var title_f0_60_960="Carpal tunnel view of the wrist";

var content_f0_60_960=[" <div id=\"graphicsToolbar\">",

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" &copy;2013 UpToDate",
" ^{",
" &reg;",
"}",
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title=\"Print this page\"/>",
" </a>",
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%2F81015&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=1\" onclick=\"\"
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" Print",
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" <a class=\"etacLink\" href=\"#\">",
" <img alt=\"Email graphic(s)\" src=\"./../images/icn_email.myextg\"
title=\"Email graphic(s)\"/>",
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" <a class=\"icontxt textLink etacLink\" href=\"#\" title=\"Email graphic(s)\">",
" Email",
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" </div>",
" <div class=\"lgnd\">",
" The radiograph above shows a carpal tunnel view of the wrist. The palmar ridge
of the trapezium can be seen in profile at the base of the first metacarpal (white
arrow). This view also shows the hook of the hamate in profile (yellow arrow).",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Courtesy of Kevin E Burroughs, MD.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var script_f0_60_960=[""].join("\n");
var outline_f0_60_960=null;
var title_f0_60_961="Acute HP chest radiograph";
var content_f0_60_961=[" <div id=\"graphicsToolbar\">",
" <div id=\"graphicsCopy\">",
" &copy;2013 UpToDate",
" ^{",
" &reg;",
"}",
" </div>",
" <div id=\"graphicsLinks\">",
" <a href=\"?imageKey=PULM
%2F84024&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=1\" onclick=\"\">",
" <img alt=\"Print this page\" src=\"./../images/icn_print.myextg\"
title=\"Print this page\"/>",
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=PULM
%2F84024&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=1\" onclick=\"\"
title=\"Print this page\">",
" Print",
" </a>",
" <a class=\"etacLink\" href=\"#\">",
" <img alt=\"Email graphic(s)\" src=\"./../images/icn_email.myextg\"
title=\"Email graphic(s)\"/>",
" </a>",
" <a class=\"icontxt textLink etacLink\" href=\"#\" title=\"Email graphic(s)\">",
" Email",
" </a>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\" style=\"width: 470px\">",
" <div class=\"ttl\">",
" Acute hypersensitivity pneumonitis",
" </div>",
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" </div>",
" <div class=\"lgnd\">",
" Chest radiograph of a patient with acute pigeon breeder's disease. Note
bilateral lower lobe nodular opacities.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Reproduced with permission from: Schuyler M. Hypersensitivity pneumonitis.
In: Baum's Textbook of Pulmonary Disease, 7th ed, Crapo JD, Glassroth J, Karlinsky
JB, King TE (Eds). Lippincott Williams &amp; Wilkins, 2004. Copyright &copy; 2004
Lippincott Williams &amp; Wilkins.",
" </div>",
" </div>",
" </div>",
" </div>",
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" </div>",
" <div class=\"lgnd\">",
" Mulitiple annular erythematous patches and plaques were present on the neck
and arms. A biopsy revealed findings consistent with annular elastolytic giant cell
granuloma.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Copyright &copy; Benjamin Ehst, MD, PhD, Dermatlas;
file://www.dermatlas.org.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
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var outline_f0_60_962=null;
var title_f0_60_963="Seborrheic keratosis 3";
var content_f0_60_963=[" <div id=\"graphicsToolbar\">",
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" &copy;2013 UpToDate",
" ^{",
" &reg;",
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" <a href=\"?imageKey=DERM
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" <img alt=\"Print this page\" src=\"./../images/icn_print.myextg\"
title=\"Print this page\"/>",
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=DERM
%2F58923&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=2\" onclick=\"\"
title=\"Print this page\">",
" Print",
" </a>",
" <a class=\"etacLink\" href=\"#\">",
" <img alt=\"Email graphic(s)\" src=\"./../images/icn_email.myextg\"
title=\"Email graphic(s)\"/>",
" </a>",
" <a class=\"icontxt textLink etacLink\" href=\"#\" title=\"Email graphic(s)\">",
" Email",
" </a>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\" style=\"width: 470px\">",
" <div class=\"ttl\">",
" Seborrheic keratoses",
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" </div>",
" <div class=\"lgnd\">",
" These \"stuck-on\" appearing lesions are most often confused with malignant
melanoma.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Reproduced with permission from: Goodheart HP. Goodheart's Photoguide of
Common Skin Disorders, 2nd Edition, Lippincott Williams &amp; Wilkins, Philadelphia
2003. Copyright &copy; 2003 Lippincott Williams &amp; Wilkins.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
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var outline_f0_60_963=null;
var title_f0_60_964="Peptic ulcer disease";
var content_f0_60_964=[" <h1 id=\"patTopicTitle\">",
" Patient information: Peptic ulcer disease (Beyond the Basics)",
" </h1>",
" <div id=\"patTopicContributors\">",
" <div class=\"rcTop\">",
" <div>",
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" </div>",
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" <a class=\"contributor contributor_credentials patTopicContributorsType\"
href=\"UTD.htm?0/60/964/contributors\">",
" Author",
" </a>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
0/60/964/contributors\" id=\"au2391\">",
" Sheila E Crowe, MD, FRCPC, FACP, FACG, AGAF",
" </a>",
" </td>",
" <td>",
" <a class=\"contributor contributor_credentials patTopicContributorsType\"
href=\"UTD.htm?0/60/964/contributors\">",
" Section Editor",
" </a>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
0/60/964/contributors\" id=\"se6265\">",
" Mark Feldman, MD, MACP, AGAF, FACG",
" </a>",
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href=\"UTD.htm?0/60/964/contributors\">",
" Deputy Editor",
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" Shilpa Grover, MD, MPH",
" </a>",
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" Print",
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" <p class=\"headingAnchor\" id=\"H1\">",
" <span class=\"h1\">",
" PEPTIC ULCER OVERVIEW",
" </span>",
" </p>",
" <p>",
" Peptic ulcers are sores or eroded areas that form in the lining of the
digestive (gastrointestinal) tract. They usually occur in the stomach (gastric
ulcer) or in the duodenum (duodenal ulcer), which is the upper region of the small
intestine (",
" <a class=\"graphic graphic_figure graphicRef55616 \" href=\"UTD.htm?
28/22/29024\">",
" figure 1",
" </a>",
" ). The two primary causes of peptic ulcers are infection with specific
bacteria (Helicobacter pylori) and use of nonsteroidal antiinflammatory
medications.",
" </p>",
" <p>",
" Peptic ulcers affect more than 4 million people each year in the United
States. Most ulcers heal while others worsen over time. Complications of peptic
ulcers can be serious or even life-threatening. Fortunately, most people who
develop peptic ulcers can be treated successfully and avoid long-term problems.",
" </p>",
" <p class=\"headingAnchor\" id=\"H2\">",
" <span class=\"h1\">",
" HOW ULCERS DEVELOP",
" </span>",
" </p>",
" <p>",
" The stomach and duodenal lining have several mechanisms that help prevent
ulcers from developing, including the following:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" A coating of mucus (mucous layer) protects the stomach lining from the
effects of acidic digestive juices.",
" </li>",
" <li>",
" Food and other substances in the stomach neutralize acid. Certain chemicals
produced by the stomach protect the cells lining the stomach.",
" </li>",
" </ul>",
" </p>",
" <p>",
" If the mucous layer is damaged or if acid neutralizing substances are not
present in normal amounts, digestive juices can cause irritation and breakdown of
the stomach or duodenal lining, allowing an ulcer to form.",
" </p>",
" <p class=\"headingAnchor\" id=\"H3\">",
" <span class=\"h1\">",
" PEPTIC ULCER SYMPTOMS",
" </span>",
" </p>",
" <p>",
" People with peptic ulcers may have a wide variety of symptoms, have no
symptoms, or, rarely, develop potentially life-threatening complications such as
bleeding. Symptoms of ulcers may include:",
" </p>",
" <p>",
" <ul class=\"bulletCompact-block\">",
" <li>",
" Pain or discomfort (usually in the upper abdomen)",
" </li>",
" <li>",
" Bloating",
" </li>",
" <li>",
" An early sense of fullness with eating",
" </li>",
" <li>",
" Lack of appetite",
" </li>",
" <li>",
" Nausea",
" </li>",
" <li>",
" Vomiting",
" </li>",
" <li>",
" Blood in the stools",
" </li>",
" </ul>",
" </p>",
" <p>",
" Moderate to severe bleeding can cause foul-smelling black or tarry stools.
Bleeding can also cause a low red blood cell count (anemia).",
" </p>",
" <p>",
" Many of these symptoms can occur in people who do",
" <strong>",
" not",
" </strong>",
" have an ulcer. For this reason, anyone who has one or more of these symptoms
should discuss their concerns with a healthcare provider to determine if further
testing or treatment is needed.",
" </p>",
" <p class=\"headingAnchor2\" id=\"H4\">",
" <span class=\"h2\">",
" Gastric versus duodenal ulcer",
" </span>",
" &nbsp;&mdash;&nbsp;Although there is much overlap, symptoms of a gastric
ulcer may be different than those of a duodenal ulcer.",
" </p>",
" <p class=\"headingAnchor2\" id=\"H5\">",
" <span class=\"h3\">",
" Duodenal ulcer",
" </span>",
" &nbsp;&mdash;&nbsp;\"Classic\" symptoms of a duodenal ulcer include burning,
gnawing, aching, or hunger-like pain, primarily in the upper middle region of the
abdomen below the breastbone (the epigastric region). Pain may occur or worsen when
the stomach is empty, usually two to five hours after a meal. Symptoms may occur at
night between 11 PM and 2 AM, when acid secretion tends to be greatest.",
" </p>",
" <p class=\"headingAnchor2\" id=\"H6\">",
" <span class=\"h3\">",
" Gastric ulcer",
" </span>",
" &nbsp;&mdash;&nbsp;Symptoms of a gastric ulcer typically include pain soon
after eating. Symptoms are sometimes not relieved by eating or taking antacids.",
" </p>",
" <p class=\"headingAnchor\" id=\"H7\">",
" <span class=\"h1\">",
" PEPTIC ULCER CAUSES",
" </span>",
" </p>",
" <p>",
" The two most common causes of peptic ulcers are:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Helicobacter pylori, a bacteria that is frequently found in the stomach
(see",
" <a class=\"medical medical_patient\" href=\"UTD.htm?13/58/14242?
source=see_link\">",
" \"Patient information: Helicobacter pylori infection and treatment (Beyond
the Basics)\"",
" </a>",
" )",
" </li>",
" <li>",
" Nonsteroidal anti-inflammatory drugs (NSAIDS) such as ibuprofen (and many
others)",
" </li>",
" </ul>",
" </p>",
" <p>",
" In addition, smoking and certain other genetic and environmental factors
(such as medications) may influence the course of peptic ulcer disease.
Psychological stress and dietary factors were once thought to be the cause of
ulcers, although these factors are no longer thought have a major role.",
" </p>",
" <p class=\"headingAnchor2\" id=\"H8\">",
" <span class=\"h2\">",
" Helicobacter pylori infection",
" </span>",
" &nbsp;&mdash;&nbsp;Helicobacter pylori, also known as H. pylori, is the most
common chronic bacterial infection in humans. Conservative estimates indicate that
the bacteria are present in the stomach in approximately one-half of the world's
population. Surprisingly, the importance of H. pylori was not appreciated until
1982. A researcher demonstrated that the bacteria were able to cause stomach
problems after he voluntarily swallowed them. H. pylori is now recognized to be an
important cause of gastric and duodenal ulcers.",
" </p>",
" <p>",
" The presence of H. pylori causes a number of changes in the normal
environment of the stomach and duodenum. In particular, it disrupts the mucous
layer and causes the release of certain enzymes and toxins that may directly or
indirectly injure the cells of the stomach or duodenum.",
" </p>",
" <p>",
" The effect of these changes is that underlying tissues become more vulnerable
to damage from digestive juices, such as stomach acid. This results in chronic
inflammation in the walls of the stomach (gastritis) or duodenum (duodenitis). Most
individuals with chronic gastritis or duodenitis have no symptoms. However, some
people develop more serious problems, most commonly a stomach or duodenal ulcer.
(See",
" <a class=\"medical medical_patient\" href=\"UTD.htm?13/58/14242?
source=see_link\">",
" \"Patient information: Helicobacter pylori infection and treatment (Beyond
the Basics)\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor2\" id=\"H9\">",
" <span class=\"h2\">",
" Nonsteroidal anti-inflammatory drugs",
" </span>",
" &nbsp;&mdash;&nbsp;Nonsteroidal anti-inflammatory drugs (NSAIDs) are
responsible for the majority of peptic ulcers not caused by H. pylori. A number of
NSAIDs are available in both prescription and over-the-counter medications,
including aspirin, ibuprofen (Advil&reg;, Motrin&reg;), naproxen (Aleve&reg;,
Anaprox&reg;), and others. The risk of developing an ulcer depends upon the
specific type of NSAID, the dose and duration of use, and individual factors. A few
other drugs increase the risk of developing an ulcer, although these cause far
fewer ulcers than NSAIDs.",
" </p>",
" <p class=\"headingAnchor2\" id=\"H10\">",
" <span class=\"h2\">",
" Other contributing factors",
" </span>",
" &nbsp;&mdash;&nbsp;H. pylori infection or NSAID use alone may not be
sufficient to cause peptic ulcer disease. Genetic and environmental factors may
also contribute. For example, people with duodenal ulcers are more likely to have
family members with duodenal ulcers compared to the general population. Another
risk factor for developing an ulcer is use of tobacco (cigarette smoking); smoking
increases the risk of developing ulcers and impairs their healing. Alcohol abuse
also appears to interfere with ulcer healing.",
" </p>",
" <p class=\"headingAnchor\" id=\"H11\">",
" <span class=\"h1\">",
" PEPTIC ULCER DIAGNOSIS",
" </span>",
" </p>",
" <p>",
" Not everyone with ulcer symptoms has an ulcer. Similar symptoms can be caused
by a wide variety of conditions such as functional dyspepsia (ie, the presence of
ulcer-symptoms without a specific cause), abnormal emptying of the stomach, acid
reflux, gallbladder problems, and, much less commonly, stomach cancer. Thus, the
process needed to diagnose an ulcer depends upon the person's medical history and
sometimes, use of specific tests. (See",
" <a class=\"medical medical_patient\" href=\"UTD.htm?5/24/5506?
source=see_link\">",
" \"Patient information: Upset stomach (functional dyspepsia) in adults
(Beyond the Basics)\"",
" </a>",
" and",
" <a class=\"medical medical_patient\" href=\"UTD.htm?37/30/38373?
source=see_link\">",
" \"Patient information: Acid reflux (gastroesophageal reflux disease) in
adults (Beyond the Basics)\"",
" </a>",
" and",
" <a class=\"medical medical_patient\" href=\"UTD.htm?7/21/7507?
source=see_link\">",
" \"Patient information: Gallstones (Beyond the Basics)\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor2\" id=\"H12\">",
" <span class=\"h2\">",
" H. pylori testing",
" </span>",
" &nbsp;&mdash;&nbsp;Many people with ulcer symptoms are tested for H. pylori
with a blood, breath, or stool test. Those who test positive for H. pylori are
treated for the infection and ideally re-tested after treatment to ensure that the
infection has been cured. However, some providers recommend further testing only if
symptoms recur.",
" </p>",
" <p class=\"headingAnchor2\" id=\"H13\">",
" <span class=\"h2\">",
" Upper endoscopy",
" </span>",
" &nbsp;&mdash;&nbsp;People who have certain \"alarm\" features such as weight
loss, difficulty swallowing, or anemia, and particularly if the person is older,
typically undergo more specific tests to better define the cause. The most common
test is an upper endoscopy, in which a small flexible tube with a camera is passed
through the mouth to examine the lining of the stomach and the duodenum. (See",
" <a class=\"medical medical_patient\" href=\"UTD.htm?21/0/21506?
source=see_link\">",
" \"Patient information: Upper endoscopy (Beyond the Basics)\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H14\">",
" <span class=\"h1\">",
" PEPTIC ULCER COMPLICATIONS",
" </span>",
" </p>",
" <p>",
" Peptic ulcers can heal spontaneously and may come and go. They can also be
associated with serious, potentially life-threatening complications, sometimes
without warning signs. This is most common in elderly patients and those who take
NSAIDs. The most common complications of ulcers are bleeding and perforation.",
" </p>",
" <p class=\"headingAnchor2\" id=\"H15\">",
" <span class=\"h2\">",
" Bleeding",
" </span>",
" &nbsp;&mdash;&nbsp;Bleeding can be gradual or abrupt; abrupt bleeding often
causes black, tarry, loose stools, and a drop in blood pressure. Most ulcer
bleeding can be controlled with endoscopy, which allows a physician to cauterize
the ulcer or inject it with epinephrine to stop the bleeding. Only about 2 to 5
percent of people with a peptic ulcer require surgery.",
" </p>",
" <p class=\"headingAnchor2\" id=\"H16\">",
" <span class=\"h2\">",
" Perforation",
" </span>",
" &nbsp;&mdash;&nbsp;Perforation is the medical term for a puncture of the
stomach lining or duodenum caused by the ulcer. Perforation usually causes sudden
severe abdominal pain and usually requires surgery.",
" </p>",
" <p class=\"headingAnchor\" id=\"H17\">",
" <span class=\"h1\">",
" PEPTIC ULCER TREATMENT",
" </span>",
" </p>",
" <p>",
" Most ulcers can be healed with medications. Surgery is rarely needed, except
when complications have developed.",
" </p>",
" <p class=\"headingAnchor2\" id=\"H18\">",
" <span class=\"h2\">",
" Identify cause of ulcer",
" </span>",
" &nbsp;&mdash;&nbsp;The initial step in treating an ulcer is to identify the
cause. NSAIDs should be stopped, regardless of the cause. People who have H. pylori
are treated with antibiotics and a medication that reduces acid production.",
" </p>",
" <p class=\"headingAnchor2\" id=\"H19\">",
" <span class=\"h2\">",
" Treating H. pylori",
" </span>",
" &nbsp;&mdash;&nbsp;No single drug effectively cures H. pylori infection.
