Dubin-Johnson syndrome

Definition

Jaundice is a condition in which the patient has a yellow hue because of high blood levels of bilirubin, a breakdown product of hemoglobin that is potentially toxic. The yellow discoloration is most noticeable in the skin, the sclera (whites of the eyes), and the inner surface of the eyelids.

Description

Jaundice is a physical sign or finding, not a disease. Many different diseases or conditions may cause a person's bilirubin level to be elevated. Most important to the understanding of causes of this sign is a good explanation of normal liver function with regard to the production and excretion of bile. Bile is a fluid excreted by the liver that aids in digestion and absorption of fats.

The liver is a large, solid organ in the right upper quadrant of the abdomen. It is the premier "chemical processing plant" in the body; most incoming and outgoing chemicals pass through it. It is the first stop for all nutrients, toxins, and drugs absorbed by the digestive tract. The liver also collects waste products from the blood for disposal. Many of these outward-bound chemicals (including bilirubin) are excreted into the bile.

Bile is made up of water; chemicals that act as detergents; and substances such as glycogen, bilirubin, cholesterol, and other byproducts of hepatic metabolism. It is formed by cellular metabolism and passes into the network of hepatic bile ducts, which join to form the common duct. A branch of this tube carries bile to the gallbladder, where it is stored and concentrated. When fats enter the stomach, the gallbladder secretes bile into the common bile duct. Before the common bile duct reaches the duodenum, it is joined by another duct from the pancreas. The bile and the pancreatic juice are triggered to enter the intestine through a valve called the ampulla of Vater by the presence of partially digested fats in the duodenum. After entering the intestine, the bile and pancreatic secretions together help to complete the process of digestion.

The liver removes toxins from the bloodstream, including bilirubin. Bilirubin is a potentially toxic waste product from the breakdown of hemoglobin, the oxygen-carrying molecule of red blood cells (RBCs). When bilirubin is first released from old RBCs or other sources, it cannot be dissolved in water. The liver changes it so that it is soluble in water. These two forms are called unconjugated (insoluble) and conjugated (soluble) bilirubin. Because of the type of laboratory test performed on the different forms of this molecule, unconjugated bilirubin is also called indirect bilirubin, and conjugated bilirubin is called direct bilirubin. Bilirubin is a bright yellow pigment and gives bile its characteristic color. If bilirubin cannot be cleared from the body in a timely fashion, it leaks into body tissues and stains them yellow temporarily, resulting in jaundice. The normal level of bilirubin in blood serum is between 0.2 mg/dL and 1.2 mg/dL. When it rises to 3 mg/dL or higher, jaundice becomes evident. "Icteric" is an adjective (based on the Greek word for jaundice) used to describe a jaundiced patient.

Causes and symptoms

There are many different causes of jaundice, but they can be divided into three categories: before, during, or after the liver has performed its task of making bilirubin soluble. These categories can also be called prehepatic, hepatic, and posthepatic causes of jaundice.

Prehepatic causes of jaundice

There are many different prehepatic causes of jaundice. When old RBCs die, hemoglobin is released into the bloodstream. When the rate of formation of new RBCs and the rate of loss of old RBCs are well balanced, the normal liver can keep pace with disposal of used hemoglobin. If the body is having difficulty making RBCs (due to mineral or vitamin deficiencies), hemoglobin may leak into circulation and overwhelm the liver. Conversely, if RBCs are destroyed rapidly, the liver may also be overwhelmed. Disorders that cause RBCs to disintegrate prematurely are called hemolytic disorders.

One cause of hemolysis (or prematurely destroyed RBCs) to be aware of starts at the neonatal point, in babies born of Rh-negative mothers. Other causes include a long list of drugs, among them rifampin, methyldopa, certain antibiotics, quinine, and levodopa. Trauma can also destroy RBCs. Some common causes of trauma include surgery for mechanical heart valves, implants, and roughened surfaces of blood vessels such as occur in microangiopathic hemolytic anemia. The parasite that causes malaria develops inside red blood cells and ruptures the RBCs when it is mature. A number of hereditary defects affect red blood cells, including glucose-6-phosphate dehydrogenase (G6PD) deficiency (in which RBCs disintegrate under certain stresses, particularly when exposed to certain drugs), sickle-cell disease (in which the structure of hemoglobin is abnormal), and spherocytosis (in which a protein in the outer membrane of the RBC causes weakness in the membrane).

