The following is identical to my lecture handout, however words that are outlined in hypertext are links to images which demonstrate the pathologic lesion being discussed. This is meant to be a study aid and is not meant to be a substitute for attending the lecture!

Goals and Objectives

At the conclusion of this lecture and after studying the notes and correlating the information with the pathology laboratory exercises, the student should:

1. Know the different types, patterns and degrees of injury to the liver.

2. Know the natural histories of alcoholic, viral, and autoimmune injury to the liver.

3. Know the similarities and differences between Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis.

4. Know the factors involved in the evolution of cirrhosis.

5. Know the major complications of cirrhosis and the anatomic explanations for them.

6. Be familiar with causes of cirrhosis.

7. Know the 2 major types of primary liver tumors, and be familiar with their etiologies and pathogenesis.


Click Here to review normal liver histology
(Portal tract)

Click Here to review normal liver histology (Central vein)

This discussion focuses on the light microscopic patterns of hepatic injury which, in turn, depends upon the understanding of basic cell injury as discussed earlier in this course.

I. Cell Injury: Histologic expressions

A. Swelling or hydropic change. Probably the result of defects in membrane and/or mitochondrial function. This is common to many hepatic injuries.

B. Fat (neutral fat, triglyceride) in liver cells: indicates some defect in lipid metabolism or lipoprotein synthesis or unusual quantities of adipose or dietary lipid brought to liver. Also referred to as "steatosis".

C. Intracellular defects in protein metabolism

1. Mallory bodies (structural filaments)
2. alpha-1-antitrypsin deficiency (packaging defect)

II. Necrosis: Two histologic types seen in liver. We are not sure if they evolve in different ways.

A. Lytic - swollen cells with nuclear changes of necrosis
B. Coagulative - dark red-staining cell outlines. Varies from single cell necrosis to big areas as seen in infarcts. The single necrotic cells appear as red fragments extruded into sinusoids.

Histologically, we see the leftovers of all forms of necrosis as debris in phagocytes, including lipofuscin and hemosiderin.

III. Responses of Hepatocytes to Injury. If they are capable (not significantly injured) they may undergo:

A. Proliferation - replication to replace dead cells.

B. Hypertrophy - enlargement of organelles produces enlargement of cells probably to increase function of individual hepatocytes.

In addition, one other proliferative response occurs in injured livers:

C. Bile Ductular Proliferation - possibly because of loss of continuity of the intrahepatic biliary passages from the canaliculi to the small or interlobular bile ducts.

IV. Injuries commonly lead to Inflammatory Reactions that differ depending on the stimulus

A. Activation (hypertrophy) of Kupffer cells: phagocytosis, response to particulate material.

B. Lymphoid and plasmacytic: immunologic response to antigens, some of which may be altered liver cell membrane proteins or viral antigens.

C. Neutrophils - response to cell debris, immune complexes, complement fractions and polymers, bacteria, toxins.

D. Eosinophils - probably many reasons for their appearance in the liver. We rarely see more than a few eosinophils in mixed cellular portal inflammation. May be important in acute transplant rejection.

E. Granulomas - very common as incidental findings in liver. May be due to the usual causes of such reactions, but most granulomas are of unknown etiology.

V. Distribution and Intensity of Damage and Inflammatory Reactions

A. Background

The liver is organized into small units, based upon blood supply, called acini. These are characterized by an incoming blood supply in the portal tracts (branches of hepatic artery and portal vein), cords of liver cells and their intervening sinusoids and a peripheral outgoing blood supply (old name: central vein; new name: terminal hepatic venule). Liver cells along the cords tend to have different degrees of metabolic activities. At the same time, the blood flowing in the sinusoids becomes progressively more deoxygenated so that the hepatocytes around the central vein are relatively anoxic compared to those around the portal tracts. These features help to explain the fact that different types of injuries lead to different distributions and degrees (extent) of damage and inflammation.

