MODULE 2 Diseases and Malfunctions


Liver, liver woe is me
Gross hepatomegaly
Pain just north of my umbilicus
My yellow face is so ridiculous
Upon my back and on my chest
Those spider angiomas nest
My serum G.O.T. is raised
And so's my alkaline phosphatase
So set 'em up  don't make a sound 
We've still got time for one more round.
Camp '76

On completion of this minicourse you will be able to:


OBJ. 1. Distinguish pathophysiological structure and function associated with:

a. hepatitis (acute viral)

b. chronic liver damage (cirrhosis)

Basic Pathophysiology of Liver Disease

The basic pathophysiology of all forms of liver disease represents failures of the numerous and complex hepatic metabolic functions. Although there is some variability in basic pathophysiology from one type of liver disease to another, all forms of liver disease can reasonably be called hepatic failure. The signs and symptoms, the natural history, and the rationale of treatment for all forms of liver disease derives from certain relatively simple basic pathophysiologic concepts.

It should be made clear at the outset that jaundice, an obvious physical sign, sometimes represents problems other than liver disease and is by no means synonymous with it. There are other, far more important and more complex metabolic problems associated with liver disease so that the problem of jaundice will be dealt with only briefly in this minicourse. The liver plays several complex roles in amino acid metabolism, protein synthesis, carbohydrate metabolism and lipid metabolism. It is also the site of manufacture of a number of blood coagulation proteins.

The basic derangements of hepatic failure will be discussed first. These will then be applied to the most common forms of liver disease, acute hepatitis and cirrhosis.

Defects in Amino Acid Metabolism

The liver is the most important single organ involved in amino acid metabolism. Amino acids are delivered to the liver either from the gut or from the general circulation. In the liver there are two major processes in the metabolism of amino acids: oxydative deamination and transamination.

Oxydative deaminiation is a process by which the amino radical is removed from the amino acid thus converting it into two products: a keto acid and ammonia.

The ammonia from these deamination reactions is transformed, in the liver, to urea by combination with CO2.

Since oxydative deamination results in the production of ammonia, any impairment of the above function results in a diminution of the blood urea nitrogen level (BUN) and an increase in the amount of circulating ammonia. Elevated serum ammonia levels can become extremely toxic, especially to the brain, often leading to a state called hepatic coma.

The ketoacid produced by deamination (Reaction 1) can follow several metabolic pathways:

Amino acid metabolism is controlled primarily by the hepatocyte, one of the three types of cells in the liver. In widespread, advanced hepatic parenchymal disease, or in severe acute hepatic failure, as can happen in severe acute hepatitis of any form, this particular hepatocyte failure results in a severe derangement of amino acid metabolism and thus of ammonia and urea levels.

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.

Impaired Production of Clotting Factors

Fibrinogen, prothrombin, Factors V, VII, and X are all produced in the liver, and impairment of their production leads to coagulation defects. In fact, production of clotting factors is so exquisitely affected in liver disease that the measurement of prothrombin time is a very sensitive indicator of the progress of acute hepatitis. For example, in the patient profoundly ill with severe acute hepatitis with a circulating bilirubin level 20 times normal, measurement of the bilirubin and observation of jaundice become far less reliable indicators than the prothrombin time. This is discussed later in this minicourse.

Impairment of Detoxification Functions

The liver is responsible for detoxifying, by chemical modification, many substances that enter it. This includes substances drained from the gut, many kinds of drugs, and circulating hormones. Some substances are converted to water soluble salts or esters and are excreted in the bile. Others are chemically modified and released into the general circulation for renal excretion. Sometimes, toxic substances are modified, released into the bile, excreted into the gut, reabsorbed from the gut in their modified form, and later find their way to the kidneys for renal excretion.

The two classic examples of the liver's role in detoxification are the effect of phenobarbital on the liver and estrogen degradation by the liver. It has been observed that the chronic ingestion of phenobarbital results in an increase in the amount of hepatocytic endoplasmic reticulum, presumably indicating a response to the presence of a toxic substance. Estrogen degradation, or lack of it, is best demonstrated in the alcoholic male who, unable to modify and excrete his circulating estrogens, develops gynecomastia,

telangiectasis (e.g. spider angiomata) and other signs of feminization.

Alcohol is not the only drug that is toxic to the liver. Many kinds of drugs in wide use are hepatotoxic and, since these hepatotoxic drugs may have to be degraded for excretion by an already diseased liver, their use in advanced or in severe acute liver disease must be approached with caution. The list of drugs that require caution for this reason is enormous.

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:

In liver disease, problems 2 and 3 usually occur together.

Portal Hypertension

As widespread, diffuse parenchymal liver disease progresses, there is loss of the hepatic vascular bed and an increase in fibrotic tissue scattered throughout the organ. If these anatomic changes progress beyond a certain point, there is, eventually, definite impairment of blood flow through the liver. Since the liver receives twothirds of its blood supply from the hepatic portal vein and onethird from the hepatic artery, circulatory impairment through the liver results primarily in an increase in venous pressure in the portal drainage system. This direct increase in hydrostatic pressure in the portal system, which drains the entire G.I. tract, results in an increase in hydrostatic pressure in all of the G.I. tract's venous drainage system. This increase in pressure is called portal hypertension. If venous pressure in the gut drainage system is raised high enough, hydrostatic pressure overcomes intravascular osmotic pressure and fluid begins to seep out of the gut capillary bed and into the peritoneal space (ascites). At the same time, the G.I. tract itself, because of impaired venous drainage, becomes somewhat edematous, and this results in impairment of gastrointestinal function. That is the basis for the nonhepatic gastrointestinal signs and symptoms that develop in advanced cirrhosis. The amount of fluid that accumulates in the peritoneal space may be enormous.

Because there is impairment of venous drainage in advanced cirrhosis, there is a natural tendency for venous drainage from the G.I. tract to flow through alternate channels. The most conspicuous of these in advanced liver disease is the umbilical venous system which connects the portal system with the systemic circulation. An increase in pressure in the umbilical veins results in the dilation of veins on the abdominal wall, producing the socalled "caput medusae" sometimes seen in faradvanced cirrhosis.

An increase in portal venous pressure also results in two common problems that are a direct result of portal hypertension. One of these is hemorrhoids, which are actually varices of the hemorrhoidal veins. Hemorrhoids certainly develop often in patients who do not have cirrhosis but they are also a rather common finding in patients who do. Similarly, esophageal varices develop in these patientsand for the same reason. Both of these phenomena are a direct result of increased portal venous pressure. Hemorrhoids tend to be more of a nuisance than a threat, but esophageal varices, which can, and often do hemorrhage massively, can be lifethreatening. These problems are discussed

in more detail in later sections of this minicourse.


All of the basic pathophysiologic mechanisms of both infectious hepatitis and cirrhosis can be classed in two major categories: those that are the result of impairment of hepatocellular and Kupffer cell functions, and those that derive from impairment of hepatic circulation in advanced cirrhosis.