Treatment involves taking several medications for 7 to 14 days.",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Most of the treatment regimens include a medication called a proton pump
inhibitor. This medication decreases the stomach's production of acid, which allows
the tissues damaged by the infection to heal. Examples of proton pump inhibitors
include lansoprazole (Prevacid&reg;), omeprazole (Prilosec&reg;), pantoprazole
(Protonix&reg;), dexlansoprazole (Dexilant&reg;), rabeprazole (AcipHex&reg;), and
esomeprazole (Nexium&reg;).",
" </li>",
" <li>",
" Two antibiotics are also generally recommended; this reduces the risk of
treatment failure and antibiotic resistance.",
" </li>",
" </ul>",
" </p>",
" <p>",
" Although the optimal treatment regimen continues to be investigated, the
American College of Gastroenterology has recommended four regimens that use a
combination of at least three medications. These regimens successfully cure
infection in up to 90 percent of people. For the treatment to be effective, the
entire course of all medications must be taken.",
" </p>",
" <p class=\"headingAnchor2\" id=\"H20\">",
" <span class=\"h3\">",
" Side effects",
" </span>",
" &nbsp;&mdash;&nbsp;Up to 50 percent of people have side effects of H. pylori
treatment. Side effects are usually mild, with fewer than 10 percent of patients
stopping treatment because of side effects. For those who do experience side
effects, it may be possible to make adjustments in the dose or timing of
medication. Some of the most common side effects are described below.",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Some of the treatment regimens use a medication called metronidazole
(Flagyl&reg;) or clarithromycin (Biaxin&reg;). These medications can cause a
metallic taste in the mouth.",
" </li>",
" <li>",
" Alcoholic beverages (eg, beer, wine) should be avoided while taking
metronidazole; the combination can cause skin flushing, headache, nausea, vomiting,
sweating and a rapid heart rate.",
" </li>",
" <li>",
" Bismuth, which is contained in some of the regimens, causes the stool to
become black and may cause constipation.",
" </li>",
" <li>",
" Many of the regimens cause diarrhea and stomach cramps.",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor2\" id=\"H21\">",
" <span class=\"h2\">",
" Ways to help ulcers heal",
" </span>",
" &nbsp;&mdash;&nbsp;A number of other measures help to ensure ulcer healing
and prevent ulcer recurrence.",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Stop smoking. (See",
" <a class=\"medical medical_patient\" href=\"UTD.htm?19/13/19670?
source=see_link\">",
" \"Patient information: Quitting smoking (Beyond the Basics)\"",
" </a>",
" .)",
" </li>",
" <li>",
" Avoid NSAIDs if possible. All medications should be reviewed with a
healthcare provider to make sure that they do not contain NSAIDs. If it is
necessary to continue NSAIDs, one or more medications may be added to aid in ulcer
healing and prevent recurrence.",
" </li>",
" <li>",
" If you had complications from your ulcer (such as bleeding or perforation),
you should be retested for H. pylori to make sure that antibiotic therapy was
successful. Although controversial, most experts recommend that a medication to
reduce acid secretion is continued, even after a complicated ulcer has healed.",
" </li>",
" <li>",
" Antacids are permissible during ulcer treatment if needed, although
antacids should not be used within one hour before or two hours after taking ulcer
medications since they can interfere with their absorption.",
" </li>",
" <li>",
" Efforts to reduce stress can benefit your overall health and may have a
small benefit in healing ulcers. However, most ulcers heal with medications, even
in people who continue to live a stressful life.",
" </li>",
" <li>",
" Herbal medications and supplements (such as licorice, marshmallow, and
glutamine) probably have no role in the treatment of peptic ulcers. In addition,
the manufacture of these treatments is not regulated and their safety and efficacy
are not known.",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H22\">",
" <span class=\"h1\">",
" PEPTIC ULCER FOLLOW-UP",
" </span>",
" </p>",
" <p class=\"headingAnchor2\" id=\"H23\">",
" <span class=\"h2\">",
" Duodenal ulcers",
" </span>",
" &nbsp;&mdash;&nbsp;People with uncomplicated duodenal ulcers should have
follow-up testing after treatment, especially if symptoms recur or do not improve.
Follow up testing is also recommended for people who have had complications (such
as bleeding or perforation) to ensure that H. pylori has been successfully cured.",
" </p>",
" <p class=\"headingAnchor2\" id=\"H24\">",
" <span class=\"h2\">",
" Gastric ulcers",
" </span>",
" &nbsp;&mdash;&nbsp;People with gastric ulcers usually undergo a repeat
endoscopy to ensure that the ulcer has healed and to ensure that the ulcer does not
contain cancer cells. Long-term treatment to suppress stomach acid is usually
recommended if a person has a high risk of ulcer recurrence (eg, a history of ulcer
complications or frequent recurrences).",
" </p>",
" <p>",
" People with ulcers due to H. pylori who have been cured of the infection are
unlikely to develop another ulcer if NSAIDs are avoided.",
" </p>",
" <p class=\"headingAnchor\" id=\"H25\">",
" <span class=\"h1\">",
" WHERE TO GET MORE INFORMATION",
" </span>",
" </p>",
" <p>",
" Your healthcare provider is the best source of information for questions and
concerns related to your medical problem.",
" </p>",
" <p>",
" This article will be updated as needed on our web site (",
" <a class=\"external\" href=\"file://www.uptodate.com/patients\">",
" www.uptodate.com/patients",
" </a>",
" ). Related topics for patients, as well as selected articles written for
healthcare professionals, are also available. Some of the most relevant are listed
below.",
" <br/>",
" </p>",
" <p class=\"headingAnchor2\" id=\"H1784966632\">",
" <span class=\"h2\">",
" Patient level information",
" </span>",
" &nbsp;&mdash;&nbsp;UpToDate offers two types of patient education
materials.",
" </p>",
" <p class=\"headingAnchor2\" id=\"H29858695\">",
" <span class=\"h3\">",
" The Basics",
" </span>",
" &nbsp;&mdash;&nbsp;The Basics patient education pieces answer the four or
five key questions a patient might have about a given condition. These articles are
best for patients who want a general overview and who prefer short, easy-to-read
materials.",
" </p>",
" <p>",
" <a class=\"medical medical_basics\" href=\"UTD.htm?5/53/5971?
source=see_link\">",
" Patient information: Peptic ulcers (The Basics)",
" </a>",
" <br/>",
" <a class=\"medical medical_basics\" href=\"UTD.htm?19/31/19954?
source=see_link\">",
" Patient information: H. pylori infection (The Basics)",
" </a>",
" <br/>",
" <a class=\"medical medical_basics\" href=\"UTD.htm?23/60/24515?
source=see_link\">",
" Patient information: GI bleed (The Basics)",
" </a>",
" <br/>",
" <a class=\"medical medical_basics\" href=\"UTD.htm?1/46/1763?
source=see_link\">",
" Patient information: Gastritis (The Basics)",
" </a>",
" </p>",
" <p class=\"headingAnchor2\" id=\"H29858774\">",
" <span class=\"h3\">",
" Beyond the Basics",
" </span>",
" &nbsp;&mdash;&nbsp;Beyond the Basics patient education pieces are longer,
more sophisticated, and more detailed. These articles are best for patients who
want in-depth information and are comfortable with some medical jargon.",
" </p>",
" <p>",
" <a class=\"medical medical_patient\" href=\"UTD.htm?13/58/14242?
source=see_link\">",
" Patient information: Helicobacter pylori infection and treatment (Beyond the
Basics)",
" </a>",
" <br/>",
" <a class=\"medical medical_patient\" href=\"UTD.htm?5/24/5506?
source=see_link\">",
" Patient information: Upset stomach (functional dyspepsia) in adults (Beyond
the Basics)",
" </a>",
" <br/>",
" <a class=\"medical medical_patient\" href=\"UTD.htm?37/30/38373?
source=see_link\">",
" Patient information: Acid reflux (gastroesophageal reflux disease) in adults
(Beyond the Basics)",
" </a>",
" <br/>",
" <a class=\"medical medical_patient\" href=\"UTD.htm?7/21/7507?
source=see_link\">",
" Patient information: Gallstones (Beyond the Basics)",
" </a>",
" <br/>",
" <a class=\"medical medical_patient\" href=\"UTD.htm?21/0/21506?
source=see_link\">",
" Patient information: Upper endoscopy (Beyond the Basics)",
" </a>",
" <br/>",
" <a class=\"medical medical_patient\" href=\"UTD.htm?19/13/19670?
source=see_link\">",
" Patient information: Quitting smoking (Beyond the Basics)",
" </a>",
" <br/>",
" </p>",
" <p class=\"headingAnchor2\" id=\"H26\">",
" <span class=\"h2\">",
" Professional level information",
" </span>",
" &nbsp;&mdash;&nbsp;Professional level articles are designed to keep doctors
and other health professionals up-to-date on the latest medical findings. These
articles are thorough, long, and complex, and they contain multiple references to
the research on which they are based. Professional level articles are best for
people who are comfortable with a lot of medical terminology and who want to read
the same materials their doctors are reading.",
" </p>",
" <p>",
" <a class=\"medical medical_review\" href=\"UTD.htm?43/40/44679?
source=see_link\">",
" Association between Helicobacter pylori infection and duodenal ulcer",
" </a>",
" <br/>",
" <a class=\"medical medical_review\" href=\"UTD.htm?13/18/13609?
source=see_link\">",
" Clinical manifestations of peptic ulcer disease",
" </a>",
" <br/>",
" <a class=\"medical medical_review\" href=\"UTD.htm?39/21/40282?
source=see_link\">",
" Overview of the complications of peptic ulcer disease",
" </a>",
" <br/>",
" <a class=\"medical medical_review\" href=\"UTD.htm?24/21/24919?
source=see_link\">",
" Diagnosis of peptic ulcer disease",
" </a>",
" <br/>",
" <a class=\"medical medical_review\" href=\"UTD.htm?12/10/12455?
source=see_link\">",
" Management of duodenal ulcers in patients infected with Helicobacter
pylori",
" </a>",
" <br/>",
" <a class=\"medical medical_review\" href=\"UTD.htm?41/18/42281?
source=see_link\">",
" Overview of the natural history and treatment of peptic ulcer disease",
" </a>",
" <br/>",
" <a class=\"medical medical_review\" href=\"UTD.htm?3/36/3658?
source=see_link\">",
" Peptic ulcer disease: Genetic, environmental, and psychological risk factors
and pathogenesis",
" </a>",
" <br/>",
" <a class=\"medical medical_review\" href=\"UTD.htm?15/61/16345?
source=see_link\">",
" Refractory or recurrent peptic ulcer disease",
" </a>",
" <br/>",
" <a class=\"medical medical_review\" href=\"UTD.htm?32/57/33688?
source=see_link\">",
" Role of surgery in the management of peptic ulcer disease",
" </a>",
" <br/>",
" <a class=\"medical medical_review\" href=\"UTD.htm?39/5/40025?
source=see_link\">",
" Surgical management of complications of peptic ulcer disease",
" </a>",
" <br/>",
" <a class=\"medical medical_review\" href=\"UTD.htm?24/15/24826?
source=see_link\">",
" Overview of the treatment of bleeding peptic ulcers",
" </a>",
" <br/>",
" <a class=\"medical medical_review\" href=\"UTD.htm?19/0/19466?
source=see_link\">",
" Unusual causes of peptic ulcer disease",
" </a>",
" <br/>",
" <br/>",
" The following organizations also provide reliable health information.",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" National Library of Medicine",
" </li>",
" </ul>",
" </p>",
" <p>",
" &nbsp; &nbsp; &nbsp;(",
" <a class=\"external\"
href=\"file://www.nlm.nih.gov/medlineplus/healthtopics.html\">",
" www.nlm.nih.gov/medlineplus/healthtopics.html",
" </a>",
" )",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Centers for Disease Control and Prevention (CDC)",
" </li>",
" </ul>",
" </p>",
" <p>",
" &nbsp; &nbsp; &nbsp;Phone: (404) 639-3534",
" <br/>",
" &nbsp; &nbsp; &nbsp;Toll-free: (800) 311-3435",
" <br/>",
" &nbsp; &nbsp; &nbsp;(",
" <a class=\"external\" href=\"file://www.cdc.gov/\">",
" www.cdc.gov",
" </a>",
" )",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" National Institute of Diabetes and Digestive and Kidney Diseases",
" </li>",
" </ul>",
" </p>",
" <p>",
" &nbsp; &nbsp; &nbsp;Phone: (301) 654-3810",
" <br/>",
" &nbsp; &nbsp; &nbsp;(",
" <a class=\"external\" href=\"file://www.niddk.nih.gov/\">",
" www.niddk.nih.gov",
" </a>",
" )",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" The American Gastroenterological Association",
" </li>",
" </ul>",
" </p>",
" <p>",
" &nbsp; &nbsp; &nbsp;(",
" <a class=\"external\" href=\"file://www.gastro.org/\">",
" www.gastro.org",
" </a>",
" )",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" The American College of Gastroenterology (ACG)",
" </li>",
" </ul>",
" </p>",
" <p>",
" &nbsp; &nbsp; &nbsp;(",
" <a class=\"external\" href=\"file://www.acg.gi.org/\">",
" www.acg.gi.org",
" </a>",
" )",
" </p>",
" <p>",
" [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/964/abstract/1-4\">",
" 1-4",
" </a>",
" ]",
" </p>",
" <p class=\"headingAnchor\" id=\"H13306778\">",
" <span class=\"h1\">",
" ACKNOWLEDGMENT",
" </span>",
" </p>",
" <p>",
" The editorial staff at UpToDate, Inc. would like to acknowledge Dr. David A.
Peura, who contributed to earlier versions of this topic review.",
" </p>",
" </div>",
" </div>",
" <div id=\"literatureReviewDate\">",
" <span class=\"emphasis\">",
" Literature review current through:",
" </span>",
" Oct 2013.",
" <span class=\"pipeSpace\">",
" |",
" </span>",
" <span class=\"emphasis\">",
" This topic last updated:",
" </span>",
" Oct 4, 2011.",
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" The content on the UpToDate website is not intended nor recommended as a
substitute",
"for medical advice, diagnosis, or treatment. Always seek the advice of your own
physician or",
"other qualified health care professional regarding any medical questions or
conditions. The",
"use of this website is governed by the",
" <a href=\"/home/terms-use\" target=\"_blank\">",
" UpToDate Terms of Use",
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" &copy;2013 UpToDate, Inc.",
" </div>",
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" </div>",
" <div id=\"patTopicRefHeaderTop\">",
" <a href=\"#top\">",
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" Top",
" </img>",
" </a>",
" </div>",
" </div>",
" <ol id=\"reference\">",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/60/964/abstract/1\">",
" Graham DY. Nonsteroidal anti-inflammatory drugs, Helicobacter pylori, and
ulcers: where we stand. Am J Gastroenterol 1996; 91:2080.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/60/964/abstract/2\">",
" Kochman ML, Elta GH. Gastric ulcers--when is enough enough? Gastroenterology
1993; 105:1583.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/60/964/abstract/3\">",
" Chey WD, Wong BC, Practice Parameters Committee of the American College of
Gastroenterology. American College of Gastroenterology guideline on the management
of Helicobacter pylori infection. Am J Gastroenterol 2007; 102:1808.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/60/964/abstract/4\">",
" Peura DA, Goldkind L. Balancing the gastrointestinal benefits and risks of
nonselective NSAIDs. Arthritis Res Ther 2005; 7 Suppl 4:S7.",
" </a>",
" </li>",
" </ol>",
" </div>",
" </div>",
" <!-- patTopicMiddle -->",
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" <div class=\"rcTop\">",
" <div>",
" </div>",
" </div>",
" <div class=\"rcContent\">",
" <p>",
" Contents of this article",
" </p>",
" </div>",
" </div>",
" <div class=\"patTopicFancySpacer\">",
" </div>",
" <div class=\"patTopicOutline\">",
" <div class=\"rcbBottom\">",
" <div class=\"rcbLeft\">",
" <div class=\"rcbRight\">",
" <div class=\"rcbBottomLeft\">",
" <div class=\"rcbBottomRight rcbBottomRightBottomOnly\">",
" <div id=\"outline\">",
" <ul>",
" <li class=\"plainItem\">",
" <a href=\"#H1\">",
" PEPTIC ULCER OVERVIEW",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a href=\"#H2\">",
" HOW ULCERS DEVELOP",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a href=\"#H3\">",
" PEPTIC ULCER SYMPTOMS",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a href=\"#H7\">",
" PEPTIC ULCER CAUSES",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a href=\"#H11\">",
" PEPTIC ULCER DIAGNOSIS",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a href=\"#H14\">",
" PEPTIC ULCER COMPLICATIONS",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a href=\"#H17\">",
" PEPTIC ULCER TREATMENT",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a href=\"#H22\">",
" PEPTIC ULCER FOLLOW-UP",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a href=\"#H25\">",
" WHERE TO GET MORE INFORMATION",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a href=\"#H13306778\">",
" ACKNOWLEDGMENT",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a href=\"#references\">",
" REFERENCES",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" GRAPHICS",
" </h1>",
" <div id=\"relatedGraphics\">",
" <ul>",
" <li class=\"plainItem\">",
" FIGURES",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"graphic graphic_figure\" href=\"UTD.htm?28/22/29024\"
title=\"figure 1\">",
" Upper GI anatomy PI",
" </a>",
" </li>",
" </ul>",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
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var title_f0_60_965="Pancreatoscope on fluoroscopy";
var content_f0_60_965=[" <div id=\"graphicsToolbar\">",
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" &copy;2013 UpToDate",
" ^{",
" &reg;",
"}",
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" <a class=\"etacLink\" href=\"#\">",
" <img alt=\"Email graphic(s)\" src=\"./../images/icn_email.myextg\"
title=\"Email graphic(s)\"/>",
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" Email",
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" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\" style=\"width: 524px\">",
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" Introduction of a cholangiopancreatoscope into the pancreatic duct",
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\">",
" </div>",
" <div class=\"lgnd\">",
" Fluoroscopic image showing a cholangiopancreatoscope being passed through a
therapeutic duodenoscope and into the pancreatic duct.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var script_f0_60_965=[""].join("\n");
var outline_f0_60_965=null;
var title_f0_60_966="Chapter 6E: Prostaglandins and the kidney";
var content_f0_60_966=[" <noscript>",
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" <!-- TC:TOPIC_PAGE -->",
" <div id=\"topicContent\">",
" <div id=\"topicTitle\">",
" Chapter 6E: Prostaglandins and the kidney",
" </div>",
" <div id=\"topicContributors\">",
" <div>",
" <a id=\"authors\">",
" </a>",
" <a class=\"contributor contributor_credentials contributorType\"
href=\"UTD.htm?0/60/966/contributors\">",
" Authors",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
0/60/966/contributors\">",
" Burton D Rose, MD",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
0/60/966/contributors\">",
" Theodore W Post, MD",
" </a>",
" <br/>",
" </div>",
" <div>",
" <a class=\"contributor contributor_credentials contributorType\"
href=\"UTD.htm?0/60/966/contributors\">",
" Section Editor",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
0/60/966/contributors\">",
" Burton D Rose, MD",
" </a>",
" <br/>",
" </div>",
" <div>",
" <a class=\"contributor contributor_credentials contributorType\"
href=\"UTD.htm?0/60/966/contributors\">",
" Deputy Editor",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
0/60/966/contributors\">",
" Theodore W Post, MD",
" </a>",
" <br/>",
" </div>",
" </div>",
" <div id=\"disclosures\">",
" <a href=\"UTD.htm?0/60/966/contributor-disclosure\" target=\"_blank\">",
" Disclosures",
" </a>",
" </div>",
" <div id=\"reviewProcess\">",
" <span>",
" All topics are updated as new evidence becomes available and our",
" </span>",
" <a href=\"/home/editorial-policy\" target=\"_blank\">",
" peer review process",
" </a>",
" <span>",
" is complete.",
" </span>",
" </div>",
" <div id=\"literatureReviewDate\">",
" <span class=\"emphasis\">",
" Literature review current through:",
" </span>",
" Oct 2013.",
" <span class=\"pipeSpace\">",
" |",
" </span>",
" <span class=\"emphasis\">",
" This topic last updated:",
" </span>",
" Sep 14, 2000.",
" </div>",
" <div id=\"topicText\">",
" <p class=\"headingAnchor\" id=\"H1\">",
" <span class=\"h1\">",
" INTRODUCTION",
" </span>",
" &nbsp;&mdash;&nbsp;Prostaglandins are derived from the metabolism of
arachidonic acid, with the initial step being catalyzed by the cyclooxygenase (COX)
enzyme (",
" <a class=\"graphic graphic_figure graphicRef66146 \" href=\"UTD.htm?
