As you have learned, the liver is responsible for many essential functions. Because of these activities, it is exposed to a wide variety of insults and is therefore one of the most frequently injured organs in the body. The impairment of these vital functions by hepatic disease leads to clinical manifestations that are often similar, regardless of the specific cause. This section first explores the numerous causes of liver disease and then describes the signs and symptoms of hepatic dysfunction.
These objectives will focus your attention on expected learning outcomes. After you complete this section, you should be able to:
1. Identify the major causes of hepatitis.
2. Describe the major causes and potential consequences of portal hypertension.
3. Identify three major metabolic diseases involving the liver.
4. Describe acute, fulminant, and chronic hepatitis.
5. Describe the significance of the designations chronic persistent hepatitis and chronic active hepatitis in chronic viral hepatitis.
6. Describe the classification and major clinical features of jaundice.
7. Identify the clinical features and significance of cirrhosis, hepatocellular carcinoma, and hepatic failure.
1. Hepatitis, or inflammation of the liver, has numerous potential causes: infections with viruses, bacteria, fungi, or protozoa; exposure to toxins such as alcohol, drugs, or chemical poisons; and autoimmunity.
2. Portal hypertension involves an increase in portal blood pressure due to obstruction of, or increased resistance to, blood flow, and it can lead to ascites, rupture of esophageal varices, and portosystemic shunting.
3. Metabolic diseases such as Wilson’s disease, hemochromatosis, and alpha 1 – antitrypsin deficiency can lead to liver damage.
4. The liver can compensate for a significant amount of damage, but eventually liver function will decline markedly (decompensation), as manifested by diminished synthesis, abnormal clearance and excretion, ascites, and portal hypertension.
5. Acute hepatitis may resolve without significant sequelae, but unresolved inflammation that persists for longer than six months is termed chronic hepatitis. Chronic hepatitis may be caused by ongoing infection and associated inflammation or by repeated exposure to toxins, such as alcohol. Whatever the offending agent, chronic inflammation may lead to irreversible liver scarring and fibrosis, a condition known as cirrhosis of the liver. Occasionally, acute infection results in massive tissue destruction and high risk of death (fulminat hepatitis).
6. Chronic persistent hepatitis and chronic active hepatitis are histologic designations developed for autoimmune chronic hepatitis; they do not carry any prognostic value in chronic viral hepatitis.
7. Jaundice is related to increased levels of serum bilirubin (hyperbilirubinemia) that lead to a yellow appearance of the skin and whites of the eyes.
8. Jaundice may involve unconjugated or conjugated hyperbilirubinemia; the latter may be due to hepatocellular or cholestatic disorders.
9. Cirrhosis is pathologically defined as irreversible, diffuse fibrosis (or scarring) of the liver that is a common endpoint for many chronic liver diseases; it carries an increased risk of liver decompensation, hepatic failure, and the development of hepatocellular carcinoma.
10. Hepatocellular carcinoma is often associated with cirrhosis and with chronic viral hepatitis; it is usually diagnosed at an advanced stage, with very poor prognosis.
11. Hepatic failure is marked by severe impairment of liver functions and is usually accompanied by encephalopathy; death occurs in over 50% of cases.
12. Cirrhosis, hepatocellular cancer, and hepatic failure can all occur as a result of chronic viral hepatitis.
A. Causes of Liver Dysfunction
Liver disease has numerous causes, ranging from microbial infections and neoplasms (tumors) to metabolic and circulatory problems.
I. Inflammatory Disorders (Hepatitis). Hepatitis involves inflammation and damage to the hepatocytes. This type of insult may result from infectious agents, toxins, or immunologic attack. In addition, other disorders such as Wilson’s disease can cause hepatitis, and some diseases such as alpha 1 -antitrypsin deficiency can imitate hepatitis. However, the most common cause of hepatitis is viral infection.
a. Infection. Infection is a very important cause of hepatitis, since primary viral infection of the liver is common and viruses cause the majority of liver infections. Three major viruses cause hepatitis in the United States: hepatitis viruses A, B, and C. Together, they infect nearly 500,000 people in the United States every year. Viral hepatitis will be discussed in detail in Module 2.
In addition, bacteria, fungi, and protozoa can infect the liver, and the liver is almost inevitably involved to some extent in all blood-borne infections.
b. Toxins. Toxins such as alcohol, drugs, or poisons can cause hepatitis directly (by damaging liver tissue) or indirectly (by reducing defenses or stimulating an autoimmune response), but the exact mechanism is not always clear.
