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Management of hepatic encephalopathy in patients with cirrhosis

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The term hepatic encephalopathy encompasses a spectrum of neuropsychiatric abnormalities seen in patients with liver dysfunction. Distinct syndromes are identified in acute liver failure and cirrhosis. Rapid deterioration in consciousness level and increased intracranial pressure that may result in brain herniation and death are a feature of acute liver failure whereas manifestations of hepatic encephalopathy in cirrhosis include psychomotor dysfunction, impaired memory, increased reaction time, sensory abnormalities, poor concentration and in severe forms, coma. In patients with acute-on-chronic liver failure the pathophysiology remains undefined. Ammonia has been considered central to its pathogenesis. In the brain, the astrocyte is the main site for ammonia detoxification, during the conversion of glutamate to glutamine. An increased ammonia level raises the amount of glutamine within astrocytes, causing an osmotic imbalance resulting in cell swelling and ultimately brain oedema. Recent studies suggest that inflammation and it modulators may play a synergistic role with ammonia in the pathogenesis of hepatic encephalopathy. Therapy of hepatic encephalopathy is directed primarily at reducing ammonia generation and increasing its detoxification. The currently accepted regimens to treat hepatic encephalopathy such as lactulose and protein restricted diets need further clinical trials and therefore placebo controlled clinical trials in hepatic encephalopathy are justified. In liver failure, ammonia metabolism involves multiple organs and therefore ammonia reduction will require simultaneous targeting of these organs. The present review describes the pathophysiological basis of hepatic encephalopathy and evaluates the available therapies.

Introduction

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that may develop with liver insufficiency. In acute liver failure (ALF), HE defines the severity of disease and may progress from confusion to coma, with potential intracranial hypertension, brain herniation and death.1 In cirrhosis,2, 3 HE usually occurs insidiously with wide ranging neuropsychiatric disturbances (e.g. psychomotor dysfunction, impaired memory, decreased reaction time, diminished attention, sensory abnormalities and poor concentration). Patients with cirrhosis can deteriorate and develop cerebral changes indistinct from ALF (acute-on-chronic liver failure; ACLF). This would suggest that the pathogenesis of HE with any acute liver injury (ALF and ACLF), is independent of chronicity.4 Ammonia, inflammation and modulation of cerebral blood flow (CBF) autoregulation are central to the development of HE, and with the predisposing factors which trigger acute liver injury, have become important therapeutic targets in the management of HE. Adherence to consensus guidelines only provides an outline to what may be differing ideas on therapeutic goals. In this chapter we will discuss, pathogenesis, nomenclature and therapeutic options involved with managing this complex neuropsychiatric syndrome.

Section snippets

Nomenclature

The wide range of neuropsychiatric presentations (especially if subclinical) has made comparative interpretation of studies into HE problematic.5, 6 This led to the development of consensus terminology by the ‘World Congress of Gastroenterology’ in 2002 to classify hepatic encephalopathy:7

  • Type A: ALF.

  • Type B: portal-systemic bypass without intrinsic hepato-cellular disease.

  • Type C: cirrhosis and portal hypertension with portal-systemic shunts.

Also, the varied clinical course that an individual

Clinical staging

Although the ‘West Haven criteria’ is a specific staging classification of altered mental state in liver injury,8 the ‘Glasgow coma scale’9 as a robust assessment of consciousness in structural and metabolic brain disorders, is a useful staging system as well.

Pathogenesis of HE

Although many factors have been implicated in the pathogenesis of HE, it is the interplay between ammonia, inflammatory responses and auto-regulation of cerebral haemodynamics (the ‘multiple-hit hypothesis’) that appears most important.

Neurotransmitters/receptors

Metabolic and degenerative brain diseases characteristically demonstrate disorders of specific neurotransmission pathways. HE is no exception, with notable effects on glutamine, monamine, serotonin (5-HT), opiate and catecholamine pathways. However, the interaction between these neurotransmitters and other key pathogenic factors of HE like ammonia and electrolyte imbalance are significant. Therefore, it is hard to elucidate the true role of neurotransmitters in this condition and as yet few

Inflammation/infection

Infection is detected in 80% of patients with acute liver injury21 and its presence at admission is a predictor for worsening HE.22 Development of sepsis may trigger decompensation of cirrhosis with progression to renal failure, encephalopathy, and gastrointestinal bleeding, with reduced survival. However, the associated proinflammatory cytokine release23 is as important as the microbial pathogen itself. The term ‘systemic inflammatory response syndrome’ (SIRS) refers to the clinical