33/29/34269\">",
" figure 1",
" </a>",
" ). These hormones are produced at a variety of sites within the kidney,
including glomerular and vascular endothelium, the medullary and to a lesser degree
the cortical collecting tubule cells, and the renomedullary interstitial cells [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/1,2\">",
" 1,2",
" </a>",
" ]. In general, the tubules primarily synthesize PGE2, while the glomeruli
produce both PGE2 and prostacyclin [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/1-3\">",
" 1-3",
" </a>",
" ]. The renal prostaglandins have important local functions but little systemic
activity, since they are rapidly metabolized in the pulmonary circulation.",
" </p>",
" <p>",
" Two related isoforms of the COX enzyme have been described: COX-1, which is
expressed in most tissues, but variably; and COX-2, which is usually",
" <strong>",
" undetectable",
" </strong>",
" in most tissues but is increased during states of inflammation [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/4\">",
" 4",
" </a>",
" ].",
" </p>",
" <p>",
" This section will primarily review the known renal actions of PGE2 and
prostacyclin. Other arachidonic acid derivatives, such as thromboxane B2, the
leukotrienes (which are formed via the lipoxygenase pathway), and the
epoxyeicosatrienoic acids (which are cytochrome P450-dependent) also can affect
renal function, but their clinical significance is at present incompletely
understood [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/5-8\">",
" 5-8",
" </a>",
" ]. Thromboxane is similar to the prostaglandins in that its rate of production
is relatively low in normal subjects and inhibition of its synthesis has little
effect on renal function [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/6\">",
" 6",
" </a>",
" ]. Thromboxane can, however, cause vasoconstriction and mesangial contraction,
and may contribute to the fall in glomerular filtration rate and increase in
protein excretion frequently seen in glomerular diseases [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/6\">",
" 6",
" </a>",
" ].",
" </p>",
" <p>",
" The intrarenal effects have important clinical implications because of the
widespread use of nonsteroidal antiinflammatory drugs (NSAIDs) (",
" <a class=\"graphic graphic_figure graphicRef71197 \" href=\"UTD.htm?
20/45/21203\">",
" figure 2",
" </a>",
" )&nbsp;[",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/9,10\">",
" 9,10",
" </a>",
" ]. Most traditional NSAIDs are nonselective inhibitors of both COX-1 and COX-2
and most of the renal toxicities described below have been associated with these
agents. Selective COX-2 inhibitors are also available. Compared to the nonselective
agents, they provide similar analgesic and antiinflammatory activity, but markedly
lower gastroduodenal toxicity [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/11,12\">",
" 11,12",
" </a>",
" ].",
" </p>",
" <p>",
" COX-2 is constitutively expressed at low levels in the kidney [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/13\">",
" 13",
" </a>",
" ], but its effect on renal function is unclear in adults. However, it appears
to have a major role in renal development, as animals with deletion of the COX-2
gene have dysplastic tubules and immature glomeruli [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/14\">",
" 14",
" </a>",
" ]. By comparison, mice without the COX-1 enzyme gene have minimal renal
abnormalities.",
" </p>",
" <p class=\"headingAnchor\" id=\"H2\">",
" <span class=\"h1\">",
" ACTIONS",
" </span>",
" &nbsp;&mdash;&nbsp;The renal prostaglandins have both vascular and tubular
actions (",
" <a class=\"graphic graphic_figure graphicRef71197 \" href=\"UTD.htm?
20/45/21203\">",
" figure 2",
" </a>",
" ). These effects result from the activation of distinct cell surface
receptors, which are all members of the G-protein coupled family of seven-
transmembrane receptors [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/15\">",
" 15",
" </a>",
" ]. Different subtypes of these receptors exist, resulting in the varied
actions of a particular prostaglandin [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/15\">",
" 15",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H3\">",
" <span class=\"h2\">",
" Renal hemodynamics",
" </span>",
" &nbsp;&mdash;&nbsp;Renal prostaglandins are primarily vasodilators (except for
PGF2a and thromboxane). They appear to play no role in the regulation of renal
perfusion in the basal state when their secretion rate is relatively low. However,
prostaglandin synthesis is increased (mostly within the glomeruli) by
vasoconstrictors such as angiotensin II, norepinephrine, vasopressin (acting via
the V1 receptor), and endothelin [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/16-19\">",
" 16-19",
" </a>",
" ]. Each of these hormones activates phosphatidylinositol turnover (",
" <a class=\"graphic graphic_figure graphicRef70144 \" href=\"UTD.htm?
19/31/19966\">",
" figure 3",
" </a>",
" ), leading to the formation of diacylglycerol, which contains arachidonic acid
at position 2 [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/20\">",
" 20",
" </a>",
" ]. The latter can then be released from diacylglycerol by the action of
phospholipase A2. The ensuing prostaglandin-induced vasodilation partially
counteracts the neurohumoral vasoconstriction, thereby minimizing the degree of
renal ischemia [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/18,21\">",
" 18,21",
" </a>",
" ].",
" </p>",
" <p>",
" The net clinical effect is that nonselective NSAIDs do not impair renal
perfusion in normal subjects, but can lead to",
" <strong>",
" reversible renal ischemia",
" </strong>",
" and renal insufficiency in a variety of disease states, particularly
hypovolemic disorders in which angiotensin II and norepinephrine secretion are
increased (",
" <a class=\"graphic graphic_table graphicRef69369 \" href=\"UTD.htm?
0/52/843\">",
" table 1",
" </a>",
" ). These include true volume depletion and edematous states associated with
effective circulating volume depletion, such as cirrhosis and congestive heart
failure (",
" <a class=\"graphic graphic_figure graphicRef78038 \" href=\"UTD.htm?
10/25/10653\">",
" figure 4",
" </a>",
" )&nbsp;[",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/9,10,22\">",
" 9,10,22",
" </a>",
" ]. In both of the last two disorders, for example, increasing severity of the
underlying disease is associated with increased secretion of the
three \"hypovolemic\" hormones, angiotensin II, norepinephrine, and ADH and, at
least initially, of the renal prostaglandins [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/23-25\">",
" 23-25",
" </a>",
" ].",
" </p>",
" <p>",
" The likelihood of inducing acute renal failure with an NSAID is related to the
intensity of the underlying renal vasoconstriction. Patients with marked sodium
retention (and higher levels of angiotensin II, norepinephrine, ADH, and renal
prostaglandins) often have a relatively large reduction in the glomerular
filtration rate if NSAIDs are given [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/26,27\">",
" 26,27",
" </a>",
" ]. This deleterious effect is usually rapidly reversible with discontinuation
of the offending drug.",
" </p>",
" <p>",
" It is unclear whether the selective COX-2 inhibitors have a similar adverse
effect. Preliminary clinical trials did not demonstrate significant changes in
renal function, but most patients were not at risk for this complication.",
" </p>",
" <p class=\"headingAnchor\" id=\"H4\">",
" <span class=\"h2\">",
" Systemic hemodynamics",
" </span>",
" &nbsp;&mdash;&nbsp;The vasodilator activity of the renal prostaglandins also
acts to lower systemic vascular resistance. Thus, the administration of a
nonselective NSAID to a hypertensive patient treated with a diuretic, &szlig;-
adrenergic blocker, or ACE inhibitor can raise the systemic blood pressure by an
average of 3 to 5 mmHg and by as much as 5 to 10 mmHg in some patients [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/28-30\">",
" 28-30",
" </a>",
" ]. The NSAID-induced increment in vascular resistance can have an additional
detrimental effect in patients with advanced heart failure. The associated increase
in afterload in this setting can lead to a further reduction in cardiac
contractility and in cardiac output [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/31\">",
" 31",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H5\">",
" <span class=\"h2\">",
" Renin secretion",
" </span>",
" &nbsp;&mdash;&nbsp;The stimulation of renin secretion induced by baroreceptors
in the afferent glomerular arteriole and by the macula densa cells in the early
distal tubule appears to be mediated in part by locally produced prostaglandins [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/32,33\">",
" 32,33",
" </a>",
" ]. These responses are blocked by an NSAID; as a result, prostaglandin
synthesis inhibition can lead to hyporeninemic hypoaldosteronism (since angiotensin
II is the major stimulus to aldosterone secretion) and an impairment in urinary K+
excretion. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?13/25/13720?
source=see_link\">",
" \"Chapter 2B: Renin-angiotensin system\"",
" </a>",
" .) The net effect is that the plasma K+ concentration rises by a mean of 0.2",
" <span class=\"nowrap\">",
" meq/L",
" </span>",
" in normal subjects [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/34\">",
" 34",
" </a>",
" ] and 0.6",
" <span class=\"nowrap\">",
" meq/L",
" </span>",
" in patients with renal insufficiency [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/35\">",
" 35",
" </a>",
" ], with the occasional development of overt hyperkalemia in the latter setting
[",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/36\">",
" 36",
" </a>",
" ]. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?9/44/9930?
source=see_link\">",
" \"Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H6\">",
" <span class=\"h2\">",
" Antagonism of ADH effect",
" </span>",
" &nbsp;&mdash;&nbsp;ADH increases the production of renal prostaglandins, which
then antagonize both its hydroosmotic and vascular effects [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/17,37,38\">",
" 17,37,38",
" </a>",
" ]. The clinical relevance of this relationship is uncertain. The
administration of NSAID to humans removes the inhibitory prostaglandin effect,
possibly leading to increased ADH-induced water reabsorption and an elevation in
urine osmolality that can exceed 200",
" <span class=\"nowrap\">",
" mosmol/kg",
" </span>",
" [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/39,40\">",
" 39,40",
" </a>",
" ]. The associated water retention can then cause a reduction in the plasma Na+
concentration. This is most likely to occur when there is nonsuppressible ADH
release, due to volume depletion or the syndrome of inappropriate ADH secretion
(see Chap. 25). In normal subjects, however, the initial fall in the plasma Na+
concentration will diminish ADH secretion, thereby minimizing the likelihood of
water retention.",
" </p>",
" <p class=\"headingAnchor\" id=\"H7\">",
" <span class=\"h2\">",
" Sodium excretion",
" </span>",
" &nbsp;&mdash;&nbsp;The renal prostaglandins also may have a natriuretic
effect, via reduced Na+ reabsorption in the thick ascending limb and in the
collecting tubules [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/9,41-43\">",
" 9,41-43",
" </a>",
" ]. It is unclear how applicable these findings are to humans, since there are
major species differences in animals: as an example, prostaglandin E2 inhibits
cortical collecting tubule Na+ reabsorption in rabbits but not in rats [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/44\">",
" 44",
" </a>",
" ].",
" </p>",
" <p>",
" If prostaglandins do promote Na+ excretion, they will again do so only when
their rate of production is increased. Thus, prostaglandins have little effect in
the basal state, but may play a role in hypovolemic states where they may modulate
the Na+-retaining as well as the renal vasoconstrictive effects of angiotensin II,
norepinephrine, and possibly endothelin [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/45\">",
" 45",
" </a>",
" ]. Consequently, inhibiting prostaglandin synthesis with an NSAID can promote
further sodium retention in this setting, both by reducing glomerular filtration
rate and by increasing tubular reabsorption [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/9\">",
" 9",
" </a>",
" ]. These effects also can limit the responsiveness of edematous patients to
diuretic therapy [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/34,46\">",
" 34,46",
" </a>",
" ].",
" </p>",
" <p>",
" In addition to regulating net Na+ excretion, the prostaglandins produced in
the medulla may help to protect the thick ascending limb cells against ischemic
injury when the patient is volume depleted. The medulla normally has a very low
PO2, due in part to countercurrent exchange of oxygen. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?35/49/36630?
source=see_link&amp;anchor=H6#H6\">",
" \"Chapter 4A: Cell model for loop of Henle transport\", section on 'Passive
Na+ reabsorption and medullary hypoxia'",
" </a>",
" .) This relative hypoxia is exacerbated when renal perfusion is diminished in
hypovolemic states. By diminishing NaCl reabsorption in the thick ascending limb,
prostaglandins reduce the energy requirement of these cells, thereby allowing them
to better tolerate the decrease in oxygen delivery [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/966/abstract/47\">",
" 47",
" </a>",
" ].",
" </p>",
" <p>",
" (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?2/36/2631?
source=see_link\">",
" \"Chapter 6F: Hormonal regulation of calcium and phosphate balance\"",
" </a>",
" .)",
" </p>",
" <p>",
" (From Rose, BD, Post, TW. Clinical Physiology of Acid-Base and Electrolyte
Disorders, 5th ed, McGraw-Hill, New York, 2001.)",
" </p>",
" </div>",
" <div id=\"topicAgreement\">",
" Use of UpToDate is subject to the",
" <a class=\"licenseLink\" href=\"./license\" id=\"sla_in_page\"
target=\"_blank\">",
" Subscription and License Agreement",
" </a>",
" .",
" </div>",
" <div class=\"headingAnchor\" id=\"references\">",
" <h1>",
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" <div id=\"topicVersionRevision\">",
" Topic 7292 Version 4.0",
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FFFFAH/9k=);\">",
" </div>",
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"</div>"].join("\n");
var script_f0_60_967=[""].join("\n");
var outline_f0_60_967=null;
var title_f0_60_968="Laboratory diagnosis of the hemoglobinopathies";
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" Laboratory diagnosis of the hemoglobinopathies",
" </div>",
" <div id=\"topicContributors\">",
" <div>",
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href=\"UTD.htm?0/60/968/contributors\">",
" Authors",
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" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
0/60/968/contributors\">",
" Abdullah Kutlar, MD",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
0/60/968/contributors\">",
" Ferdane Kutlar, MD",
" </a>",
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href=\"UTD.htm?0/60/968/contributors\">",
" Section Editor",
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" <br/>",
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0/60/968/contributors\">",
" William C Mentzer, MD",
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" <a class=\"contributor contributor_credentials contributorType\"
href=\"UTD.htm?0/60/968/contributors\">",
" Deputy Editor",
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" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
0/60/968/contributors\">",
" Stephen A Landaw, MD, PhD",
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" Literature review current through:",
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" Oct 2013.",
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" Mar 13, 2012.",
" </div>",
" <div id=\"topicText\">",
" <p class=\"headingAnchor\" id=\"H11822024\">",
" <span class=\"h1\">",
" INTRODUCTION",
" </span>",
" &nbsp;&mdash;&nbsp;Human hemoglobins (Hb) are tetrameric proteins composed of
two unlike pairs of globin chains:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Normal adult Hb (HbA), is composed of two alpha chains and two beta chains
(&alpha;2&beta;2), and constitutes approximately 97 percent of the total Hb in
adult red blood cells (RBCs).",
" </li>",
" <li>",
" Adult RBCs also contain a minor Hb (HbA",
" _{",
" 2",
"}",
" ), composed of two alpha chains and two delta chains (&alpha;2&delta;2),
which accounts for approximately 2.5 percent of total Hb.",
" </li>",
" <li>",
" Fetal Hb (HbF), composed of two alpha chains and two gamma chains
(&alpha;2&gamma;2), is found in minute amounts (usually &lt;1 percent) in normal
adults and is confined to a small proportion of RBCs, termed F-cells.",
" </li>",
" </ul>",
" </p>",
" <p>",
" The number of hemoglobin variants (ie, hemoglobinopathies) discovered to date
totals more than one thousand. The vast majority do not cause any clinical or
hematologic problems, while others are associated with varying degrees of morbidity
and mortality (eg, sickle cell anemia, beta thalassemia major). The laboratory
diagnosis of the various hemoglobinopathies will be reviewed here. Overviews of the
structure and function of normal hemoglobins and of hemoglobin mutations are
presented separately. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?22/29/23001?
source=see_link\">",
" \"Structure and function of normal human hemoglobins\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?16/37/16984?
source=see_link\">",
" \"Introduction to hemoglobin mutations\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H11822052\">",
" <span class=\"h1\">",
" GLOBIN CHAIN PHYSIOLOGY",
" </span>",
" &nbsp;&mdash;&nbsp;Globin gene physiology is discussed elsewhere in UpToDate,
but portions relevant to an understanding of the laboratory diagnosis of the
hemoglobinopathies will be briefly reviewed here. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?22/29/23001?
source=see_link\">",
" \"Structure and function of normal human hemoglobins\"",
" </a>",
" .)",
" </p>",
" <p>",
" Globin genes are expressed in embryos as early as four to six weeks. Embryonic
&alpha;-like chains are called &zeta; (zeta) chains, whereas &beta;-like globin
chains are called &epsilon; (epsilon) chains. Tetramers of these chains form the
three embryonic Hbs: Gower-1 (&zeta;2&epsilon;2), Gower-2 (&alpha;2&epsilon;2), and
Portland (&zeta;2&gamma;2), which disappear around the eighth week of gestation [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/968/abstract/1,2\">",
" 1,2",
" </a>",
" ]. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?22/29/23001?
source=see_link&amp;anchor=H13#H13\">",
" \"Structure and function of normal human hemoglobins\", section on 'Embryonic
hemoglobins'",
" </a>",
" .)",
" </p>",
" <p>",
" The genes encoding &alpha;-like and &beta;-like globin chains are organized in
clusters on different chromosomes (",
" <a class=\"graphic graphic_figure graphicRef65642 \" href=\"UTD.htm?
6/32/6656\">",
" figure 1",
" </a>",
" ). The &alpha;-globin gene cluster is on the short arm of chromosome 16
(16p13.3) and the &beta;-like globin gene cluster is on the short arm of chromosome
11 (11p15.5). In both clusters, the genes are organized from 5&rsquo; to 3&rsquo;
in order of their expression during different developmental stages (ie, embryonic
to fetal to adult). In the &alpha;-globin gene cluster, the organization follows
the order 5&rsquo;-&zeta;-&alpha;2-&alpha;1-3&rsquo;, whereas in the &beta;-globin
cluster it is 5&rsquo;-&epsilon;-G&gamma;-A&gamma;-&delta;-&beta;-3&rsquo;.",
" </p>",
" <p>",
" In both clusters, far upstream of the structural globin genes are DNAse I
hypersensitive sites, which have important regulatory functions in controlling the
expression of the genes located in the cluster. In the &beta;-globin cluster, 5
DNAse hypersensitive sites (HS1-5) are located approximately 20 kb upstream of the
embryonic &epsilon;-gene and form the locus control region (LCR). Deletion of the
LCR abolishes the expression of all &beta;-like genes.",
" </p>",
" <p>",
" The duplicated &alpha;-globin genes, &alpha;2 and &alpha;1, encode identical
peptides (globin chains). The &alpha;2 gene is expressed at a higher level (3:1)
compared with the &alpha;1 gene.",
" </p>",
" <p>",
" In the &beta;-cluster, G&gamma; and A&gamma; genes differ only in one position
(codon 136). In G&gamma;, this position is occupied by glycine, while in A&gamma;
chains this position is occupied by alanine. The ratio of G&gamma; to A&gamma; in
HbF of newborns is 70:30; with the perinatal fetal to adult (&gamma; to &beta;)
switch, the proportion of G&gamma; to A&gamma; chains in the minute amount of HbF
present in adults changes to approximately 40:60 [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/968/abstract/2-4\">",
" 2-4",
" </a>",
" ]. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?22/29/23001?
source=see_link&amp;anchor=H16#H16\">",
" \"Structure and function of normal human hemoglobins\", section on 'Structure
of the gamma globin chain'",
" </a>",
" .)",
" </p>",
" <p>",
" The synthesis of &alpha;-like chains and &beta;-like chains is balanced at all
developmental stages, so that normally there are no excess globin chains [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/968/abstract/3\">",
" 3",
" </a>",
" ]. Disruption of this balance is a hallmark of thalassemia syndromes. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?8/58/9129?
source=see_link\">",
" \"Molecular pathology of the thalassemic syndromes\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H11822192\">",
" <span class=\"h2\">",
" Prevalence of the hemoglobinopathies",
" </span>",
" &nbsp;&mdash;&nbsp;Hemoglobinopathies can be broadly classified into
qualitative (Hb variants) and quantitative (thalassemias) disorders of globin
synthesis. Although accurate prevalence data are not available for most of the
developing countries (sub-Saharan Africa, Mediterranean region, Southeast Asia,
India), limited population surveys conducted in these areas and estimates based
upon these surveys suggest that the carrier state for certain variants (HbS, HbE,
HbC) and both &alpha;- and &beta;-thalassemias can reach very high frequencies (up
to 30 to 35 percent for HbS in some populations in Africa and India, up to 40 to 45
percent for HbE in parts of Southeast Asia, 80 to 90 percent for deletional
&alpha;-thalassemia among some tribal populations in India, and up to 15 to 20
percent for &beta;-thalassemia), presumably as a result of selective pressure from
malaria. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?20/23/20858?