OBJECTIVE 1 Questions

1. Why is the liver sometimes called the "metabolic factory"?

2. How do you explain a decrease in BUN and an increase in serum ammonia level in severe acute liver disease or in advanced cirrhosis?

3. What do the Kupffer cells do?

4. Where is albumin produced?

5. Why do people with liver disease have episodes of hypoglycemia and hyperglycemia?

6. How do you explain the deposition of triglycerides in fatty liver?

7. List three broad categories of hepatic detoxification activity.

  1. .
  2. .
  3. .

8. Hepatic failure develops to some degree in every case of acute hepatitis.

9. What is the cause of most cases of cirrhosis?

10. What is cirrhosis?

11. Cirrhosis tends to be progressive. Why?

12. List the four problems that may produce jaundice.

13. What is portal hypertension? Why does it occur in cirrhosis?

OBJECTIVE 1 Answers to Section 2.2.3 Questions

1. The terms "metabolic factory" and "enzyme factory" were not used in the text, but the reason for their common use is obvious: the liver has many complex roles in amino acid and protein metabolism, carbohydrate metabolism, lipid metabolism and detoxification.

2. Hepatocytes convert ammonia to urea. If this function is impaired, ammonia levels rise and urea levels fall hence, BUN levels fall.

3. The Kupffer cells are the greatest producers of immunoglobulins.

4. Albumin is produced only by the hepatocytes.

5. The hepatocytes convert arriving glucose to the starch glycogen. Glycogen is then broken back down into glucose as needed. When storage is impaired, hyperglycemia occurs; when breakdown is impaired, hypoglycemia occurs. In severe acute liver disease, or in advanced cirrhosis, both occur.

6. By some unknown mechanism, the presence of ethanol in the hepatocytes directly fouls hepatocyte lipid metabolism and results in excess production of triglycerides, which then accumulate in the liver.

7. Important detoxification mechanisms:

1. drug modification

2. hormone modification

3. modification of toxins arising from the gut

8. The viruses of acute hepatitis produce a widespread inflammatory reaction in the liver. This interferes with many hepatocyte functions. The inflammatory reaction also produces edema, which further fouls many liver functions.

9. Alcohol.

10. Cirrhosis is a loosely used word that describes many patterns of progressive, widespread, anatomic change in the liver. The most common form is Laennec's cirrhosis. In all forms of cirrhosis, there is replacement of normal hepatic microanatomy, usually some fatty change, and, usually, some degree of diffuse fibrosis.

11. Most drinkers continue to drink. In addition, though, one must remember that once hepatic microanatomy is widely deranged, mild bile stasis (cholestasis) tends to produce further changes.

12. The four basic reasons for jaundice:

1. excess RBC breakdown

2. impaired hepatocyte conjugation of bilirubin

3. impaired hepatocyte excretion of bilirubin

4. extrahepatic obstruction

13. Portal hypertension is an increase in venous pressure in the gut drainage bed. This occurs in cirrhosis because widespread changes in hepatic microanatomy, and particularly diffuse fibrosis, impair blood flow through the liver.



OBJ. 2. List the signs, symptoms, causes and natural history of:

Liver Disease - Prime Clinical Features

Acute Viral Hepatitis

Acute viral hepatitis is a systemic infection which affects the liver. Two viruses have been identified (A and B). The third type is referred to as non A, non B. Hepatitis A has also been referred to as infectious hepatitis, short-incubation hepatitis and MS-1 hepatitis. Hepatitis B has been referred to as serum hepatitis, long- incubation hepatitis, MS-2 hepatitis, or hepatitis B surface antigen (HBsAg) positive hepatitis.

It is recognized that a distinction between hepatitis A and B cannot be made solely by clinical features or by epidemiologic features because ways of transmission overlap. The distinction must be made by specific serologic testing. The table on page 238 summarizes the differences.

Because it is not possible to separate these entities on the basis of history and physical examination, they will be considered together here in that regard. All, in fact, can be so mild that they appear in the anicteric form--that is, without jaundice.

Hepatitis compromises hepatic function. With hepatic function impaired, hepatocyte formation and excretion of bile are also impaired. Since bile salts are necessary for the degradation of foodstuffs in the gut, particularly of fatty foodstuffs, obvious gastrointestinal signs and symptoms are likely to develop early. In fact, all signs and symptoms of hepatitis fall broadly into three categories:

  1. 1. gastrointestinal symptoms produced by impairment of bile flow
  2. 2. signs and symptoms referable to the liver itself, such as enlargement and tenderness
  3. 3. those signs and symptoms that develop from disruption of hepatic functions that affect the whole body, such as jaundice, evidence of coagulation defects, and weight loss
Comparisons of Type A, Type B. And non-A, non-B Hepatitis
                          Hepatitis A                   Hepatitis B
                          Infectious,	                Serum, Long
		       Short Incubation	                Incubation

Feature	               Hepatitis                        Hepatitis               Non-A, Non-B Hepatitis

Incubation period	15-45 days	                45-160 days             15-160 days

Onset                   Acute                           Often subtle            Subtle or insidious

Seasonal variation   Most common, fall, winter	        Year round              Year round

Age of patient        Children, young adults		Any age                More common in adults
most affected

Route of Transmission:

   Fecal/oral           + + +                            + / +                       Unknown

   Percutaneous         + / -                            + + +                        + + +

   Other nonpercutaneous + / -                            + +                          + +

Severity                Mild                           Often severe                 Moderate

Prognosis               Good                           Worse with age               Moderate

Chronicity              None                           Occasional                   Occasional

Immune serum globulin

  (ISG) prophylaxis     Good                            Partial                       ?

Hepatitis B immune globulin

   (very high titer anti-HBs) (N/A)                    Good after                   (N/A)
   prophylaxis                                         needle stick

Carrier state         Rare, if ever                    0.1 - 1.0%                   Present but prevalence

	*For example, sexual or maternal-fetal contact

The clinical course of acute viral hepatitis has three major phases: the pre-icteric stage, the icteric stage, and the recovery stage. The signs and symptoms tend to vary considerably from one stage to the next. The first symptoms that appear in the preicteric phase are vague constitutional symptoms and, usually, symptoms directly referable to the G.I. tract. Thus, this infectious disease is heralded by fatigue, malaise, and anorexia. There may be fever of 100 to 104 and, with hepatitis A, there may be upper respiratory symptoms, which are unusual in hepatitis B. During the course of the first week or so, the patient's anorexia is likely to become nausea, possibly with vomiting and diarrhea. During the pre-icteric stage, a mild polyarthritis may develop. In other words, during the pre- icteric stage both hepatitis A and B may resemble a "flu-like" illness. At this stage of the disease, the clinician who associates liver disease with jaundice, or who does not examine abdomens, may be misled. Hepatitis B is more likely than hepatitis A to be somewhat insidious in onset, and may not present with the sequential symptomatology just described. In fact, some patients with hepatitis B do not present clinically until they have developed some degree of jaundice. Even these patients, though, usually give a history of a mild flu-like illness during the preceding days. Subclinical hepatitis may occur with lack of jaundice or fatigue. Mild elevations in liver enzymes or screening for hepatitis surface antigens (done frequently in hospital employee physicals) may inadvertently be found during routine testing.

