Hereditary spherocytosis

Definition

Jaundice is a condition in which a person's skin and the whites of the eyes are discolored yellow due to an increased level of bile pigments in the blood resulting from liver disease. Jaundice is sometimes called icterus, from a Greek word for the condition.

Description

In order to understand jaundice, it is useful to know about the role of the liver in producing bile. The most important function of the liver is the processing of chemical waste products like cholesterol and excreting them into the intestines as bile. The liver is the premier chemical factory 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 chemicals from the blood for processing. Many of these outward-bound chemicals are excreted into the bile. One particular substance, bilirubin, is yellow. Bilirubin is a product of the breakdown of hemoglobin, which is the protein inside red blood cells. If bilirubin cannot leave the body, it accumulates and discolors other tissues. The normal total 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, the person's skin and the whites of the eyes become noticeably yellow.

Bile is formed in the liver. It then passes into the network of hepatic bile ducts, which join to form a single tube. A branch of this tube carries bile to the gallbladder, where it is stored, concentrated, and released on a signal from the stomach. Food entering the stomach is the signal that stimulates the gallbladder to release the bile. The tube, which is now called the common bile duct, continues to the intestines. Before the common bile duct reaches the intestines, it is joined by another duct from the pancreas. The bile and the pancreatic juice enter the intestine through a valve called the ampulla of Vater. After entering the intestine, the bile and pancreatic secretions together help in the process of digestion.

Causes & symptoms

There are many different causes for jaundice, but they can be divided into three categories based on where they start--before, in, or after the liver (pre-hepatic, hepatic and post-hepatic). When bilirubin begins its life cycle, it cannot be dissolved in water. The liver changes it so that it is soluble in water. These two types of bilirubin are called unconjugated (insoluble) and conjugated (soluble). Blood tests can easily distinguish between these two types of bilirubin.

Hemoglobin and bilirubin formation

Bilirubin begins as hemoglobin in the blood-forming organs, primarily the bone marrow. If the production of red blood cells (RBCs) falls below normal, the extra hemoglobin finds its way into the bilirubin cycle and adds to the pool.

Once hemoglobin is in the red cells of the blood, it circulates for the life span of those cells. The hemoglobin that is released when the cells die is turned into bilirubin. If for any reason the RBCs die at a faster rate than usual, bilirubin can accumulate in the blood and cause jaundice.

Hemolytic disorders

Many disorders speed up the death of red blood cells. The process of red blood cell destruction is called hemolysis, and the diseases that cause it are called hemolytic disorders. If red blood cells are destroyed faster than they can be produced, the patient develops anemia. Hemolysis can occur in a number of diseases, disorders, conditions, and medical procedures:

• Malaria. The malaria parasite develops inside red blood cells. When it is mature it breaks the cell apart and swims off in the blood. This process happens to most of the parasites simultaneously, causing the intermittent symptoms of the disease. When enough cells burst at once, jaundice may result from the large amount of bilirubin formed from the hemoglobin in the dead cells. The pigment may reach the urine in sufficient quantities to cause "blackwater fever," an often lethal form of malaria.
• Side effects of certain drugs. Some common drugs can cause hemolysis as a rare but sudden side effect. These medications include some antibiotic and anti-tuberculosis medicines; drugs that regulate the heartbeat; and levodopa, a drug used to treat Parkinson's disease.
• Certain drugs in combination with a hereditary enzyme deficiency known as glucose-6-phosphate dehydrogenase (G6PD). G6PD is a deficiency that affects over 200 million people in the world. Some of the drugs listed above are more likely to cause hemolysis in people with G6PD. Other drugs cause hemolysis only in people with this disorder. Most important among these drugs are anti-malarial medications such as quinine, and vitamins C and K.
• Poisons. Snake and spider venom, certain bacterial toxins, copper, and some organic industrial chemicals directly attack the membranes of red blood cells.
• Artificial heart valves. The inflexible moving parts of heart valves damage RBCs as they flutter back and forth. This damage is one reason to recommend pig valves and valves made of other organic materials.
• Hereditary RBC disorders. There are a number of hereditary defects that affect the blood cells. There are many genetic mutations that affect the hemoglobin itself, the best-known of which is sickle cell disease. Such hereditary disorders as spherocytosis weaken the outer membrane of the red cell. There are also inherited defects that involve the internal chemistry of RBCs.
• Enlargement of the spleen. The spleen is an organ that is located near the upper end of the stomach and filters the blood. It is supposed to filter out and destroy only worn-out RBCs. If it has become enlarged, it filters out normal cells as well. Malaria, other infections, cancers and leukemias, some of the hereditary anemias mentioned above, obstruction of blood flow from the spleen--all these and many more diseases can enlarge the spleen to the point where it removes too many red blood cells.
• Diseases of the small blood vessels. Hemolysis that occurs in diseased small blood vessels is called microangiopathic hemolysis. It results from damage caused by rough surfaces on the inside of the capillaries. The RBCs squeeze through capillaries one at a time and can easily be damaged by scraping against the vessel walls.
• Immune reactions to RBCs. Several types of cancer and immune system diseases produce antibodies that react with RBCs and destroy them. In 75% of cases, this reaction occurs all by itself, with no underlying disease to account for it.
• Transfusions. If a patient is given an incompatible blood type, hemolysis results.
• Kidney failure and other serious diseases. Several diseases are characterized by defective blood coagulation that can destroy red blood cells.
• Erythroblastosis fetalis. 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's mother has a different blood type, antibodies from the mother may leak into the baby's circulation and destroy blood cells. This reaction can produce severe hemolysis and jaundice in the newborn. Rh factor incompatibility is the most common cause.
• High bilirubin levels in newborns. Even in the absence of blood type incompatibility, the newborn's bilirubin level may reach threatening levels.