An enlarged spleen can also cause hemolysis. The spleen is the reservoir organ, located near the upper end of the stomach, that filters the blood. It is supposed to filter out and destroy only worn-out RBCs. If it becomes enlarged, it filters out normal cells as well. A wide variety of conditions, including many causes of hemolysis listed above, can enlarge the spleen to the point where it removes too many red blood cells. Also, in several types of cancer (such as chronic leukemia) and immune-system diseases, antibodies are produced that react with RBCs and destroy them. In addition, if a patient is given an incompatible blood type, it sets off an immune reaction, and hemolysis results.

In all causes of prehepatic jaundice, the predominant bilirubin is insoluble-that is, unconjugated. Hemolysis alone will rarely cause the total bilirubin level to rise above 7 mg/dL.

Hepatic causes of jaundice

Liver diseases of all kinds, whether temporary or life-long, threaten the organ's ability to keep up with bilirubin processing. Some of the more common causes of jaundice include infectious hepatitis (types A, B, C, D, and E, and various other viruses), alcoholic hepatitis, and cirrhosis (scarring of the liver, due to various diseases, to the degree that it can no longer function). Starvation, circulating infections, and certain medications (acetaminophen overdose, isoniazid, and others) can cause inefficiency in bilirubin disposal. Certain hereditary defects also affect how the liver processes bilirubin (such as Gilbert's syndrome and Crigler-Najjar syndrome), causing elevated levels of unconjugated bilirubin. Also, there are several inherited conditions in which the liver cannot excrete bilirubin after it is made soluble (such as Dubin-Johnson syndrome and Rotor syndrome), resulting in direct (or conjugated) bilirubin being the predominant form of the molecule. Unlike hemolytic causes of jaundice, which always involve unconjugated bilirubin, the hepatic sources of jaundice often represent mixed results.

Posthepatic causes of jaundice

Posthepatic forms of jaundice include those caused when soluble bilirubin does not reach the intestines after it has left the liver, resulting in elevated direct bilirubin levels. These disorders are called obstructive jaundices. The most common cause of obstructive jaundice is the presence of gallstones in the ducts of the biliary system. Other causes include diseases where the bile ducts have been destroyed, such as the autoimmune disease primary biliary sclerosis, lesions (whether benign or malignant), and trauma. Some drugs (such as anabolic and contraceptive steroids), and occasionally pressures caused by a normal pregnancy, cause the bile in the ducts to stop flowing. This process is called cholestasis.

Neonatal jaundice

Several conditions can cause jaundice in a newborn baby. Erythroblastosis fetalis is a disease of newborns marked by the presence of too many immature red blood cells (erythroblasts) in the baby's blood. When a baby and mother have different Rh factors (positive-RH baby and negative-Rh mother), antibodies from the mother may leak into the baby's circulation through the placental exchange and destroy blood cells. This reaction may produce severe hemolysis and jaundice in the newborn. Rh-factor incompatibility is the most common cause. These births are usually induced a week or two early to keep third-trimester hemolysis to a minimum.

Even in the absence of Rh-factor incompatibility, the newborn's bilirubin level may reach threatening levels. Normal newborn jaundice is the result of two conditions occurring at the same time: a prehepatic and a hepatic source of excess bilirubin. During development, the fetal-type hemoglobin is important to extract oxygen from the mother's blood. At birth, the infant extracts oxygen directly from the lungs and no longer needs the fetal hemoglobin. So, fetal hemoglobin is removed from the system and replaced with mature hemoglobin. The resulting hemoglobin overload overwhelms the immature system, and bilirubin levels may rise until the third day of life, and then decline by day five to day 10. During that time, the baby is jaundiced.

These forms of jaundice in the newborn may result in high levels of unconjugated bilirubin. If conjugated bilirubin is found, it is usually due to serious causes, such as obstruction of the biliary system or overwhelming infection.

