Information on the following diseases can be found in the Related Disorders section of this report:

• Cholangitis
• Gilbert Syndrome
• Dubin-Johnson Syndrome
• Hepatitis

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 affects 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 and loss of coordination. (For more information, choose "Vitamin E Deficiency" as your search term in the Rare Disease Database.)

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. Itchiness and yellowing of the skin may follow. The liver may be enlarged. Excessive fat in the feces and weight loss may also occur.

Estrogen-related cholestasis refers to two types of the disorder; one is due to pregnancy, and the other to oral contraceptive use. These cholestases are characterized by itchiness, occasionally followed by yellowing of the skin and dark urine. 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.

Postoperative cholestasis may occur after surgery requiring multiple blood transfusions. In the severe, less common form, consequences may include shock, internal bleeding (hemorrhage), and/or acute renal failure. In this 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 approximately half of the patients.

Cholestasis may be "intrahepatic", that is, originating from causes within the liver, or "extrahepatic", originating from causes outside the liver.

The more common intrahepatic causes are viral infections, such as hepatitis; the use of 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 formed or deposited 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 infections 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 an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.

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 the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.

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 percent 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 percent 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.

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.)

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 individuals with the hereditary forms of cholestasis and their families. Other treatment is symptomatic and supportive.

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.)

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