Normal jaundice in newborns

Normal newborn jaundice is the result of two conditions occurring at the same time--a pre-hepatic and a hepatic source of excess bilirubin. First of all, the baby at birth immediately begins converting hemoglobin from a fetal type to an adult type. The fetal type of hemoglobin was able to extract oxygen from the lower levels of oxygen in the mother's blood. At birth the infant can extract oxygen directly from his or her own lungs and does not need the fetal hemoglobin any more. So fetal hemoglobin is removed from the system and replaced with adult hemoglobin. The resulting bilirubin loads the system and places demands on the liver to clear it. But the liver is not quite ready for the task, so there is a period of a week or so when the liver has to catch up. During that time the baby is jaundiced.

Hepatic jaundice

Liver diseases of all kinds threaten the organ's ability to keep up with bilirubin processing. Starvation, circulating infections, certain medications, hepatitis, and cirrhosis can all cause hepatic jaundice, as can certain hereditary defects of liver chemistry, including Gilbert's syndrome and Crigler-Najjar syndrome.

Post-hepatic jaundice

Post-hepatic forms of jaundice include the jaundices caused by failure of soluble bilirubin to reach the intestines after it has left the liver. 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 have to do with birth defects and infections that damage the bile ducts; drugs; infections; cancers; and physical injury. Some drugs--and pregnancy on rare occasions--simply cause the bile in the ducts to stop flowing.

Symptoms and complications associated with jaundice

Certain chemicals in bile may cause itching when too much of them ends up in the skin. In newborns, insoluble bilirubin may get into the brain and do permanent damage. Long-standing jaundice may upset the balance of chemicals in the bile and cause stones to form. Apart from these potential complications and the discoloration of skin and eyes, jaundice by itself is inoffensive. Other symptoms are determined by the disease producing the jaundice.

Diagnosis

Physical examination

In many cases the diagnosis of jaundice is suggested by the appearance of the patient's eyes and complexion. The doctor will ask the patient to lie flat on the examining table in order to feel (palpate) the liver and spleen for enlargement and to evaluate any abdominal pain. The location and severity of abdominal pain and the presence or absence of fever help the doctor to distinguish between hepatic and obstructive jaundice.

Laboratory tests

Disorders of blood formation can be diagnosed by more thorough examination of the blood or the bone marrow, where blood is made. Occasionally a bone marrow biopsy is required, but usually the blood itself will reveal the diagnosis. The spleen can be evaluated by an ultrasound examination or a nuclear scan if the physical examination has not yielded enough information.

Liver disease is usually assessed from blood studies alone, but again a biopsy may be necessary to clarify less obvious conditions. A liver biopsy is performed at the bedside. The doctor uses a thin needle to take a tiny core of tissue from the liver. The tissue sample is sent to the laboratory for examination under a microscope.

Assessment of jaundice in newborns

Newborns are more likely to have problems with jaundice if:

• They are premature.
• They are Asian or Native Americans.
• They have been bruised during the birth process.
• They have lost too much weight during the first few days.
• They are born at high altitude.
• The mother has diabetes.
• Labor had to be induced.

Imaging studies

Disease in the biliary system can be identified by imaging techniques, of which there are many. X rays are taken a day after swallowing a contrast agent that is secreted into the bile. This study gives functional as well as anatomical information. There are several ways of injecting x ray dye directly into the bile ducts. It can be done through a thin needle pushed straight into the liver or through a scope passed through the stomach that can inject dye into the Ampulla of Vater. CT and MRI scans are very useful for imaging certain conditions like cancers in and around the liver or gall stones in the common bile duct.