During the pre-icteric stage of the disease, there may be no findings on physical examination except slight fever, right upper quadrant tenderness, and splenomegaly (occasionally).

Jaundice develops in hepatitis because the widespread hepatic parenchymal inflammation and edema interfere with bilirubin conjugation and with bile excretion. Most patients who contract infectious hepatitis do develop jaundice. Hepatitis in children is more apt to be anicteric. During the icteric phase, gastrointestinal symptoms tend to subside. A mild to moderate anorexia, though, may persist and may be a fairly substantial management problem. Many patients will observe that their urine has become dark, due to renal excretion of excess conjugated bilirubin.

There is invariably hepatic enlargement and right upper quadrant abdominal tenderness in the icteric phase. Also, during this phase of the illness, splenomegaly and posterior cervical lymphadenopathy appear in about one-fifth of the cases. Fever usually subsides when jaundice appears, and the persistence of fever into the icteric stage of the illness suggests the possibility of problems other than acute infectious viral hepatitis. It is usually at about this point that the famous clay-colored (acholic) stools appear. This color is produced by lack of bile pigments.

Jaundice usually progresses slowly over two to four days, peaks, and then subsides slowly, usually over a span of about two weeks. A three-week subsidence, however, is not unusual. Since the clearing of jaundice represents a return toward normal hepatic function, the patient usually feels generally well by the time jaundice has cleared. Generalized weakness, however, persists for two to six weeks after clearing of jaundice. Also, the liver returns only slowly to a normal size and so hepatic enlargement may still be evident throughout this recovery phase. Except in truly severe

cases, with massive liver damage, there is usually no permanent impairment of liver function and so almost all patients feel quite well and have no demonstrable biochemical abnormality after about three to four months.


Much has already been said about the cause and clinical course of cirrhosis. Although the basic pathophysiology of cirrhosis is straight-forward, the signs and symptoms are not. Many of the physical signs encountered in cirrhosis are difficult to describe and must be seen to be appreciated. Some are poorly understood. With regard to symptoms in cirrhosis, it is fair to say that, except in far-advanced disease, there are no symptoms directly attributable to the hepatic dysfunction present. The reason for this is that very little normal hepatic function is required for successful carrying- on of everyday activities. The normal liver, in fact, is at least four times as competent as needed for survival. This has been demonstrated repeatedly in those patients in whom it has been necessary, most often because of tumor, to remove large portions of the liver surgically. Thus, the development of signs and symptoms in the patient with cirrhosis indicates, by definition, far-advanced disease and severe compromise of hepatic function. Physical signs will be discussed first, then symptoms.

The physical evidences of cirrhosis fall broadly into these categories:

As cirrhosis progresses, and as fatty infiltration continues, there is a tendency for the liver to enlarge. This may continue slowly and steadily for many years. Because there is persistent necrosis, there is a steady accumulation of fibrous scar tissue within the organ, and so, as the organ enlarges, it tends to become firmer than normal. Eventually, necrosis and fibrosis supersede fatty enlargement, and the liver begins to shrink under the influence of fibrotic retraction. The post-necrotic liver (also known as post-cirrhotic liver) may shrink to about one-half the normal size. As the organ enlarges, its borders can usually be easily percussed and, by percussion, the lower border is often found to be a hand's breadth or more below the right costal margin. Later, as the organ begins to shrink under the influence of fibrotic retraction, its lower border may be three to four centimeters above the right costal margin (the lower liver edge is normally one to two centimeters above the right costal margin).

During the period of enlargement the lower border may also become palpable, and is usually firmer than normal. As diffuse interstitial fibrosis progresses, the liver edge is often felt to be much firmer than normal and may become quite hard. If fibrotic retraction shrinks the organ to such an extent that the lower border is far above the right costal margin, then the edge is no longer palpable.

There is little correlation between changes in size and consistency, and the degree of physiologic insult that produces the cirrhosis. A young adult alcoholic, for example, can, by heavy and persistent drinking, easily double his liver size in the span of a year or less and, if the alcohol insult is carried on long enough and at a great enough level, that same liver could easily be smaller than normal a year later, and the patient could easily be on the verge of death from acute hepatic failure. On the other hand, a more moderate brand of alcoholism or a mild degree of chronic biliary obstruction may produce significant cirrhotic changes only after many years, and post-cirrhotic retraction may never occur. Thus, there are really only two safe rules of thumb with regard to liver size and consistency: 1) hepatic enlargement strongly suggests ongoing pathologic processes, and 2) a liver size definitely less than normal strongly suggests late pathologic changes. (The normal liver span from top to bottom on the midclavicular line is 8 to 10 centimeters.)

Portal hypertension, a serious consequence of advanced liver disease, often exists for years before evidence of its presence is observed. The usual evidence of portal hypertension, ascites, the caput medusae and hemorrhoids, are late findings that develop after the gastrointestinal vasculature is no longer able to compensate for the persistent increase in venous pressure. On physical examination, the presence of ascites can be demonstrated only by techniques that identify bilateral flank dullness and shifting dullness or demonstrate a fluid wave in the abdomen.

If hepatic production of plasma proteins is impaired, the level of circulating plasma proteins drops, their osmotic effect is lost, and intravascular water begins to escape into interstitial spaces. This tends to be most marked in the dependent portions of the body, as one would expect, and in the abdomen, where portal hypertension exaggerates the process. The resultant edema is usually slight to moderate but can be profound.

Patients with advanced cirrhosis tend to have evidence of multiple vitamin deficiencies. The vast majority of these patients are alcoholics, many of whom have grossly inadequate diets, with a large percentage of caloric needs supplied by alcohol rather than by other foodstuffs. Folic acid and B12 deficiencies produce peripheral neuropathies and anemia and these can be easily demonstrated in most patients with advanced liver disease. Vitamin A deficiency produces visual impairment, vitamin D deficiency produces abnormal calcium metabolism, and vitamin K deficiency produces the expected impairment of blood coagulation. Since the vitamin K deficiency is likely to be superimposed on an impaired ability to synthesize coagulation proteins, the tendency toward bleeding disorders is strong, and some of these patients may have physical evidences of this, including petechiae, ecchymoses and pallor.

Jaundice in a patient with advanced, diffuse, parenchymal disease is an ominous sign. In these patients, the development of jaundice frequently heralds the arrival of terminal hepatic failure. Jaundice is discussed separately at the end of this section.

Evidence of impairment of degradation abilities is manifested primarily by the signs of inability to degrade certain circulating hormones. In the male, the inability to degrade circulating estrogens results in some degree of feminization with the development of gynecomastia, testicular atrophy and alteration of hair distribution. In the female, inability to degrade circulating androgens produces some degree of masculinization and may also produce amenorrhea. Since they may also have diminished circulating plasma proteins, this secondary hyperaldosteronism may simply contribute to the further development of the edema state. Since these patients may not be able to chemically modify and excrete many kinds of drugs adequately, they may have an exaggerated and prolonged response to many drugs.

