Liver
A variety of agents, including viruses, drugs, environmental pollutants, genetic disorders, and systemic diseases, can affect the liver. The resulting disorders usually affect one of the three functional components: the hepatocyte (liver cell), the bile secretory (cholangiolar) apparatus, or the blood vascular system. Although an agent tends to cause initial damage in only one of these areas, the resulting disease may in time also involve other components. Thus, although viral hepatitis (inflammation of the liver) predominantly affects hepatocytes, it commonly leads to damaged canaliculi, small channels that transport bile from hepatocytes.
Most acute liver diseases are self-limiting, and liver function returns to normal once the causes are removed or eliminated. In some cases, however, the acute disease process destroys massive areas of liver tissue in a short time, leading to extensive death (necrosis) of hepatic cells. For example, when acute hepatitis lasts for six months or more, a slow but progressive destruction of the surrounding liver cells and bile ducts occurs, a stage called chronic active hepatitis. If hepatocellular damage is severe enough to destroy entire acini (clusters of lobules), healthy tissue is often replaced with fibrous scar tissue. Bile canaliculi and hepatocytes regenerate in an irregular fashion adjacent to the scar tissue and result in a chronic condition called cirrhosis of the liver. Where inflammatory activity continues after the onset of cirrhosis, the disorderly regeneration of hepatocytes and cholangioles may lead to the development of hepatocellular or cholangiolar cancer.
Acute hepatocellular hepatitis
Although a number of viruses affect the liver, including cytomegalovirus and Epstein-Barr virus, which causes infectious mononucleosis, there are three distinctive transmissible viruses that are specifically known to cause acute damage to liver cells: hepatitis A virus (HAV), hepatitis B virus (HBV), and hepatitis C virus (HCV).
The hepatitis A virus is transmitted almost exclusively via the fecal–oral route, and it thrives in areas where sanitation and food handling are poor and hand washing is infrequent. HAV proliferates in the intestinal tract during the two weeks following the onset of symptoms, but it then disappears. Many infected persons are unaware of being ill, since their disease remains asymptomatic or quite mild. The incubation period of HAV infections, from viral ingestion to the onset of symptoms, averages four to five weeks. Acute illness in an otherwise healthy pregnant woman does not appear to have adverse effects upon the fetus. Persons can become passively immunized against HAV for several months with either the hepatitis A vaccine or a single injection of immunoglobulin. Persons can be actively immunized to HAV by acquiring the virus subsequent to becoming passively immunized, but such infections are either inapparent or very mild.
Hepatitis B virus is present throughout the world in asymptomatic human carriers who may or may not have ongoing liver disease. Formerly, the disease was widely spread by the transfusion of whole blood or blood products, such as the cryoprecipitate used in the treatment of hemophilia. Since the signs of infection have become so readily identifiable, this mode of transmission is much less common, comprising only about 10 percent of cases, compared with 60 percent in the past. Virus particles in carriers are found in bodily secretions, especially saliva and sexual emissions, as well as in blood. The incidence of B antigens is high among persons engaging in promiscuous sexual activity, drug addicts who share syringes, health care workers, and infants of mothers who are carriers. Many newly infected persons develop the acute disease within three weeks to six months after exposure, while some develop an asymptomatic form of hepatitis that may appear only as chronic disease years later. Others eliminate the virus completely without any symptoms beyond the appearance of antibodies to surface antigen, while still others become carriers of surface antigen and thus presumably are infective to others.
There are two methods of preventing hepatitis B: passive immunization, through the use of a specific immunoglobulin derived from patients who have successfully overcome an acute HBV infection; and active immunization, through the injection of noninfective, purified HBV surface antigen. The first method is used following specific exposures that carry a high risk of infection, such as using needles contaminated with HBV particles, the ingestion of body secretions likely to be infected, or the birth of an infant to a surface-antigen-positive mother. The second method, active immunization, is used for those who belong to groups with a high risk of HBV infection, such as children living in endemic areas, medical personnel in high-risk specialties, drug addicts, sexually promiscuous persons, and family groups living close to known carriers. Active immunization, involving a series of three injections of vaccine over a period of three to six months, has been shown to confer a high degree of resistance to infection.
Hepatitis C appears to be transmitted in a manner similar to HBV transmission. The incidence for HCV is high among persons engaging in promiscuous sexual activity, intravenous drug users, homosexual males, children living in endemic areas, infants born to infected mothers, health care workers, and hemodialysis patients. The average incubation period of the disease is about seven weeks, and an acute attack of hepatitis C is usually less severe than acute hepatitis B. Hepatitis C, however, is more likely to become chronic than is hepatitis B, and it may recur episodically with acute flares. The two approved treatments for hepatitis C are alpha interferon and ribavirin; only about half of those receiving the drugs respond to them.