Symptoms

Certain chemicals in bile may cause itching in jaundiced patients. Fatigue is a very common symptom in people with liver disease. In more severe illness, nausea may occur. Poor appetite and weight loss can be a problem for some patients, usually those with acute infection or advanced scarring of the liver (cirrhosis). Depending on the cause of jaundice, patients may or may not have pain over the liver (upper right quadrant). Liver pain is common if there are gallstones, and may also occur in acute hepatitis. Patients whose bile does not drain into the small intestine adequately will have clay-colored stools. The conjugated form of bilirubin may be excreted by the kidneys and result in dark urine. Long-standing jaundice may upset the balance of chemicals in the bile and cause stones to form in the gallbladder or in the ducts.

In newborns, the concern about jaundice is that insoluble or unconjugated bilirubin may get into the brain and do permanent damage to the central nervous system. This serious condition is called kernicterus. It becomes a concern as bilirubin levels approach 20 mg/dL. Newborns are more likely to have problems with jaundice if they are premature, Asian or Native American, or bruised significantly during the birth process. Jaundice is also more common if a newborn was born after an induced labor, has lost too much weight during the first few days of life, was born at high altitude, or was born to a diabetic mother.

Diagnosis

In most cases, the sign of jaundice is identified based on the appearance of the patient's sclera and complexion. The liver and spleen are palpated to check for enlargement and to evaluate any abdominal pain. The location and severity of abdominal pain and the presence of masses in the abdomen, together with the presence of fever, help to distinguish among the causes for jaundice. The differential diagnosis of the cause of jaundice is primarily based on blood-test results.

Laboratory testing reveals the total bilirubin and its components. The capability to evaluate total bilirubin levels and the fractionation into direct (conjugated) and indirect (unconjugated) components is available in most laboratories. The jaundice may be determined to be of indirect (prehepatic sources, Gilbert's syndrome, or Crigler-Najjar syndrome) or direct (primarily obstructive posthepatic sources, and some hepatic diseases) origin. Liver enzymes, such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT), should be evaluated; elevations would be signs of inflammation or destruction of liver cells. If the AST is at least twice the level of the ALT, this finding strongly supports the suggestion of alcohol abuse as a source of liver disease. If alkaline phosphatase is elevated, this suggests an obstructive (posthepatic) component in the cause of jaundice. Albumin levels and prothrombin times will be abnormal (elevated) if the liver is severely damaged. Microscopic analysis of blood smears for signs of hemolysis is performed.

Liver disease is usually assessed from blood studies and physical-examination findings, but a biopsy may be necessary to clarify less obvious disease. A liver biopsy may be performed at the bedside. A thin, cannulated needle is inserted to draw a core of tissue from the liver. The tissue sample is sent for patholic examination.

Diseases of the biliary system may be identified by imaging techniques, especially with the use of contrast dye. The most common and cost-effective method for beginning to assess the liver and bile ducts is ultrasound. Dilated bile ducts are very suggestive of obstruction, and abnormal amounts of fat or scar tissue may be noticed. Much more detailed information about the structure of the liver and biliary tree is gained with computed tomography (CT) or magnetic resonance imaging (MRI). Very detailed investigation of the bile ducts is achieved with endoscopic retrograde cholangiopancreatography (ERCP), for which a fiber-optic scope is put down the gastrointestinal tract via the mouth, all the way to the ampulla of Vater. Dye is injected to map the bile ducts and identify obstruction. A tiny brush-tipped device at the end of the scope light is used to scrape tissue from the duct lining for analysis. Treatment can also be achieved at the same time, as stones can be removed or stents placed to aid in passage of a stone or maintaining bile flow in spite of a tumor.

Treatment

Newborns are the one group of patients in whom the jaundice itself requires attention. Because the insoluble bilirubin can get into the brain, the amount in the blood must not go over certain levels. If there is reason to suspect increased hemolysis in the newborn, the bilirubin level must be measured repeatedly during the first few days of life. If the level of bilirubin shortly after birth threatens to go too high, treatment must begin immediately. Exchanging most of the baby's blood (an exchange transfusion) was the only way to reduce the amount of bilirubin until the late 1960s. Then it was discovered that bright blue light renders the bilirubin harmless. Now jaundiced babies are fitted with eye protection and placed under special lights, wearing only a diaper so that more skin surface can be exposed. The phototherapy alters the bilirubin in the blood as it passes through and close to the baby's skin. Under certain conditions, exchange transfusions are still done to rapidly gain control over bilirubin levels.