B. Distribution - (Often Reproducible for a Given Insult):

1. Diffuse or Non-Zonal - all parts of acinus involved randomly or haphazardly.

2. Zonal - specific part of each acinus involved such as centrilobular, midzonal, periportal. Indicates different susceptibility to certain injuries by different populations of cells within the acinus. Often related to blood supply and oxygen tensions in different acinar zones. Most zonal injuries involve the hepatocytes around the central veins.

C. Intensity (amount): Usually Refers to Necrosis or Liver Cell Damage, Rather Than Inflammation.

1. Patchy or Spotty - single cells or tiny clusters die.

2. Confluent - progressively larger masses of liver cells die. This results in collapse of stroma.

VI. Cholestasis - bile not adequately excreted (interference with bile flow). Bile includes bilirubin, bile acids, phospholipids, cholesterol, etc. What we see in tissue is the bilirubin hung up in the liver cells, in canaliculi, in ductules, in ducts. Basic understanding of bilirubin metabolism is necessary. A common accompaniment of cholestasis due to obstruction anywhere in the duct system is proliferation of ductules at the edges of the portal tracts.

VII. The whole gamut of liver diseases is defined by the types and patterns of injury, inflammation, and cholestasis they induce. We know of drugs or toxins which can selectively produce almost any combination of the features.


The basic patterns of injury, as presented above, are those which are continually used by tissue pathologists to make diagnoses of liver disease. The following is a brief discussion of two forms of liver disease, both potentially progressive, in which these injury patterns can be recognized and used to make specific diagnoses.

The Viral Hepatitis and Viral-Like Hepatitis Group, including autoimmune hepatitis and rare drug-induced hepatitis.

1. Acute viral hepatitis is characterized by diffuse cell injury with swelling, and by spotty necrosis, both of the lytic and the coagulative types. In general, the process seems to be mediated by lymphocytes, possibly responding to alterations in liver cell membrane antigens. Some viruses may kill the hepatocytes by themselves (cytopathic effect). At the same time as the damage is occurring, compensatory hypertrophy and replication of viable liver cells occur. Finally, the inflammatory reaction, most intense in and about the portal tracts, but also diffusely through the sinusoids, is lymphoid, again suggesting immunologic injury.

Most cases resolve, but the likelihood of resolution depends upon the specific virus. Essentially, all cases of type A and type E viral hepatitis resolve. B and C disease can become chronic. Resolution is characterized by diminution in intensity of the diffuse injury and the spotty necrosis with reappearance of the liver cell cords, early on a prominence of debris-filled macrophages, withdrawal of the lymphocyte mediators from the lobules and more tight aggregation of the portal lymphocytes.

2. Mild Chronic Viral Hepatitis
Occasionally, some cases of viral hepatitis enter into a mild smoldering prolonged phase which appears to be something of a stand-off between the virus and the host's immunologic responsiveness. As a result, the injury is kept at low levels. Often, the injury ceases completely and the inflammation resolves, although it may take several years. If the cause is the C virus, then the outcome is unpredictable. Histologically, mild chronic hepatitis is characterized by a dense lymphocytic portal reaction, again a manifestation of immunologic injury. However, there is very little spillage of these lymphoid cells into the lobules, suggesting the antigenic stimulation is not as intense as in acute viral hepatitis. In addition, there is spotty necrosis, but necrotic cells are quite rare. Finally, there is no evidence of diffuse liver cell injury.

3. Severe Chronic Viral Hepatitis. On rare occasions, the virus and the immune system seem to come into open conflict, producing bouts of damage or continuous fairly intense damage. This can result in destruction of large chunks of parenchyma, even tracts or bridges, leaving good sized holes in which collagen is eventually deposited, the beginnings of scars. This severe, potentially progressive disease is characterized by an exaggeration of the lymphoid infiltrate with prominent extension into the periphery of the lobule and further extension deeper into the parenchyma where it is associated with considerable spotty necrosis and occasionally with confluent necrosis as well, which may bridge between central and portal zones. Liver cells may be trapped within these zones of confluent necrosis, a degree and pattern of necrosis that is a potential precursor of cirrhosis. The lymphoid reaction is more intense than is usually seen in acute viral hepatitis and there is a degree and pattern of necrosis that is a potential precursor of cirrhosis. This reaction may quiet down for variable periods, sometimes assisted by appropriate therapy. During such periods, the liver contains scars, mild portal or periportal inflammation and little, if any, lobular damage and inflammation.

