Defects in Protein Synthesis

Two of the liver's cell types, the hepatocyte and the Kupffer cell, are responsible for synthesizing many kinds of proteins. The
hepatocyte synthesizes albumin and some immune globulins. The Kupffer cells, which line the hepatic sinusoids, and which
are a part of the socalled reticuloendothelial system, synthesize several kinds of immune globulins. Since the functions of
both of these kinds of cells can be impaired in either chronic diffuse liver disease or in severe acute liver disease, a
diminution of the levels of circulating albumin and of the immune globulins often appears in liver disease. Since impaired
amino acid metabolism may also be found in liver disease, protein synthesis may be doubly impaired because of a decreased
availability of amino acids and because of direct impairment of the synthetic processes themselves in the hepatocyte and in
the Kupffer cell.
Defects in protein synthesis are responsible for some of the more protean manifestations of severe diffuse chronic liver
disease and of severe acute liver disease. These will be discussed in later sections.

Defects in Carbohydrate Metabolism

The hepatocyte actively stores glucose by converting it to the longchain starch, glycogen. Glycogen can then be later broken
down to release glucose into the general circulation. The factors that control thisinsulin, epinephrine, growth hormone (STH),
glucagon and the thyroid hormonestend to counterbalance each other so that the hepatocytes store glycogen as the blood
sugar rises and break it back down into glucose as blood sugar level falls. Again, this is a critical function, an impairment of
which produces some of
the more serious manifestations of liver disease hyperglycemia and hypoglycemia. In fact, patients with severe liver disease
often have glucose tolerance curves very much like those seen in diabetes mellitus. That is to say, with food ingestion, they
tend to become hyperglycemic because the hepatocytes cannot store glycogen while, as dietary intake is decreased or
absent, the hepatocytes are not well able to mobilize glucose from what little stored glycogen there is, and so these patients
have episodes of hypoglycemia. This phenomenon is sometimes called "hepatic diabetes."

Defects in Lipid Metabolism

The liver has an extremely complex role in lipid metabolism, very little of which will be discussed here. In the diseased liver,
there are two prime manifestations of liver failure with regard to lipid metabolism. The first of these is the deposition of
triglycerides within the organ itself. This is the basic mechanism of socalled "fatty liver," which develops most often as a
result of chronic alcoholism. The second prime feature of disordered hepatic lipid metabolism is a diminution in the rate of
synthesis of cholesterol. In fact, a decrease below the normal level of serum cholesterol is often found in advanced diffuse
liver disease or in severe acute liver disease.
Mechanisms of Hepatic Failure in Acute Hepatitis
The basic problem in acute hepatitis is a widespread inflammatory reaction throughout the liver. This results in edema and
congestion, and these compromise hepatic function. Kupffer cell functions are impaired. Hepatocyte functions are impaired.
Formation and excretion of bile is impaired. In every case, all of the basic pathophysiologic mechanisms already discussed
become operative. In other words, every case of acute hepatitis represents acute hepatic failure with all of its attendant
interruptions of normal physiologic functions. The pathologic changes (tissue changes) that occur within the liver itself
include hepatocyte necrosis, hyperplasia of the Rupffer cells, and some microscopic anatomic changes. As the liver becomes
edematous and engorged, bile canaliculi become obstructed, and bile stasis develops. This undoubtedly contributes further to
degeneration of liver tissue.
Most of the basic pathophysiologic problems in infectious hepatitis are transitory. They disappear after the infection has
cleared and after hepatic anatomy returns to normal. In a more severe infection with extreme, widespread acute
inflammation and edema, there may be some residual impairment of hepatic function.