There are a number of other physical signs associated with advanced cirrhosis. The mechanisms by which some of these are produced are not well understood. The two most famous phenomena of advanced cirrhosis are the so-called spider angioma and palmar erythema. A spider angioma is classically, as its name implies, a spider-shaped superficial spoke-like series of very small arterioles radiating from a central slightly larger arteriole. One can compress the central arteriole with the tip of a pencil and thus blanche the spokes of the wheel. Spiders range in size from one to three centimeters. Often, one sees many variations of the so-called spider, very few of which actually have the classical spoked wheel configuration. Spiders occur most often on the upper chest and upper back, sometimes on the face. Palmar erythema is most often observed at the thenar and hypothenar eminences and across the volar aspect of the MP joints. Both of these peripheral vascular phenomena are believed to be related to increased levels of circulating estrogens.

The Problem of Jaundice

As an indicator of liver disease, jaundice is overrated. Jaundice (French-yellowness) indicates the deposition of bilirubin in skin and mucous membranes. Normally, all bilirubin is conjugated in the liver and excreted in the bile. There are four basic mechanisms by which jaundice develops:

In acute viral hepatitis, direct and indirect (that is, conjugated and unconjugated) bilirubin levels tend to rise together, then to fall back toward normal together. In severe cases, where serum bilirubin concentrations may rise to 20-30 times normal, large amounts of bilirubin are deposited in the skin and mucous membranes, and their presence in the skin may produce fairly severe itching. The itching tends to resolve only slowly, usually more slowly than does the apparent jaundice.

Jaundice is not a common feature of cirrhosis. In fact, the development of jaundice in a patient with far-advanced cirrhotic liver disease may herald the development of terminal hepatic failure.

A review of the four mechanisms of jaundice above suggests that there are many ways for jaundice to develop besides the acquisition of viral hepatitis or the end stage of cirrhotic liver disease. From a clinical point of view, probably the two most other important mechanisms are surgical jaundice and jaundice produced by massive hemolytic reaction.

Surgical jaundice is the name given to jaundice that develops in the absence of all other signs and symptoms in a patient in whom there is no reason to suspect infectious hepatitis and in whom it is observed that the bulk of the jaundice is produced by conjugated bilirubin rather than unconjugated bilirubin. This means of jaundice production suggests the presence of extra-hepatic obstruction. Most extra-hepatic obstructions are relatively benign. A stone in the common duct, for example, can produce surgical jaundice. Certain serious problems, such as carcinoma of the head of the pancreas, also frequently produce obstruction to bile flow from common duct compression. The name surgical jaundice is applied in these situations because, often, laparotomy is required for a definitive diagnosis.

Symptoms in Cirrhosis

Patients with various kinds of cirrhosis tend to have many kinds of symptoms simultaneously. Most of them are not directly referable to the liver and suggest extensive multisystem disease. The alcoholic, for example, with advanced portal cirrhosis is very likely to have the symptoms of a peripheral neuropathy, such as numbness and tingling (paraesthesia) as well as impairment of the sense of touch and of the vibratory sense, usually in all four extremities but more often in the feet and hands.

Patients with biliary cirrhosis are most likely to present with generalized, intractable pruritus. Although there are not many definitive signs and symptoms, pale-colored stools, dark urine, Uterus and melanosis of exposed skin frequently accompany pruritus of biliary cirrhosis. Signs of early liver failure are few. Although pruritus may be the only symptom, xanthalasmas, xanthomas, hepatomegaly, splenomegaly and clubbing of the finger may be noted.

These patients also frequently have variable gastrointestinal complaints that include periods of nausea, vomiting and diarrhea. It is usually quite difficult to separate the direct effect of heavy drinking from the indirect effects of chronic liver disease. Obviously the patient with severe compromise of liver function and a frank edematous state with ascites is likely to have the discomfort of a constantly bloated, distended abdomen as well as the obvious discomfort associated with the swelling of the feet and legs.

Signs and Symptoms in Severe Hepatic Failure

Severe, acute, life-threatening hepatic failure produces many complex and bizarre alterations of metabolic functions. Patients may develop an elevated serum ammonia level because of a disordered amino acid and urea metabolism, and the elevated serum ammonia level may produce, by the way of cerebral toxicity, profound alterations in the state of consciousness. In these patients, jaundice may be profound and total serum bilirubin may rise to 30 times normal. By way of a poorly understood hepato-renal physiologic link, renal failure may be superimposed and, consequently, there may be severe disorders of fluid and electrolyte balance. This is known as the "hepato-renal syndrome," (much more common in alcoholic hepititis and uncommon in infectious hepititis). It is in these patients that the most extreme forms of hepatic diabetes are seen, and so very careful external control of blood sugar levels becomes necessary.

Hyperglycemia and Hypoglycemia in Cirrhosis

Patients who have widespread parenchymal disease, and who have impairment of glycogen storage and release, often have episodes of hyperglycemia and of hypoglycemia. Transitory episodes of hyperglycemia tend not to produce symptoms but, rather, episodes of hypoglycemia. These episodes are most likely to happen during the early morning hours after overnight fasting, when blood sugar level may drop to about 50 mg. They produce drowsiness and shaking chills accompanied by frank hunger.


OBJECTIVE 2 Questions


OBJECTIVE 2 Answers to questions in section 2.3.2


OBJ. 3. Describe laboratory procedures and data which are useful in the diagnosis of the entities listed in Objective l.

Laboratory Evaluation of Liver Disease _ _


Adequate laboratory evaluation of liver disease is really evaluation of the liver's many complex metabolic functions. Since there is a great deal more involved than bilirubin, and since hyperbilirubinemia is usually made obvious by jaundice, other problems will be considered first - and bilirubin last.

There are many similarities between the hepatic biochemical changes of acute hepatitis and those of chronic liver disease, as in cirrhosis. In fact, the patient with prolonged, severe acute hepatitis is very likely to have essentially the same hepatic biochemical changes as the patient with far-advanced chronic parenchymal disease. Since either of these two problems may require extensive laboratory determination of hepatic status, the basic principles will be discussed first, and these will then be applied to acute hepatitis and then to cirrhosis.