Alcohol. Alcohol is primarily metabolized by the liver, and these metabolites can cause liver damage. The risk of hepatic toxicity increases if more than 40 grams, or about four drinks, are consumed per day.
Drugs. Numerous medications can damage the liver, ranging from mild, asymptomatic alteration in liver chemistries to hepatic failure and death. Liver toxicity may or may not be dose-related. Dilantin (an anti-convulsant) and isoniazid (an anti-tuberculosis agent) are examples of drugs that can cause “viral-like” hepatitis.
Chemicals/Poisons. Both environmental and industrial toxins can cause a wide variety of changes in the liver. Hepatic damage is not necessarily dose-dependent and can range from mild, asymptomatic inflammation to fulminant failure or progressive fibrosis and cirrhosis.
c. Immunologic mechanisms. The immune system functions primarily to recognize “foreign” or ‘non-self” antigens, for example, invading viruses, bacteria, and their proteins. These antigens may be recognized by antibodies, proteins that can specifically bind to them and help remove them from the body. Occasionally, autoimmunity develops, whereby the immune system incorrectly reacts against “self” antigens, (one’s own cells). This occurs in autoimmune hepatitis and primary biliary cirrhosis, two diseases in which the immune system attacks and destroys portions of the liver. If unchecked, persistent inflammation can eventually lead to cirrhosis.
2. Vascular Disorders. Obstruction of portal blood flow that drains the intestines, stomach and spleen results in portal hypertension (elevation in portal blood pressure). Think of the liver as a sieve that filters portal blood; with scarring from repeated injury, the holes of the sieve become progressively smaller, resisting flow. Resistance to blood flow can also occur before the portal blood reaches the liver.
Portal hypertension can lead to ascites, an accumulation of fluid that fills and distends the abdomen. Two serious consequences of portal hypertension include:
· rupture of dilated esophageal blood vessels ( varices) causing massive bleeding
· portosystemic shunting, in which substances from the gut (including drugs, bacteria, and toxic substances such as ammonia) bypass the liver and thus have access to other body tissues (for example, hepatic encephalopathy due to brain exposure to ammonia or other nitrogen-containing materials)
3. Metabolic Disorders. Problems with metabolic processes in the liver can be either congenital (present at birth) or acquired. Some of these disorders, such as Wilson’s disease and hemochromatosis, can present as hepatitis or cirrhosis and must be distinguished from other causes of these forms of liver disease.
As explained earlier, Wilson’s disease is a rare inherited condition, mostly affecting young people, that is characterized by an inability to excrete copper into bile, resulting in the toxic accumulation of copper in the liver and nervous system. Manifestations include liver disease (including fulminant hepatitis, chronic active hepatitis, and cirrhosis) and neuropsychiatric symptoms.
Hemochromatosis is an iron overload syndrome causing iron deposits and consequent damage to various organs, including the liver (cirrhosis), heart (heart failure), pancreas (diabetes), and pituitary gland (decreased sex drive and impotence). The disease may be due to an inherited increase in gut absorption of iron or to multiple blood transfusions, since iron is normally found in circulating red blood cells.
Alpha 1 – antitrypsin deficiency is an inherited disease that predisposes the affected person toemphysema (or lung destruction), especially with smoking. Alpha 1 – antitrypsin inactivates other enzymes, causing damage to organs if left unchecked. The lung is the most severely affected organ in patients with this disease, but approximately 10% of adult patients will also develop cirrhosis.
4. Neoplastic Disorders. Benign (non-cancerous) hepatic tumors are generally asymptomatic. The most common are hemangiomas, blood-filled vascular channels which occur more often in women and are present in about 5% of the population.
The liver is the most frequent site for blood-borne malignant tumor metastases, including colorectal, breast, lung, stomach, pancreas, and ovarian cancers, and malignant melanoma (a skin cancer), among others. Primary malignant liver cancer – hepatocellular carcinoma (HCC) – most commonly occurs in patients with cirrhosis from viral infection, alcoholism, hemochromatosis, or alpha 1 – antitrypsin deficiency. Men are affected more frequently than women, and the prognosis is dismal, with an average survival of about six months after symptoms begin. Hepatocellular carcinoma will be discussed in more detail later in Section II – B-5.
