Dr Matthew Roberts,
Royal Army Medical Corps
Dr Ray Towey,
Mwanza Hospital, Tanzania

Introduction		Liver Function Tests
Liver Functions		Hepatorenal Failure
The Effect of Anaesthesia and Surgery on Liver Function		Drug Elimination
Halothane and Jaundice		Regional Anaesthesia
Anaesthesia and Surgery in Patients with Liver or Biliary Dysfunction		Conclusions

Introduction

Anaesthesia and surgery in patients with problems related to the liver cause concern because of the central role of the liver in many of the body's metabolic and synthetic functions. The process of anaesthesia may adversely effect these functions and equally the patient's response to anaesthetic drugs and surgery may be influenced by hepatic dysfunction. It is therefore necessary for those practicing anaesthesia anywhere in the world to have an understanding of liver function in normal physiology. 

Liver Functions

The liver conjugates bilirubin, produced from the degradation of the haemoglobin of red cells that are at the end of their normal life span. This now water-soluble form of bilirubin is then excreted into the bile ducts and thence into the small intestine. Also passed to the gut are the bile salts produced by the liver and necessary for the absorption of the fat-soluble vitamins A, D, E and K. Vitamin K is essential for the production of prothrombin and some other protein factors that are essential for the normal clotting of blood.

Synthesis of many proteins takes place in the liver including most clotting factors and many carrier proteins, such as albumin, which to a varying degree bind drugs used during anaesthesia. The liver is also central in lipid metabolism with cholesterol and triglycerides synthesised here. The synthesis and breakdown of glycogen in the liver is pivotal in carbohydrate metabolism. It stores glycogen and releases glucose into the blood when the blood glucose falls for any reason.

The liver is responsible for the biotransformation of drugs either by oxidation or conjugation in order to render them water-soluble and therefore more easily excreted in the urine or bile. 

The Effect of Anaesthesia and Surgery on Liver Function

Inhalational anaesthetics effect carbohydrate metabolism in several ways. Ether, unlike the newer agents, enhances the breakdown of glycogen in the liver. Halothane has been shown, experimentally, to decrease the rate of glycogenesis, inhibit insulin release and inhibit the effect of insulin on the tissues. The catacholamine mediated stress response to surgery and trauma also increases glycogenolysis, so the overall effect of both surgery and inhalational anaesthesia is to elevate blood glucose

Protein synthesis is reduced by halothane but this is of questionable clinical significance.

Halothane and ether both inhibit the Cytochrome P450 enzyme system, slowing the oxidative metabolism of drugs; gluconuride conjugations are not effected. The following drugs, as a result, have a prolonged half-life in the presence of halothane, fentanyl, ketamine, lignocaine, pancuronium and propranolol.

Hepatic blood flow is decreased by halothane in parallel with an overall decrease in cardiac output. Intermittent positive pressure ventilation and decreases in carbon dioxide potentiate this effect while hypoventilation and increased carbon dioxide results in an increase in hepatic blood flow. These effects are unlikely in isolation to lead to liver hypoxia or damage.

Opioids such as morphine, pethidine and fentanyl are known to be able to cause spasm of the Sphincter of Oddi and increase biliary pressure, the effect lasting about two hours in the case of morphine. This should not preclude their use to provide adequate analgesia in biliary surgery. 

Halothane and Jaundice

It was discovered some years ago that some adult patients can,very rarely, become jaundiced from severe hepatic damage after a second halothane anaesthetic. The incidence of this halothane hepatitis in adults is thought to be 1:7000-30,000 halothane anaesthetics. It is even rarer in paediatric patients and with the newer volatile agents. The risk is thought to be higher in women, the middle aged and the obese.

The cause of so-called halothane hepatitis is not fully established and may be multifactorial. The effect seems to be related to the degree of metabolism of the volatile agent, so toxic metabolites may be involved. The onset time of the jaundice is shorter with increasing numbers of exposures to halothane and there have been suggestions of a possible immunological cause. It has also been suggested that reduced hepatic blood flow and hypoxia are to blame. In most cases of post operative jaundice halothane is unlikely to be the cause so given the rarity of the condition, and the limited choice of agents in the developing world, anaesthetists under these circumstances should not hesitate to use halothane whenever it is appropriate.

Interestingly there is no evidence that halothane will precipitate hepatic deterioration in patients with jaundice of a different origin. Ether may cause a transient depression of liver function but does not cause significant damage. 

Anaesthesia and Surgery in Patients with Liver or Biliary Dysfunction

Before the anaesthetist can assess the implications of a patient's hepatic disease for the conduct of an anaesthetic, it is necessary to understand the various causes of jaundice - the cardinal sign of liver disease.

Jaundice can be prehepatic (haemolytic), hepatic (hepatocellular) or posthepatic (obstructive) in origin. An example of prehepatic jaundice is in the haemolysis that accompanies the breakdown of a large haematoma, or the jaundice that can occur when there is a massive intravascular haemolysis - as in some forms of malaria or in sickle cell anaemia. In these situations the hepatocellular function is normal but overwhelmed and so the increased bilirubin is for the most part unconjugated. Protein and carbohydrate metabolism is intact and there is no reduction in the absorption of Vitamin K or production of clotting factors.

Where there is actual hepatocellular dysfunction, as in hepatitis or cirrhosis, there may be evidence of decreased protein synthesis, with oedema and ascites, signs of delayed clotting only partly reversed by vitamin K administration, and even encephalopathy. Hepatic encephalopathy is a condition of progressive deterioration of cerebral function from drowsiness to coma, in patients with liver disease, probably caused by toxic metabolites of proteins in the large intestine not adequately detoxified by the liver. These patients may show other signs of chronic liver disease as listed in Table 1.

Patients with active liver disease, such as hepatitis, are at high risk of deterioration during surgery and this should be avoided or delayed where possible. The poorest outcome is predicted by the combination of deranged clotting, oedema and encephalopathy.

Obstructive JaundiceBiliary obstruction is the most likely cause of jaundice to be encountered by the anaesthetist in the developing world. It can result from a stone in the common bile duct, pancreatic tumour or ascending cholangitis where the bile and biliary tree are infected. Hepatocellular function is normal (although it may deteriorate in prolonged obstruction) so the excess plasma bilirubin is chiefly conjugated. As conjugated bilirubin is water-soluble it will be excreted in the urine which becomes dark. Stools are pale as a result of poor lipid absorption. Although protein synthesis is normal, the production of vitamin K dependant clotting factors will be reduced, as the absorption of vitamin K is dependent on the excretion of bile salts into the small intestine. The clotting time can, therefore, be prolonged but this can be readily reversed by parenteral administration of vitamin K. Surgery in these cases is to remove or bypass the obstruction or to drain infected obstructed bile. 

(Continued ...)

---

© World Federation of Societies of Anaesthesiologists WWW implementation by the NDA Web Team, Oxford

---