Tests of Enzymatic Functions

There are five major kinds of hepatic enzymes that can be measured indirectly by measuring their level in the circulating blood. Some of these enzymes are released from tissues other than the liver. As a rule, increased levels of all five of these enzymes are found in the circulating blood in acute inflammatory liver disease (e.g. acute hepatitis), but this picture is quite variable. These levels are increased because hepatocellular damage results in leakage of these normally intracellular enzymes, which are then absorbed into the venous drainage of the liver. The five enzymes most useful in evaluation of liver disease are these:

  1. SGOT - Serum Glutamic Oxaloacetic Transaminase (also called Serum Aspartate Aminotransferase - AST)
  2. SGPT - Serum Glutamic Pyruvic Transaminase (also called Serum Alanine Aminotransferase - ALT)
  3. LDH - Lactic Acid Dehydrogenase
  4. Alkaline Phosphatase
  5. 5' Nucleotidase

    SGOT, LDH, and Alkaline Phosphatase are liberated by a number of kinds of tissues, and the levels of these enzymes rise when any of these tissues are injured. Alkaline phosphatase is also associated with osteoblastic activity as well as with tissue damage. Thus, a rise in the levels of these enzymes occurs in a number of kinds of tissue injury. For example, the levels of SGOT and LDH usually rise after myocardial infarction.

    lsoenzyme analysis is availaba e to identify particular types of LDH and alkaline phosphatase but is not available for SGOT. SGOT is the enzyme most often and most strikingly elevated in liver disease, but since it can derive from sources other than liver tissue, this enzyme's chemical relative, SGPT, which is found almost exclusively in liver tissue, is usually measured to help confirm the source of an SGOT elevation.

    There are two isoenzymes of alkaline phosphatase. One of these originates primarily in the liver, and the other primarily in bone. The isoenzyme originating in liver tissue is heat labile, and the isoenzyme originating in the bone is heat stable. Although the distinction between heat-stable and heat-labile isoenzymes can be determined easily, the differentiation yields only suggestive data. For that reason, the origin of an observed alkaline phosphatase elevation in circulating blood is always unsure. Another enzyme, the level of which tends to rise and fall with that of alkaline phosphatase of hepatic origin, is 5' nucleotidase. This enzyme is derived almost exclusively from liver tissue, and so elevations in 5' nucleotidase are the surest, most specific indicators of the hepatic origin of other enzyme elevations. (Measurement of 5' nucleotidase is now available at most major laboratories.)

    Since elevations of the circulating levels of the enzymes mentioned above tend to occur with acute liver cell injury, measurements of them are far more useful in acute hepatitis than in cirrhosis.

    The levels of these enzymes are quantified according to a number of different scales. For that reason, the clinician must know the name of the scale being used to report the level of the particular enzyme, and must know the norms for the laboratory in which the analyses are done.

    Four of the enzymes mentioned above, SGOT, SGPT, LDH and alkaline phosphatase, are involved in protein metabolism. However, they are measured primarily to evaluate the degree of active liver injury. They are not used as measures of the liver's abilities in protein metabolic and anabolic functions. Those functions can be measured much more directly by a simple determination of the plasma albumin and immunoglobulin levels and by measurement of the blood urea nitrogen level (BUN) and, in some cases, bv measurement of the serum ammonia level.

    Albumin, the most prominent single circulating plasma protein, is produced entirely by the hepatocyte. The immunoglobulins, with the exception of the gammaglobulins, are produced almost exclusively by the Kupffer cells lining the hepatic sinusoids. (Gammaglobulin is produced elsewhere in the reticulo-endothelial system, primarily in the spleen and in bone marrow.)

    Obviously, severe impairment of hepatocyte function is likely to reduce the level of albumin in the plasma. Similarly, Kupffer cell impairment is likely to reduce that cell type's output of the immunoglobulins. If one type of impairment occurs to a greater extent than does the other, the ratio between albumin and globulins in the circulating blood is shifted from normal. This is called a "shift in the A/G ratio."

    Albumin and the immunoglobulins have long half-lives. This means that impairment of albumin and immunoglobulin production does not result in an immediate drop in the circulating levels of these proteins.

    Since severe liver disease may result in impairment of the organ's ability to convert ammonia to urea, the blood urea nitrogen level (BUN) may fall. This can be seen in either severe acute hepatitis or in far-advanced cirrhotic parenchymal disease. Similarly, as the level of BUN drops, the free ammonia level in the blood rises, and this can be measured directly. A rising ammonia level interferes with central nervous system function and is believed to be responsible for the more protean (means "readily assuming different shapes or roles") manifestations of acute hepatic failure with hepatic coma. With severe derangement of hepatocyte protein metabolism, the level of free amino acids in the blood also rises, and this can be measured directly. If the level of circulating amino acids rises beyond a specific threshold, the excess is lost in the urine; this is called aminoaciduria, and the level of amino acids in the urine can also be measured.

    Carbohydrate Metabolism

    Impairment of glycogen storage and of glycogen release may be seen in moderate acute hepatitis and in moderate cirrhotic disease. The degree of this so-called "glycogen storage disease" can be quantified by means of the five-hour glucose tolerance test and can be further evaluated by means of overnight fasting blood sugar levels.

    Test of LiDid Metabolism

    The most useful tests of hepatic lipid metabolism are direct measurement of serum cholesterol and of cholesterol esters. Severe liver injury, as in severe acute hepatitis or in late cirrhosis, may result in a measureable decrease in serum cholesterol and of serum cholesterol esters. If there is marked bile stasis, however, total serum cholesterol, and to a lesser extent, serum cholesterol esters, may rise rather than fall. Serum triglycerides may also be elevated by cholestasis (bile stasis).

    Measurements of Clotting Factors

    A number of clotting factors in the blood can be measured directly. In liver disease, however, the most useful single test is measurement of the prothrombin time. This tends to be elevated in both acute hepatitis and in far-advanced cirrhotic disease. Since intestinal absorption of vitamin K can be impaired by a number of conditions, and since that impairment may result in a prolongation of the prothrombin time, one can enhance the specificity of the defect by administering parenteral vitamin K and then rechecking the prothrombin time after 24 to 48 hours. As a rule, measurement of prothrombin time is done not so much to establish the presence or absence of liver disease, but, rather, to quantify the current degree of hepatocyte failure. That is why, for example, serial prothrombin times give useful indications of the progress of acute hepatitis when other laboratory values have become so grossly abnormal that they show little day-to-day change.

    Immunologic Tests

    With increased understanding of the morphology and immunology of the hepatitis viruses, serologic screening is mandatory for accurate diagnosing, as well as predicting and monitoring outcome. Currently there are seven serological diagnostic tests that measure the presence of unique serological markers associated with HBV and HAV. They will be listed here but not described further:

    	         Hepatitis                 Hepatitis A
    	HBsAG - surface antigen	           Anti-HAV (IgG)
            Anti-HBs - antibody-surface        Anti-HAv (IgM) antibodies
            Anti-HBc - antibody-core
            HBeAG - "e" antigen
            Anti-HBe antibody

    Note: serologic markers do not necessarily identify the presence of liver disease, but prove the presence of infection and identify the type of virus responsible.


    It is possible to perform needle liver biopsy directly through the skin without surgical incision. By extricating liver tissue for direct examination under the microscope, liver biopsy produces answers that can be obtained in no other way. However, this is a dangerous procedure, especially if a coagulation defect is present, and should be resorted to only by a gastroenterologist.