The symptoms characteristic of acute hepatitis caused by HAV, HBV, and HCV are essentially similar. Patients often complain of a flulike illness for several days, with chills, fever, headache, cough, nausea, occasional diarrhea, and malaise. Abdominal pain caused by swelling of the liver is a common complaint. As many as half of the infected patients develop only mild symptoms or none at all. A small percentage of patients, especially those with HBV infections, may develop hives, painful skin nodules, acute arthritis, or urinary bleeding caused by the deposition of large immune antigen-antibody complexes in the small blood vessels of adjacent organs. After several days of such symptoms, jaundice commonly develops. At times the jaundice is so mild that it is not noticed by patients, although they often do note that the urine has become dark amber in colour because of the high levels of water-soluble bilirubin transmitted to the kidneys by the bloodstream.
The onset of jaundice usually brings with it a marked improvement in other symptoms. Jaundice lasts about two weeks but may continue for several months, even in those who have complete recovery. Some patients complain of itching during this period, and they notice the light colour of their stools. These symptoms probably result from the compression of bile canaliculi and intralobular bile ducts by the swelling of hepatocytes and Kupffer cells. The changes result in the reduced secretion of bile pigments into the biliary system, their reflux into the bloodstream, and the deposition of bile salts and other biliary constituents in the skin and subcutaneous tissues, a condition called obstructive jaundice. After the phase of jaundice subsides, almost all patients with hepatitis A, and at least 90 percent of those with hepatitis B, recover completely.
Aside from jaundice, the physical examination of patients with acute viral hepatitis may reveal nothing more than a detectable enlargement and, at times, tenderness of the liver. Some also show an enlarged spleen. Signs of confusion or disorientation indicate severe damage to the liver. The diagnosis of hepatitis is confirmed by blood tests that show marked elevations of enzymes (aminotransferases) released from damaged liver cells and by the presence of viral antigens or acute viral antibodies (IgM).
A small number, perhaps 1 percent, of patients with viral hepatitis, especially the elderly, develop a sudden, severe (fulminant) form of hepatic necrosis that can lead to death. In this form of the disease jaundice increases to high levels during the first 7 to 10 days, spontaneous bleeding occurs because of reductions of blood-clotting proteins, and irrational behaviour, confusion, or coma follow, caused by the accumulation in the central nervous system of the breakdown products of protein normally metabolized by the liver. Beyond supportive measures there is no effective treatment of fulminant hepatic failure except liver transplantation.
Acute hepatitis also may be caused by the overconsumption of alcohol or other poisons, such as commercial solvents (e.g., carbon tetrachloride), acetaminophen, and certain fungi. Such agents are believed to cause hepatitis when the formation of their toxic intermediate metabolites in the liver cell is beyond the capacity of the hepatocyte to conjugate, or join them with another substance for detoxification and excretion.
Acute canalicular (cholestatic) hepatitis
Acute canalicular (cholestatic) hepatitis is most commonly caused by certain drugs, such as psychopharmacologics, antibiotics, and anabolic steroids or, at times, by hepatitis viruses. The symptoms are generally those of biliary obstruction and include itching, jaundice, and light-coloured stools. Drug-induced cholestasis almost invariably disappears within days or weeks after exposure to the agent is discontinued. Acute congestive liver disease usually results from the sudden engorgement of the liver by fluids after congestive heart failure. The liver may enlarge and become tender. The levels of hepatocytic enzymes in the blood are often greatly increased, and recovery is rapid once the heart failure improves. Jaundice is uncommon in acute hepatic congestion.
Chronic active hepatitis
Chronic hepatitis is the result of unresolved acute injury and is associated with ongoing liver damage. The course of the disease is usually slow but relentlessly progressive. A milder form of chronic disease, called persistent hepatitis, does not appear to lead to progressive liver damage despite evidence of a continuing mild inflammation. These conditions may result from viral hepatitis, drug-induced hepatitis, autoimmune liver diseases (lupoid hepatitis), or congenital abnormalities. A prominent autoimmune liver disease is Wilson disease, which is caused by abnormal deposits of large amounts of copper in the liver. Granulomatous hepatitis, a condition in which localized areas of inflammation (granulomas) appear in a portion of the liver lobule, is a type of inflammatory disorder associated with many systemic diseases, including tuberculosis, sarcoidosis, schistosomiasis, and certain drug reactions. Granulomatous hepatitis rarely leads to serious interference with hepatic function, although it is often chronic.
Chronic viral hepatitis B and C can be treated with interferon. Cirrhosis of the liver, and occasionally liver cancer, usually result from a gradual loss of liver function. Chronic hepatitis that is the result of autoimmune disorders usually responds to the administration of immunosuppressive medications and adrenal corticosteroids, which moderate the inflammatory reaction.