5. Liver Involvement in Extrahepatic Disorders. The liver may be affected by numerous conditions, particularly autoimmune disorders, in which the immune system attacks the body’s own normal tissues. Some examples include rheumatic diseases (such as systemic lupus erythematosus and rheumatoid arthritis) and inflammatory bowel diseases (such as ulcerative colitis and Crohn’s disease).
Systemic infections, such as tuberculosis, candidiasis, and toxoplasmosis, may spread to the liver. In addition, heart failure can lead to liver congestion, scarring, and ascites, because blood cannot drain from the liver properly when the heart is not pumping effectively.
Clinical Manifestations of Liver Dysfunction
A variety of insults can damage the liver, but their signs and symptoms are similar and may be due to hepatic dysfunction and/or obstruction to blood or bile flow. These manifestations include symptoms and signs of hepatitis, jaundice, cirrhosis, hepatocellular carcinoma, and hepatic failure.
1. Natural History of Hepatic Disease. Hepatocyte injury, such as occurs in acute viral hepatitis infection, stimulates an inflammatory response designed to try to eliminate the cause of the injury. Hepatocytes are frequently damaged and destroyed during the course of the inflammation; the death of these cells is termed hepatocellular necrosis. This type of injury may be initially well tolerated due to a large reserve of functioning hepatic tissue (compensated liver disease), and the injury may be repaired by regeneration with minimal loss.
However, with severe, continuing, or repeated damage, such as in chronic hepatitis, compensatory regeneration eventually fails to repair the whole injury (it may be too large and/or the framework may have been destroyed), and the destroyed hepatocytes are replaced by scar tissue (fibrosis), leading to cirrhosis. The liver is a resilient organ and can tolerate a certain amount of cell loss, but eventually a threshold is reached and liver function declines markedly. Such decompensation may be manifested by the following:
· synthetic defect – fewer normally functioning liver cells reduce the amounts of serum albumin and coagulation factors (a marked abnormality in blood clotting is associated with a poor prognosis)
· abnormal clearance – decreased hepatic clearance of gut-absorbed proteins and ammonia can produce hepatic encephalopathy, a poisoning of the brain with symptoms ranging from confusion to coma
· abnormal excretion – accumulation of serum bilirubin, which is normally taken up by the liver and excreted into bile, resulting in jaundice
· ascites – increased sinusoidal pressure, as with severe inflammation or scarring of the liver, leads to fluid accumulation in the abdomen that becomes more difficult to control with progressive decompensation
· portal hypertension – scarred liver tissue acts as a barrier to blood flow and causes increased portal blood pressure; a major risk is the rupture of esophageal varices, resulting in massive bleeding that may be fatal
2. Inflammation/Hepatitis. As described previously, hepatitis involves inflammation and damage of normal liver cells and is most commonly associated with viral and toxic insults. In general, the diagnosis is often made by excluding various viral, toxic, and metabolic etiologies until only one remains. For hepatitis B and hepatitis C, however, tests are available that may definitively detect the presence of virus in the blood.
a. Acute hepatitis. Clinically, patients with hepatitis may be completely asymptomatic and without jaundice. More commonly, they complain of such symptoms as anorexia (loss of appetite), nausea, weakness, headache, muscle aches, altered small or taste, aversion to foods or tobacco, fever, abdominal pain, and jaundice. Hepatitis is generally considered acute if it resolves without sequelae (long-term changes) within six months. Serological tests for hepatitis A IgM should be positive if the person has acute hepatitis A. If the person has acute hepatitis B, the serological markers that may be positive include hepatitis B surface antigen, hepatitis B e antigen or hepatitis B IgM core antibody.
b. Fulminant hepatitis. Rarely, a severe hepatitis results in acute, massive destruction of large portions of the liver or the entire organ. The most common causes are viruses and drug reactions. Decompensation rapidly occurs, manifested by encephalopathy, fever, marked jaundice, and either an enlarged tender liver or a shrunken liver, with a severe decline in liver function. The risk of death is high, and survival depends on the ability of the liver to regenerate. If patients recover, they do so fully. Hepatitis B is most likely to cause fulminant hepatitis; hepatitis C is a less frequent cause, while A causes fulminant hepatitis only rarely.
c. Chronic hepatitis. Chronic hepatitis implies ongoing liver inflammation that has existed for more than six months. Chronic hepatitis is most likely caused by hepatitis B or C, if there is an infectious etiology. The anti-HCV test will be positive in the case of the latter, and HBsAg test positive in the former. The presence of HBEAG is indicative of ongoing hepatitis B infection. Symptoms vary greatly and may include fatigue, abdominal pain, and jaundice. A symptomatic or mildly symptomatic patients may escape diagnosis until a routine checkup reveals abnormal liver chemistries or an enlarged liver. Importantly, such persistent inflammation may lead to progressive liver scarring and cirrhosis.