    Measurements of Bilirubin

    Hyperbilirubinemia usually produces clinical jaundice when the total bilirubin level exceeds 3 mgZ. Thus, the presence of jaundice automatically means hyperbilirubinemia. In an adult, jaundice itself is not harmful, although it does indicate hepatic dysfunction. In an infant, hyperbilirubinemia can be dangerous, especially if total bilirubin exceeds 20 mgZ. A substantial percentage of normal, healthy newborns do develop mild hyperbilirubinemia with total bilirubin below 5 mgZ, others as high as 12 mgZ. This is called "physiologic newborn jaundice." The more problematic kinds of neonatal jaundice will not be dealt with here.

    In an adult, the presence of jaundice almost always indicates the presence of serious disease. The single exception to this is pregnancy, where a mild hyperbilirubinemia without jaundice or a definite hyperbilirubinemia with slight jaundice often occur during the last days of the third trimester. Invariably, hepatic function returns to normal shortly after delivery and the hyperbilirubinemia and jaundice, if present, resolve.

    There are three major mechanisms by which hyperbilirubinemia, and hence jaundice, are produced: 1) prehepatic jaundice from hemolysis, 2) hepatic jaundice from hepatocyte failure or from intrahepatic obstruction and 3) post-hepatic jaundice from extrahepatic obstruction, such as a stone in the common duct.

    Hemolytic hyperbilirubinemia is usually easily identified because there is no underlying liver disease and so the hepatocytes are able to conjuga: bilirubin well. The increase in circulating bilirubin is almost entirely unconjugated, the level of conjugated bilirubin remains normal, and total bilirubin rarely exceeds 10 mg%. In addition, there is usually hematologic evidence of hemolysis. Since the hepatocytes are able to conjugate the arriving mass of bilirubin well, stool pigments are increased, intestinal production of urobilinogen is increased, and urinary urobilinogen is also increased.

    When the defect lies within the liver, the picture is somewhat more complex. In advanced cirrhosis, for example, there is both hepatocyte failure and, usually some degree of obstructive pathology as a result of diffuse fibrotic changes within the liver. In acute hepatitis, there is hepatocyte derangement and, because of edema (due to inflammation), there may also be obstructive impairment of bile exeretion. The result of this is that the amount of unconjugated bilirubin circulating in the blood may rise because of the hepatocyte failure present, and the amount of conjugated bilirubin circulating may increase because of the obstructive pathology present. Because hepatic output of conjugated bilirubin into the bile is diminished, there is diminished intestinal production of urobilinogen and so, in both of these situations, urinary urobilinogen is diminished.

    In the case of extrahepatic obstruction, there is no hepatocyte impairment initially. Therefore, the hepatocytes are able to conjugate and excrete bilirubin normally and to release it into the bile ducts. However, because the bile cannot move into the intestinal tract, the water soluble conjugated bilirubin is reabsorbed from the hepatic duct system and released into the general circulation. The stools become light in colorf urinary urobilinogen is greatly diminished, and the increase in total bilirubin circulating in the blood is almost entirely water soluble conjugated bilirubin. If severe cholestasis persists, however, the presence of large amounts of bile in the hepatic duct system interferes with normal hepatic function, and so there may eventually be an increase in the level of unconjugated bilirubin. This type of hyperbilirubinemia and jaundice is called "surgical jaundice" because surgical exploration of the right upper abdominal quadrant is often needed to produce a definitive diagnosis. These processes are illustrated in the following set of drawings.

    Laboratory Findings in Acute Hepatitis

    A number of terms are used to describe the various stages of the clinical course of infectious hepatitis. The first stage is usually called the preicteric stage (prejaundice). The second stage is usually called the icteric or obstructive stage. The third stage is usually called the convalescent stage.

    During the preicteric stage, when the patient is usually symptomatic with flu-like symptoms and anorexia, there is usually a mild elevation in SGOT. In fact, there is usually a slight elevation of SGOT even before the patient becomes symptomatic. Alkaline phosphatase is usually also elevated. SGOT usually remains elevated through the icteric phase. SGPT is also usually elevated and follows a course similar to that of SGOT but tends to remain elevated longer. It may not return to normal for three or four months. (The usual pattern of enzyme elevations is this: SGOT, SGPT, LDH, alkaline phosphatase, and 5' nucleotidase. All tend to rise together and to fall together, although there is some variability in this picture.)

    Bilirubin levels rise just before the development of jaundice. (Jaundice usually persists for about two weeks.) Total bilirubin usually does not exceed 20 mg% but may reach 30 mg%. Because jaundice is produced by deposition of bilirubin in fatty tissues, it persists for some time after bilirubin has returned to a normal level. Many abnormalities of liver function, which can be measured by the tests already discussed, appear and then resolve in the natural course of the disease.

    Approximately 7% of the patients with viral hepatitis experience relapses during convalescence. Some of these relapses represent second infections with other hepatitis viruses (A, B. non A/non B). Some relapses represent simultaneous infection with the delta virus. The delta virus is a unique RNA virus that is replication defective. The virus core is surrounded by HbsAg (Hepatitis B surface antigen) necessary for replication. The delta virus is dependent on the genetic information provided by the Hepatitis B virus. The delta virus can cause hepatitis only in the presence of Hepatitis B virus. Delta virus is endemic in the Mediterranean area, the Middle East, and Africa. It occurs in the United States usually among drug addicts and multiple transfusion patients. Delta infection is diagnosed by the appearance of the antigen in serum or by the development of IgM or IgG antidelta antibodies.

    Laboratory Findings in Cirrhosis

    Laboratory findings in cirrhosis reflect the degree of loss of hepatic function. In mild cirrhosis, if there is no continuing hepatic insult, all laboratory studies may be entirely normal. In far-advanced cirrhosis, there may be many marked abnormalities in laboratory data. There may be a definite diminution of total plasma protein, including both albumin and immunoglobulins. There may be multiple coagulation defects measureable by clotting time, bleeding time, and prothrombin time. There may be multiple, chronic, mild enzyme elevations. There may be a lower than normal serum cholesterol level. The five hour glucose tolerance test may be abnormal and the fasting blood sugar may be low. There may be chronic, mild hyperbilirubinemia without jaundice. The BSP test is always abnormal in these patients. Liver biopsy reveals grossly deranged hepatic microanatomy.

    Most patients with cirrhosis have a long history of alcoholism. If they continue to drink, the toxin alcohol may, if taken in large enough amounts, produce superimposed "alcoholic hepatitis." This is chemical inflammation, and may exaggerate all previously abnormal studies, and may produce severe acute, perhaps even terminal, hepatic failure.

    The problem with cirrhosis, from the technical point of view, is not so much whether or not it is present, but, rather, the extent of anatomic changes present. Furthermore, one must bear in mind that patients with cirrhosis can and do develop other liver diseases. There is nothing to prevent them from developing infectious hepatitis. Alcoholics have a higher incidence of primary carcinoma of the liver than do other people. There is nothing to prevent them from getting metastatic liver disease. Alcoholics also acquire certain infectious diseases more than do other people and some of these may include hepatic involvement.