The Mechanisms of Cirrhosis

Over the years, the term "cirrhosis" has been used to label a wide variety of patterns of chronic diffuse parenchymal liver disease. The single common
denominator among all forms of "cirrhosis" is the presence of widespread microscopic, hepatic anatomic changes.
There are many causes of cirrhosis. Certainly the most common kind of chronic diffuse parenchymal liver disease is that seen in alcoholism. This form of
cirrhosis, which is also called alcoholic cirrhosis, portal cirrhosis, fatty cirrhosis and Laennec's cirrhosis, is believed to be primarily the result of ethanol's
direct effect on normal hepatocyte lipid metabolism. The presence of ethanol in the hepatocyte impairs the usual lipid metabolic pathways within the
hepatocyte and results in the deposition of fat throughout the organ. There is also scattered fine scarring that follows patchy necrosis; this results in diffuse
hepatic fibrosis. Histologically, the pattern of cirrhosis found by liver biopsy in patients with a history of alcoholism is quite variable. In some cases there may
be a great deal of fatty change and very little fibrosis; in others, there may be very little fatty change and a great deal of fibrosis. Since fibrosis is the result of
parenchymal necrosis, there must be the necessary antecedent necrosis and, this, too, is also often found by biopsy.
Alcohol probably accounts for ninetyfive percent of all cirrhosis. The remaining small percentage of cases develop from various metabolic abnormalities.
Socalled "biliary cirrhosis," which occurs almost exclusively in middleaged women, for example, is believed to be produced by an autoimmune abnormality
that results in necrosis of bile ducts. This leads to bile stasis which, in turn, leads to further necrotic changes, further duct damage, further bile stasis, and so
on. This same vicious cycle may develop in a person who suffers a severe episode of acute infectious hepatitis that produces widespread scarring and
obstructive ductal changes.
All forms of cirrhosis tend to be progressive. This should not be taken as an iron rule, however, lest the clinician be tempted to pass a sentence of hepatic
doom on every patient with alcoholic liver disease, a history of hepatitis, or primary or secondary biliary cirrhosis.
Since any kind of cirrhosis involves widespread diffuse parenchymal disease, there is usually some impairment of every kind of hepatic function. Again, this
should not be taken as an unchallengable axiom because, as can be demonstrated by biopsy, the actual pattern of histologic changes is quite variable.
Nevertheless, there does tend to be impairment of many kinds of hepatic function, including impaired amino acid metabolism, impaired storage and release of
glycogen, impaired lipid metabolism, some impairment of formation of coagulation factors, and some impairment of the liver's ability to modify and excrete
toxic substances (including drugs).
One should bear in mind that most patients with acute infectious hepatitis do not slip into this cyclic pattern of hepatic damage, bile stasis, further damage and
selfperpetuating, progressive, cirrhotic changes. This pattern is seen most often in patients with noninfectious diffuse liver disease, most often alcoholinduced
Laennec's cirrhosis.

Jaundice and Bilirubin

Bilirubin, a yellow pigment, is one of several products of hemoglobin breakdown. Since hemoglobin synthesis and breakdown are continuous processes,
small amounts of bilirubin (and other products of hemoglobin breakdown) are released into the general circulation continuously. Many kinds of cells can,
given enough time, modify bilirubin chemically so that it can be excreted. The hepatocyte, though, is the prime bilirubin processor, and so hepatocyte
impairment results in disordered bilirubin metabolism.
In its original form, bilirubin is fatsoluble, not watersoluble. A hepatocyte enzyme, glucuronyl transferase, modifies bilirubin as it arrives at the liver, and
converts it to a watersoluble compound. This process is called bilirubin conjugation because one of the steps involved is the attachment of bilirubin to another
molecule. The conjugated bilirubin is then excreted into the bile and is released into the gut. Impairment of any of these steps results in distribution of
bilirubinunconjugated, conjugated, or boththroughout the body. The unconjugated bilirubin, which is fatsoluble, accumulates in fatty tissues, most notably the
skin, where the presence of this yellow pigment produces jaundice. If exeretion of watersoluble, conjugated bilirubin is impaired, jaundice may also occur.
Most bilirubin is produced by RBC breakdown in the spleen. Some, about 1520X of the total, is produced by destruction of RBC precursors in the marrow.
Jaundice indicates one of four problems:
1. increased RBC breakdown
2. failure of hepatocyte conjugation
3. failure of hepatocyte excretion of conjugated bilirubin into the bile canaliculi
4. extrahepatic obstruction
In liver disease, problems 2 and 3 usually occur together.