Disclaimer
This is the expanded content of a lecture that I gave in 1998. I do not claim that this material is composed entirely of original content - rather, it is a review of some of the classic textbooks and other lectures that I have attended on the subject. Think of it as a traditional medical student or resident lecture

Introduction
This broad area of disease can be classified as parenchymal liver disease (this includes hepatitis and cirrhosis) and non-parenchymal (also can be called cholestatic or extra-hepatic). The second category can then be further subdivided into "with obstruction" and "without obstruction".

Surgery and anesthesia impact hepatic function primarily due to their impact on hepatic blood flow and not primarily as a result of the medications or anesthetic technique utilized. Liver function tests have been used to diagnose pre-existing liver disease as well as in the evaluation of liver dysfunction that may become evident in the post-operative period.

PHYSIOLOGY
Proper management of anesthesia for patients with hepatic disease requires an understanding of the physiology of the liver. Here is a quick review of normal physiology:

The liver is primarily made up of hepatocytes (80% of the cells in the liver). These hepatocytes are the cells that are responsible for the complex functions of the liver which include:

• metabolism of carbohydrates
• metabolism of fats
• protein synthesis and metabolism
• drug metabolism and the synthesis and
• excretion of bilirubin.

In terms of carbohydrate metabolism, the main role of the liver is the storage of glycogen. Normally, about 75 grams of glycogen is found in the liver. This can be depleted by 24-48 hours of starvation. In the peri-operative period, poor nutrition or pre-existing liver disease may lower glycogen stores and leave the patient prone to hypoglycemia. This will require glucose-containing intravenous fluids in some situations.

In terms of fat metabolism, the liver functions in the beta oxidation of fatty acids and the formation of lipoproteins.

The liver serves to deaminate amino acids and to form urea for the removal of ammonia. However, a more important function of the liver is the synthesis of plasma proteins. All proteins, except gamma globulins and antihemophiliac factor, are produced in the liver. These proteins have importance in the binding of drugs, clotting and hydrolysis of ester-linked molecules.

Normally, 10-15 grams of albumin are produced daily which maintain normal albumin concentrations (3.5-5.5 g/dl). This production of albumin can be decreased with liver disease and, as a result of this, colloid osmotic pressure will be reduced. In addition, there will be fewer binding sites for drugs and the unbound, active portion of protein-bound drugs will be increased. One example of a drug that acts this way is Thiopental.

Important facts:

• Increased drug sensitivity is usually not clinically relevant until the albumin drops below 2.5 g/dl
• Acute liver dysfunction is unlikely to be associated with low levels of albumin since the elimination half-life of albumin is 14-21 days

The clotting factors V, VII, IX, X, prothrombin and fibrinogen are all dependent on the liver for synthesis. Clotting problems must be suspected in patients with liver disease. Since many of the factors require only 20-30% of normal levels to stop bleeding, significant impairment of liver function must occur before problems begin.

Important facts:

• Plasma half-lives of clotting factors are measured in hours. Therefore, acute liver dysfunction can lead to coagulopathies.
• Both severe parenchymal disease and biliary disease may lead to coagulopathy - the former due to impaired synthesis and the second by decreased vitamin K absorption due to the absence of bile salts secondary to biliary obstruction.

Pseudocholinesterase is also a protein which is made in the liver. Severe liver disease may result in levels low enough to prolong the action of succinylcholine. Since the half-life of pseudocholinesterase is 14 days, acute liver dysfunction is unlikely to cause this.

The liver also serves a function in drug metabolism. The microsomal enzymes convert lipid-soluble drugs to more water-soluble and less active products. This elimination is dependent on hepatic blood flow and the microsomal enzyme actvity. Drugs with high hepatic extraction ratios depend more on blood flow as their limiting factor whereas drugs with lower extraction ratios depend on the enzyme activity and protein binding.

Important facts:

• Chronic liver disease can lead to decreased metabolism due to decreased number of enzymes or to decreased blood flow (or obviously a combination of both).
• Cirrhosis may actually be associated with increased drug metabolism due to upregulation of enzyme activity (due to decreased number of hepatocytes exposed to drugs for metabolism).

LIVER FUNCTION TESTS
These can be used to diagnose and classify liver disease pre-operatively as well as in the workup of post-operative liver dysfunction. Liver function tests are rarely specific and considerable damage to the liver usually must occur before the tests are abnormal. Cirrhosis may actually lead to little change in liver function until additional insult requires reserves that do not exist.

Post-operatively, liver function tests may be increased by operations close to the liver. The specific anesthetic drug does not influence the magnitude of post-operative laboratory abnormalities.

Bilirubin
Normal plasma bilirubin is 0.3 to 1.1. mg/dl. Jaundice usually occurs once bilirubin exceeds 3 mg/dl. Unconjugated bilirubin (the protein bound portion or the indirect bilirubin) cannot be excreted by the kidneys whereas conjugated or direct bilirubin may appear in the urine.

Important facts:

• Unconjugated bilirubin may increase with hemolysis.
• Increased conjugated bilirubin reflects a problem with secretion either due to hepatocellular disease or biliary tract obstruction.
• There is little correlation between the severity of liver disease and the level of bilirubin.

Transaminases
These include aspartate aminotransferase (AST - formerly called SGOT), alanine aminotransferase (ALT - formerly called SGPT) which are enzymes contained in hepatocytes that can be released when these cells are damaged. Other tissues also contain transaminases and because of this the measurement of their levels in plasma is not specific for liver damage.

Alkaline Phosphatase
This enzyme is present in the cells of the bile duct and even slight obstruction will cause elevation of plasma levels. This test helps differentiate parenchymal hepatic disorders from those due to biliary obstruction. There are extrahepatic sources of this enzyme (notably bone) so it is not specific for hepatic disease.

Albumin
All albumin is made in the liver (see above) and liver disease will obviously lead to lower levels of albumin due to decreased production. Again, this decrease is a marker for more chronic problems since the plasma half-time for albumin is 14 to 21 days.

Go on to PART TWO of this three part article...