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

Read PART ONE of this three part article first...

INTRODUCTION
Hepatic dysfunction is most commonly suspected and subsequently diagnosed because the patient develops jaundice post-operatively. We'll review the general principles involved in working up this problem. Then we'll go on to address some specific disease states associated with the liver and biliary tract. Next week we will discuss anesthetic management of these patients.

GENERAL COMMENTS ABOUT POSTOPERATIVE HEPATIC DYSFUNCTION
In terms of differential diagnosis, the diseases of the liver can be broadly classified as intrahepatic (or parenchymal/hepatocellular) or extraheptic. The extrahepatic disorders can additionally be divided into pre- and post- hepatic (posthepatic problems are also called cholestatic). These categories can usually be distinguished by serial measurements of laboratory tests.

• Prehepatic refers to jaundice due to increased bilirubin loads (see below)
• Posthepatic refers to all causes of obstruction as well as cholestatic causes (for example, sepsis is a non-obstructive cause of cholestasis).

Most hepatic dysfunction is:

• Due to multiple factors
• Difficult to diagnose and
• Often requires no treatment.

What is known is that hypoxia of the hepatocytes is a common endpoint of many possible causes (hypotension, mechanical factors, etc.) and many times there is little or no relationship to the actual drugs or anesthetic technique utilized.

Other causes to be looked at include:

• All drugs administered (not just anesthetic agents)
• Possible developing sepsis
• Large bilirubin load (due to transfusion, hematomas, hemolysis, etc.)
• Hypoperfusion (due to hypotension, hypoxemia, hypovolemia, hypoventilation etc.)
• Extrahepatic causes (congestive heart failure, respiratory failure, pulmonary disease, renal disease)
• Benign cholestasis (see further discussion below)

SPECIFIC DISORDERS
This area includes acute hepatitis (viral and drug induced), chronic hepatitis (viral, drug and immune causes), cirrhosis and its associated problems, idiopathic hyperbilirubinemia and diseases of the biliary tract (cholecystitis, cholelithiasis, choledocholithiasis).

ACUTE HEPATITIS
Almost always associated with a viral infection or toxic drug. Rarely, pregnancy induced hepatitis can be seen. Other causes of an acute hepatitis include sepsis and congestive heart failure.

Most frequently, viral hepatitis is due to type A virus, type B virus, or type C virus (formerly known as non-A, non-B hepatitis). Less commonly, type D virus, Epstein Barr virus or cytomegalovirus may be implicated. Many cases of viral hepatitis are subclinical, do not result in jaundice and therefore are never recognized.

The specifics of each type of viral hepatitis and the epidemiology of each is beyond the scope of this lecture. There are distinctive modes of transmission, clinical courses, antibody testing methods and mortality rates for each. Testing for antigens and antibodies is utilized for definitive diagnosis. General common symptoms are variable but may include the following:

• Dark urine
• Fatigue
• Anorexia
• Vomting and dehydration
• Low grade fever
• May have enlarged/tender liver

Lab tests often show anemia and lymphocytosis. Aminotransferases will be elevated during the early phase of the infection (preceding jaundice). Treatment is symptomatic. Usually, clinical course lasts about 1-2 weeks and is relatively uneventful with liver function returning to normal after the infection resolves. Some patients do have persistent symptoms and hepatic coma. More severe disease is indicated by asterixis, peripheral edema or ascites.

DRUG INDUCED HEPATITIS
Many different classes of drugs can cause hepatitis that may be clinically and histologically indistinguishable from viral hepatitis. These include antibiotics, antihypertensives, anticonvulsants, analgesics, tranquilizers, etc. It also includes many anesthetics. Treatment in this case is recognition and discontinuation of the causative agent. In many, this will result in resolution of symptoms - but in some patients the problem may persist even once the drug is removed.

Anesthetic drugs have been shown to produce a pattern of centrilobular necrosis. The incidence is greatest with Halothane (as many of you already know) - but interestingly the next two drugs on the list of potential drug causes are fentanyl and nitrous oxide. The principal mechanism of this damage seems to be inadequate oxygenation of hepatocytes. Any anesthetic drug that decreases ventilation, hepatic blood flow, or both could theoretically cause hepatic damage. Pre-existing liver disease may predispose hepatocytes to this problem.

Halothane as a cause of hepatitis deserves some special discussion. There is a mild, self-limited form of hepatitis seen after halothane anesthesia that likely represents what is discussed above with regard to inadequate oxygenation of hepatocytes. This is not specifically a problem with hepatitis - as noted before, this can happen with any anesthetic drug or technique.