Historically, histologic patterns such as chronic persistent hepatitis (CPH) and chronic active hepatitis (CAH) were used to predict disease progression and prognosis. These classifications were originally developed to describe types of idiopathic autoimmune chronic active hepatitis (IACAH). It has since been recognized that in chronic viral hepatitis, histological activity is not directly related to prognosis. Instead, the presence and replicative activity of the virus are most important in determining disease progression. Although histologic examination is still important in clinical assessment, it has been proposed that chronic hepatitis be classified primarily by etiology see Figure 10., without using histology to imply prognosis.
d. Carrier state. Carriers are completely asymptomatic individuals who harbor the virus without evidence of liver inflammation or damage. Liver chemistries and tissue biopsies are normal. Lifespan is considered normal, barring additional independent insults to the liver. The carrier state most commonly occurs with hepatitis B infection, in about 5% of those infected as adults.
3. Jaundice. A patient with jaundice has a yellow appearance, due to increased serum bilirubin (hyperbilirubinemia) , with deposition of bile pigment in the skin, mucous membranes, and sclera (whites of the eyes).
Jaundice does not occur until the serum bilirubin exceeds 2 to 2.5 mg/dL and is generally asymptomatic. However, a jaundiced person may complain of pruritus , or itching of the skin; this is more common with chronic cholestasis. In addition, stools may be “clay-colored” (due to decreased biliary pigment excreted into the gut) and urine may be dark (due to increased bilirubin excreted in the urine).
4. Cirrhosis. Cirrhosis is the common endpoint of many chronic liver diseases, since inflammation and cell death eventually yield to fibrosis, or scar formation. Cirrhosis involves irreversible damage to the lobular architecture, with diffuse fibrous bands of scar tissue surrounding nodules of regenerating hepatocytes. A pathologic diagnosis based on liver biopsy, cirrhosis is described as micronodular if the nodule diameter is less than 3 mm and macronodular if it is more than 3 mm.
Patients with cirrhosis have significantly shortened life spans and are at risk for decompensation and hepatic failure, as well as the development of hepatocellular carcinoma.
Chronic viral hepatitis, chronic autoimmune hepatitis, and alcoholic liver disease are the predominant causes of cirrhosis in the United States. Viral infection can be investigated by checking specific blood tests, such as serum antigens or antibodies (discussed in Section III). Autoimmune liver disease may be detected by discovering certain autoimmune antibodies in the blood. Alcoholic cirrhosis can usually be inferred from a history of chronic alcohol consumption. A liver biopsy may be helpful in distinguishing causes, but in some patients, an exact etiology cannot be determined (cryptogenic cirrhosis). Cirrhosis may also be caused by metabolic diseases (Wilson’s disease, hemochromatosis, and alpha 1 – antitrypsin deficiency, all of which can be diagnosed by laboratory tests and/or liver biopsy) or toxins (diagnosed by positive history for drugs, environmental or industrial toxins, and confirmatory lab investigation).
Cirrhosis may be clinically silent for many years except for progressive weight loss, fatigue, and chronic jaundice. Eventually, liver failure and portal hypertension develop, with deepening jaundice, bleeding from esophageal varices, intractable ascites, and encephalopathy. Death usually occurs as a result of bleeding, hepatic coma, infections (such as spontaneous bacterial peritonitis, or infection of ascitic fluid), or kidney failure.
5. Hepatocellular Carcinoma. Primary malignant cancer of the liver, or hepatocellular carcinoma (HCC), is associated with a dismal prognosis since it is usually diagnosed at a late stage. Cirrhosis often progresses to the development of this tumor; in fact, about 75% to 95% of patients who develop HCC have cirrhosis. This tumor is also associated with certain hepatitis viruses (B and C), as indicated by its prevalence in certain areas of the world where the incidence of viral hepatitis is high.
a. Etiology/epidemiology. HCC is most common in Africa, the Far East (Taiwan, southeast China, Japan), and southern Europe, probably due to the high incidence of chronic viral hepatitis in these areas.