    Not all people who develop cirrhosis have a history of alcoholism. For example, a person who has a severe bout of infectious hepatitis and who then develops one of the atypical courses, such as chronic relapsing viral hepatitis, may, over time, develop cirrhotic changes. This person, too, may also develop problems other than hepatitis or cirrhosis.


    OBJECTIVE 3 Questions

    OBJECTIVE 3 Answers

    • 1. serum glutamic oxaloacetic transaminase serum glutamic pyruvic transaminase lactic acid dehydrogenase alkaline phosphatase 5' nucleotidase
    • 2. Serum levels increase because hepatocellular damage results in the leakage of these normally intracellular enzymes into the venous drainage of the liver.
    • 3. SGOT
    • 4. Since SGOT elevation can be from sources other than the liver, SGPT, an almost exclusively "liver" enzyme, is monitored to aid in the confirmation of a hepatic source of SGOT.
    • 5. These enzyme levels are measured primarily to determine the degree of acute liver injury. A more direct measurement of hepatic protein metabolic functions can be made by determining plasma albumin and immunoglobulin levels, BUN' and, sometimes, serum ammonia level.
    • 6. Serum ammonia. The liver is the organ responsible for the conversion of serum ammonia into urea; hence, when this function is impaired, the level of serum ammonia rises.
    • 7. the 5-hour glucose tolerance test 2. overnight fasting blood sugar levels
    • 8. When there is a condition of marked bile stasis.
    • 9. Measurement of prothrombin time is a useful indicator of changes in liver function at a time when other laboratory values are grossly abnormal.
    • 10. Causing internal hemorrhage when a clotting defect is present.
    • 11.
       		Preicteric             Icteric          Convalescent
          SGOT	mild elevation         elevated         returns to normal
          Alk. Phos.	mild elevation         elevated         returns to normal
          SGPT	elevated               elevated         stays elevated,
                                                              returns to normal
          Bilirubin	may be very	       elevated	        returns to normal
      		slighty elevated
    • 12. To determine the degree of loss of hepatic function. This can range from normal values to grossly abnormal values, reflecting the degree of hepatic damage and failure.


      OBJ. 4. Describe the advantages and disadvantages of the currently acceptable pharmacologic approaches in the treatment of those entities listed in Objective 1. OBJ. 5. Construct a treatment plan which includes both pharmacologic and nonpharmacologic approaches for each of the entities in Objective 1.

      Treatment of Hepatitis and Cirrhosis


      Most patients with acute infectious viral hepatitis have relatively mild forms of the disease, do not become profoundly ill, and can be treated successfully at home. The main stays of management are bed rest and diet as tolerated. Large meals and high-fat content meals are to be avoided; this is usually not a problem because the patient will avoid these things himself. If nausea and vomiting are a problem, they can be controlled with antiemetics. Alcohol is to be forbidden until the patient is completely asymptomatic.

      Close contacts (family members and sexual partners) of the infected person should be given immune serum globulin injections for prophylaxis. Immune serum globulin contains hepatitis antibodies and are efficacious to exposed individuals that do not have enough time to make their own antibodies. In hepatitis B exposed patients (uninfected), a concentrated Hepatitis B Immune Globulin (HBIG) is available. Immune serum globulin is often given to individuals that have come into close familial or sexual contact with patients that have been diagnosed with acute hepatitis A. School, occupational or hospital contacts of patients with hepatitis A are generally not given gamma globulin. Clinics, emergency rooms, and physicians have standard protocols for dosage and procedures to be followed.

      Once the diagnosis is established, the progress of the disease can be monitored by obtaining, at appropriate intervals, serial determinations of selected blood chemistries. For most patients, the SGOT level, prothrombin time, and measurement of direct and indirect bilirubin are the most useful. When it becomes obvious that the clinical course has become one of improvement, the patient can be followed by history, physical examination, and determination of the SGOT alone.

      The patient who becomes more profoundly ill and who requires hospitalization may very well have extreme expressions of all of the basic pathophysiologic mechanisms discussed in Section 1. These patients should be managed by a competent internist.

      One should bear in mind that these patients may have impaired hepatic metabolism of many kinds of drugs. For this reason it is wise to use the lowest possible dosages of those drugs that are metabolized in the liver. Drugs that are known to be hepatotoxic should be avoided.

      Treatment of Cirrhosis

      There is no real treatment for cirrhosis. Since the offending agent in almost all cases is the ethanol molecule, drinking must be stopped. Beyond this, there is little to do except to manage complications. The widespread hepatic anatomic changes are for the most part permanent. If hepatic impairment has progressed to the point at which the full-blown picture of far-advanced cirrhosis appears, then certain particular supportive measures are reasonable. For example, the patient with a decreased plasma protein level who has ascites and a superimposed edema state should be given diuretics. Use of diuretics in this circumstance reduces total body water and thus draws the extracellular water back into the vascular compartment. This is likely in most cases to be only partially successful and requires aggressive use of diuretics. Since masculinization of the cirrhotic female and feminization of the cirrhotic male are both likely to be permanent, sex hormone therapy should be avoided. In any event, these are the least of the cirrhotic patient's problems.

      Patients with ascites, and particularly those receiving diuretics, can be evaluated best by measurement of the abdominal girth at each office visit. This is a far more reliable indicator of changes in ascites than is body weight, which may change for reasons other than increases or decreases in total body water.

      Because these patients have impaired immunoglobulin production, they should be given aggressive treatment for all bacterial infections. As in severe acute hepatitis, drugs should be used with caution because hepatic metabolism may be impaired.

      There is very little in the way of real therapy for these patients.

      EXERCISE 4 OBJECTIVES 4 & 5 Questions

      1. In the treatment of viral hepatitis, what would you modify, if anything, about the patient's diet?
      2. What precautionary measures should be taken for close family contact of patients with hepatitis?
      3. What is the pharmacologic treatment of choice in the management of a patient with cirrhosis?
      4. In a cirrhotic patient with decreased levels of plasma protein who has ascites and a superimposed edematous condition, what pharmacologic approach may be appropriate?
      5. What method of evaluation is useful in a patient with ascites who is using diuretics?
      6. What are the confounding conditions in cirrhotic patients which makes the treatment of bacterial infections particularly hazardous?
      7. What prophylaxis should be administered to individuals that are in close contact with hepatitis patients?


      1. Avoid large meals and high-fat content meals.
      2. Close family contacts should be given immune serum globin injections for prophylaxis.
      3. There is none!
      4. Diuretics can be used to decrease the total body water and draw the extracellular water levels in the vascular system.
      5. Measurement of abdominal girth. This is much better than measuring the body weight, such changes in body weight are often due to other factors than increases or decreases in total body water.
      6. The fact that patients with cirrhosis have an impaired immunoglobulin production requires that they be given aggressive treatment for all bacterial infections. However, should hepatic metabolism also be impaired (this is likely), the metabolism of drugs will be impaired, and so dosages may have to be reduced considerably. Caution - know which antibiotics are metabolized in the liver.
      7. Hepatitis A - Immune serum globulin Hepatitis B - Hepatitis B Immune globulin


      OBJ. 6. Construct a differential diagnosis for each of the entities listed in Objective 1, given signs, symptoms, and laboratory data.