source=see_link\">",
" \"Protection against malaria in the hemoglobinopathies\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H11822149\">",
" <span class=\"h2\">",
" Public health issues",
" </span>",
" &nbsp;&mdash;&nbsp;Hemoglobinopathies constitute the most common inherited
disorders in humans as a result of selective pressure of endemic falciparum
malaria. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?20/23/20858?
source=see_link\">",
" \"Protection against malaria in the hemoglobinopathies\"",
" </a>",
" .)",
" </p>",
" <p>",
" While heterozygosity for HbS and &beta;-thalassemia may protect against
malaria,",
" <strong>",
" homozygosity",
" </strong>",
" for variants such as HbS, and &beta;-thalassemias, as well as compound
heterozygosity for HbS, HbC, HbE, and different types of &beta;-thalassemia
alleles, produce clinically significant disorders and pose a huge public health
problem in countries with limited resources [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/968/abstract/3\">",
" 3",
" </a>",
" ]. As a result of the large population movements of past several decades,
hemoglobinopathies are now commonly seen in industrialized Western societies as
well. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?40/51/41783?
source=see_link\">",
" \"Community public health issues and the thalassemic syndromes: Lessons from
other countries\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H11822059\">",
" <span class=\"h1\">",
" GLOBIN CHAIN MUTATIONS",
" </span>",
" &nbsp;&mdash;&nbsp;The number of hemoglobin variants discovered to date totals
more than one thousand. The vast majority of these variants do not cause any
clinical or hematological problems, and therefore are mainly of interest to
geneticists and biochemists. A compilation of the various hemoglobinopathies is
available on the web (",
" <a class=\"external\" href=\"file://globin.cse.psu.edu/\">",
" Globin Gene Server",
" </a>",
" ).",
" </p>",
" <p>",
" Most of the hemoglobin variants are missense mutations in the globin genes
(&alpha;, &beta;, &gamma;, or &delta;) resulting from single nucleotide
substitutions. Other uncommon mechanisms include the following:",
" </p>",
" <p>",
" <ul class=\"bulletCompact-block\">",
" <li>",
" Deletion or insertion of one or more nucleotides, altering the reading frame
(eg, Hb Geneva &beta;114 &ndash;CT, +G)",
" </li>",
" <li>",
" Fusion of adjacent globin genes with deletion of intergenic DNA sequences
(eg, &gamma;&beta; fusion in Hb Kenya and &delta;&beta; fusion in Hb Lepore)",
" </li>",
" <li>",
" Mutations of the termination codon leading to the production of elongated
globin chains (eg, Hb Constant Spring, &alpha;142TAA&rarr;AAA, +31 residues) [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/968/abstract/1\">",
" 1",
" </a>",
" ]",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H11822211\">",
" <span class=\"h2\">",
" Clinical consequences",
" </span>",
" &nbsp;&mdash;&nbsp;Hemoglobin variants that significantly alter the structure,
stability, synthesis, or function of the molecule have hematologic",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" clinical consequences. These can be classified into specific categories, as
follows (",
" <a class=\"graphic graphic_table graphicRef79795 \" href=\"UTD.htm?
4/8/4236\">",
" table 1",
" </a>",
" ):",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" <strong>",
" Change in physical properties",
" </strong>",
" &mdash; HbS and HbC are two examples of mutations on the surface of the
hemoglobin molecule that alter both the charge and the",
" <span class=\"nowrap\">",
" physical/chemical",
" </span>",
" properties of the molecule. This leads to abnormal polymer formation in the
case of deoxyhemoglobin S and crystallization in the case of HbC, with profound
effects on the function, morphology, rheology, and lifespan of the affected red
cells. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?29/25/30104?
source=see_link\">",
" \"Sickle hemoglobin polymer: Structure and functional properties\"",
" </a>",
" .)",
" </li>",
" <li>",
" <strong>",
" Globin instability",
" </strong>",
" &mdash; Several mechanisms account for the pathogenesis of unstable
hemoglobin variants. The common mechanism involves the precipitation of the
unstable hemoglobin molecule within the red cell, with subsequent attachment to the
inner layer of the red cell membrane (ie, &ldquo;Heinz body&rdquo; formation). Red
cells containing membrane-attached Heinz bodies have impaired deformability and
filterability leading to their premature destruction (ie, congenital Heinz body
hemolytic anemia). (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?0/38/616?
source=see_link\">",
" \"Unstable hemoglobin variants\"",
" </a>",
" .)",
" </li>",
" <li>",
" <strong>",
" Altered oxygen affinity",
" </strong>",
" &mdash; Mutations in certain globin chain residues alter the oxygen (O2)
affinity of the hemoglobin molecule; a stabilization of the R (relaxed, oxy) state
will result in high O2 affinity variants and erythrocytosis. Conversely, a
stabilization of the T (tense, deoxy) configuration will result in a variant with
low O2 affinity with enhanced unloading of O2 to the tissues with resultant
cyanosis and anemia in certain cases (due to the suppression of the O2 sensing
pathway). (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?41/4/42055?
source=see_link\">",
" \"Genetic disorders of hemoglobin oxygen affinity\"",
" </a>",
" .)",
" </li>",
" <li>",
" <strong>",
" Oxidation of heme iron",
" </strong>",
" &mdash; Mutations of the heme binding site, particularly those affecting the
conserved proximal (F8) and distal (E7) histidine residues, lead to the oxidation
of the iron atom in heme from ferrous (Fe++ ) to ferric (Fe+++) state with
resultant methemoglobinemia (M-hemoglobins) and cyanosis (",
" <a class=\"graphic graphic_figure graphicRef65311 \" href=\"UTD.htm?
18/24/18821\">",
" figure 2",
" </a>",
" ). (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?4/46/4841?
source=see_link\">",
" \"Genetics and pathogenesis of methemoglobinemia\"",
" </a>",
" .)",
" </li>",
" <li>",
" <strong>",
" Altered structure and synthetic rate",
" </strong>",
" &mdash; A group of mutations alter both the structure and the synthetic rate
of the globin chain leading to a &ldquo;thalassemic&rdquo; phenotype. These include
fusion hemoglobins (eg, Hb Lepore, where the 5&rsquo; &delta;-globin sequences are
fused to 3&rsquo; &beta;-globin sequences with deletion of the intergenic DNA; this
puts the &delta;&beta;-fusion gene under the transcriptional control of the
inefficient &delta;-globin promoter with low expression of the fusion globin and
hence the thalassemic phenotype), mutations that cause both a missense mutation and
create an aberrant splice site (such as HbE, Hb Knossos, and Hb Malay), and
&ldquo;hyper-unstable&rdquo; globins where the nascent globin chains are highly
unstable, undergo rapid proteolytic degradation, and result in a reduction in the
affected globin [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/968/abstract/1-4\">",
" 1-4",
" </a>",
" ].",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H2640222\">",
" <span class=\"h2\">",
" Expression of the abnormal hemoglobin",
" </span>",
" &nbsp;&mdash;&nbsp;Except for the commonly occurring hemoglobin variants (eg,
HbS, HbC, HbE, and HbD-Los Angeles), very few abnormal hemoglobins have been
observed in the homozygous state. Accordingly, variant hemoglobins are usually
found in the heterozygous state. Their expression will vary depending upon whether
the mutation is in an alpha, beta, or gamma globin, as follows:",
" </p>",
" <p>",
" <ul class=\"bulletCompact-block\">",
" <li>",
" Gamma-chain variants are expressed in fetal life and their level gradually
decreases as the &gamma; to &beta; (fetal to adult) globin switch progresses during
the post-natal period.",
" </li>",
" <li>",
" Alpha-chain variants are expressed throughout fetal, neonatal, and adult
life.",
" </li>",
" <li>",
" Beta-chain variants are expressed to a small extent at the time of birth,
but become more apparent as the fetal to adult globin switch progresses.",
" </li>",
" <li>",
" Delta-globin variants are expressed at very low levels and can be detected
only after the switch to adult globin synthesis is complete.",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H2640236\">",
" <span class=\"h3\">",
" Factors affecting the type and amount of abnormal hemoglobin",
" </span>",
" </p>",
" <p class=\"headingAnchor\" id=\"H2640300\">",
" <span class=\"h4\">",
" Alpha globin mutations",
" </span>",
" &nbsp;&mdash;&nbsp;Since &alpha;-globin chains are present in all of the
hemoglobins expressed after the embryonic stage (HbF-&alpha;2&gamma;2; HbA-
&alpha;2&beta;2, and HbA",
" _{",
" 2",
"}",
" -&alpha;2&delta;2), &alpha;-chain variants are associated with the production
of variant HbF (&alpha;",
" ^{",
" x",
"}",
" 2&gamma;2) and HbA",
" _{",
" 2",
"}",
" (&alpha;",
" ^{",
" x",
"}",
" 2&delta;2) as well as HbA.",
" </p>",
" <p class=\"headingAnchor\" id=\"H2640307\">",
" <span class=\"h4\">",
" Beta globin mutations",
" </span>",
" &nbsp;&mdash;&nbsp;In heterozygous states, &beta;-chain variants constitute 40
to 50 percent of the hemoglobin in red cells [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/968/abstract/2\">",
" 2",
" </a>",
" ]. It should, however, be kept in mind that certain factors affect the amount
of variant &beta;-chains in carriers. These include the stability of the variant,
the surface charge of the variant &beta;-chain, and the presence of concomitant
&alpha; or &beta;-thalassemia. The more unstable the variant, the lower the
quantity.",
" </p>",
" <p class=\"headingAnchor\" id=\"H2640293\">",
" <span class=\"h4\">",
" Surface charge",
" </span>",
" &nbsp;&mdash;&nbsp;Surface charge of the variant also plays a role in
determining its quantity in red cells; this is because the formation of the
&alpha;&beta;-dimers (&alpha;1&beta;1 and &alpha;2&beta;2 contacts) is the critical
first step in hemoglobin tetramer formation. This step is primarily driven by
electrostatic interactions between &alpha; and &beta;-chains. The &alpha;-globin
chains have a relatively positive surface charge and therefore interact more
readily with relatively negatively charged &beta;-globin variants to form
&alpha;&beta;-dimers. This is reflected in the higher percentage of negatively
charged &beta;-globin variants, such as HbN-Baltimore (&beta;95Lys&rarr;Glu), which
is found at approximately 50 percent in heterozygotes compared with &beta;-globin
variants with a positive surface charge, HbS (&beta;6Glu&rarr;Val) or HbC
(&beta;6Glu&rarr;Lys), whose quantity in the heterozygote is 40 to 45 percent (",
" <a class=\"graphic graphic_figure graphicRef72950 \" href=\"UTD.htm?
0/58/942\">",
" figure 3",
" </a>",
" ). (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?16/37/16984?
source=see_link&amp;anchor=H4#H4\">",
" \"Introduction to hemoglobin mutations\", section on 'Assembly of the mutant
hemoglobin'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H2640329\">",
" <span class=\"h4\">",
" Concomitant alpha thalassemia",
" </span>",
" &nbsp;&mdash;&nbsp;In the presence of &alpha;-thalassemia, negatively charged
&beta;-globin variants compete more favorably for the available &alpha;-chains;
this phenomenon is reflected in even lower percentages of HbS and HbC in
heterozygous carriers of these variants in the presence of common deletional forms
of &alpha;-thalassemia (HbS of 30 to 35 percent in individuals with heterozygous
&alpha;+-thalassemia,",
" <span class=\"nowrap\">",
" -&alpha;/&alpha;&alpha;;",
" </span>",
" 25 to 30 percent in homozygous &alpha;+-thalassemia,",
" <span class=\"nowrap\">",
" -&alpha;/-&alpha;)",
" </span>",
" (",
" <a class=\"graphic graphic_table graphicRef70184 \" href=\"UTD.htm?
16/17/16667\">",
" table 2",
" </a>",
" ) [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/968/abstract/5,6\">",
" 5,6",
" </a>",
" ].",
" </p>",
" <p>",
" Conversely, the amount of a &beta;-globin variant will increase if there is a
&beta;-thalassemia allele in trans; the percentage of the variant will be inversely
proportional to the output of the &beta;-thalassemia allele; thus, the higher the
variant the lower the output of the &beta;+-thalassemia allele. In the case of a
beta(0)-thalassemia allele in trans, the variant will amount to &ge;90 percent of
the Hb in red cells, with HbA",
" _{",
" 2",
"}",
" and HbF constituting the remainder. The quantity of &alpha;-globin variants is
also variable depending on the &alpha;-globin gene involved and the presence of
concomitant &alpha;- or &beta;-thalassemia. Since there are normally four &alpha;-
globin loci",
" <span class=\"nowrap\">",
" (&alpha;&alpha;/&alpha;&alpha;)",
" </span>",
" and the 5&rsquo;&alpha;-globin genes (&alpha;2) are expressed at a higher
level, some of the variation in the level of &alpha;-globin variants will depend on
which &alpha;-globin gene carries the mutation; &alpha;2 globin mutations are
usually present at 20 to 25 percent of the total hemoglobin, whereas &alpha;1-
globin variants are expressed at a lower level (15 to 20 percent).",
" </p>",
" <p>",
" Concomitant &alpha;-thalassemia results in a higher level of expression of
&alpha;-globin variants. Observations on the different levels of expression of the
common &alpha;-globin variant, HbG-Philadelphia (&alpha;68Asn&rarr;Lys), is a case
in point [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/968/abstract/7\">",
" 7",
" </a>",
" ]. While this variant is found at approximately 25 percent in Northern
Italians, its percentages in Americans of African descent can be either 33 or
approximately 50 percent. This is clearly related to the different genotypes found
in these two distinct populations; In Northern Italy and Sardinia, the genotype
is",
" <span class=\"nowrap\">",
" &alpha;",
" ^{",
" G",
"}",
" &alpha;/&alpha;&alpha;",
" </span>",
" with an expression level of 25 percent, whereas in Americans of African
descent, the G-Philadelphia mutation is commonly found on a hybrid &alpha;2&alpha;1
gene associated with the common 3.7 kb &alpha;+-thalassemia deletion",
" <span class=\"nowrap\">",
" (-&alpha;",
" ^{",
" G",
"}",
" /&alpha;&alpha;)",
" </span>",
" with approximately 33 percent expression. When there is an &alpha;+-
thalassemia deletion in trans",
" <span class=\"nowrap\">",
" (-&alpha;",
" ^{",
" G",
"}",
" /-&alpha;",
" </span>",
" genotype), as expected, the level of Hb G-Philadelphia will be approximately
50 percent. Co-inheritance of &alpha;-chain variants with &beta;-thalassemia
results in the reduction of the &alpha;-chain variant.",
" </p>",
" <p class=\"headingAnchor\" id=\"H11822071\">",
" <span class=\"h1\">",
" INITIAL EVALUATION",
" </span>",
" &nbsp;&mdash;&nbsp;The vast majority of the over 1000 known Hb variants do not
cause any clinical and hematologic problems [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/968/abstract/2\">",
" 2",
" </a>",
" ]. Nevertheless, many laboratories are referred specimens where clinically
significant Hb variants such as HbS [&beta;6(A3) Glu&rarr;Val, GAG&rarr;GTG] or
thalassemia mutations are found in compound heterozygosity with an
&ldquo;unknown&rdquo; Hb variant. Thus, an important function of the reference
laboratory is characterization of an &ldquo;unknown&rdquo; variant and delineation
of its role, or lack thereof, in the clinical",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" hematological phenotype in question [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/968/abstract/2\">",
" 2",
" </a>",
" ]. A stepwise approach and algorithm to the laboratory diagnosis of
hemoglobinopathies is summarized in the table (",
" <a class=\"graphic graphic_table graphicRef57389 \" href=\"UTD.htm?
24/40/25227\">",
" table 3",
" </a>",
" ) [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/968/abstract/8,9\">",
" 8,9",
" </a>",
" ].",
" </p>",
" <p>",
" The evaluation of the hematologic picture, complemented by concise clinical
information, is an important starting point. The ascertainment of the presence and
type of anemia or erythrocytosis, red blood cell (RBC) indices [with particular
emphasis on mean corpuscular volume (MCV)], and review of peripheral blood smears
are simple initial steps that can provide useful information and guide the next
step in laboratory evaluation. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?34/45/35543?
source=see_link&amp;anchor=H19#H19\">",
" \"Mean corpuscular volume\", section on 'Causes of microcytosis'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H11822078\">",
" <span class=\"h2\">",
" Hemoglobin electrophoresis",
" </span>",
" &nbsp;&mdash;&nbsp;The most commonly utilized method for the detection of
hemoglobinopathies has been hemoglobin electrophoresis. The initial screening is
performed at an alkaline pH (pH 8.6) usually on cellulose acetate. This simple
method provides separation of the normal hemoglobins, HbA, HbF, and HbA",
" _{",
" 2",
"}",
" , as well as the common variants HbS and HbC.",
" </p>",
" <p>",
" On a cellulose acetate strip, HbA migrates the most toward the anode followed
by HbF, HbS, and HbC. Although this is a simple, rapid, and inexpensive method, it
has certain limitations. A significant number of Hb variants co-migrate with HbS
and HbC on cellulose acetate, thereby decreasing the utility of this simple method
in the definitive identification of variant hemoglobins. Variants that have the
same mobility as HbS include HbD, HbG, and Hb Lepore. Variants that co-migrate with
HbC include HbE and HbO-Arab (",
" <a class=\"graphic graphic_diagnosticimage graphicRef68806 \" href=\"UTD.htm?
8/51/9023\">",
" image 1",
" </a>",
" ).",
" </p>",
" <p>",
" Such co-migration often necessitates the utilization of a second
electrophoretic procedure on citrate agar in acid pH. This method is not solely
charge-dependent. It also relies on the chemical interaction of the electrophoresis
medium (agar) with Hb molecules in a pH-dependent manner.",
" </p>",
" <p>",
" <ul class=\"bulletCompact-block\">",
" <li>",
" HbF, HbA, HbS, and HbC have distinct mobility patterns on citrate agar,
which are different from those on cellulose acetate.",
" </li>",
" <li>",
" HbD and HbG co-migrate with HbS on cellulose acetate and have a mobility
identical to HbA on citrate agar.",
" </li>",
" <li>",
" HbE co-migrates with HbA on citrate, whereas HbO-Arab has a distinct
mobility pattern (between HbA and HbS).",
" </li>",
" </ul>",
" </p>",
" <p>",
" Thus, application of cellulose acetate and citrate agar electrophoresis in
succession leads to the definitive identification of HbS, HbC, HbE, and HbO-Arab
[",
" <a class=\"abstract\" href=\"UTD.htm?0/60/968/abstract/2,4\">",
" 2,4",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H11822085\">",
" <span class=\"h2\">",
" Isoelectric focusing",
" </span>",
" &nbsp;&mdash;&nbsp;Methods with higher resolution capacity than hemoglobin
electrophoresis have been applied to the screening and diagnosis of
hemoglobinopathies. These include isoelectric focusing on either acrylamide or thin
layer agarose (",
" <a class=\"graphic graphic_figure graphicRef52896 \" href=\"UTD.htm?
42/6/43106\">",
" figure 4",
" </a>",
" ).",
" </p>",
" <p>",
" Isoelectric focusing (IEF) is a method of electrophoresis in a medium in which
there is a pH gradient established by the presence of ampholytes in the medium.