Most adult patients are treated based on the underlying cause of the jaundice. Surgical removal of the spleen (splenectomy) may arrest hemolytic anemia. Drugs that cause hemolysis or arrest the flow of bile are discontinued or replaced with alternate therapy. The abuse of alcohol or street drugs must stop if the liver is to begin to heal and the jaundice given a chance to subside. Obstructive jaundice frequently requires surgical repair. The gallbladder may need to be removed, or small stones removed from lower in the biliary tract. If there is neoplasm of the liver or biliary tree, partial or total removal is necessary. If the original biliary passageways cannot be restored, new ones are created in surgery.

Prognosis

Prognosis is based on the underlying cause of jaundice. The liver is a very resilient organ, and many patients do well after supportive therapy or surgical intervention for acute causes of jaundice. High bilirubin levels themselves are not dangerous to patients other than neonates, so all symptoms of high bilirubin levels are reversible if the underlying condition is treatable.

Health care team roles

Good supportive care of the jaundiced patient, regardless of the underlying disorder, is important. If alcohol abuse has been an acute or long-standing problem, nursing staff can contribute much in educating the patient about the importance of avoiding alcohol.

Prevention

Many of the numerous causes of jaundice cannot be anticipated or avoided. Alcohol abuse in patients should be identified and support provided to aid in recovery. Erythroblastosis fetalis can be prevented by giving an Rh-negative mother a gamma globulin solution called RhoGAM as a routine part of prenatal care. This will decrease the chances her antibody titer will rise against her baby's blood. Liver problems due to medications can be minimized with appropriate screening blood tests and cessation of the drug if necessary. One cause of liver failure not mentioned previously is anorexia nervosa, in which patients intentionally starve themselves, disabling the body's immune-defense system and overwhelming the liver's ability to detoxify the blood. Patients with this condition need specific psychiatric therapy in addition to adequate nutritional supplementation therapy to prevent liver failure. If it occurs, transplantation may be the only recourse. Malaria may be prevented by taking certain precautions when traveling in tropical or subtropical countries and climates.

Key Terms

Ampulla of Vater

A valve at the distal end of the widened portion of the common bile duct, through which the bile and pancreatic juices enter the duodenum.

Anemia

A condition in which the blood does not contain enough hemoglobin. There are many causes of anemia, including hemolysis, bleeding, and problems producing red blood cells (RBCs).

Biliary system/bile ducts

The gallbladder and the system of tubes that carries bile from the liver into the intestines.

Bilirubin

A breakdown product of hemoglobin that is potentially toxic. The liver collects bilirubin from the bloodstream, alters it, and secretes it into bile.

Hemoglobin

The red pigment in red blood cells that carries oxygen.

Hemolysis

The premature destruction of red blood cells.

Hepatic jaundice

A cause of jaundice; jaundice that occurs while the liver is performing its task of making bilirubin soluble.

Icteric

An adjective, based on the Greek word for jaundice, used to describe a jaundiced patient.

Liver

A large, solid organ in the right upper quadrant of the abdomen that is the body's premier "chemical processing plant" of drugs, nutrients, and toxins.

Neonatal jaundice

Jaundice in a newborn baby, resulting from various conditions.

Pancreas

The organ adjacent to the stomach that produces digestive juices, insulin, and other hormones.

Posthepatic jaundice

A cause of jaundice; jaundice that occurs after the liver has performed its task of making bilirubin soluble.

Prehepatic jaundice

A cause of jaundice; jaundice that occurs before the liver has performed its task of making bilirubin soluble.

Rh incompatibility

When a baby and mother have different Rh factors; a common cause of jaundice in newborns.

Splenectomy

Surgical removal of the spleen, sometimes necessary to control certain types of hemolytic anemia.