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Marvin Jose Lopez, M.D. and Young-Mee Lee,
M.D., Division of Gastroenterology,
New England Medical Center, Boston, MA
PRIMARY SCLEROSING CHOLANGITIS
(PSC)
What is PSC?
Primary sclerosing cholangitis (PSC) is an uncommon, chronic disorder that involves scarring and inflammation of the large bile ducts of the liver. The disease leads to progressive destruction and blockage of the bile ducts and inability of the liver to secrete bile into the intestines. Bile is a substance that is produced by the liver and helps with digestion of dietary fat. Bile ducts function as the liver’s plumbing system and allow bile to flow out of the liver. When bile backs up in the liver, a progressive scarring of the liver occurs which leads to cirrhosis.
What causes PSC?
The cause of PSC is unknown. Studies suggest impairment
of the immune system or chronic infections as likely causes.
It is not known if heredity plays a role, that is, if a person
can inherit PSC if other members in the family are affected.
How common is PSC?
PSC is rare. Seventy percent of patients with PSC are men.
The average age at diagnosis is forty years. Up to ninety
percent of patients with PSC have some form of inflammatory
bowel disease. Ulcerative colitis is the more common of the
two forms of inflammatory bowel disease and occurs in approximately
eighty-seven percent of PSC patients. Crohn's disease is
seen in the remaining thirteen percent. Alternatively, only
four percent of all patients with inflammatory bowel disease
have PSC.
What are the symptoms of PSC?
The majority of patients with PSC have no symptoms. However,
some patients complain of tiredness, itching or diarrhea.
Fevers, chills, jaundice (yellow discoloration of the eyes
and skin) and abdominal pain may occur in some patients.
Some patients have a slow progressive course where the disease
does not cause symptoms or complications for many years.
Other patients may have a rapidly progressive course with
the early development of bile duct obstruction, cirrhosis
and liver failure.
What tests are needed to evaluate PSC?
The first step to screen patients for PSC is to do blood
tests. In PSC, the blood test called alkaline phosphatase
is often abnormal, though a small percent of patients with
PSC may have normal levels. Other liver enzymes including
the aminotransferases (ALT and AST) may also be abnormal.
Bilirubin levels are normal early in the disease, then begin
to increase in a fluctuating manner depending on the degree
of blockage or stricturing of the bile ducts. A significant
rise in the alkaline phosphatase and bilirubin can indicate
a stricture in the main bile duct. The albumin and prothrombin
time are proteins made only in the liver and are secreted
into blood. When these blood tests are abnormal, they signify
worsening liver function.
A cholangiogram is a useful test for diagnosing PSC. Cholangiography
can be performed several ways. Cholangiography is an X-ray
test that involves injection of dye into the bile ducts.
A cholangiogram is usually performed using an endoscopic
retrograde cholangiopancreatographic (ERCP) scope, which
is a special upper endoscopy instrument useful for examining
the bile, liver and pancreatic ducts. ERCP is a test that
involves the insertion of a small flexible tube through the
mouth into the esophagus, stomach then into the first part
of the small intestine called the duodenum. In the duodenum
there is a tiny opening called the ampulla, which is connected
to the main bile duct. Bile flows from the liver through
this opening into the small intestine. A small plastic catheter
can be passed through the scope, into the ampulla and advanced
into the bile duct where dye can be injected and any strictures
viewed using X-ray pictures. If a patient cannot undergo
an ERCP, a transhepatic cholangiogram may be performed instead.
The transhepatic cholangiogram involves taking x-ray pictures
of the bile ducts following insertion of a needle through
the skin directly into the liver and the dye being injected
into the bile ducts. In PSC, the bile ducts both within and
outside of the liver may have areas of narrowing (strictures)
and dilatations producing a beaded appearance that is characteristic
of this disease. Both tests are done using sedation (medication
to improve patient comfort during the procedure).
- Magnetic Resonance Imaging
Magnetic resonance cholangiopancreatography (MRCP) is an
alternative diagnostic test to ERCP and transhepatic cholangiogram
for making the diagnosis of PSC. MRCP is a safe and non-invasive
test that takes images of the bile pancreatic ductsand has
replaced ERCP as the first imaging test in patients suspected
of having PSC. Published data has demonstrated that the predictive
positive and predictive negative values for MRI in diagnosis
of PSC are both 80%.
A liver biopsy is a test used to obtain liver tissue that
is examined under a microscope. It involves the insertion
of a needle, typically between the ribs on the right side
of the abdomen, into the liver for the purpose of obtaining
a tiny sample. Local anesthesia is used before inserting
the needle. The tissue specimen is then examined under a
microscope. A liver biopsy can be helpful in making the diagnosis
of PSC and in assessing the severity of scarring and extent
of liver damage. Hence, a biopsy may be helpful in determining
prognosis.
What are the complicatons of PSC?
Patients with PSC are at risk for developing other associated
problems.