4. On very rare occasions during the acute attack of viral hepatitis, resolution does not occur, but there is continued widespread destruction which leads to the wiping out of most, or even all, of the parenchyma, resulting in total collapse, a process known as massive hepatic necrosis. This process, when it results in complete liver cell death, is fatal. It must be remembered that the clinicians use the term "fulminant hepatitis" to define those patients who have clinical liver cell failure during any type of acute hepatitis; however, possibly 20% of this clinically defined population actually recover. It is very doubtful that this 20% had massive hepatic necrosis. They just had temporary liver cell insufficiency instead.

5. Many drugs or toxic injuries can produce hepatitides that are much like the viral types. Thus, there can be acute hepatitis, mild to severe chronic hepatitis, and even massive necrosis, resulting from drug injury. Another group of chronic hepatitides is considered to be autoimmune.


Alcoholic Liver Injury

This is quite different from viral hepatitis. It is really a form of toxicity, rather than an immunological response, although evidence is accumulating that suggests an immune component to some of the injury. It has a number of very specific, reproducible and easily recognizable features.

1. The Fatty Liver of the Alcoholic. Any time large quantities of alcohol are consumed, the liver cells accumulate triglyceride. This can be extensive, occasionally resulting in huge livers with rounded edges. Alcohol and its metabolites affect virtually every aspect of lipid metabolism in the liver, and the net effect appears to be accumulation of triglycerides within the cells. These large livers in alcoholics are not only the result of lipid accumulation. Alcoholic livers tend to accumulate protein as well, presumably as a result of a defect in protein secretion by the hepatocytes. This protein retention by the alcoholic hepatocytes also increases liver weight.

2. Ultrastructural Changes. Chronic alcoholic intake induces changes in mitochondrial size and shape and orientation of the cristae. Alcoholic mitochondria have defects in Kreb's cycle enzymes and are thus sluggish energy producers. The mitochondria may sometimes reach huge size, periodically becoming larger than the nucleus. Then they can be seen as large sharply rounded cytoplasmic red inclusions in routine preparations. In addition, alcohol is an excellent inducer of the smooth endoplasmic reticulum. Although most alcohol is metabolized by the cytosolic enzyme system known as alcohol dehydrogenase, perhaps 20% is metabolized in the smooth endoplasmic reticulum. Thus, there is likely to be expansion of this membrane system. Expansion of the SER results in enlargement of the liver cells and relative clearing of the cytoplasm, producing a picture very much like cellular swelling due to increased water and electrolytes.

3. Alcoholic Hepatitis. A select number of alcoholics develop a central zone hepatitis which is characterized by cellular swelling, spotty necrosis, and Mallory bodies with a variably intense neutrophilic infiltrate. The portal tracts are spared. The reason for the neutrophils and the reason for this sharp zonal injury is not clear. The neutrophils may be responding to immune complexes on the surface of the Mallory bodies, but this has not been proven. It is not clear if alcoholic hepatitis must develop from a fatty liver, since every chronic alcoholic gets a fatty liver anyway. Alcoholic hepatitis probably is not the necessary precursor lesion of the more severe forms of chronic alcoholic injury, including cirrhosis.

4. Central Sclerosis or Perivenular Sclerosis. Some alcoholics deposit collagen in the spaces of Disse along the central zone sinusoids and around the central vein, eventually obliterating that vein. It is not clear if this is the same population that develops alcoholic hepatitis, or if it is another population. However, it is suspected that this lesion is a precursor of alcoholic cirrhosis; in fact, it may be the most important precursor.