      Problem Cases

      Case 1

      Your patient is a 46-year old man who presents at the office on a Tuesday morning in January as a walk-in patient. Chief complaint "Well, doc, I been drinking too much again, and I feel like hell. My nerves is all tore up and I feel like my gut's about to bust.” History of the present illness: Your patient tells you that he has been drinking about a fifth of whiskey a day for the past two weeks. You ask him how long he has been drinking altogether, and he says, “well, I guess I've been drinking all my life.” He says that he has been drinking heavily off and on for 25 years. For the last 5 years, he has frequently been drunk for periods of 1 to 3 weeks, a pint to a fifth a day. He says that he has probably had at least one drink every week for the past 25 years. He has been hospitalized four times for acute alcoholism. Last admission for this was 2 years ago. At times, he has been unable to work for months at a time and has had to get by as best he can with no income. Even during those periods, though, he says he always manages to get something to drink every day.

      Beginning about a week ago, he began to experience widespread upper abdominal discomfort. You ask him to point with one finger to the area that hurts the most and he indicates the right upper quadrant, the epigastric area, and the left upper quadrant as well as the periumbilical area. He also tells you that he has had some left shoulder and upper posterior chest pain during the same period. Over the past week he has been frequently nauseated and has vomited every morning. Vomitus has been liquid, yellow, and vile-smelling. He has not vomited any blood. He has been having, for the past 10 days, loose stools that are tan to light brown in color. He says that these have a vile odor. Over the past 2 or 3 days, the upper abdominal discomfort has become more marked and is now severe and he has been persistently nauseated for the last 2 days and has been vomiting for the past 24 hours. He has had no blood in his stools.

      He smokes 3 packs a day, and has for 20 years. He says that although he does have a chronic cough productive of about half a cup of whitish or light yellowish sputum per day, usually in the morning, there has been no change in his cough for the past 2 weeks. Similarly, there has been no change in quantity or character of sputum.

      When you ask him about constitutional symptoms, he tells you that he has lost about 10 pounds over the last 3 weeks, that he has felt feverish much of the time, and that he has for some time felt generally weak. Weakness has been most marked over the past 10 days and he now finds it difficult even to be up and about and walking.

      Past medical history: To the best of his knowledge, he believes he had no unusual illnesses as a child. He has had no operations. He is currently taking 10 medications of any kind except aspirin, which he has been taking for his abdominal pain. He has taken intermittently for many years 2 or 3 Nervine tablets nightly for sleep.

      Physical examination: On physical examination you find the following: temperature 100, pulse 110, blood pressure 110/88, respirations 24. The patient is 5' 10" tall and weighs 144 pounds. He looks to you thinner than he ought to be and is somewhat pale and appears to be in obvious discomfort. He coughs occasionally while sitting and holds his upper abdomen much of the time with his forearms.


      1. Of the following, which do you most expect to find on further physical examination (choose three out of nine).
        1. RUQ abdominal tenderness
        2. LUQ abdominal tenderness
        3. Shifting dullness
        4. Petechiae
        5. Jaundice
        6. Pedal edema
        7. Enlarged liver
        8. Smaller-than-normal liver
        9. Normal liver size
      2. Assume you found the things you expected to find on physical examination. What laboratory tests, among the following, would you select as appropriate (choose four)?
        1. BUN
        2. Serum cholesterol
        3. CBC
        4. Serum bilirubin
        5. SGOT _
        6. Urinalysis
        7. LDH
        8. HBsAg
        9. Total plasma protein
        10. Prothrombin time
      3. With regard to this man's liver, what two hepatic problems does he probably have currently?



      4. What other problems might account for this man's galaxy of GI and abdominal complaints?



      Physical Findings

      Regardless of what you expected to find on physical examination, here is what you found: 1) right upper quadrant abdominal tenderness, 2) left upper quadrant abdominal tenderness, 3) shifting dullness, 4) normal-sized liver with edge firmer than normal, 5) a few scattered petechiae on the lower extremities, 6) a trace of pitting pedal and pretibial edema.

      Lab Results

      You should have selected the following studies, which produce these results:

      1) SGOT - elevated to three times normal
      2) measurement of total plasma protein is 6 grams, normal upper limit 8 grams
      3) prothrombin time - his is 21
      4) CBC, which reveals the following:

      white count - 4,000 hemoglobin - 10.9 grams MCV - 90 differential - 60 neutrophils, 30 lymphocytes, 9 monocytes, 1 basophil

      Now what do you think this man's current problems are?







      Justify each of the problems you listed. Now keep reading for problem definitions and discussion.

      Problem Definitions and Discussion

      This man's current problems, on the basis of history, physical examination and the laboratory data available at the moment, are:

      1. Chronic alcoholism

      2. Probable acute alcoholic hepatitis (toxic hepatitis)

      3. Probable acute pancreatitis

      4. Portal cirrhosis - basis of history and PE only - no tissue diagnosis at this time

      5. Alcoholic gastritis

      6. Normocytic, normochromic anemia - probably secondary to advanced cirrhotic liver disease with superimposed acute alcoholic hepatitis

      7. Chronic bronchitis

      Discussion of Problems

      With regard to history, we know that this man is an alcoholic and has been drinking for a very long time. We know that chronic alcoholism is associated with a number of chronic problems including liver disease, ulcer disease, acute pancreatitis, toxic marrow suppression, and complications of all of these things. Therefore, on the basis of history alone, we expect this man to be a veritable museum of disease.

      You were told very little about physical examination, and so the reasonable thing for you to do was to play the odds - pick the most probable problems on the basis of the available data, and select the most critical laboratory tests relevant to those problems. Since this man has been drinking steadily for a great many years, certainly we would expect fairly advanced fatty cirrhotic liver changes and fairly severe compromise of many hepatic functions. In addition, since he has been drinking very heavily for the past two weeks, it is entirely reasonable to expect that the recent alcoholic deluge flowing up his portal vein and into his liver has produced superimposed acute alcoholic hepatitis. As is often the case, one must consider in the alcoholic not only liver disease, but also a great multitude of other problems that are directly attributable to long-standing heavy drinking. This man does indeed have multiple problems, some chronic and some acute. The most threatening acute problem may be acute pancreatitis. This is suggested by the left upper quadrant and periumbilical discomfort and by the referred left shoulder pain. (Subdiaphragmatic problems that produce diaphragmatic irritation often include pain referred to the shoulder area on the same side.) Although history and physical examination suggest this particular problem, a definitive diagnosis could be made on the basis of serum amylase level which we have not measured.

      This particular case is quite typical of the presentation of multiple gastrointestinal problems encountered in the alcoholic who has been on a recent binge.

      For the sake of learning a little more about liver disease, construct a scenario for the next three weeks, ask a friend to do the same, and then compare notes. Predict changes in physical findings, in the patient's complaints, and in laboratory values.