Hemoglobinopathies are best detected within a pH range of 6.0 to 8.0. The method
takes advantage of the mobility of the proteins (in this case, hemoglobins) based
upon their isoelectric point (pI). When an electric current is applied to an IEF
gel, Hb variants will migrate to a pH where they have a neutral surface charge
(pI). The advantage of this method is its capability to separate Hb variants whose
isoelectric points differ by as little as 0.1 pH units. Thus, this method has the
distinct advantage of separating HbD from HbS and HbC from HbE and HbO-Arab (",
" <a class=\"graphic graphic_figure graphicRef63606 \" href=\"UTD.htm?
10/54/11108\">",
" figure 5",
" </a>",
" ).",
" </p>",
" <p>",
" In many laboratories, electrophoresis on cellulose acetate and citrate agar
have now been replaced with IEF on agarose gels, especially for neonatal screening
for hemoglobinopathies.",
" </p>",
" <p class=\"headingAnchor\" id=\"H11822099\">",
" <span class=\"h2\">",
" High performance liquid chromatography",
" </span>",
" </p>",
" <p class=\"headingAnchor\" id=\"H2640398\">",
" <span class=\"h3\">",
" Cation exchange",
" </span>",
" &nbsp;&mdash;&nbsp;The next step in evaluation of an abnormal hemoglobin after
isoelectric focusing is usually cation exchange, either on a commercially available
system (such as the Biorad Variant) or using a weak cation exchange column,
SynChropak CM-300 (SynChrom Eprogen, Darien, IL, USA) [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/968/abstract/2,10\">",
" 2,10",
" </a>",
" ]. With these methods, a positive diagnosis of commonly occurring &beta; chain
variants such as HbS, HbC, HbE, HbD-Los Angeles, and HbO-Arab, as well as the
&alpha; chain variant HbG-Philadelphia can be established (",
" <a class=\"graphic graphic_figure graphicRef72323 \" href=\"UTD.htm?
20/56/21376\">",
" figure 6",
" </a>",
" and",
" <a class=\"graphic graphic_figure graphicRef63052 \" href=\"UTD.htm?
11/58/12199\">",
" figure 7",
" </a>",
" and",
" <a class=\"graphic graphic_figure graphicRef50316 \" href=\"UTD.htm?
13/56/14215\">",
" figure 8",
" </a>",
" ).",
" </p>",
" <p>",
" Quantitative data obtained from cation exchange high performance liquid
chromatography (HPLC) will allow the initial diagnosis of &beta;-thalassemia trait
as well as other &beta;-thalassemia syndromes and hereditary persistence of fetal
Hb [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/968/abstract/2,10,11\">",
" 2,10,11",
" </a>",
" ]. The percentage of the uncommon or unusual variant on cation exchange HPLC
will often yield clues as to whether the variant in question is a mutant &alpha;-
or &beta;-globin: in most cases, &alpha; chain variants are 15 to 25 percent of the
total Hb, whereas &beta; chain variants comprise 30 to 45 percent. However, there
are many exceptions to this general rule, including unstable Hb variants",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" the presence of concomitant &alpha;- or &beta;-thalassemia.",
" </p>",
" <p class=\"headingAnchor\" id=\"H2640405\">",
" <span class=\"h3\">",
" Reverse phase",
" </span>",
" &nbsp;&mdash;&nbsp;The next step if the diagnosis remains uncertain is the
application of reverse phase HPLC to separate the individual globin chains using a
Vydac C4 column (The Separations Group, Hesperia, CA, USA). This technique is
helpful in localizing the abnormality to &alpha; or &beta; (and &gamma;) chains,
and in quantifying G&gamma; and A&gamma; chains of HbF in cases with elevated fetal
hemoglobin, and thus aid in the diagnosis of different types of hereditary
persistence of fetal Hb and &delta;&beta;-thalassemia (",
" <a class=\"graphic graphic_figure graphicRef77931 \" href=\"UTD.htm?
34/9/34967\">",
" figure 9",
" </a>",
" and",
" <a class=\"graphic graphic_figure graphicRef56378 \" href=\"UTD.htm?
10/17/10518\">",
" figure 10",
" </a>",
" ) [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/968/abstract/2,10,11\">",
" 2,10,11",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H11822121\">",
" <span class=\"h2\">",
" Capillary electrophoresis",
" </span>",
" &nbsp;&mdash;&nbsp;A capillary electrophoresis-based system has been developed
and marketed (Sebia Electrophoresis, Evry, France). The resolution of this method
is superb and comparable to that obtained with HPLC. Quantification of Hb
components is accurate and has been validated by a comparison to HPLC. The
advantage of this method is its capability to run 8 channels simultaneously, thus
allowing rapid processing of multiple specimens at a rate of 34",
" <span class=\"nowrap\">",
" samples/hour",
" </span>",
" (",
" <a class=\"graphic graphic_figure graphicRef65032 \" href=\"UTD.htm?
14/19/14647\">",
" figure 11",
" </a>",
" ).",
" </p>",
" <p class=\"headingAnchor\" id=\"H11822128\">",
" <span class=\"h1\">",
" DEFINITIVE EVALUATION",
" </span>",
" &nbsp;&mdash;&nbsp;The final step in the diagnostic approach to the presence
of an abnormal hemoglobin is the definitive identification of the unknown or
uncommon variant. In the Hemoglobinopathy Laboratory at the Medical College of
Georgia, this is achieved by the sequencing of the polymerase chain reaction (PCR)-
amplified globin gene in question [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/968/abstract/12,13\">",
" 12,13",
" </a>",
" ]. The sequencing reaction can be performed on genomic DNA extracted from
peripheral blood (eg, from white blood cells) [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/968/abstract/12-14\">",
" 12-14",
" </a>",
" ].",
" </p>",
" <p>",
" However, in many cases, we have increasingly applied the method of sequencing
the complementary DNAs (cDNAs) of the respective globin gene, which are obtained
from the reverse transcription of total red blood cell (RBC) mRNA that contains an
abundance of the globin message. The advantage of this method over the sequencing
of genomic DNA is that all of the globin cDNAs can easily be sequenced with one set
of primers with a single sequencing reaction [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/968/abstract/12\">",
" 12",
" </a>",
" ]. In the case of the &beta;-thalassemias, identification of the mutation
involves sequencing of the genomic DNA, particularly the important regulatory
regions such as the promoter,",
" <span class=\"nowrap\">",
" exon/intron",
" </span>",
" boundaries, introns, and the 3&rsquo; untranslated region (3&rsquo;UTR) up to
the polyadenylation signal (",
" <a class=\"graphic graphic_figure graphicRef75837 \" href=\"UTD.htm?
16/24/16776\">",
" figure 12",
" </a>",
" ) [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/968/abstract/13\">",
" 13",
" </a>",
" ].",
" </p>",
" <p>",
" Another application of the molecular diagnostic methods involves the detection
of deletions in the globin genes by PCR amplification and the detection of the
amplicon sizes (",
" <a class=\"graphic graphic_figure graphicRef66522 \" href=\"UTD.htm?
14/5/14419\">",
" figure 13",
" </a>",
" and",
" <a class=\"graphic graphic_figure graphicRef55893 \" href=\"UTD.htm?
21/58/22439\">",
" figure 14",
" </a>",
" ) on agarose gels (Gap PCR). These include the detection of common deletional
&alpha;+-thalassemias (&minus;&alpha;",
" ^{",
" 3.7",
"}",
" , &minus;&alpha;",
" ^{",
" 4.2",
"}",
" ) and &alpha;",
" ^{",
" 0",
"}",
" -thalassemias (&ndash; &ndash;",
" ^{",
" SEA",
"}",
" , &ndash; &ndash;",
" ^{",
" MED",
"}",
" , &ndash; &ndash;",
" ^{",
" 20.5",
"}",
" , &ndash; &ndash;",
" ^{",
" FIL",
"}",
" , &ndash; &ndash;",
" ^{",
" THAI",
"}",
" ) [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/968/abstract/15\">",
" 15",
" </a>",
" ]. With this approach, some of the relatively common forms of deletional
&beta;-thalassemias (such as the 619 bp Indian deletion and the 1394 bp deletion of
African-Americans) can be detected. This approach also allows the molecular
characterization of hybrid Hbs such as the &delta;&beta; hybrid Hb Lepore and
different types of deletional hereditary persistence of fetal hemoglobin and
&delta;&beta;-thalassemia [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/968/abstract/13,15,16\">",
" 13,15,16",
" </a>",
" ].",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Identification of mutations leading to &beta;-thalassemia requires
sequencing of genomic DNA, spanning approximately 1.8 kb from the &beta;-globin
promoter, downstream to the polyadenylation signal. This includes the important
regulatory elements in the promoter (CACC, CAT, and TATA boxes), the 5&rsquo;
untranslated region (UTR), exons, exon-intron boundaries, and the two introns, as
well as the 3&rsquo; UTR and the polyadenylation signal. As a result of wide
availability of efficient commercial sequencing and the decrease in cost, this
approach has now been adopted in many laboratories.",
" </li>",
" <li>",
" Identification of non-deletional &alpha;-thalassemia mutations can be
achieved with a similar strategy by sequencing the PCR products of differentially
amplified &alpha;2 and &alpha;1 globin genes.",
" </li>",
" <li>",
" A reverse dot-blot technique has been available and widely utilized for the
identification of &beta;-thalassemia mutations. In this method, probes for
mutations most commonly seen in certain populations (eg, Mediterraneans) are
blotted on a strip. The patient&rsquo;s PCR amplified &beta;-globin gene is then
hybridized to the commercially available strip. The detection method does not
require the use of radioactive isotopes",
" <span class=\"nowrap\">",
" (streptavidin/",
" <a class=\"drug drug_pediatric\" href=\"UTD.htm?9/25/9618?
source=see_link\">",
" biotin",
" </a>",
" </span>",
" labeling) and is relatively rapid. This technique has been utilized in
prenatal diagnosis in countries where &beta;-thalassemia is common [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/968/abstract/17\">",
" 17",
" </a>",
" ].",
" </li>",
" <li>",
" Microarray-based detection methods for the identification of &beta;-globin
mutations have been developed and validated in small sample sizes. Although
currently in its infancy, this technology has the potential to vastly expedite the
molecular diagnosis of hemoglobinopathies. A detailed overview of the application
of microarray technology to the detection of globin mutation is available [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/968/abstract/18\">",
" 18",
" </a>",
" ].",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H2640489\">",
" <span class=\"h1\">",
" SUMMARY",
" </span>",
" &nbsp;&mdash;&nbsp;The number of hemoglobin variants (ie, hemoglobinopathies)
discovered to date totals more than one thousand. The vast majority do not cause
any clinical or hematologic problems, while others are associated with varying
degrees of morbidity and mortality (eg, sickle cell anemia, beta thalassemia
major).",
" </p>",
" <p>",
" Evaluation of the clinical and hematological picture of the patient in
question is an important starting point (eg, presence of anemia or polycythemia,
cyanosis, abnormal red blood cell indices, abnormal red cell sizes and shapes on
the peripheral smear), followed by characterization of the abnormal hemoglobin
using a variety of separation techniques (",
" <a class=\"graphic graphic_table graphicRef57389 \" href=\"UTD.htm?
24/40/25227\">",
" table 3",
" </a>",
" ). (See",
" <a class=\"local\" href=\"#H11822071\">",
" 'Initial evaluation'",
" </a>",
" above.)",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Initial screening is classically performed at alkaline pH (pH 8.6) on
cellulose acetate. This simple method provides separation of the normal
hemoglobins, HbA, HbF, and HbA",
" _{",
" 2",
"}",
" , as well as the common variants HbS and HbC. (See",
" <a class=\"local\" href=\"#H11822078\">",
" 'Hemoglobin electrophoresis'",
" </a>",
" above.)",
" </li>",
" <li>",
" Additional screening can be performed via a second electrophoretic procedure
on citrate agar in acid pH. This leads to the definitive identification of HbS,
HbC, HbE, and HbO-Arab.",
" </li>",
" <li>",
" In many laboratories, electrophoresis on cellulose acetate and citrate agar
have now been replaced with isoelectric focusing (IEF) on agarose gels, pH
6.0&ndash;8.0. (See",
" <a class=\"local\" href=\"#H11822085\">",
" 'Isoelectric focusing'",
" </a>",
" above.)",
" </li>",
" <li>",
" Additional separation and identification of the mutant hemoglobin can be
obtained by using high performance liquid chromatographic methods. (See",
" <a class=\"local\" href=\"#H11822099\">",
" 'High performance liquid chromatography'",
" </a>",
" above.)",
" </li>",
" <li>",
" Definitive characterization of the abnormal hemoglobin is obtained via DNA
sequencing techniques. (See",
" <a class=\"local\" href=\"#H11822128\">",
" 'Definitive evaluation'",
" </a>",
" above.)",
" </li>",
" </ul>",
" </p>",
" </div>",
" <div id=\"topicAgreement\">",
" Use of UpToDate is subject to the",
" <a class=\"licenseLink\" href=\"./license\" id=\"sla_in_page\"
target=\"_blank\">",
" Subscription and License Agreement",
" </a>",
" .",
" </div>",
" <div class=\"headingAnchor\" id=\"references\">",
" <h1>",
" REFERENCES",
" </h1>",
" <ol id=\"reference\">",
" <li>",
" Natarajan K, Townes TM, Kutlar A. Disorders of hemoglobin structure: sickle
cell anemia and related abnormalities. In: Williams Hematology, 8th ed, Kaushansky
K, Lichtman MA, Beutler E, et al. (Eds), McGraw-Hill, 2010. p.ch.48.",
" </li>",
" <li>",
" Huisman TH. The structure and function of normal and abnormal haemoglobins.
In: Bailliere's Clinical Haematology, Higgs DR, Weatherall DJ (Eds), W.B.
Saunders, London 1993. p.1.",
" </li>",
" <li>",
" Weatherall DJ. The New Genetics and Clinical Practice, Oxford University
Press, Oxford 1991.",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/60/968/abstract/4\">",
" Trent RJ. Diagnosis of the haemoglobinopathies. Clin Biochem Rev 2006;
27:27.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/60/968/abstract/5\">",
" Steinberg MH, Adams JG 3rd, Dreiling BJ. Alpha thalassaemia in adults with
sickle-cell trait. Br J Haematol 1975; 30:31.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/60/968/abstract/6\">",
" Wong SC, Ali MA, Boyadjian SE. Sickle cell traits in Canada. Trimodal
distribution of Hb S as a result of interaction with alpha-thalassaemia gene. Acta
Haematol 1981; 65:157.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/60/968/abstract/7\">",
" Sciarratta GV, Sansone G, Ivaldi G, et al. Alternate organization of alpha
G-Philadelphia globin genes among U.S. black and Italian Caucasian heterozygotes.
Hemoglobin 1984; 8:537.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/60/968/abstract/8\">",
" Kutlar F. Diagnostic approach to hemoglobinopathies. Hemoglobin 2007;
31:243.",
" </a>",
" </li>",
" <li>",
" Huisman TH. Introduction and review of standard methodology for the detection
of hemoglobin abnormalities. In: The Hemoglobinopathies, Huisman TH (Ed), Churchill
Livingstone, Edinburgh 1986. p.1.",
" </li>",
" <li>",
" Kutlar A, Huisman TH. Detection of hemoglobinopathies. In: Techniques in
Diagnostic Human Biochemical Genetics: A Laboratory Manual, Hommes FA (Ed), Wiley,
New York 1991. p.519.",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/60/968/abstract/11\">",
" Kutlar F, Kutlar A, Huisman TH. Separation of normal and abnormal hemoglobin
chains by reversed-phase high-performance liquid chromatography. J Chromatogr 1986;
357:147.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/60/968/abstract/12\">",
" Smetanina NS, Molchanova TP, Huisman TH. Analysis of mRNA from red cells of
patients with thalassemia and hemoglobin variants. Hemoglobin 1997; 21:437.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/60/968/abstract/13\">",
" Clark BE, Thein SL. Molecular diagnosis of haemoglobin disorders. Clin Lab
Haematol 2004; 26:159.",
" </a>",
" </li>",
" <li>",
" Coleman WB, Tsongalis GJ. Molecular Diagnostics: for the Clinical
Laboratorian, 2nd ed, Human Press, Totowa 2006.",
" </li>",
" <li>",
" Higgs DR. 5 alpha-Thalassaemia. In: Bailliere's Clinical Haematology, Higgs
DR, Weatherall DJ (Eds), W.B. Saunders, London 1993. p.118.",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/60/968/abstract/16\">",
" Bhardwaj U, McCabe ER. Multiplex-PCR assay for the deletions causing
hereditary persistence of fetal hemoglobin. Mol Diagn 2005; 9:151.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/60/968/abstract/17\">",
" Sutcharitchan P, Saiki R, Huisman TH, et al. Reverse dot-blot detection of
the African-American beta-thalassemia mutations. Blood 1995; 86:1580.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/60/968/abstract/18\">",
" Cremonesi L, Ferrari M, Giordano PC, et al. An overview of current
microarray-based human globin gene mutation detection methods. Hemoglobin 2007;
31:289.",
" </a>",
" </li>",
" </ol>",
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" <a href=\"#\" title=\"Collapse Topic Outline\">",
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" <div id=\"innerOutline\">",
" <h1>",
" TOPIC OUTLINE",
" </h1>",
" <div id=\"outline\">",
" <ul>",
" <li>",
" <a class=\"sr_button\" href=\"#H2640489\" id=\"summRecButton\">",
" <span>",
" SUMMARY",
" </span>",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H11822024\">",
" INTRODUCTION",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H11822052\">",
" GLOBIN CHAIN PHYSIOLOGY",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H11822192\">",
" Prevalence of the hemoglobinopathies",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H11822149\">",
" Public health issues",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H11822059\">",
" GLOBIN CHAIN MUTATIONS",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H11822211\">",
" Clinical consequences",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H2640222\">",
" Expression of the abnormal hemoglobin",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" <a class=\"outlineLink\" href=\"#H2640236\">",
" - Factors affecting the type and amount of abnormal hemoglobin",
" </a>",
" </li>",
" <li class=\"bulletItem2\">",
" <a class=\"outlineLink\" href=\"#H2640300\">",
" Alpha globin mutations",
" </a>",
" </li>",
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" <a class=\"outlineLink\" href=\"#H2640307\">",
" Beta globin mutations",
" </a>",
" </li>",
" <li class=\"bulletItem2\">",
" <a class=\"outlineLink\" href=\"#H2640293\">",
" Surface charge",
" </a>",
" </li>",
" <li class=\"bulletItem2\">",
" <a class=\"outlineLink\" href=\"#H2640329\">",
" Concomitant alpha thalassemia",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H11822071\">",
" INITIAL EVALUATION",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H11822078\">",
" Hemoglobin electrophoresis",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H11822085\">",
" Isoelectric focusing",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H11822099\">",
" High performance liquid chromatography",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" <a class=\"outlineLink\" href=\"#H2640398\">",
" - Cation exchange",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" <a class=\"outlineLink\" href=\"#H2640405\">",
" - Reverse phase",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H11822121\">",
" Capillary electrophoresis",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H11822128\">",
" DEFINITIVE EVALUATION",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H2640489\">",
" SUMMARY",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a href=\"#references\">",
" REFERENCES",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" <div class=\"openRelatedGraphics\" id=\"HEME/13941\" rel=\"outline_link\">",
" GRAPHICS",
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" View All",
" </a>",
" </div>",
" </h1>",
" <div id=\"relatedGraphics\">",
" <ul>",
" <li class=\"plainItem\">",
" <div class=\"openRelatedGraphics\" id=\"HEME/13941|DiagnosticImage\">",
" <a href=\"#\" title=\"DIAGNOSTIC IMAGES\">",
" DIAGNOSTIC IMAGES",
" </a>",
" </div>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"graphic graphic_diagnosticimage\" href=\"UTD.htm?8/51/9023\"
title=\"diagnostic image 1\">",
" Hemoglobin electrophoresis at alkaline pH",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <div class=\"openRelatedGraphics\" id=\"HEME/13941|FIG\">",
" <a href=\"#\" title=\"FIGURES\">",
" FIGURES",
" </a>",
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" </li>",
" <li class=\"bulletItem\">",
" <a class=\"graphic graphic_figure\" href=\"UTD.htm?6/32/6656\" title=\"figure
1\">",
" Alpha and beta globin gene clusters",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"graphic graphic_figure\" href=\"UTD.htm?18/24/18821\"
title=\"figure 2\">",
" Hemoglobin tetramer",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"graphic graphic_figure\" href=\"UTD.htm?0/58/942\" title=\"figure
3\">",
" Effect of globin charge on hemoglobin assembly",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"graphic graphic_figure\" href=\"UTD.htm?42/6/43106\"
title=\"figure 4\">",
" Isoelectric focusing of hemoglobins",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"graphic graphic_figure\" href=\"UTD.htm?10/54/11108\"
title=\"figure 5\">",
" Isoelectric focusing Hgb variants",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"graphic graphic_figure\" href=\"UTD.htm?20/56/21376\"
title=\"figure 6\">",
" HPLC normal hemoglobins",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"graphic graphic_figure\" href=\"UTD.htm?11/58/12199\"
title=\"figure 7\">",
" HPLC alpha chain variants",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"graphic graphic_figure\" href=\"UTD.htm?13/56/14215\"
title=\"figure 8\">",
" HPLC beta chain variants",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"graphic graphic_figure\" href=\"UTD.htm?34/9/34967\"
title=\"figure 9\">",
" Beta chain variants reverse HPLC",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"graphic graphic_figure\" href=\"UTD.htm?10/17/10518\"
title=\"figure 10\">",
" Alpha chain variants reverse HPLC",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"graphic graphic_figure\" href=\"UTD.htm?14/19/14647\"
title=\"figure 11\">",
" Capillary electrophoresis of hemoglobins",
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title=\"figure 12\">",
" Beta globin gene sequencing",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"graphic graphic_figure\" href=\"UTD.htm?14/5/14419\"
title=\"figure 13\">",
" Alpha thalassemia variants by gap PCR",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"graphic graphic_figure\" href=\"UTD.htm?21/58/22439\"
title=\"figure 14\">",
" Alpha thalassemia by gap PCR",
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" <li class=\"bulletItem\">",
" <a class=\"graphic graphic_table\" href=\"UTD.htm?4/8/4236\" title=\"table
1\">",
" Clinically significant hemoglobin variants",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"graphic graphic_table\" href=\"UTD.htm?16/17/16667\" title=\"table
2\">",
" Sickle trait alpha thalassemia",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"graphic graphic_table\" href=\"UTD.htm?24/40/25227\" title=\"table
3\">",
" Detection methods for abnormal hemoglobins",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" RELATED TOPICS",
" </h1>",
" <div id=\"relatedTopics\">",
" <ul>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_review\" href=\"UTD.htm?40/51/41783?