A dominant stricture is a blockage in one of the large bile
ducts that serve to drain bile from the smaller bile ducts
of the liver and deliver it into the small intestine. A dominant
stricture occurs in seven to twenty percent of patients with
PSC. When a dominant stricture is present, bile is blocked
from flowing through the bile duct and, therefore, may back
up in the liver. Substances that are normally excreted into
bile accumulate in the bloodstream and body tissues. This
can lead to jaundice (yellowish discoloration of the eyes
and skin), stone formation in the bile ducts and infection
in the bile ducts known as cholangitis. At ERCP a piece of
plastic tubing called a “stent”can be placed
across a dominant stricture in an effort to relieve the blockage.
- Fat Soluble Vitamin Deficiencies
Vitamins A, D, E and K, are known as fat-soluble vitamins
because they dissolve in oils rather than water. One function
of bile is that it improves the intestine’s ability
to dissolve and absorb these vitamins. If bile from the liver
does not get into the intestines in adequate amounts, fat-soluble
vitamins may not get absorbed and deficiencies can occur.
Blockage of bile ducts may also cause diarrhea because fat
in the diet will be poorly absorbed.
Osteoporosis or bone thinning is another complication of
PSC. The cause of osteoporosis in PSC is unclear.
The risk of developing cancer involving the bile ducts (known
as cholangiocarcinoma) is higher in patients with PSC than
in a healthy population. Cholangiocarcinoma may occur in
7 to 15% of patients with PSC. Patients with a long history
of inflammatory bowel disease and smokers are at the highest
risk. As there are no early symptoms of cholangiocarcinoma
that make it easy to distinguish from symptoms of PSC, it
is difficult to diagnose early. Researchers and physicians
continue to work on ways of making early diagnosis of cholangiocarcinoma.
Cirrhosis is a process of advanced scarring of the liver..
The fibrosis or scarring of the liver seen in cirrhosis leads
to obstruction of blood flow through the liver. This prevents
the liver from performing its critical functions of purifying
the blood and nutrients absorbed from the intestines. The
end result is liver failure.
Cirrhosis is the seventh leading cause of death in the United
States and can be caused by genetic disorders, such as hemochromatosis,
viral infections, such as hepatitis or by alcoholism. To
learn more about cirrhosis and its potential complications,
please click here to access a patient brochure published
by the ACG on cirrhosis.
In all patients with PSC problems can develop that result
in irreversible liver failure. These problems include bleeding
from swollen veins (varices) most commonly in the esophagus,
collection of fluid in the abdomen (ascites) and legs, and
episodes of confusion (hepatic encephalopathy) due to the
inability of the scarred liver to remove toxins from the
blood stream.
There is an increased risk of colon cancer in patients with
PSC and inflammatory bowel disease. Colonoscopy with biopsies
throughout the colon once a year is recommended.
What are the treatments for PSC?
Many medications have been studied but none have proven
to alter the course of PSC. This is primarily due to uncertainty
regarding its cause. Medications such as ursodeoxycholic
acid (UDCA), colchicine, steroids and methotrexate have been
used to treat PSC. Studies evaluating higher doses of UDCA
than had been used previously are ongoing.
Therapy is directed towards treating symptoms, preventing
and managing complications of PSC. Patients with PSC should
avoid alcohol, which may cause or worsen liver damage. Vaccinations
for hepatitis A and B should be administered. Vitamin supplements
should be prescribed for patients with advanced disease at
risk for deficiencies. Medications such as diphenhydramine,
cholestyramine, rifampin and phenobarbital have been helpful
in relieving itching. Osteoporosis is managed with supplemental
calcium and vitamin D. Treatment of itching and osteoporosis
in PSC is similar to that used for treating Primary Biliary
Cirrhosis (see below). Alendronate is a medication often
used to decrease further bone loss that may help in PSC.
ERCP can be used to open the bile duct blockage with balloons
inserted into the area of narrowing. This can lead to improved
bile flow. Antibiotics are given when infections occur.
When should liver transplantation be
considered?
Patients who develop complications of cirrhosis and those with recurrent cholangitis are candidates for liver transplantation. Liver transplantation is the only effective treatment for patients who have developed late stage PSC (cirrhosis). Studies have shown that approximately eighty to ninety percent of patients who undergo liver transplantation for late stage PSC are alive one to three years later. After transplantation, many patients report having a good quality of life.
PRIMARY BILIARY CIRRHOSIS
(PBC)
What is PBC?
Primary Biliary Cirrhosis (PBC) is a chronic liver disease
that is characterized by inflammation and destruction of
the bile ducts. PBC is usually diagnosed in patients between
the ages of 35 to 60 years. About 90 to 95 percent of patients
are women. Liver inflammation over a long period of time
may cause scarring which leads to cirrhosis. The cause of
PBC is unknown, but it is most likely an autoimmune disease.