Treatment

Jaundice in newborns

Newborns are the only major category 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 was the only way to reduce the amount of bilirubin until a few decades ago. Then it was discovered that bright blue light will render the bilirubin harmless. Now jaundiced babies are fitted with eye protection and placed under bright fluorescent lights. The light chemically alters the bilirubin in the blood as it passes through the baby's skin.

Hemolytic disorders

Hemolytic diseases are treated, if at all, with medications and blood transfusions, except in the case of a large spleen. Surgical removal of the spleen (splenectomy) can sometimes cure hemolytic anemia. Drugs that cause hemolysis or arrest the flow of bile must be stopped immediately.

Hepatic jaundice

Most liver diseases have no specific cure, but the liver is so robust that it can heal from severe damage and regenerate itself from a small remnant of its original tissue.

Post-hepatic jaundice

Obstructive jaundice frequently requires a surgical cure. If the original passageways cannot be restored, surgeons have several ways to create alternate routes. A popular technique is to sew an open piece of intestine over a bare patch of liver. Tiny bile ducts in that part of the liver will begin to discharge their bile into the intestine, and pressure from the obstructed ducts elsewhere will find release in that direction. As the flow increases, the ducts grow to accommodate it. Soon all the bile is redirected through the open pathways.

Prevention

Erythroblastosis fetalis can be prevented by giving an Rh negative mother a gamma globulin solution called RhoGAM whenever there is a possibility that she is developing antibodies to her baby's blood. G6PD hemolysis can be prevented by testing patients before giving them drugs that can cause it. Medication side effects can be minimized by early detection and immediate cessation of the drug. Malaria can often be prevented by certain precautions when traveling in tropical or subtropical countries. These precautions include staying in after dark; using prophylactic drugs such as mefloquine; and protecting sleeping quarters with mosquito nets treated with insecticides and mosquito repellents.

Key Terms

Ampulla of Vater

The widened portion of the duct through which the bile and pancreatic juices enter the intestine. Ampulla is a Latin word for a bottle with a narrow neck that opens into a wide body.

Anemia

A condition in which the blood does not contain enough hemoglobin.

Biliary system/Bile ducts

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

Bilirubin

A reddish pigment excreted by the liver into the bile as a breakdown product of hemoglobin.

Crigler-Najjar syndrome

A moderate to severe form of hereditary jaundice.

Erythroblastosis fetalis

A disorder of newborn infants marked by a high level of immature red blood cells (erythroblasts) in the infant's blood.

Gilbert's syndrome

A mild hereditary form of jaundice.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency

A hereditary disorder that can lead to episodes of hemolytic anemia in combination with certain medications.

Hemoglobin

The red chemical in blood cells that carries oxygen.

Hemolysis

The destruction or breakdown of red blood cells.

Hepatic

Refers to the liver.

Icterus

Another name for jaundice.

Microangiopathic

Pertaining to disorders of the small blood vessels.

Pancreas

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

Sickle cell disease

A hereditary defect in hemoglobin synthesis that changes the shape of red cells and makes them more fragile.

Splenectomy

Surgical removal of the spleen.

Further Reading

For Your Information

Books

• Balistreri, William F. "Manifestations of Liver Disease." In Nelson Textbook of Pediatrics, edited by Waldo E. Nelson, et al. Philadelphia: W. B. Saunders, 1996.
• "Jaundice." In Sleisenger & Fordtran's Gastrointestinal and Liver Disease, edited by Mark Feldman, et al. Philadelphia: W. B. Saunders, 1998.
• Kaplan, Lee M., and Kurt J. Isselbacher. "Jaundice." In Harrison's Principles of Internal Medicine, edited by Kurt Isselbacher et al. New York: McGraw-Hill, 1998.
• McQuaid, Kenneth R. "Alimentary Tract." In Current Medical Diagnosis and Treatment, edited by Lawrence M. Tierney, Jr., et al. Stamford, CT: Appleton & Lange, 1996.
• Scharschmidt, Bruce F. "Bilirubin Metabolism, Hyperbilirubinemia, and Approach to the Jaundiced Patient." In Cecil Textbook of Medicine, edited by J. Claude Bennett, and Fred Plum. Philadelphia: W. B. Saunders, 1996.

  Organizations

• American Liver Foundation. 1425 Pompton Avenue, Cedar Grove, New Jersey 07009. 800 223-0179.

Gale Encyclopedia of Medicine. Gale Research, 1999.