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$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
     [phone]

     American Liver Foundation
     1425 Pompton Ave.
     Cedar Grove, N.J.  07009
     [phone]
     [phone]

     The United Liver Foundation
     11646 West Pico Blvd.
     Los Angeles, CA  90064
     [phone] or 445-4200

     Children's Liver Foundation
     14245 Ventura Blvd.
     Sherman Oaks, CA  91423
     [phone]

     National Digestive Diseases Information Clearinghouse
     Box NDDIC
     Bethesda, MD  20892
     [phone]

     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
     [phone]

     Alliance of Genetic Support Groups
     35 Wisconsin Circle, Suite 440
     Chevy Chase, MD  20815
     (800) 336-GENE
     [phone]

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.