$Unique_ID{BRK03596} $Pretitle{} $Title{Cholestasis} $Subject{Cholestasis Benign Recurrent Intrahepatic Cholestasis (BRIC or Summerskill Syndrome) Estrogen-related Cholestasis (Cholestasis of Pregnancy and of Oral Contraceptive Users) Postoperative Cholestasis Cholangitis Gilbert Syndrome Dubin-Johnson Syndrome Hepatitis} $Volume{} $Log{} Copyright (C) 1989, 1990 National Organization for Rare Disorders, Inc. 655: Cholestasis ** IMPORTANT ** It is possible that the main title of the article (Cholestasis) is not the name you expected. Please check the SYNONYM listing to find the alternate names and disorder subdivisions covered by this article. Synonyms Disorder Subdivisions: Benign Recurrent Intrahepatic Cholestasis (BRIC or Summerskill Syndrome) Estrogen-related Cholestasis (Cholestasis of Pregnancy and of Oral Contraceptive Users) Postoperative Cholestasis Information on the following diseases can be found in the Related Disorders section of this report: Cholangitis Gilbert Syndrome Dubin-Johnson Syndrome Hepatitis General Discussion ** REMINDER ** The information contained in the Rare Disease Database is provided for educational purposes only. It should not be used for diagnostic or treatment purposes. If you wish to obtain more information about this disorder, please contact your personal physician and/or the agencies listed in the "Resources" section of this report. Cholestasis is a relatively rare syndrome that results when the flow of bile from the liver is impaired. Bile is a fluid secreted by the liver into the intestine that helps in the digestion of fat. The many causes of Cholestasis produce different symptoms. Common symptoms are dark urine, pale stools, and itchy (pruritus) and yellowed (jaundice) skin. Symptoms A characteristic sign of Cholestasis is a very high level of alkaline phosphatase (an enzyme) in the blood. Impaired bile flow may cause an excess of bilirubin in the blood (hyperbilirubinemia) which may produce yellowing of the skin (jaundice). Intense itching of the skin, especially the palms of the hands and the soles of the feet, commonly occurs. Excess bilirubin in the urine may darken it and decreased bilirubin in the stools may lighten them. Prolonged impairment of bile flow may affect the digestion of fat and absorption of certain vitamins in the body. Excess fat is excreted into the feces (steatorrhea). Continued loss of fat usually results in weight loss. Malabsorption of vitamins may lead to serious vitamin deficiencies. Prolonged calcium and vitamin D malabsorption may lead to bone problems. Prolonged vitamin E malabsorption may cause a neurological syndrome characterized by impaired speech, unusual sensations, loss of coordination (ataxia), eye control (ophthalmoplegia), and reflexes (areflexia). (For more information, choose "Vitamin E Deficiency" as your search term in the Rare Disease Database.) Other symptoms such as loss of appetite (anorexia), vomiting, fever, and excessive tiredness are due to the underlying cause, and not due to the Cholestasis itself. DISORDER SUBDIVISIONS There are many different types of Cholestasis. The following are the more commonly known forms. Benign Recurrent Intrahepatic Cholestasis (BRIC or Summerskill Syndrome) is characterized by prolonged recurrent attacks of Cholestasis lasting from a few weeks to several months. Months or years may separate attacks. Symptoms usually begin in childhood or adolescence and may occur with regularity. Attacks typically begin with tiredness, weakness, and loss of appetite (anorexia). Itchiness (pruritus) and yellowing (jaundice) of the skin without fever follows. The liver may be enlarged (hepatomegaly) and occasionally tender. Excessive fat in the feces (steatorrhea) and weight loss may occur. Estrogen-related Cholestasis refers to two types of Cholestasis; one type is due to pregnancy, and the other due to oral contraceptive use. These Cholestases are characterized by itchiness occasionally followed by yellowing of the skin and dark urine. Enlarged liver, abdominal pain, fever, and other symptoms are usually absent. Symptoms of Cholestasis due to pregnancy may appear during the eighth or ninth month and usually subside after childbirth. Symptoms of Cholestasis due to oral contraceptives may begin soon after use and usually subside upon termination of the medication. Women with Estrogen- related Cholestasis, and those with affected relatives have an increased risk of developing cholesterol gallstones. Steroid drugs may also cause a similar type of Cholestasis. Postoperative Cholestasis occurs after surgery