Cerebral blood flow modulation

In ALF, cerebral hyperaemia often develops, especially in those with malignant intracranial hypertension.26 Even with medical treatment, malignant hypertension precedes death which can only be treated by orthotopic liver transplantation (OLT).26 With the 2–3× increased blood–brain barrier permeability and cerebral metabolic rate for ammonia with HE,17 elevated cerebral blood volume, besides increasing intracranial pressure, may serve to promote osmotic movement of water across the blood–brain

Nutritional factors

Patients with cirrhosis (especially if alcohol-induced), usually have a poor nutritional reserve due to anorexia, poor diet, malabsorption, and altered metabolic state. Hospitalised patients are often hypermetabolic and hypercatabolic, worsened by complications such as gastrointestinal bleeding, continued anorexia and fasting for tests. Clinicians were previously advising dietary protein restriction in liver failure to prevent a rise in blood ammonia levels. Recently, the European Society for

Biotics

Most of the ammonia produced by the gut is from the deamination of dietary amino acids by bacteria, with a small contribution from the urea produced by urease-positive bacteria. In the critically ill and malnourished patient, levels of the predominant defensive bacteria strains (Bifidobacterium and Lactobacillus) decline. Antibiotics may further lead to ammonia-producing bacteria ameliorating hyperammonaemia. Biotics (e.g. pre-, pro-, and synbiotics) are thought to exert an effect in HE by: (1)

History and examination

The need for a detailed history and examination are fundamental to the diagnosis of HE given a broad spectrum of differential diagnosis (e.g. vascular, metabolic, intracranial and other neuropsychiatric disorders). To establish a diagnosis of HE it is necessary for there to be a history or clinical evidence of liver disease with or without the presence of a precipitating factor(s). With early diagnosis there is an increasing reliance on laboratory and imaging modalities to establish a diagnosis

Laboratory tests

Routine biochemical tests with a full hepatic screen are necessary to exclude other causes of chronic liver disease which could impact on treatment options. The diagnosis of precipitating factors like infection (e.g. cultures) and electrolyte imbalance is critical. Laboratory diagnosis of SBP is confirmed by the presence of ascitic fluid polymorphonuclear count (>250 cm3) or positive ascitic fluid culture, usually monomicrobial (e.g. Escherichia coli or other gram-negative bacteria). The use of

Management

Given the wide clinical presentation of HE and lack of large randomised placebo-controlled trials it is hard to translate even the most robust research outcomes into discernable clinical applications. However, the central role of ammonia and precipitating factors in disease progression influence current ‘best treatment’ which we will outline in this chapter. Most treatment modalities aim to improve on the poor outcome with acute liver injury. However, it is also important that primary and

Acute liver injury

Improved outcomes for patients with acute liver injury are due to earlier specialist intensive care, treatment of precipitating factors (e.g. variceal bleeds40) and the judicious use of OLT. As ‘time is tissue’, early resuscitation limits end-organ failure and corresponding mortality. Energy/oxygen expenditure is important to cerebral effects in patients with severe progressive HE. Oxygen delivery can be maximised by improving available haemoglobin (e.g. packed red cells) and by reducing

Ammonia-lowering therapies

The most widely used ammonia lowering therapies are purgatives (disaccharides, antimicrobials, and enemas).

Liver support and transplantation

The incongruity that exists between donor organs and recipients has led to a plethora of extracorporeal liver assist devices (ELADs) to aid or supplant the failing liver. ELADs are either:

  • Biological (including hybrid & combination) devices: which use either immortalised hepatocytes cultured in bio-reactors or whole animal livers to mimic endogenous excretory and synthetic liver function.

  • Non-biological devices: which use extracorporeal blood purification to dialyse albumin-bound hydrophobic

Management of predisposing factors

It is necessary to identify precipitating events and implement immediate therapy as prompt action may lead to a permanent improvement in HE. Though ACLF may be triggered by such uncommon events, such as sedatives or tranquillisers, vascular occlusion (hepatic vein or portal vein thrombosis) and hepatocellular carcinoma transformation, it is important to outline the management of the more common precipitants.

Precipitating factors are:

  • constipation

  • electrolyte and acid-base imbalance

  • infection

Neurotransmitters

The use of pharmacological agents to manipulate neurotransmission has shown some benefit when trailed on animal models of liver failure. However, though the spectrum of neurological and neuropsychiatric symptoms to target is identifiable, research is needed to clarify specific therapeutic goals given the inter-relationship between multiple neurotransmission pathways. Also much of the established alterations in neurotransmission are due to the direct effect of ammonia, which is easier to target.

Conclusion

A new approach to the treatment HE is needed. The current lack of conclusive data supports the view that placebo-controlled trials of new agents are needed and ethical. Ammonia is still the main therapeutic target and more focused research on its inter-organ metabolism is required. The small intestine and kidneys are important producers of ammonia, and muscle is an important organ that can remove ammonia. Novel therapies targeting these organs are likely to offer worthwhile clinical

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