grade hepatic encephalopathy (levels over 100M) and intracranial hypertension (level >200M), or as a threshold below which the development of intracranial hypertension is unlikely (<75M).(2)

High grade encephalopathy (grades III and IV), mandates intubation and ventilation and institution of neurological care bundles. The causative cerebral oedema may warrant intracranial pressure (ICP) monitoring which is a process that may carry significant risk in the coagulopathic, immunocompromised patient. Such monitoring may lead to more aggressive ICP lowering treatment while maintaining cerebral perfusion, but this has not been shown to necessarily improve outcomes.(3)

Enteral lactulose may help to reduce ammonia levels and may prevent or treat cerebral oedema in acute liver failure. However a matched retrospective cohort study found a small increase in survival time, but no overall difference in encephalopathy severity or overall outcome in patients receiving lactulose compared to those who did not. High dose lactulose therapy may cause bowel distension that can make eventual transplantation surgery more technically difficult.(4)

Another drug that reduces ammonia levels has shown recent promise. Rifaximin in has orphan drug status in the United States for the treatment of hepatic encephalopathy. A recent randomised controlled trial compared the antibiotic rifaximin with lactulose therapy to lactulose alone in cirrhotic patients with hepatic encephalopathy. They showed a increased reversal of encephalopathy, decreased mortality, shorter hospital stay and fewer deaths from sepsis in the combined treatment group.(5) Evidence of its efficacy is awaited in non-cirrhotic patients with acute liver failure.

Mannitol has been shown in a small series to correct elevated ICP in patients with ALF and to improve survival, but its effect on ICP is transient.(6) It is recommended as a first line therapy.(3) Hypertonic saline has been shown to reduce the incidence of intracranial hypertension in patients at high risk of developing cerebral oedema (high serum ammonia, high grade encephalopathy, renal failure or need for vasopressor) and so is recommended as a prophylactic therapy in these patients to drive the serum sodium to145-155mmol/L.(7)

Definitive treatment remains the domain of specialist liver transplant centres. There are no reliable models for predicting survival or the need for organ transplantation yet. Acute liver failure secondary to paracetamol poisoning, hepatitis A, shock liver and pregnancy-related liver disease carry better transplant-free survival (>50%) whereas other aetiologies have less than 25% survival without transplant. The King’s College criteria are the most commonly used system for listing patients for orthotopic liver transplant. They have a sensitivity of ~68%, specificity of 82-92% according to meta-analysis.(8)

Whole organ cadaveric liver transplantation is the definitive treatment for acute liver failure. However, live donor liver transplantation accounts for a small fraction of liver transplants. It improves survival in patients with ALF, and allows for the possibility of auxiliary liver transplantation where the recipient liver is left in-situ to allow for the possibility of regeneration and eventual cessation of immunosuppressants.(3)

Liver support systems can be divided into artificial or bioartificial support systems. Artificial sorbent-based systems such as the molecular-absorbent recirculation system (MARS) have so far failed to show significant survival benefit. A NICE guidance document states that current evidence on its efficacy is inadequate in quality and quantity.(9) Bioartificial support systems that are based around functioning hepatocyte cartridges have only shown limited promise and, so far, no system has been approved by the FDA or NICE.


Lessons learnt:

Acute liver failure is a rare but devastating condition. Early referral to a specialist liver centre is mandated, but temporising stabilisation may be required in the referring hospital. Careful intensive care management and regular frequent monitoring of neurologic status is required when managing these patients in the district general hospital. Hepatic encephalopathy is one of the defining characteristics of this condition and may need early aggressive monitoring and therapeutic interventions to limit increases in intracranial pressure.


References:

1. Trey C, Davidson CS. The management of fulminant hepatic failure.In: Popper H, Schaffner F, eds. Progress in Liver Diseases. New York: Grune & Stratton, 1970:282-298.

2. Bernal W, Hall C, Karvellas CJ, Auzinger G, Sizer E, Wendon J. Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure. HEPATOLOGY 2007;46: 1844-1852.

3. Lee WM, Stravitz T, Larson AM. AASLD Position Paper. The Management of Acute Liver Failure: Update 2011. Hepatology 2012; 55: 965-967
4. Alba L, Hay JE, Angulo P, Lee WM. Lactulose therapy in acute liver failure. J Hepatol 2002;36:33A

5. Sharma. A Randomized, Double-Blind, Controlled Trial Comparing Rifaximin Plus Lactulose With Lactulose Alone in Treatment of Overt Hepatic Encephalopathy. Am J Gastroenterol 2013;108:1458-1463

6. Canalese J, Gimson AES, Davis C, Mellon PJ, Davis M, Williams R. Controlled trial of dexamethasone and mannitol for the cerebral oedema of fulminant hepatic failure. Gut 1982;23:625-629.

7. Murphy N, Auzinger G, Bernal W, Wendon J. The effect of hypertonic sodium chloride on intracranial pressure in patients with acute liver failure. Hepatology 2002;39:464-470.

8. McPhail MJ, Wendon JA, Bernal W. Meta-analysis of performance of King’s College Hospital Criteria in prediction of outcome in nonparacetamol-induced acute liver failure. J Hepatol 2010;53: 492-499.

9. NICE interventional procedure guidance IPG316. Extracorporeal albumin dialysis for acute liver failure. Sept 2009

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