source=related_link\">",
" Community public health issues and the thalassemic syndromes: Lessons from
other countries",
" </a>",
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source=related_link\">",
" Genetic disorders of hemoglobin oxygen affinity",
" </a>",
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" Protection against malaria in the hemoglobinopathies",
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" Sickle hemoglobin polymer: Structure and functional properties",
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source=related_link\">",
" Structure and function of normal human hemoglobins",
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source=related_link\">",
" Unstable hemoglobin variants",
" </a>",
" </li>",
" </ul>",
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" </div>"].join("\n");
var title_f0_60_969="Clinical characteristics of carcinoid tumors";
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" <span class=\"h1\">",
" INTRODUCTION",
" </span>",
" &nbsp;&mdash;&nbsp;The term &ldquo;carcinoid&rdquo; is generally applied to
well-differentiated neuroendocrine tumors originating in the digestive tract,
lungs, or rare primary sites such as kidneys or ovaries. Use of the term carcinoid
implies well-differentiated (low- to intermediate-grade) histology and is not
traditionally used to describe high-grade or poorly differentiated neuroendocrine
tumors (which are rare). In the digestive system, well-differentiated
neuroendocrine tumors of the luminal gastrointestinal tract have been designated
carcinoid tumors while those arising in the pancreas (and rarely in the duodenum)
have been referred to as pancreatic neuroendocrine (islet cell) tumors (",
" <a class=\"graphic graphic_table graphicRef60365 \" href=\"UTD.htm?
17/14/17644\">",
" table 1",
" </a>",
" ). (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?6/40/6794?
source=see_link&amp;anchor=H440387068#H440387068\">",
" \"Pathology, classification, and grading of neuroendocrine tumors arising in
the digestive system\", section on 'Pathology, tumor classification, and
nomenclature'",
" </a>",
" .)",
" </p>",
" <p>",
" &ldquo;Carcinoid syndrome&rdquo; is the term applied to a constellation of
symptoms mediated by various humoral factors that are elaborated by some carcinoid
tumors (",
" <a class=\"graphic graphic_table graphicRef79329 \" href=\"UTD.htm?
34/59/35771\">",
" table 2",
" </a>",
" ) [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/1\">",
" 1",
" </a>",
" ]. The typical carcinoid syndrome, consisting primarily of flushing and
diarrhea (",
" <a class=\"graphic graphic_table graphicRef63079 \" href=\"UTD.htm?
37/54/38763\">",
" table 3",
" </a>",
" ), occurs predominantly in patients with metastatic carcinoid tumors
originating in the small intestine. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?8/63/9206?
source=see_link\">",
" \"Clinical features of the carcinoid syndrome\"",
" </a>",
" .)",
" </p>",
" <p>",
" Carcinoid tumors are rare overall, but their age-adjusted incidence in the
United States has increased significantly, partly due to increased detection on
radiographic imaging and endoscopy.",
" </p>",
" <p>",
" This topic will cover the epidemiology, classification, and clinical features
of primary carcinoid tumors arising in the gastrointestinal and genitourinary
systems. The pathology and nomenclature of carcinoid tumors, clinical features and
diagnosis of the carcinoid syndrome, issues related to tumor localization,
bronchial carcinoid tumors, thymic carcinoid tumors, and the management of patients
with non-metastatic and metastatic carcinoid tumors are discussed separately.",
" </p>",
" <p>",
" <ul class=\"bulletCompact-block\">",
" <li>",
" (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?6/40/6794?
source=see_link\">",
" \"Pathology, classification, and grading of neuroendocrine tumors arising
in the digestive system\"",
" </a>",
" .)",
" </li>",
" <li>",
" (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?8/63/9206?
source=see_link\">",
" \"Clinical features of the carcinoid syndrome\"",
" </a>",
" .)",
" </li>",
" <li>",
" (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?11/8/11400?
source=see_link\">",
" \"Diagnosis of the carcinoid syndrome and tumor localization\"",
" </a>",
" .)",
" </li>",
" <li>",
" (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?8/55/9082?
source=see_link\">",
" \"Bronchial carcinoid tumors: Epidemiology, risk factors, classification,
histology, diagnosis, and staging\"",
" </a>",
" .)",
" </li>",
" <li>",
" (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?4/43/4794?
source=see_link&amp;anchor=H14#H14\">",
" \"Pathology of mediastinal tumors\", section on 'Thymic neuroendocrine
tumors'",
" </a>",
" .)",
" </li>",
" <li>",
" (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?38/61/39897?
source=see_link\">",
" \"Treatment and surveillance of non-metastatic carcinoid tumors\"",
" </a>",
" .)",
" </li>",
" <li>",
" (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?38/46/39658?
source=see_link&amp;anchor=H190949019#H190949019\">",
" \"Metastatic gastroenteropancreatic neuroendocrine tumors: Systemic therapy
options to control tumor growth and symptoms of hormone hypersecretion\", section
on 'Poorly differentiated tumors'",
" </a>",
" .)",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H2\">",
" <span class=\"h1\">",
" EPIDEMIOLOGY",
" </span>",
" &nbsp;&mdash;&nbsp;Carcinoids are relatively rare tumors. In a series of
35,618 neuroendocrine tumors (which included pancreatic neuroendocrine tumors as
well as carcinoids at all sites) reported to the Surveillance, Epidemiology and End
Results (SEER) program of the National Cancer Institute, the age-adjusted incidence
for non-pancreatic primaries was 4.7 per 100,000 [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/2\">",
" 2",
" </a>",
" ]. The annual incidence rate for African Americans was higher than for
Caucasians (6.46 versus",
" <span class=\"nowrap\">",
" 4.60/100,000),",
" </span>",
" and the incidence for males was slightly higher than for females (4.97
versus",
" <span class=\"nowrap\">",
" 4.49/100,000).",
" </span>",
" The median age at diagnosis for all patients with neuroendocrine tumors was 63
years.",
" </p>",
" <p>",
" Roughly similar incidence rates were found in a database study from a Swedish
registry that focused on 5184 carcinoid tumors seen between 1958 and 1998 [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/3\">",
" 3",
" </a>",
" ]. Incidence rates for men and women were 2.0 and",
" <span class=\"nowrap\">",
" 2.4/100,000,",
" </span>",
" respectively. Although clear risk factors have not been identified, a
regression analysis of this database suggested that risk was increased in the
setting of a family history of carcinoid in a first-degree relative (relative risk
3.6).",
" </p>",
" <p>",
" The incidence of carcinoid tumors has been rising over time in the US and
elsewhere [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/2,4\">",
" 2,4",
" </a>",
" ]. As an example, in the above mentioned SEER analysis of 35,618
neuroendocrine tumors, there was a significant increase in the age-adjusted
incidence for both pancreatic and nonpancreatic primary sites [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/2\">",
" 2",
" </a>",
" ]. For all neuroendocrine tumors, the incidence rose from 1.09 to 5.25 per
100,000 between 1973 and 2004. The increase is probably partly due to increased
detection on radiographic imaging and endoscopy.",
" </p>",
" <p class=\"headingAnchor\" id=\"H3796865\">",
" <span class=\"h2\">",
" Distribution",
" </span>",
" &nbsp;&mdash;&nbsp;In a report from the SEER database of 11,427 carcinoid
cases treated between 1973 and 1997, the majority were located in the
gastrointestinal (GI) tract (55 percent) and bronchopulmonary system (30 percent)
[",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/5\">",
" 5",
" </a>",
" ]. Within the GI tract, most carcinoids arose in the small intestine (45
percent, most commonly in the ileum), followed by rectum (20 percent), appendix (16
percent), colon (11 percent), and stomach (7 percent).",
" </p>",
" <p>",
" Distribution may differ in other geographic areas. As an example, colorectal
carcinoids may be more frequent in the",
" <span class=\"nowrap\">",
" Asia/Pacific",
" </span>",
" region as compared to Europe, where carcinoids are more commonly found in the
stomach and ileum [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/6,7\">",
" 6,7",
" </a>",
" ]. An important point is that the SEER database may be inconsistent in
recording tumors that are not considered &ldquo;malignant&rdquo; (ie, trivial
gastric carcinoids that are encountered at endoscopy in patients with chronic
atrophic gastritis). &nbsp;",
" </p>",
" <p class=\"headingAnchor\" id=\"H3\">",
" <span class=\"h1\">",
" PATHOLOGY AND GRADING",
" </span>",
" &nbsp;&mdash;&nbsp;Carcinoid tumors were so named because they seemed
morphologically different and clinically less aggressive than the more common GI
tract adenocarcinomas [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/8\">",
" 8",
" </a>",
" ]. Carcinoids arise from enterochromaffin (neuroendocrine) cells of the
aerodigestive tract. The term enterochromaffin refers to the ability to stain with
potassium chromate (chromaffin), a feature of cells that contain serotonin.",
" </p>",
" <p>",
" While most carcinoid tumors are relatively slow-growing neoplasms, some behave
aggressively. Histologic grade and differentiation correlate closely with clinical
behavior. Grade refers to the proliferative activity of tumors, commonly measured
by the mitotic rate (number of mitotic figures per 10 high-powered fields) or the
Ki-67 index. In contrast, differentiation refers to the extent to which neoplastic
cells resemble their non-neoplastic counterparts [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/9\">",
" 9",
" </a>",
" ].",
" </p>",
" <p>",
" The most recent nomenclature for neuroendocrine tumors of the digestive system
from the World Health Organization (WHO) distinguishes two broad subgroups (",
" <a class=\"graphic graphic_table graphicRef60365 \" href=\"UTD.htm?
17/14/17644\">",
" table 1",
" </a>",
" ) [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/10\">",
" 10",
" </a>",
" ]:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Well-differentiated neuroendocrine tumors, which are further subdivided into
low-grade and intermediate grade according to proliferative rate. Intermediate
grade carcinoid tumors arising in the lung (but not elsewhere) are referred to as
atypical carcinoids. In general, clinical behavior is relatively indolent. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?21/43/22201?
source=see_link&amp;anchor=H1176454#H1176454\">",
" \"Pathology of lung malignancies\", section on 'Neuroendocrine tumors'",
" </a>",
" .)",
" </li>",
" <li>",
" Poorly differentiated neuroendocrine tumors are high-grade carcinomas that
resemble small cell or large cell neuroendocrine carcinoma of the lung (",
" <a class=\"graphic graphic_picture graphicRef74630 \" href=\"UTD.htm?
26/10/26794\">",
" picture 1",
" </a>",
" ) [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/11\">",
" 11",
" </a>",
" ]. They generally behave in a biologically aggressive fashion. &nbsp;",
" </li>",
" </ul>",
" </p>",
" <p>",
" A more detailed discussion of pathology and classification of neuroendocrine
tumors arising in the digestive tract is presented elsewhere. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?6/40/6794?
source=see_link\">",
" \"Pathology, classification, and grading of neuroendocrine tumors arising in
the digestive system\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H4\">",
" <span class=\"h1\">",
" EMBRYONIC CLASSIFICATION",
" </span>",
" &nbsp;&mdash;&nbsp;Carcinoid tumors have traditionally been classified based
upon their origin from the embryonic divisions (foregut, midgut, or hindgut) of the
alimentary tract (",
" <a class=\"graphic graphic_figure graphicRef83185 \" href=\"UTD.htm?
2/9/2198\">",
" figure 1",
" </a>",
" ) [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/12\">",
" 12",
" </a>",
" ]. In general, midgut carcinoid tumors produce serotonin and other vasoactive
substances that give rise to the typical carcinoid syndrome (",
" <a class=\"graphic graphic_table graphicRef56015 \" href=\"UTD.htm?
17/7/17531\">",
" table 4",
" </a>",
" ). In contrast, tumors derived from the embryonic hindgut are rarely
associated with a hormonal syndrome. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?8/63/9206?
source=see_link&amp;anchor=H2#H2\">",
" \"Clinical features of the carcinoid syndrome\", section on
'Pathophysiology'",
" </a>",
" .)",
" </p>",
" <p>",
" While this classification has some utility as a means of grouping together
carcinoid tumor sites according to their likelihood of producing a hormonal
syndrome, it is increasingly evident that each specific primary site possesses its
own unique clinical characteristics.",
" </p>",
" <p class=\"headingAnchor\" id=\"H7\">",
" <span class=\"h1\">",
" FOREGUT TUMORS",
" </span>",
" &nbsp;&mdash;&nbsp;The symptoms associated with foregut carcinoid tumors vary
with the site.",
" </p>",
" <p class=\"headingAnchor\" id=\"H8\">",
" <span class=\"h2\">",
" Stomach",
" </span>",
" &nbsp;&mdash;&nbsp;Gastric carcinoids are subdivided into three categories
that have differing biologic behavior and prognoses [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/13,14\">",
" 13,14",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H9\">",
" <span class=\"h3\">",
" Type 1",
" </span>",
" &nbsp;&mdash;&nbsp;Type 1 gastric carcinoids account for 70 to 80 percent of
all gastric carcinoids [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/14-16\">",
" 14-16",
" </a>",
" ]. They are associated with chronic atrophic gastritis and often pernicious
anemia (65 percent in one series) [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/14\">",
" 14",
" </a>",
" ]. The disease is more common in women [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/17-19\">",
" 17-19",
" </a>",
" ]. &nbsp;(See",
" <a class=\"medical medical_review\" href=\"UTD.htm?23/39/24185?
source=see_link\">",
" \"Metaplastic (chronic) atrophic gastritis\"",
" </a>",
" .)",
" </p>",
" <p>",
" Endoscopically, the tumors are usually smaller than 1 cm, often multiple, and
may appear as polypoid lesions with a small central ulceration (",
" <a class=\"graphic graphic_picture graphicRef81095 graphicRef73158
graphicRef53130 \" href=\"UTD.htm?7/26/7593\">",
" picture 2A-C",
" </a>",
" ). The tumors are derived from enterochromaffin-like (ECL) cells.",
" </p>",
" <p>",
" The prevailing hypothesis is that ECL cells develop into carcinoid tumors
after chronic stimulation by the high gastrin levels that occur in patients with
atrophic gastritis. This is supported by the observation that regression of gastric
carcinoids can be achieved by antrectomy, which is occasionally recommended. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?38/61/39897?
source=see_link&amp;anchor=H6#H6\">",
" \"Treatment and surveillance of non-metastatic carcinoid tumors\", section on
'Stomach'",
" </a>",
" .)",
" </p>",
" <p>",
" The importance of gastrin in ECL transformation is supported by the
observation that carcinoid tumors develop in certain animals treated with high
doses of proton pump inhibitors, which are associated with hypergastrinemia,
because of loss of feedback [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/20\">",
" 20",
" </a>",
" ]. However, carcinoid tumors have not been observed in humans treated with
proton pump inhibitors, suggesting that other factors may be important.",
" </p>",
" <p>",
" Patients with gastric carcinoids related to chronic atrophic gastritis are
usually diagnosed in their 60s or 70s during endoscopic evaluation for abdominal
pain or anemia [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/14\">",
" 14",
" </a>",
" ]. They are usually non-functioning tumors. These gastric carcinoid tumors are
usually indolent and generally represent a benign condition. Metastases occur in
less than 10 percent of tumors &le;2 cm, but in approximately 20 percent of larger
tumors [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/21\">",
" 21",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H10\">",
" <span class=\"h3\">",
" Type 2",
" </span>",
" &nbsp;&mdash;&nbsp;Type 2 gastric carcinoids occur in association with
gastrinomas (Zollinger-Ellison syndrome), often in the setting multiple endocrine
neoplasia (MEN) type 1. They account for approximately 5 percent of gastric
carcinoids. Similar to carcinoids in atrophic gastritis, the tumors are thought to
arise from ECL cells stimulated by elevated serum gastrin levels. The
hypergastrinemia is produced by a gastrinoma in the pancreas or duodenum. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?37/61/38871?
source=see_link\">",
" \"Multiple endocrine neoplasia type 1: Treatment\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?6/51/6968?
source=see_link\">",
" \"Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma)\"",
" </a>",
" .) &nbsp; &nbsp;",
" </p>",
" <p>",
" Type 2 gastric carcinoids behave similarly to type 1 tumors; they are
frequently multifocal, and usually indolent [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/22\">",
" 22",
" </a>",
" ]. Management is addressed elsewhere. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?38/61/39897?
source=see_link&amp;anchor=H6#H6\">",
" \"Treatment and surveillance of non-metastatic carcinoid tumors\", section on
'Stomach'",
" </a>",
" .) &nbsp;",
" </p>",
" <p class=\"headingAnchor\" id=\"H11\">",
" <span class=\"h3\">",
" Type 3",
" </span>",
" &nbsp;&mdash;&nbsp;Type 3 gastric carcinoids are known as sporadic carcinoids
because they occur in the absence of atrophic gastritis or the Zollinger-Ellison or
MEN1 syndromes. They account for 20 percent of gastric carcinoids, and are the most
aggressive; local or hepatic metastases are present in up to 65 percent of patients
who come to resection [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/13,22\">",
" 13,22",
" </a>",
" ]. Unlike type 1 and 2 gastric carcinoids, the fasting serum gastrin is
usually normal in patients with type 3 gastric carcinoid tumors.",
" </p>",
" <p>",
" Type 3 gastric carcinoids often contain a variety of endocrine cells and they
may be associated with an atypical carcinoid syndrome (",
" <a class=\"graphic graphic_table graphicRef56015 \" href=\"UTD.htm?
