ANAESTHESIA AND LIVER DISEASE

Dr Robert Ginsburg FRCA, Consultant Anaesthetist, King's College Hospital, London, England

Reprinted with permission of the Royal College of Anaesthetists and the Association of Anaesthetists of Great Britian and Ireland.

Liver disease can vary in severity from sub-clinical to end-stage liver disease (ESLD), with life threatening, multi-organ multi- system failure. Anaesthetic and operative risks are related to the severity of liver dysfunction, so thorough pre-operative assessment is essential for safe peri-operative care. A good understanding of the pathophysiology of liver dysfunction is vital for assessment of operative risk.

PATHOPHYSIOLOGY OF ESLD

While the severity of liver dysfunction may vary widely, a limited review of the pathophysiology of severe disease is appropriate. The range of symptoms depends largely upon whether the disease presentation is acute or chronic. If chronic, features may be superimposed on a background of poor nutrition and chronic ill health. The acute presentations have been subject to re-classification in recent times in order to take into account differing survival rates with medical treatment alone. The first formal definition was proposed by Trey and Davidson who defined fulminant liver failure (FHF) as the appearance of encephalopathy within eight weeks of onset of jaundice. The King's College group now recognises three levels of acute presentation within FHF (Table 1). Contrary to expectation, survival rates are better in the acute and hyper-acute groups on medical management alone. Gimson has written a useful review of fulminant hepatic failure.

Impaired liver function

Impaired liver function gives rise to effects directly attributable to the failing liver itself and also to indirect effects expressed via other organ systems. Effects directly attributable include hypoglycaemia, lactic acidosis, hypermetabolism, azotemia and impaired urea synthesis. Jaundice appears when serum bilirubin exceeds 35 µmol/l and defects in cholesterol metabolism together with intra-hepatic cholestasis may lead to production of poor quality bile and malabsorbtion of fat and fat-soluble vitamins. There is reduced synthesis of proteins such as albumin, clotting factors, thyroid binding globulin and pseudo-cholinesterase. Impaired hormone biotransformation, reduced production of modulator proteins and reduced protein binding lead to increased circulating levels of hormones such as insulin, thyroxine, T₃, aldosterone and oestrogen.

Impaired hormone modulation, failure to clear by-products of metabolism, activation of cytokines and release of vasoactive substances from the damaged liver result in patho-physiological changes in many organ systems. These indirect effects include:

Cardiovascular changes

Vasodilatation and vascular shunting are almost invariable in ESLD. Low systemic vascular resistance (SVR) results in high cardiac output and high mixed venous oxygen saturations. Pulmonary hypertension may develop, while portal venous hypertension can lead to varices, variceal bleeding and porto- systemic shunting. Low flow in the portal vein can result in portal venous thrombosis. Variceal bleeding may be life threatening.

Pulmonary changes

Pulmonary problems are both vascular and mechanical. Intra- pulmonary shunt dilatation (hepato-pulmonary syndrome), impaired hypoxic vaso-constriction and ventilation perfusion mismatch lead to arterial desaturation and clubbing if chronic. Pleural effusions together with ascites can cause considerable mechanical embarrassment of respiration and a reduction in functional residual lung capacity.

Electrolytes and Renal

There are numerous causes of renal impairment in liver failure, including hepato-renal syndrome, sepsis and renin-angiotensin activation. Hyponatraemia due to water retention and inhibition of membrane bound Na/K ATPase, hypoalbuminaemia and oedema are common. Saline should be avoided but hypomagnesaemia and hypo-phosphataemia should be corrected.

Neurological problems

Mechanisms leading to deepening encephalopathy, loss of vascular auto-regulation, cerebral oedema and death are incompletely understood. A number of processes may act in parallel, but can be summarised as the accumulation of neurotoxic compounds penetrating an impaired blood-brain barrier. At the same time, lack of nutrients and substrates may impair brain metabolism and alter neuro-transmitter synthesis. Of particular interest are a group of endogenous benzodiazepine-like substances that are thought to act at a site closely linked to the g- amino butyric acid (GABA) receptor. Drowsiness can be transiently reversed by flumazenil, but not in all cases. Symptoms can occur in chronic as well as in acute disease, may be rapid in onset and may be precipitated by a gastrointestinal bleed, dietary protein overload or sepsis. Somnolence can be exacerbated by sedative drugs and narcotics.