Cirrhosis
The end result of many forms of chronic liver injury is cirrhosis, or scarring of liver tissue in response to previous acinar necrosis and irregular regeneration of liver nodules and bile ducts. Among the congenital disorders producing cirrhosis are Wilson disease, hemochromatosis (over-deposition of iron pigment), cystic fibrosis, biliary atresia (congenital absence of a part of the bile ducts), and alpha1-antitrypsin deficiency, or the congenital absence of a proteolytic enzyme inhibitor that results in the accumulation of abnormal forms of carbohydrate in hepatocytes. In the Western world, cirrhosis of the liver most commonly results from chronic heavy intake of alcohol. This type of cirrhosis is known as Laënnec, or portal, cirrhosis. Chronic viral hepatitis is probably the leading cause of cirrhosis in underdeveloped countries. Primary biliary cirrhosis, a geographically widespread, though uncommon, autoimmune inflammatory disease of bile ducts, is a disorder primarily affecting middle-aged and older women. The inflammation leads to necrosis and gradual disappearance of bile ducts over a period of one or more decades. Secondary biliary cirrhosis results from chronic obstruction or recurrent infection in the extrahepatic bile ducts caused by strictures, gallstones, or tumours. Infestation of the biliary tract with a liver fluke, Clonorchis sinensis, is a cause of secondary biliary cirrhosis in Asia. Cirrhosis occasionally is the result of chronic vascular congestion of the liver in persons with prolonged heart failure and in those with chronic obstruction of the hepatic veins caused by benign blood clots or metastatic cancer.
Symptoms of cirrhosis are usually absent during the early stages of the disease. Occasionally, cirrhosis is detected during a physical examination when an enlargement of the liver, spleen, or veins in the upper abdominal wall is found. More often, patients develop symptoms related either to the failure of the liver to perform its functions or to complications caused by the circulatory changes that a cirrhotic liver imposes on the venous blood flow from the intestinal tract (portal hypertension). Thus, common symptoms of cirrhosis include jaundice, resulting from reduced passage of conjugated bilirubin into the biliary tract; increased bleeding, from sequestration of blood platelets in a congested spleen; or deficient production of short-lived coagulation proteins by the liver. There may be certain changes in the skin, such as the appearance of small spiderlike vascular lesions on the hands, arms, or face, a marked reddening of portions of the palms, or enlargement of the breast in females or reduction in testicular size in males. These symptoms are believed to occur because of the liver’s inability to metabolize the female sex hormones normally produced by the body. The gradual accumulation of fluid in the abdominal cavity (ascites), sometimes accompanied by swelling of the ankles, is attributable to portal hypertension and to reduced hepatic production of albumin, while failure of the liver to metabolize amino acids and other products of protein digestion may lead to the state of confusion called hepatic encephalopathy. Loss of appetite, reduction of muscle mass, nausea, vomiting, abdominal pain, and weakness are other symptoms of hepatic cirrhosis. Diabetes in a patient with cirrhosis is frequently caused by hemochromatosis (excessive deposition of iron in tissues, especially in the liver and pancreas), since iron deposits compromise the production of insulin by the islets of Langerhans in the pancreas. Severe spastic disorders of the muscles in the limbs, head, and face suggest the presence of Wilson disease, especially if there is a family history, since the copper deposits characteristic of that disorder are toxic to the liver and to structures in the base of the brain. A history of chronic lung infections or of progressive obstructive lung disease may be present in patients with cystic fibrosis or a deficiency of alpha1-antitrypsin.
A diagnosis of cirrhosis is confirmed by blood tests that show an elevated concentration of hepatocytic enzymes, reduced levels of coagulation proteins, elevated levels of bilirubin, and, most important, reduced amounts of serum albumin (a major protein of human blood plasma) and increases in serum globulin (a specific group of proteins found in blood plasma and including immunoglobulins). Although other tests may also be abnormal in patients with acute liver disease, serum albumin levels are usually not reduced in the acute stage of the disease because that protein is rather long-lived (up to one month) and levels do not decrease until the liver disease becomes chronic. Elevated levels of serum iron or copper support a diagnosis of hemochromatosis or Wilson disease, respectively, while a positive test for serum antibodies to cellular mitochondria is associated almost solely with primary biliary cirrhosis. The presence of HBV surface antigen or of delta agent suggests viral cirrhosis. A biopsy of the liver is the most valuable diagnostic test, since this procedure makes available an actual specimen of liver tissue for microscopic examination. Treatment of cirrhosis of the liver never results in a completely normal organ, since the process of scarring and nodular regeneration is permanent. The process itself, however, can be prevented or its progress halted by managing the precipitating factors of the disease.