17/7/17531\">",
" table 4",
" </a>",
" ). (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?8/63/9206?
source=see_link&amp;anchor=H16#H16\">",
" \"Clinical features of the carcinoid syndrome\", section on 'Gastric
carcinoid variant syndrome'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H12\">",
" <span class=\"h2\">",
" Lung",
" </span>",
" &nbsp;&mdash;&nbsp;Bronchial carcinoids are classified among other pulmonary
neuroendocrine tumors such as small cell and large cell neuroendocrine lung cancer.
(See",
" <a class=\"medical medical_review\" href=\"UTD.htm?21/43/22201?
source=see_link&amp;anchor=H1176454#H1176454\">",
" \"Pathology of lung malignancies\", section on 'Neuroendocrine tumors'",
" </a>",
" .)",
" </p>",
" <p>",
" Patients with bronchial carcinoids rarely develop carcinoid syndrome in the
absence of liver metastases. They may have a variant carcinoid syndrome with
flushes or sweats that are severe and prolonged, lasting hours to days. These
flushes may be associated with disorientation, anxiety, and tremor. The clinical
features of bronchial carcinoid tumors are discussed separately. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?8/63/9206?
source=see_link&amp;anchor=H17#H17\">",
" \"Clinical features of the carcinoid syndrome\", section on 'Bronchial
carcinoid variant syndrome'",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?8/55/9082?
source=see_link&amp;anchor=H9#H9\">",
" \"Bronchial carcinoid tumors: Epidemiology, risk factors, classification,
histology, diagnosis, and staging\", section on 'Clinical features'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H13\">",
" <span class=\"h1\">",
" MIDGUT TUMORS",
" </span>",
" </p>",
" <p class=\"headingAnchor\" id=\"H14\">",
" <span class=\"h2\">",
" Jejuno-ileal small bowel tumors",
" </span>",
" &nbsp;&mdash;&nbsp;Small bowel carcinoids have increased in frequency in the
last several decades, in part due to increased detection on endoscopy and imaging
studies [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/23\">",
" 23",
" </a>",
" ]. In the year 2000, carcinoid tumors surpassed adenocarcinomas as the most
common small bowel tumor reported to the National Cancer Data Base [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/24\">",
" 24",
" </a>",
" ]. Between 1985 and 2005, the proportion of patients with carcinoids increased
from 28 to 44 percent, while the proportion of adenocarcinoma decreased from 42 to
33 percent. Patients usually present in their 60s or 70s. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?18/31/18938?
source=see_link&amp;anchor=H3#H3\">",
" \"Epidemiology, clinical features, and types of small bowel neoplasms\",
section on 'Malignant tumors'",
" </a>",
" .)",
" </p>",
" <p>",
" Small bowel carcinoids are thought to arise from intraepithelial endocrine
cells, in contrast to appendiceal carcinoids, which arise from subepithelial
endocrine cells [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/25\">",
" 25",
" </a>",
" ]. Small intestinal carcinoid tumors are most commonly located in the ileum
within 60 cm of ileocecal valve; they may arise from a Meckel&rsquo;s diverticulum
[",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/23,26-28\">",
" 23,26-28",
" </a>",
" ]. Approximately 25 percent of patients will have more than one small bowel
carcinoid at the time of discovery.",
" </p>",
" <p>",
" Many small bowel carcinoids are asymptomatic at presentation and found
incidentally [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/29\">",
" 29",
" </a>",
" ]. Among symptomatic patients, abdominal pain is the most common initial
symptom, occurring in approximately 40 percent [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/30\">",
" 30",
" </a>",
" ]. The pain is usually vague and nonspecific, and may be incorrectly assumed
to represent irritable bowel syndrome for years before the diagnosis is made.
Intermittent obstruction occurs in 25 percent of small intestinal carcinoids [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/30,31\">",
" 30,31",
" </a>",
" ]. Duodenal carcinoids may produce duodenal or biliary obstruction.",
" </p>",
" <p>",
" Abdominal pain may be due to intussusception, the mechanical effect of the
tumor, or mesenteric ischemia. Obstruction may be caused by intussusception or by
intraluminal tumor bulk, but often results from mesenteric kinking and distortion
brought on by tumor invasion, lymph node metastases,",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" a secondary desmoplastic response (",
" <a class=\"graphic graphic_diagnosticimage graphicRef78186 \" href=\"UTD.htm?
42/57/43921\">",
" image 1",
" </a>",
" ). The latter produces a characteristic radiographic abnormality: a
combination of abrupt angulation with a filling defect in the small bowel (",
" <a class=\"graphic graphic_diagnosticimage graphicRef60836 \" href=\"UTD.htm?
31/63/32767\">",
" image 3",
" </a>",
" ).",
" </p>",
" <p>",
" Pain may also arise from ischemia that is due to local fibrosis or vascular
compromise [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/31\">",
" 31",
" </a>",
" ]. Vascular compromise may be secondary to large bulky mesenteric nodal
metastasis, mesenteric vascular invasion,",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" microvascular metastasis [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/31\">",
" 31",
" </a>",
" ]. Possibly contributing to the ischemic process is the vasospastic effect of
serotonin produced by the tumor.",
" </p>",
" <p>",
" Patients often have metastases to lymph nodes or the liver, even if the
primary tumor is small (",
" <a class=\"graphic graphic_table graphicRef82306 \" href=\"UTD.htm?
14/6/14444\">",
" table 5",
" </a>",
" ) [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/32,33\">",
" 32,33",
" </a>",
" ]. The carcinoid syndrome is present in the majority of patients who have a
small bowel primary carcinoid and liver metastases [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/32,34-36\">",
" 32,34-36",
" </a>",
" ]. Staging, treatment, and prognosis of small bowel carcinoid tumors are
addressed elsewhere. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?38/61/39897?
source=see_link&amp;anchor=H4#H4\">",
" \"Treatment and surveillance of non-metastatic carcinoid tumors\", section on
'Small intestine'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H15\">",
" <span class=\"h2\">",
" Appendix",
" </span>",
" &nbsp;&mdash;&nbsp;Carcinoid tumors are the most common neoplasms in the
appendix. In approximately 1 in 300 appendectomies, carcinoid tumors are discovered
incidentally, most often in the tip of the appendix. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?35/14/36074?
source=see_link&amp;anchor=H2#H2\">",
" \"Cancer of the appendix and pseudomyxoma peritonei\", section on 'Carcinoid
tumors'",
" </a>",
" .)",
" </p>",
" <p>",
" Appendiceal carcinoids are detected most commonly in the patients in their 40s
or 50s, which most likely reflects the younger age of patients who undergo
appendectomy. They are probably more common in women, although this association has
in part been attributed to the greater frequency of incidental appendectomies in
women who undergo pelvic surgery. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?35/14/36074?
source=see_link&amp;anchor=H2#H2\">",
" \"Cancer of the appendix and pseudomyxoma peritonei\", section on 'Carcinoid
tumors'",
" </a>",
" .)",
" </p>",
" <p>",
" The majority of carcinoids are submucosal and located in the distal one-third
of the appendix where they are unlikely to cause obstruction (",
" <a class=\"graphic graphic_picture graphicRef50408 graphicRef80087 \"
href=\"UTD.htm?21/28/21958\">",
" picture 4A-B",
" </a>",
" ). As a result, most patients are asymptomatic. Symptoms are more likely with
large tumors and in the rare patient with metastases beyond the regional lymph
nodes. Approximately 10 percent of appendiceal carcinoids are located at the base
of the appendix, where they can cause obstruction, leading to appendicitis.",
" </p>",
" <p>",
" The likelihood of regional and distant metastases is related to tumor size,
but generally lower than for small intestinal carcinoids (",
" <a class=\"graphic graphic_table graphicRef82306 \" href=\"UTD.htm?
14/6/14444\">",
" table 5",
" </a>",
" ). Features of the carcinoid syndrome may be present in patients with tumors
that have metastasized to the liver. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?8/63/9206?
source=see_link\">",
" \"Clinical features of the carcinoid syndrome\"",
" </a>",
" .)",
" </p>",
" <p>",
" A rare type of appendiceal tumor, sometimes referred to as an adenocarcinoid
(also termed &ldquo;goblet cell&rdquo; or &ldquo;mucous&rdquo; carcinoid) contains
chromogranin A and is composed largely of goblet cells. These tumors are discussed
in detail elsewhere. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?35/14/36074?
source=see_link&amp;anchor=H15#H15\">",
" \"Cancer of the appendix and pseudomyxoma peritonei\", section on 'Goblet
cell carcinomas'",
" </a>",
" .)",
" </p>",
" <p>",
" Staging, prognosis and treatment of appendiceal carcinoids are discussed
separately. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?35/14/36074?
source=see_link&amp;anchor=H4#H4\">",
" \"Cancer of the appendix and pseudomyxoma peritonei\", section on 'Staging
and prognosis'",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?35/14/36074?
source=see_link&amp;anchor=H5#H5\">",
" \"Cancer of the appendix and pseudomyxoma peritonei\", section on
'Treatment'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H16\">",
" <span class=\"h1\">",
" HINDGUT TUMORS",
" </span>",
" &nbsp;&mdash;&nbsp;The hindgut carcinoids (transverse and descending colon and
rectum) are usually nonsecretory and not associated with the carcinoid syndrome,
even when metastatic (",
" <a class=\"graphic graphic_table graphicRef56015 \" href=\"UTD.htm?
17/7/17531\">",
" table 4",
" </a>",
" ) . When symptoms do occur, they are the same as those of a colorectal
adenocarcinoma: changes in bowel habits, obstruction, or bleeding. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?17/33/17946?
source=see_link&amp;anchor=H2#H2\">",
" \"Clinical manifestations, diagnosis, and staging of colorectal cancer\",
section on 'Clinical manifestations'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H17\">",
" <span class=\"h2\">",
" Colon",
" </span>",
" &nbsp;&mdash;&nbsp;Colonic carcinoids are usually detected in patients who are
in their 70s during evaluation for diarrhea, abdominal pain, anorexia, or weight
loss [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/37,38\">",
" 37,38",
" </a>",
" ]. The incidence of functioning tumors is very low. Features of the carcinoid
syndrome were present in only 1 of 36 patients in one series from the Alberta
Cancer registry [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/39\">",
" 39",
" </a>",
" ].",
" </p>",
" <p>",
" The majority of colonic carcinoids are located in the right colon,
particularly in the cecum [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/37,39,40\">",
" 37,39,40",
" </a>",
" ]. Most patients do not become symptomatic until the tumors are large. In two
series, the average size of tumors was approximately 5 cm at diagnosis [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/37,40\">",
" 37,40",
" </a>",
" ], and approximately two-thirds were associated with local nodal or distant
metastasis (",
" <a class=\"graphic graphic_table graphicRef82306 \" href=\"UTD.htm?
14/6/14444\">",
" table 5",
" </a>",
" ).",
" </p>",
" <p>",
" Staging, treatment, and prognosis are discussed elsewhere. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?38/61/39897?
source=see_link&amp;anchor=H432448#H432448\">",
" \"Treatment and surveillance of non-metastatic carcinoid tumors\", section on
'Colon'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H18\">",
" <span class=\"h2\">",
" Rectum",
" </span>",
" &nbsp;&mdash;&nbsp;The vast majority of rectal carcinoids are asymptomatic and
found incidentally by rectal examination or endoscopy that is performed for another
reason [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/38,41\">",
" 38,41",
" </a>",
" ]. They are most commonly diagnosed in patients in their 60s [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/42\">",
" 42",
" </a>",
" ]. Uncommon manifestations include rectal bleeding, change in bowel habits or
pain; the carcinoid syndrome is rare because most are nonsecretory.",
" </p>",
" <p>",
" The majority of rectal carcinoids (75 to 85 percent) are localized at
diagnosis [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/38\">",
" 38",
" </a>",
" ]. However, as with other gastrointestinal tract carcinoids, size correlates
closely with the likelihood of metastases. Tumors smaller than 1 cm are rarely
metastatic [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/21,43\">",
" 21,43",
" </a>",
" ], while approximately 6 percent of tumors between 1 and 1.9 cm, and 24
percent of those over 2 cm metastasize to the liver [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/26,43-45\">",
" 26,43-45",
" </a>",
" ]. Other poor prognostic features include deep invasion (into the muscularis
propria or deeper), lymphovascular invasion, and a high mitotic rate (&ge;2 per 50
high-power fields) [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/45,46\">",
" 45,46",
" </a>",
" ].",
" </p>",
" <p>",
" Staging, prognosis, and treatment are discussed in detail elsewhere. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?38/61/39897?
source=see_link&amp;anchor=H5#H5\">",
" \"Treatment and surveillance of non-metastatic carcinoid tumors\", section on
'Rectum'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H19\">",
" <span class=\"h2\">",
" Genitourinary",
" </span>",
" &nbsp;&mdash;&nbsp;Hindgut carcinoids rarely arise in the genitourinary
system; however, both renal and testicular primary carcinoid tumors have been
described in case reports and case series [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/47-50\">",
" 47-50",
" </a>",
" ]. In addition to primary tumors, renal and testicular carcinoids may
represent metastatic spread from another site [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/50,51\">",
" 50,51",
" </a>",
" ]. These lesions commonly present as an abdominal or testicular mass, but some
have manifestations of the carcinoid syndrome. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?8/63/9206?
source=see_link\">",
" \"Clinical features of the carcinoid syndrome\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H20\">",
" <span class=\"h1\">",
" OVARY",
" </span>",
" &nbsp;&mdash;&nbsp;Ovarian carcinoid tumors are rare neoplasms that may be
primary or metastatic. Primary ovarian carcinoid tumors are usually unilateral,
localized to the ovary, and composed of gastrointestinal or respiratory epithelium;
they often arise within a cystic teratoma or dermoid tumor [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/52,53\">",
" 52,53",
" </a>",
" ]. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?5/37/5721?
source=see_link\">",
" \"Ovarian germ cell neoplasms: Pathology, clinical manifestations, and
diagnosis\"",
" </a>",
" .)",
" </p>",
" <p>",
" The coexistence of an ovarian germ cell tumor may have prognostic
implications. In one report, 189 of 329 primary ovarian carcinoids (57 percent)
coexisted with cystic",
" <span class=\"nowrap\">",
" teratomas/dermoid",
" </span>",
" tumors [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/53\">",
" 53",
" </a>",
" ]. When compared to carcinoids without associated germ cell tumors, these
carcinoids were significantly smaller (45 versus 90 cm), less likely to have liver
metastases (2 versus 15 percent) or the carcinoid syndrome (14 versus 23 percent),
and the five-year survival rates were modestly better (94 versus 84 percent).",
" </p>",
" <p>",
" Metastatic ovarian carcinoids are less common, and most arise from a primary
tumor within the small intestine [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/54\">",
" 54",
" </a>",
" ]. Unlike primary ovarian carcinoid tumors, which are typically unilateral,
metastatic carcinoid tumors to the ovaries are usually bilateral, originate in the
small intestine, and are associated with peritoneal carcinomatosis [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/54\">",
" 54",
" </a>",
" ].",
" </p>",
" <p>",
" Ovarian carcinoids can produce the carcinoid syndrome without hepatic
metastases due to their direct drainage into the systemic circulation.",
" </p>",
" <p class=\"headingAnchor\" id=\"H1304714531\">",
" <span class=\"h1\">",
" METASTATIC CARCINOID TUMORS",
" </span>",
" &nbsp;&mdash;&nbsp;Regardless of primary site, carcinoid tumors are
characterized by a strong propensity to metastasize to the liver [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/35\">",
" 35",
" </a>",
" ]. Patients with liver metastases may experience symptoms related to tumor
burden (eg, pain, jaundice, early satiety) or hormonal symptoms (eg, flushing and
diarrhea). Even when extensive, metastatic well-differentiated carcinoid tumors can
often cause significant hepatomegaly without any abnormalities of liver function.
(See",
" <a class=\"medical medical_review\" href=\"UTD.htm?8/63/9206?
source=see_link&amp;anchor=H8#H8\">",
" \"Clinical features of the carcinoid syndrome\", section on 'Clinical
features'",
" </a>",
" .) &nbsp;",
" </p>",
" <p>",
" Other common metastatic sites associated with small-intestinal (midgut)
carcinoid tumors include mesentery and peritoneum. Tumors in the root of the
mesentery may be unresectable and lead to recurrent bowel obstruction or ischemia.