There is another, less frequent but much more severe form of hepatotoxicity seen after halothane hepatitis. It occurs in approximately 1 in 35,000 halothane administrations. It seems this form of halothane hepatotoxicity is likely an immune-mediated phenomena.

The things that suggest that this is an immune-mediated problem are eosinophilia, rash, fever, arthralgia and the history of prior exposure to halothane. Specific antibodies have been found in patients that react to liver antigens - ones that are induced by halothane administration. Apparently, these antigens are formed by covalent bonding between a metabolite of halothane and hepatic microsomal proteins. The substance in question is the oxidative trifluotoacetyl halide metabolite of halothane. In essence, this reaction changes the proteins from self (not antigenic) to non-self (antigenic). There is a possbile genetic predisposition to this type of liver injury.

This type of hepatitis is a diagnosis of exclusion unless specific antibodies can be demonstrated (difficult, expensive and not a routine test). Enflurane and isoflurane both exhibit oxidative halide metabolites as well and these metabolites seem to also be able to interact with the same microsomal proteins. Therefore, theory would suggest that these agents could induce a similar response as well as a cross-reactivity with each other. Since these agents are less metabolized than halothane, it is likely that the incidence of this is extremely low. However, patients who have received halothane in the past and developed these antibodies may be more susceptible to liver injury even with isoflurane and enflurane.

CHRONIC HEPATITIS
There are two types: chronic active hepatitis and chronic persistent hepatitis. Chronic hepatitis does not occur with hepatitis type A but is seen after acute hepatitis type B infections (1-10% of cases) and in patients with hepatitis type C infection. Chronic hepatitis can also be drug-induced (examples include methyldopa, aspirin, dantrolene) but usually resolves when the drug is stopped.

In some patients, there may be an autoimmune process occuring with circulating antibodies to antigens seen in liver membranes. Again, this may prove to have some genetic predisposition (similar to halothane hepatitis).

Chronic active hepatitis is the more serious form of the disease leading to death of hepatocytes, cirrhosis and hepatic failure. Chronic persistent hepatitis is a benign, nonprogressive disease involving inflammation of the portal area.

CIRRHOSIS
Cirrhosis can occur as a result of any chronic disease of the liver. It is characterized by scarring of the liver parenchyma. Many etiologies exist including:

• Excessive intake of alcohol (the most common cause)
• Postnecrotic due to chronic active hepatitis
• Primary Biliary Cirrhosis
• Hemochromatosis
• Wilson's Disease
• Alpha-1-antitrypsin Deficiency

Regardless of the cause, the result is the same - increased resistance to blood flow through the portal vein. This leads to a decrease in the percentage of blood flow coming from the portal vein and an increased dependence on hepatic artery flow to supply the oxygen needs of the liver. Decreased blood pressure during anesthesia and surgery can thus lead to decreased perfusion of the liver and these patients are at an increased risk of hepatic injury when compared to non-cirrhotic patients.

Other complications of cirrhosis include:

• Portal Hypertension
• Varices
• Ascites
• Hyperdynamic circulation
• Cardiomyopathy
• Anemia
• Coagulopathy
• Arterial hypoxemia
• Hypoglycemia
• Encephalopathy

We will discuss anesthetic management of patients with cirrhosis later in the lecture.

IDIOPATHIC HYPERBILIRUBINEMIA
This will not be discussed in detail. Causes of this include:

• Gilbert syndrome
• Crigler-Najjar syndrome
• Dubin-Johnson syndrome and
• Benign Postoperative Intrahepatic Cholestasis.

Suffice it to say that these represent defects in the conjugation steps (leading to unconjugated hyperbilirubinemia) ot defects in transport mechanisms (leading to conjugated hyperbilirubinemia).

The exception to this generalization is the Benign Postoperative Intrahepatic Cholestasis which may occur with prolonged surgery, especially if hypotension, hypoxemia or blood transfusions are involved. It is more common in the elderly. It seems to be a self-limited process and prognosis depends on the surgical and medical condition of the patient.

DISEASES OF THE BILIARY TRACT
Included here for completeness, this category of disease includes:

• Acute cholecystitis (almost always due to obstruction by gallstones)
• Chronic cholelithiasis and
• Choledocholithiasis.

Treatment of these diseases involve relief of obstruction by removal of the stones and/or cholecystectomy (open and laparoscopic). Management of anesthesia for cholecystectomy will be discussed later in the lecture.

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