with multiple blood transfusions. Shock, internal bleeding (hemorrhage), and acute renal failure may only occur in the severe, less common form. The level of bilirubin in the blood is very high, as is the level of alkaline phosphatase. In the less severe form, the bilirubin level is only slightly elevated and the alkaline phosphatase level is normal in half of the patients. Causes The causes of Cholestasis may be intrahepatic, originating within the liver, or extrahepatic, originating outside the liver. The more common intrahepatic causes are viral (such as hepatitis), drugs such as phenothiazines and steroids, and alcoholic liver disease. Some less common causes are primary biliary cirrhosis, excessive estrogen in women usually caused by pregnancy or oral contraceptives, metastatic cancer, and numerous other rare disorders. Long and difficult surgeries with multiple blood transfusions may also cause intrahepatic Cholestasis. Extrahepatic causes are most often stones in the bile duct or carcinoma of the pancreas. Less common causes are constricture of the bile duct (usually related to previous surgery), carcinoma of the bile duct, inflammation or pseudocysts of the pancreas, and hardening and inflammation of one or more bile ducts (sclerosing cholangitis). Hepatitis B can cause Cholestasis in the newborn. Failure of the bile ducts to develop normally (biliary atresia) usually results in Cholestasis within several weeks of birth. (For more information on this disorder, choose "Hepatitis B" as your search term in the Rare Disease Database.) Some forms of Cholestasis may be inherited or have a hereditary predisposition. Benign Recurrent Intrahepatic Cholestasis may be due to an abnormality in bile secretion that may be autosomal recessively inherited. Estrogen-related Cholestasis may have a hereditary predisposition or may be autosomal dominantly inherited. Human traits including the classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If one receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will show no symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is twenty-five percent. Fifty percent of their children will be carriers, but healthy as described above. Twenty-five percent of their children will receive both normal genes one from each parent, and will be genetically normal. In dominant disorders a single copy of the disease gene (received from either the mother or father) will be expressed "dominating" the other normal gene and resulting in appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is fifty percent for each pregnancy regardless of the sex of the resulting child. Affected Population The number of people affected by Cholestasis is hard to determine since the disorder has many varied causes and can occur as a symptom or complication of other diseases. It is thought to be a relatively rare disorder affecting men and women equally. Cholestasis can occur at any age. It is estimated that 1 to 2% of women who are pregnant or who use oral contraceptives will develop Cholestasis in the United States. However, this figure varies worldwide and occurs in over 25% of susceptible women in a subpopulation of Chile. Approximately 1 in 5,000 infants have an obstruction of their bile flow causing Cholestasis. It is usually caused by newborn hepatitis or biliary atresia. Related Disorders Symptoms of the following disorders can be similar to those of Cholestasis. Comparisons may be useful for a differential diagnosis: Primary Sclerosing Cholangitis is a rare disorder predominantly affecting males. It is characterized by inflamed and blocked bile and gallbladder ducts. Pain and discomfort affects the upper right section of the abdomen. Loss of appetite, nausea, vomiting, and weight loss may occur. The liver may be enlarged and tender. Yellowed skin with chills, fever, or itchiness may also occur. The cause is unknown. (For more information on this disorder, choose "Cholangitis" as your search term in the Rare Disease Database). Gilbert Syndrome is a hereditary metabolic disorder involving complex defects that affect the liver's capacity to metabolize bilirubin. This results in an excess level of bilirubin in the blood (hyperbilirubinemia). Yellowed skin with tiredness, nausea, and abdominal pain may occur. Males are affected four times as often as females. (For more information on this disorder, choose "Gilbert" as your search term in the Rare Disease Database). Dubin-Johnson Syndrome is a hereditary metabolic disorder. The excretion of bilirubin and other organic materials is impaired. Jaundice