In autoimmune diseases, the immune system attacks a specific
tissue in the body. In PBC, it is thought that the immune
system attacks and destroys small bile duct cells in the
liver. In addition, there are environmental factors such
as infections, which may trigger the disease. Due to widespread
laboratory screening, the number of patients being diagnosed
at the early, asymptomatic stage has risen dramatically over
the past decade. More than 60 percent of newly diagnosed
PBC patients now are asymptomatic.
What are the signs and symptoms of PBC?
Many patients may not have symptoms for years, and some
may never have complaints relating to their disease. Because
of the varying and sometimes subtle symptoms, doctors may
have difficulty making the diagnosis. Signs and symptoms
may include the following:
- Hypercholesterolemia
- Intense itching of the skin (pruritus)
- Dry eyes and mouth (sicca syndrome)
What type of tests are needed to evaluate
PBC?
Many patients are now diagnosed before symptoms are present.
Typically, the blood tests show a higher than normal alkaline
phosphatase level with a normal bilirubin. Usually, the bilirubin
does not increase until a late stage of the disease. Your
doctor may decide to conduct one or more of the following
tests.
- Anti-mitochondrial antibody (AMA) blood test
Up to 95% of patients with PBC will have a positive AMA
test. This test is used to help confirm a diagnosis of
PBC.
- Liver function tests
Blood tests that are specific for liver disease are total
bilirubin, alkaline phosphatase, aminotransferase levels
(ALT, AST), albumin and prothrombin time.
- Cholesterol and triglyceride levels
These blood tests are often increased.
- Ultrasound exam of the liver
Images of the liver and bile ducts are taken to assess
for liver abnormalities.
- Liver biopsy
A small sample of liver tissue helps to confirm the diagnosis
and determines the severity of the liver damage.
Treatment of complications of PBC
Some patients have complications of PBC that require therapy.
In many cases, doctors find that symptoms can be controlled
by lifestyle modifications and medications.
Itching can be a troublesome symptom of PBC. Itching may
range from mild to severe, where a patient’s lifestyle
may be impaired. Itching may be worse with fatty meals or
at night, interfering with sleep. The first medications that
are used by doctors include diphenhydramine, cholestyramine
and colestipol. Rifampin is used in patients who fail or
are intolerant to cholestyramine and colestipol. In resistant
cases, opioid antagonists such as nalmefene, naloxone and
naltrexone are used. Plasmapheresis and ultraviolet light
have been utilized in extreme cases. Liver transplantation
is indicated for patients with uncontrolled itching.
When the diagnosis of PBC is made, bone mineral density should
be assessed to determine if a patient has osteoporosis or bone
thinning. In many cases, doctors may suggest that their patients
start exercise if possible, stop smoking and take calcium 1500
mg/day with vitamin D 1,000 IU/day. Hormone replacement therapy
(estrogen) is safe in PBC and is recommended where appropriate.
When osteoporosis is evident, therapy with medications such
as Fosamax® (alendronate) and Actonel® may be helpful
in PBC.
- Fat-soluble vitamin deficiencies
As PBC progresses, some patients lose the ability to absorb
fat-soluble vitamins A, D, E and K. Measurement and replacement
of these vitamins is recommended.
Treatment of underlying disease
Ursodiol is currently the only drug approved by the FDA
for the treatment of PBC. It is often the initial therapy
for patients. The drug is a “gentler” bile acid
than those normally made by the body and is well tolerated.
Studies have shown that ursodiol, given in a dose of 13 to
15 mg/kg daily up to four years, delays the time to liver
transplantation. In addition to improving blood tests, there
are some patients with PBC whose disease appears to become
inactive (remission) on ursodiol.
Colchicine is associated with improvement of liver tests
in some patients with PBC and improved itching in two recent
studies. However, there was no improvement in liver biopsy
findings.
In early studies, methotrexate had appeared to be associated
with improvement in symptoms, liver function tests and liver
biopsies. However, an 8-year multicenter NIH trial has clearly
documented that the use of Methotrexate is not associated
with improvements in liver disease and the development of
complications of cirrhosis.
Liver Transplantation
Many people with PBC may never develop cirrhosis or liver
failure. However, as can be seen in PSC, a late stage of
PBC can be liver failure. For those people who reach the
late stages of PBC, liver transplantation may be considered.
The signs and symptoms of liver failure, which may or (depending
on the specific aspects of the symptoms / disease) may not
prompt consideration of any potential role for liver transplant,
are the following:
- Persistent jaundice
- Fluid retention with swelling of hands, feet and abdomen
- Variceal bleeding (internal bleeding from swollen intestinal
blood vessels, commonly in upper stomach and esophagus)
- Bone thinning and/or fractures
- Hepatic coma or encephalopathy
The survival for PBC patients after liver transplantation
is excellent. With better understanding of the nature of
PBC and its complications, many patients will have improved
outcomes.
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