In the United States, approximately 3 people per 100,000 develop HCC each year. HCC is more common in men, particularly in their 50s and 60s. It generally occurs in those with long-standing cirrhosis associated with alcoholism, post-viral hepatitis B and C, hemochromatosis, or alpha 1 – antitrypsin deficiency. HCC rarely develops in patients with cirrhosis due to Wilson’s disease or primary biliary cirrhosis.
b. Pathogenesis. Chronic inflammatory diseases of the liver, as in other tissues, may increase the risk of developing cancer. Nodular regeneration in cirrhotic livers may lead to cellular dysplasia (alteration in shape, size, and organization of cells), since errors are more likely to be made in more actively dividing cells. This is most likely an intermediate step in the progression to carcinoma, the proliferation of mutated cells. Additionally, excessive cell turnover probably increases the susceptibility to carcinogens (agents that may induce cancer) and may promote the expression of oncogenes (“cancer geners”). Hepatitis B genomic material (fragments of hepatitis B virus DNA) has been found integrated in cancer cells, but the significance of this finding is not clear.
c. Clinical features and prognosis. Hepatocellular carcinoma is usually well advanced by the time patients present with symptoms, which include right-upper quadrant pain (often a “dull ache”), weight loss, anorexia, nausea, fever, or sudden worsening of jaundice or ascites. Severe pain may be associated with bleeding into the liver or abdomen. On physical exam, the liver may be stony hard. Unfortunately, the prognosis is dismal, primarily because the disease is at an advanced stage at diagnosis (extensive hepatic enlargement and/or metastatic spread to the lungs). Complete surgical removal of the affected tissue offers the only potential cure. Chemotherapy is ineffective, and most patients die within 3-6 months of presentation (primarily from liver failure or bleeding).
6. Hepatic Failure. Hepatic failure involves the systemic complications associated with severe liver injury and dysfunction. It may occur in a patient without pre-existing liver disease or may be superimposed on chronic liver injury. The diagnosis of acute liver failure requires the presence of symptoms, including jaundice and encephalopathy. Mortality exceeds 50%, even in the best circumstances. Management involves general supportive measures until the liver can regenerate and resume function. In acute liver failure without pre-existing disease, liver transplant may be life-saving.
a. Underlying conditions. About 2000 patients a year develop fulminant hepatic failure in the United States. The most common cause is viral hepatitis, followed by hepatotoxic drugs.
b. Clinical features. Fulminant hepatic failure impairs all liver functions, causing decreased bilirubin metabolism (jaundice), decreased clearance of ammonia and gut-derived proteins (encephalopathy), and decreased clotting factor production (coagulopathy ). It may also cause kidney failure (such as hepatorenal syndrome respiratory failure (due to infection, water accumulation, or inflammation of the lungs), shock (severe fall in blood pressure), and sepsis (systemic infection, probably a result of decreased clearance of portal bacteria by the liver).
Without a liver transplant, more than 50% of patients will die, usually from a combination of the above conditions. However, if patients survive without transplantation, their livers may regenerate to normal functional capacity, especially if the liver was healthy before failure began.
Liver disease may have a variety of origins. Inflammation, or hepatitis, may be caused by infection (especially viral infection), exposure to toxins (including alcohol and drugs), or autoimmune reactions. Portal hypertension and metabolic diseases, such as Wilson’s disease and hemochromatosis, can also cause significant liver problems. In addition to benign primary tumors and malignant metastases, the liver may develop hepatocellular carcinoma, which carries a dismal prognosis. The liver may also become involved in a number of systemic conditions, including autoimmune disorders, infections, and heart failure.
Regardless of the specific cause, liver disease frequently presents similar clinical manifestations. Initially, symptoms may be mild, since this resilient organ can compensate for a certain amount of damage. However, eventually decompensation occurs, characterized by a marked decline in liver functions and the development of ascites and portal hypertension.
Hepatitis may be acute (with recovery within six months), fulminant (acute critical illness with high mortality rate), or chronic (persistent disease for more than six months). Manifestations of hepatic desease include jaundice (hyperbilirubinemia), cirrhosis (irreversible fibrosis and scarring), hepatocellular carcinoma (primary malignant cancer of the liver), and hepatic failure (severe decline in all liver functions).