with upper abdominal pain, nausea, or vomiting is common. Enlarged and tender liver may also occur. This syndrome usually begins between 10 to 40 years of age. (For more information on this disorder, choose "Dubin-Johnson" as your search term in the Rare Disease Database.) Hepatitis is a group of inflammatory liver diseases. The different forms of Hepatitis have the following symptoms in varying degrees: Loss of appetite (anorexia), weakness, nausea and vomiting, and fever usually are the first signs. An itchy skin rash may develop. Dark urine and yellowing of the skin (jaundice) usually occur next. The liver may be enlarged and tender. Features of Cholestasis may also develop. Hepatitis can be caused by viruses, alcohol, or drugs. Hepatitis occurs worldwide usually affecting men and women equally of any age including newborns. Viral Hepatitis is contagious. (For more information on this disorder, choose "Hepatitis" as your search term in the Rare Disease Database). Therapies: Standard It is important to differentiate between intrahepatic and extrahepatic causes of Cholestasis since their therapies differ. Extrahepatic obstruction of the bile ducts may require surgical intervention. Treatment of the underlying cause usually will be sufficient to restore normal bile flow. Cholestyramine, which removes bile salts from the body, may control itching. Supplements of calcium and vitamins might be prescribed. Liver transplantation may be an alternative for infants with Cholestasis who cannot be treated with other methods. Genetic counseling may be of benefit for patients affected with the hereditary forms of Cholestasis and their families. Other treatment is symptomatic and supportive. Therapies: Investigational The drug S-Adenosylmethionine is being investigated to treat Estrogen-related Cholestasis. Bile acid therapy, specifically Ursodeoxycholic acid (UDCA), is being investigated to treat Neonatal Cholestasis. This orphan drug study, conducted by Dr. William Balistreri of the Children's Hospital Medical Center in Cincinnati, Ohio, was made possible by a grant from the Food and Drug Administration (FDA) through its orphan drug grant program. Preliminary studies of UDCA indicate that it may increase the flow of bile from the liver, improve liver injury, and modify possible metabolic abnormalities. Another study funded by the National Organization for Rare Disorders (NORD) is being conducted at the University of Colorado by Dr. Ronald Sokol. This study is aimed at replacing vitamin E in children with Cholestasis through a water-soluble drug known as TPGS that does not require bile to be absorbed through the intestines. (For more information, choose "Vitamin E" as your search term in the Rare Disease Database.) This disease entry is based upon medical information available through January 1990. Since NORD's resources are limited, it is not possible to keep every entry in the Rare Disease Database completely current and accurate. Please check with the agencies listed in the Resources section for the most current information about this disorder. Resources For more information on Cholestasis, please contact: National Organization for Rare Disorders (NORD) P.O. Box 8923 New Fairfield, CT 06812-1783 (203) 746-6518 American Liver Foundation 1425 Pompton Ave. Cedar Grove, N.J. 07009 (201) 857-2626 (800) 223-0179 The United Liver Foundation 11646 West Pico Blvd. Los Angeles, CA 90064 (213) 445-4204 or 445-4200 Children's Liver Foundation 14245 Ventura Blvd. Sherman Oaks, CA 91423 (818) 906-3021 National Digestive Diseases Information Clearinghouse Box NDDIC Bethesda, MD 20892 (301) 468-6344 Dr. William Balistreri, M.D. Director, Division of Pediatric Gastroenterology and Nutrition Children's Hospital Medical Center Elland and Bethesda Avenues Cincinnati, OH 45229 For Genetic Information and genetic counseling referrals: March of Dimes Birth Defects Foundation 1275 Mamaroneck Avenue White Plains, NY 10605 (914) 428-7100 Alliance of Genetic Support Groups 35 Wisconsin Circle, Suite 440 Chevy Chase, MD 20815 (800) 336-GENE (301) 652-5553 References MENDELIAN INHERITANCE IN MAN, 7th ed.: Victor A. McKusick; Johns Hopkins University Press, 1986. Pp. 430, 1019. THE METABOLIC BASIS OF INHERITED DISEASE, 5th Ed.: John B. Stanbury, et al., eds.; McGraw Hill, 1983. Pp. 1410. INTERNAL MEDICINE, 2nd Ed.: Jay H. Stein, ed.-in-chief; Little, Brown and Co., 1987. Pp. 28, 173-187, 2302. VITAMIN E DEFICIENCY LINKED TO LIVER DISEASE IN CHILDREN: C. Pierce; Research Resources Reporter (October, 1986); National Institutes of Health. Pp. 7-9.