5. Progressive Chronic Alcoholic Injury Leading to Cirrhosis. It appears that the central zone injury or injuries, be it sclerosis alone or with alcoholic hepatitis, may progress across the lobule with collagen deposition. Eventually, this hooks up with the portal tracts, possibly along low oxygen tension zones in the parenchyma. Once the hookup is made, the central zones and portal tract become incorporated in the same scar, and beginning division of the micro-anatomy into smaller sub-units has occurred. Further progression of this is the basis for alcoholic cirrhosis.

6. Other conditions that lead to alcoholic-like liver diseases include morbid obesity, diabetes mellitus, Vitamin A intoxication, amiodarone toxicity and hyperlipidemias.

Cholestatic Liver Diseases

While a wide variety of things can cause cholestatic changes in the liver, there are 2 primary diseases which serve as good models to study. Both have destruction of bile ducts as a cardinal feature.

1. Primary Biliary Cirrhosis (PBC) This is a chronic disease that typically effects middle aged women. Patients present with fatigue, pruritus, and eventually jaundice. These patients have an elevated alkaline phosphatase and autoantibodies directed against mitochondrial enzymes (AMA) This is thought to be an "autoimmune process". Histologically, the hallmark of PBC is the presence of granulomatous inflammation surrounding a damaged and inflamed bile duct. Eventually this process destroys the majority of bile ducts, and one is left with ductopenic liver. Cholestatic changes such as bile ductule proliferation and peri-portal Mallory's hyaline develop and cirrhosis often ensues. Early on in the disease, lymphocytes and plasma cells cause most of the damage. In end-stage disease, the inflammatory process may be long gone, leaving only cirrhosis.

2. Primary Sclerosing Cholangitis (PSC) This is another chronic cholestatic condition, which unlike PBC, is more common among men. Again the bile ducts bear the brunt of the attack, as they become encased in fibrous scars and become obstructed. Lymphocytes are thought to play a role in this fibrosing process. This disease may effect the common bile duct and gallbladder as well as the intrahepatic bile ducts. Histologically one may see fibrosis or loss of bile ducts with ductuolar proliferation. End stage disease may resemble PBC. PSC is associated with ulcerative colitis, leaving many to speculate that toxins from the gut play a role in its pathogenesis. Patients with PSC have an increased risk of developing carcinomas of the bile ducts (cholangiocarinoma)


I. Definition of hepatic cirrhosis - a liver in which:

A. diffuse septate scars separate.

B nodules of regenerating hepatocytes.

C. The major complication of these architectural
distortions is alteration in blood flow and
blood supply to residual parenchyma.

II. Cirrhosis begins with insult to the parenchyma which usually destroys part of it. This may occur as:

A. single or repeated episodes of confluent necrosis.

B. Gradual expansion of zones of necrosis by gradually destroying adjacent hepatocytes - cellular inflammation important.

C. combination of A and B.

D. non-necrotizing injuries which stimulate scar formation.

III. Regeneration is impaired in the necrotic zones so that destroyed parenchyma is not replaced. Possible explanations (speculations):

A. Necrotic zone may be too big.

B. Destruction of reticulin fiber scaffold impedes orderly regeneration.

C. Potentially regenerative hepatocytes may be injured.

D. Persistent cellular inflammatory reaction may interfere spatially or chemically. Lymphokines in alcoholic hepatitis have been implicated.

E. Disturbances in blood supply to potentially regenerative hepatocytes.

F. Undernutrition.

G. Chemical or hormonal suppressers (inhibitors) of hepatocyte proliferation? Speculative.

H. Chemical stimulators of regeneration may be deficient: decreased production, inactivation or inhibition.

IV. Most fibrosis occurs in the non-regenerative necrotic areas producing scars. Cells capable of collagen production include portal fibroblasts, primitive sinusoidal stromal cells and hepatocytes. Other fibrosis occurs in the absence of necrosis so that regeneration or its failure may not be important.

V. Fibrotic zones interconnect to produce septa which surround residual parenchyma.

VI. Depending upon functional requirements, residual parenchyma may proliferate in order to compensate for the destruction and disturbances in blood supply. This proliferation is limited by the enveloping scars, leading to nodules of hepatocytes.