Rapid correction of hyponatraemia can lead to osmotic demyelination and central pontine myelinolysis and should be avoided.

Haematological

Anaemia may be the result of nutritional deficiency, toxic bone marrow depression or gastrointestinal bleeding from varices or erosions. Coagulation defects arise from thrombocytopenia, platelet dysfunction and decreased levels of circulating clotting factors. Clotting factor levels fall because of impaired synthesis, vitamin K malabsorbtion and intravascular consumption. The short half-life of clotting factors means that INR or Prothrombin Ratio (PTR) can reliably be used to evaluate residual hepatic function.

Susceptibility to infection

There may be a wide variety of defects in host defences that can contribute to a substantial risk of sepsis, with up to 80% of patients with FHF developing bacterial sepsis (frequently Gram positive organisms) and 30% fungal sepsis. Clearly, particular attention must be paid to aseptic technique when inserting lines.

Drug disposition

There may be considerable derangement of drug handling in the patient with liver dysfunction. Aetiology may influence pharmacokinetics and the nature and extent of hepatocellular damage may alter drug metabolism. Cholestasis will reduce absorbtion of fat-soluble drugs after oral administration, while other drugs with limited systemic availability due to high hepatic extraction, may achieve high peak plasma concentrations if there is porto-systemic shunting. Compartment changes and altered protein binding will affect volume of distribution, clearance and re-distribution. Patients with liver dysfunction may be particularly sensitive to opiates and benzodiazepines due to altered end-organ sensitivity (see 'Neurological problems' above).

Causes of Liver Failure

The commonest causes of acute and chronic liver failure (ALF) are listed in Table 2. In the UK, paracetamol poisoning was until two years ago the most frequent cause of FHF. When a change in regulations reduced over-the-counter pack size of paracetamol to a maximum of 8 tablets, the incidence of paracetamol poisoning fell dramatically. Worldwide, by far the major cause of liver disease is viral infection, with Hepatitis B (HBV) and C (HCV) together accounting for 75% of all cases. The natural history of chronic infection with both HBV and HCV includes progression to cirrhosis and an increased risk of developing hepatocellular carcinoma (HCC).

Infection with HCV deserves special mention. The nature of HCV replication is such that during the course of a single infection, HCV frequently changes its antigenic signature. As a result of this and of other mechanisms, the virus is able to confuse host immune responses, with the result that 85% of HCV infections become chronic, as opposed to about 5% in the case of HBV. Chronic HCV infection is insidious and it may take up to 15 years for overt signs of liver failure to develop. Not only can apparently stable, asymptomatic patients decompensate acutely as a result of anaesthesia, but they can also represent a significant infection risk for the anaesthetist.

Risk and severity scoring

In 1964, Child and Turcotte classified risk for patients with liver cirrhosis undergoing porto-caval anastomosis for management of portal hypertension. Pugh et al at King's College Hospital published a severity scoring system for patients undergoing oesophageal transection for bleeding oesophageal varices. The two systems have been amalgamated and provide a disease severity assessment based on two clinical and three laboratory variables (Table 3).

Surgery in patients with liver dysfunction

The Child-Pugh classification is a useful method of staging the progress of liver decompensation. However, despite its surgical pedigree, it is of limited predictive value in anaesthesia and surgery, because Group B and C patients all represent a high perioperative risk. In general surgical practice, only emergency or life-saving procedures should be undertaken in these patients. In a unit where liver transplantation is an option, other procedures can be considered, particularly those intended to 'buy time' until a suitable donor organ is available. Group A patients are lower risk and with sufficient care can be considered as candidates for most types of surgery.

Hepatocellular carcinoma is a recognised complication in those with chronic HBV or HCV infection. Rates are reported to run between 800 and 2000 cases per year per 100,000 chronically infected. Even in Group A patients, operative mortality for hepatic resection of tumour runs at 5%-10%.

Group B/C patients present an extremely high operative risk and surgical procedures in these patients should be avoided if possible. Considerable morbidity and a high mortality rate invariably accompany all but minor surgery. Procedures that might be performed in these patients include:

• Laparotomy for perforation or bleeding - often following previous surgery
• Porto-systemic anastomosis for portal hypertension: includes meso-caval and distal lieno-renal anastomosis. Encephalopathy is a common post-operative complication.
• Peritineo-venous shunting for intractable ascites where liver transplantation is not an option.

Hepatic resection of tumour in Group B/C patients carries an operative mortality of about 50%.