VII. Destruction, scarring and nodularity result in vascular distortions:

A. Compression of portal vein branches by expanding nodules leads to obstruction in portal system and portal hypertension. Contraction of scars may also obstruct portal venous flow. Compression of central or sublobular veins may contribute to the hypertension.

B. In zones of confluent necrosis, loss of hepatocytes decreases sinusoidal pressures leading to shunts between inflow (hepatic artery, portal vein) and outflow (hepatic vein) systems. This routes blood supply away from residual parenchyma leading to inefficient perfusion and functional (biochemical) impairment. Shunts persist in resulting scars.

C. In these same zones of confluent necrosis, high pressure of hepatic arterial system is transmitted to low pressure in portal venous system, leading to portal hypertension.

D. Central zone vascular obliteration, as in alcoholic cirrhosis, may cause portal hypertension by preventing venous outflow.

VIII. Complications of Cirrhosis:

A. Portal hypertension (see VII above).

B. Obstruction of excretory (biliary tract) within liver leading to excretory defects.

C. Declining hepatocyte function, including biochemical failure, as a result of:

1. defects in blood supply with deficient perfusion of remaining hepatocytes.

2. continuous destruction of remaining hepatocytes if original insult persists or if new insults supervene.

3. Emergence of basement membranes between sinusoidal endothelium and hepatocytes.

D. Loss of biologic controls governing hepatocyte proliferation within the nodules. This may be the mechanism for development of hepatocellular carcinomas in cirrhotic livers. Viral genome is probably important here.


IX. Anatomic Patterns of Cirrhosis:

A. Simple system of pattern designation:

l. Regular (micronodular). Uniform nodules and scars. Nodules generally formed from fragments of single liver lobules.

2. Irregular (macronodular). Nodules and scars of various sizes. Many nodules formed from multiple adjacent liver lobules.

B. Pattern of nodularity and scars reflects pattern of injury and size of necrotic zones. Uniform lobular insult leads to regular cirrhosis. Non-uniform confluent necrosis leads to irregular cirrhosis.

C. Irregular cirrhosis is usually the true end-stage pattern, since small, simple nodules can be converted to bigger, complex ones by ingrowth of new portal tracts, by other changes in blood flow, or by destruction of small nodules, thus converting small scars to bigger ones and allowing adjacent nodules to expand. A cirrhotic liver is constantly being remodeled.

D. Anatomic classification of cirrhosis often poorly correlates with etiology. Ideal classification is purely etiologic, not morphologic.

Primary Malignant Tumors of the Liver

In the US, metastases to the liver are much more common than are primary malignant tumors. However, in other parts of the world (Africa and China) these tumors are much more common. As the two major types of primary liver tumors often arise in the setting of long-standing chronic liver injury, we will briefly mention them here.

1. Hepatocellular Carcinoma (Hepatoma or HCC) These tumors are thought to be "derived" from hepatocytes. Hepatitis B and C are both important risk factors for developing this tumor. Cirrhosis from any cause is also a risk factor for HCC, but the incidence of developing tumors depends on the underlying cause of the cirrhosis. In Africa, aflatoxin (produced by rotting peanuts) is a major cause of tumors which may act synergistically with Hepatitis B. These tumors may make Alpha-fetoprotein (AFP) which can be detected in the blood. In countries with a high incidence of HCCs, widespread AFP screening is used to detect these tumors at an early stage. Histologically these tumors have a growth pattern which mimics normal liver. Some well-differentiated tumors even make bile.

2. Cholangiocarcinoma ( Klatskin tumor) These tumors are derived from bile duct epithelium and have a completely different set of risk factors than HCCs. Primary sclerosing cholangitis, exposure to thorotrast (used for radiologic imaging many years ago), and invasion of the biliary tract by liver flukes (Opisthorchis sinensis, found only in Asia). Histologically these tumors may look identical to metastatic adenocarcinomas from other sites, such that another primary tumor must always be excluded on clinical grounds before making a definitive diagnosis.