Likewise, patients with peritoneal carcinomatosis may experience chronic
obstruction, weight loss and malnutrition [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/34\">",
" 34",
" </a>",
" ].",
" </p>",
" <p>",
" Bone metastases are a relatively late occurrence in patients with metastatic
carcinoid tumors and typically affect the axial skeleton [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/969/abstract/55\">",
" 55",
" </a>",
" ]. Other metastatic sites include retroperitoneal lymph nodes, ovaries,
breasts, and supraclavicular lymph nodes. &nbsp; &nbsp;",
" </p>",
" <p class=\"headingAnchor\" id=\"H21\">",
" <span class=\"h1\">",
" SUMMARY",
" </span>",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Carcinoid tumors are rare neuroendocrine tumors that can arise at several
body sites. The majority originate in the gastrointestinal tract (55 percent) and
bronchopulmonary system (30 percent). (See",
" <a class=\"local\" href=\"#H3796865\">",
" 'Distribution'",
" </a>",
" above.)",
" </li>",
" <li>",
" Carcinoid tumors arise from enterochromaffin cells. They have traditionally
been classified based upon their origin from the embryonic divisions of the
alimentary tract; the foregut (bronchial, stomach), midgut (small intestine,
appendix, cecum), or hindgut (distal colon, rectum, genitourinary). (See",
" <a class=\"local\" href=\"#H4\">",
" 'Embryonic classification'",
" </a>",
" above.)",
" </li>",
" <li>",
" Histologically, neuroendocrine tumors such as carcinoid tumors are
classified based upon histologic grade and differentiation (see",
" <a class=\"local\" href=\"#H3\">",
" 'Pathology and grading'",
" </a>",
" above).",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"hyphen-block\">",
" <li>",
" Well-differentiated neuroendocrine tumors, which are further subdivided into
low-grade and intermediate grade according to proliferative rate. In general,
clinical behavior is relatively indolent.",
" </li>",
" <li>",
" Poorly differentiated carcinoids are high-grade carcinomas that resemble
small cell or large cell neuroendocrine carcinoma of the lung. They generally
behave in a biologically aggressive fashion. &nbsp;",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" The metastatic potential of localized carcinoid tumors correlates with tumor
size, location, and histologic grade.",
" </li>",
" <li>",
" Clinical symptoms may be general, or they may correlate with the location of
the tumor and be organ related. Symptoms of the carcinoid syndrome (eg, flushing
and diarrhea) typically occur in patients with metastatic carcinoid tumors of the
small bowel. Rarely, the carcinoid syndrome is observed in non-metastatic tumors
which can release hormones directly into the systemic circulation (eg, lungs,
ovaries). (See",
" <a class=\"local\" href=\"#H12\">",
" 'Lung'",
" </a>",
" above and",
" <a class=\"local\" href=\"#H20\">",
" 'Ovary'",
" </a>",
" above.)",
" </li>",
" <li>",
" Gastric tumors are subclassified into three types which have different
clinical presentation and malignant potential. (See",
" <a class=\"local\" href=\"#H8\">",
" 'Stomach'",
" </a>",
" above.)",
" </li>",
" <li>",
" Small intestinal carcinoids often present with abdominal pain",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" intermittent obstruction. (See",
" <a class=\"local\" href=\"#H14\">",
" 'Jejuno-ileal small bowel tumors'",
" </a>",
" above.)",
" </li>",
" <li>",
" Appendiceal carcinoids are the most common neoplasm found in the appendix;
they are most often discovered incidentally during appendectomy. (See",
" <a class=\"local\" href=\"#H15\">",
" 'Appendix'",
" </a>",
" above.)",
" </li>",
" <li>",
" Transverse and descending colon and rectal carcinoids may present with
changes in bowel habit, obstruction, or bleeding. (See",
" <a class=\"local\" href=\"#H16\">",
" 'Hindgut tumors'",
" </a>",
" above.)",
" </li>",
" <li>",
" The great majority of rectal carcinoids are discovered incidentally at the
time of rectal examination or endoscopy.",
" </li>",
" <li>",
" Ovarian carcinoids may be primary or metastatic. Primary ovarian carcinoids
are often associated with an ovarian germ cell tumor. They can produce the
carcinoid syndrome without hepatic metastases due to their direct drainage into the
systemic circulation. (See",
" <a class=\"local\" href=\"#H20\">",
" 'Ovary'",
" </a>",
" above.)",
" </li>",
" </ul>",
" </p>",
" </div>",
" <div id=\"topicAgreement\">",
" Use of UpToDate is subject to the",
" <a class=\"licenseLink\" href=\"./license\" id=\"sla_in_page\"
target=\"_blank\">",
" Subscription and License Agreement",
" </a>",
" .",
" </div>",
" <div class=\"headingAnchor\" id=\"references\">",
" <h1>",
" REFERENCES",
" </h1>",
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" Burke AP, Thomas RM, Elsayed AM, Sobin LH. Carcinoids of the jejunum and
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carcinoid tumor of the small intestine. Cancer 1961; 14:901.",
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" Strosberg J, Gardner N, Kvols L. Survival and prognostic factor analysis of
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" Jann H, Roll S, Couvelard A, et al. Neuroendocrine tumors of midgut and
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" Rosenberg JM, Welch JP. Carcinoid tumors of the colon. A study of 72
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" Caplin M, Sundin A, Nillson O, et al. ENETS Consensus Guidelines for the
management of patients with digestive neuroendocrine neoplasms: colorectal
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" Spread C, Berkel H, Jewell L, et al. Colon carcinoid tumors. A population-
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" Ballantyne GH, Savoca PE, Flannery JT, et al. Incidence and mortality of
carcinoids of the colon. Data from the Connecticut Tumor Registry. Cancer 1992;
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" Jetmore AB, Ray JE, Gathright JB Jr, et al. Rectal carcinoids: the most
frequent carcinoid tumor. Dis Colon Rectum 1992; 35:717.",
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" Modlin IM, Sandor A. An analysis of 8305 cases of carcinoid tumors. Cancer
1997; 79:813.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?0/60/969/abstract/43\">",
" Koura AN, Giacco GG, Curley SA, et al. Carcinoid tumors of the rectum:
effect of size, histopathology, and surgical treatment on metastasis free survival.
Cancer 1997; 79:1294.",
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" Mani S, Modlin IM, Ballantyne G, et al. Carcinoids of the rectum. J Am Coll
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" Hansel DE, Epstein JI, Berbescu E, et al. Renal carcinoid tumor: a
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" Shurtleff BT, Shvarts O, Rajfer J. Carcinoid tumor of the kidney: case
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" Zavala-Pompa A, Ro JY, el-Naggar A, et al. Primary carcinoid tumor of
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" Stroosma OB, Delaere KP. Carcinoid tumours of the testis. BJU Int 2008;
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" Tal R, Lask DM, Livne PM. Metastatic renal carcinoid: case report and review
of the literature. Urology 2003; 61:838.",
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" Davis KP, Hartmann LK, Keeney GL, Shapiro H. Primary ovarian carcinoid
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" Soga J, Osaka M, Yakuwa Y. Carcinoids of the ovary: an analysis of 329
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" <a class=\"nounderline abstract\" href=\"UTD.htm?0/60/969/abstract/54\">",
" Strosberg J, Nasir A, Cragun J, et al. Metastatic carcinoid tumor to the
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106:65.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?0/60/969/abstract/55\">",
" Zuetenhorst JM, Hoefnageli CA, Boot H, et al. Evaluation of (111)In-
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" INTRODUCTION",
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" SUMMARY",
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" Malignant carcinoid ileum CT",
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" Classification carcinoid tumors by embryonic derivation",
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var title_f0_60_970="Classification and evaluation of dystonia";
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" </div>",
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" <div id=\"disclosures\">",
" <a href=\"UTD.htm?0/60/970/contributor-disclosure\" target=\"_blank\">",
" Disclosures",
" </a>",
" </div>",
" <div id=\"reviewProcess\">",
" <span>",
" All topics are updated as new evidence becomes available and our",
" </span>",
" <a href=\"/home/editorial-policy\" target=\"_blank\">",
" peer review process",
" </a>",
" <span>",
" is complete.",
" </span>",
" </div>",
" <div id=\"literatureReviewDate\">",
" <span class=\"emphasis\">",
" Literature review current through:",
" </span>",
" Oct 2013.",
" <span class=\"pipeSpace\">",
" |",
" </span>",
" <span class=\"emphasis\">",
" This topic last updated:",
" </span>",
" Feb 28, 2013.",
" </div>",
" <div id=\"topicText\">",
" <p class=\"headingAnchor\" id=\"H1\">",
" <span class=\"h1\">",
" INTRODUCTION AND DEFINITION",
" </span>",
" &nbsp;&mdash;&nbsp;Dystonia is a movement disorder characterized by
involuntary, sustained muscle contractions that result in twisting and repetitive
movements or abnormal postures [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/1-3\">",
" 1-3",
" </a>",
" ].",
" </p>",
" <p>",
" Dystonia can be classified by the age of onset, body distribution, and
etiology. Primary dystonia is defined as dystonia without any additional neurologic
signs or history of possible acquired causes. There are now at least 15 genetic
subtypes of dystonia.",
" </p>",
" <p>",
" This topic will review the classification, clinical features, and evaluation
of dystonia. Treatment options for dystonia are discussed elsewhere. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?11/52/12105?
source=see_link\">",
" \"Treatment of dystonia\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H2\">",
" <span class=\"h1\">",
" CLASSIFICATION",
" </span>",
" &nbsp;&mdash;&nbsp;Dystonia is classified in three ways: according to age of
onset, body areas affected (anatomic distribution), and etiology (",
" <a class=\"graphic graphic_table graphicRef59278 \" href=\"UTD.htm?
38/52/39755\">",
" table 1",
" </a>",
" ) [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/3\">",
" 3",
" </a>",
" ]:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Classification by age of onset [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/4\">",
" 4",
" </a>",
" ]:",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"hyphen-block\">",
" <li>",
" Early onset (childhood and young adulthood, generally &lt;26 years old)",
" </li>",
" <li>",
" Late onset (generally &ge;26 years old)",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Classification by anatomic distribution [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/5\">",
" 5",
" </a>",
" ]:",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"hyphen-block\">",
" <li>",
" Focal (involving a single body area)",
" </li>",
" <li>",
" Segmental (involving two or more contiguous body areas)",
" </li>",
" <li>",
" Generalized (involving at least one leg, the trunk, and another body area)",
" </li>",
" <li>",
" Multifocal (involving two or more noncontiguous body areas)",
" </li>",
" <li>",
" Hemidystonia (involving one side of the body)",
" <br/>",
" <br/>",
" Of these, multifocal dystonia and hemidystonia are less common than focal,
segmental, or generalized dystonia.",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Classification by etiology (",
" <a class=\"graphic graphic_table graphicRef59044 \" href=\"UTD.htm?
33/63/34813\">",
" table 2",
" </a>",
" ), which broadly separates the spectrum of dystonia into two main
categories, primary and secondary:",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"hyphen-block\">",
" <li>",
" Primary dystonia presents with signs related solely to dystonia and lacks
additional neurologic, laboratory, or imaging abnormalities. The onset and
progression of symptoms is gradual and usually without fixed postures. However,
contractures may sometimes develop in areas chronically affected by dystonia,
particularly if the dystonia is present at rest as well as with action.",
" <br/>",
" <br/>",
" Primary torsion dystonia, previously called idiopathic torsion dystonia, may
be sporadic or inherited. Most early-onset primary torsion dystonia is inherited in
an autosomal dominant pattern with a reduced penetrance of 30 percent. (See",
" <a class=\"local\" href=\"#H16\">",
" 'Genetic etiologies'",
" </a>",
" below.)",
" <br/>",
" <br/>",
" Historically, primary torsion dystonia has also been called dystonia
musculorum deformans and Oppenheim dystonia. These terms are no longer used.",
" </li>",
" <li>",
" Secondary dystonia is associated with a known acquired cause or additional
neurologic signs, such as muscle weakness, spasticity, ataxia, ocular motility
abnormalities, retinal abnormalities, cognitive impairment, or seizures. Secondary
dystonia usually arises from a specific underlying condition, such as perinatal
asphyxia or exposure to dopamine receptor blocking drugs (eg, tardive dystonia).
The presence of other neurologic abnormalities may provide the clue to the cause of
the dystonia [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/6\">",
" 6",
" </a>",
" ]. Brain MRI findings vary with the etiology.",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H3\">",
" <span class=\"h2\">",
" Age of onset and anatomic distribution",
" </span>",
" &nbsp;&mdash;&nbsp;The age and anatomic distribution of dystonia at onset are
important clinical clues.",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Early onset dystonia most often begins with symptoms in the limbs, typically
the leg, and spreads to other body areas to become generalized in over 50 percent
of patients [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/7\">",
" 7",
" </a>",
" ]. (See",
" <a class=\"local\" href=\"#H6\">",
" 'Early onset primary dystonia'",
" </a>",
" below.)",
" </li>",
" <li>",
" In contrast, late onset dystonia most frequently begins in the neck, arm, or
face and tends to remain focal or segmental. (See",
" <a class=\"local\" href=\"#H7\">",
" 'Late onset primary dystonia'",
" </a>",
" below.)",
" </li>",
" <li>",
" Atypical presentations of dystonia (eg, a child with onset in the neck or
face, or an adult with onset in the leg, or an adult who develops generalized
dystonia) indicate the need to evaluate for an underlying cause. (See",
" <a class=\"local\" href=\"#H24\">",
" 'Diagnosis'",
" </a>",
" below.)",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H4\">",
" <span class=\"h1\">",
" EPIDEMIOLOGY",
" </span>",
" &nbsp;&mdash;&nbsp;Dystonia affects approximately 0.6 to 732 per 100,000
people, depending on the populations assessed and the methods of ascertainment,
with focal dystonia being the most frequent in an office setting [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/8-14\">",
" 8-14",
" </a>",
" ]. In a 2012 systematic review and meta-analysis, the overall prevalence of
primary dystonia was 16.4 per 100,000 [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/15\">",
" 15",
" </a>",
" ]. The variability among these studies may arise from different methodologies
of case identification, and differences in the demographic and ethnic composition
of the populations assessed. However, focal dystonia is more common in all studies,
and is estimated to be approximately 10 times more frequent than generalized
dystonia. Cervical dystonia is the most frequent type of focal dystonia.",
" </p>",
" <p>",
" Efforts are ongoing to develop a practical, reliable, and validated screening
tool for dystonia that can be applied to large populations [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/16,17\">",
" 16,17",
" </a>",
" ]. In the absence of such an instrument, under-diagnosis and misdiagnosis are
likely major confounders. As an example, a study of familial dystonia found that
one-half of the cases were not previously diagnosed [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/18\">",
" 18",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H5\">",
" <span class=\"h1\">",
" CLINICAL FEATURES",
" </span>",
" &nbsp;&mdash;&nbsp;Dystonia is characterized by involuntary, sustained muscle
contractions that result in twisting and repetitive movements or abnormal postures
[",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/1,2\">",
" 1,2",
" </a>",
" ]. The sustained movements of dystonia may have overlying spasms that resemble
tremor but can be distinguished from essential tremor by the directional quality of
the movement [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/19\">",
" 19",
" </a>",
" ].",
" </p>",
" <p>",
" Dystonia is a dynamic disorder that changes in severity, depending upon
activity and posture. An example of this is writer's cramp, a dystonia that
involves the hand and arm, which is present only during the action of writing but
not during any other activity.",
" </p>",
" <p>",
" A common feature of dystonia is the sensory trick or \"geste antagoniste\".
The sensory trick is a maneuver (eg, lightly touching the affected body part) that
reduces or abolishes the dystonic symptoms. It is found in approximately 60 percent
of patients. In some patients, these tricks may be effective if imagined but not
performed physically [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/20\">",
" 20",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H6\">",
" <span class=\"h2\">",
" Early onset primary dystonia",
" </span>",
" &nbsp;&mdash;&nbsp;Early onset dystonia usually begins in a leg, often as
inversion of the foot. Initially, the dystonia might be triggered only by vigorous
physical activity such as running. Over time, the posturing becomes susceptible to
triggering by minimal physical activity, such as walking or standing. Subsequently,
the dystonia may be present even at rest.",
" </p>",
" <p>",
" With early onset focal dystonia, spread from one leg to other body areas,
including the other leg, torso, arms, and upper body, occurs in approximately 50 to
90 percent of children, usually within five years of onset. However, when early
onset dystonia begins in the arm in late childhood and adolescence, it tends to
have a lower likelihood of subsequent spread.",
" </p>",
" <p>",
" In primary dystonia, cognition and intellectual abilities remain intact
despite the presence of significant movement abnormalities.",
" </p>",
" <p class=\"headingAnchor\" id=\"H7\">",
" <span class=\"h2\">",
" Late onset primary dystonia",
" </span>",
" &nbsp;&mdash;&nbsp;In contrast to early onset dystonia, late onset primary
dystonia often begins in the upper body, usually in the arm, neck, face, or larynx
[",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/21\">",
" 21",
" </a>",
" ]. Although symptoms may worsen in the area of involvement or spread to
contiguous body regions (segmental dystonia), adult-onset dystonia rarely becomes
generalized [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/7\">",
" 7",
" </a>",
" ]. Regional spread to contiguous body areas is most frequently observed with
blepharospasm [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/22,23\">",
" 22,23",
" </a>",
" ].",
" </p>",
" <p>",
" Infrequently, late onset primary dystonia begins in the leg. However, onset in
the leg in an adult is usually secondary to an underlying etiology such as early
onset Parkinson disease [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/24\">",
" 24",
" </a>",
" ].",
" </p>",
" <p>",
" As noted earlier, generalized dystonia is rare with adult onset. In such
cases, a secondary etiology should be sought, such as exposure to dopamine receptor
antagonists. Hemidystonia is infrequent, and is usually due to an underlying
structural or metabolic cause. (See",
" <a class=\"local\" href=\"#H24\">",
" 'Diagnosis'",
" </a>",
" below.)",
" </p>",
" <p>",
" Late onset primary focal dystonia may involve different body areas. Common",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" important types of focal dystonia include:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Cervical dystonia (dystonia of neck and shoulders)",
" </li>",
" <li>",
" Blepharospasm (dystonia of periocular muscles)",
" </li>",
" <li>",
" Oromandibular, lingual, or facial dystonia (dystonia of jaw, oral muscles,
tongue, or facial muscles)",
" </li>",
" <li>",
" Spasmodic dysphonia (dystonia of laryngeal muscles)",
" </li>",
" <li>",
" Limb dystonia (dystonia of arm or leg)",
" </li>",
" <li>",
" Occupational or task-specific dystonia (dystonia that occurs only with
certain activities such as writer's cramp, musicians dystonia, or embouchure
dystonia)",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H8\">",
" <span class=\"h2\">",
" Cervical dystonia",
" </span>",
" &nbsp;&mdash;&nbsp;Cervical dystonia, also known as spasmodic torticollis, is
the most common primary focal dystonia [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/11\">",
" 11",
" </a>",
" ]. It affects the muscles of the neck and shoulders. It may appear as
horizontal turning of the head (torticollis), lateral flexion of the neck
(laterocollis), forward flexion of the head (anterocollis), or posterior extension
of the head (retrocollis). Overlying spasms may give rise to a head tremor that is
distinguished from essential tremor by the directional preponderance of the
movement. Approximately one-half of patients with cervical dystonia will complain
of pain associated with the dystonia [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/25,26\">",
" 25,26",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H9\">",
" <span class=\"h2\">",
" Blepharospasm",
" </span>",
" &nbsp;&mdash;&nbsp;Blepharospasm is a focal dystonia involving the orbicularis
oculi muscles and other periocular muscles, including the procerus and corrugator
muscles [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/27,28\">",
" 27,28",
" </a>",
" ]. Clinical manifestations include increased blinking and spasms of
involuntary eye closure. Symptoms are usually bilateral but may be asymmetric.
Involuntary eye closure caused by dystonic spasms of the orbicularis oculi should
be distinguished from apraxia of eyelid opening due to failure of levator palpebrae
contraction. In some patients, the two conditions can coexist.",
" </p>",
" <p>",
" Blepharospasm may be mild and nondisabling, or it may cause significant
disability through interference with vision as a result of the eye closure.
Patients with blepharospasm typically complain of increased spasms under conditions
of bright light or stress, such as driving a car in traffic. Pain is infrequently
associated with blepharospasm, although a feeling of irritation in the eyes may be
one of the first symptoms [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/29\">",
" 29",
" </a>",
" ].",
" </p>",
" <p>",
" Blepharospasm may be associated with dystonia of the lower face",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" jaw (Meige syndrome or Brueghel syndrome) [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/30\">",
" 30",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H10\">",
" <span class=\"h2\">",
" Oromandibular dystonia and facial dystonia",
" </span>",
" &nbsp;&mdash;&nbsp;Oromandibular dystonia and facial dystonia are
characterized by involuntary movements involving masticatory, lingual, and
pharyngeal muscles.",
" </p>",
" <p>",
" Oromandibular dystonia can manifest as jaw clenching, jaw opening, jaw
deviation, and tongue protrusion. It is often found in combination with dystonia of
adjacent body regions, including blepharospasm and cervical dystonia. Symptoms can
result in difficulty speaking and swallowing and may be cosmetically disfiguring.",
" </p>",
" <p class=\"headingAnchor\" id=\"H11\">",
" <span class=\"h2\">",
" Spasmodic dysphonia",
" </span>",
" &nbsp;&mdash;&nbsp;Spasmodic dysphonia is a focal dystonia involving the
laryngeal muscles. The most common type of spasmodic dysphonia is the adductor
type, with apposition of the vocal cords only during the action of vocalization.
This causes voice breaks and a strained pattern of vocalization. Abductor spasmodic
dysphonia is characterized by an abduction of the vocal cords during vocalization,
resulting in a voice that is whispering and breathy [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/31\">",
" 31",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H12\">",
" <span class=\"h2\">",
" Vocal tremor",
" </span>",
" &nbsp;&mdash;&nbsp;Vocal tremor occurs with oscillation of the vocal cords and
can be seen in association with craniofacial and cervical dystonia, and in patients
with essential tremor of the hands and head [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/32\">",
" 32",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H13\">",
" <span class=\"h2\">",
" Arm dystonia",
" </span>",
" &nbsp;&mdash;&nbsp;Arm dystonia is manifested as a posturing of the hand",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" arm. This problem may be variably present with arms outstretched, but is often
not present at rest. Overlying dystonic spasms may occur and resemble essential
tremor. However, in contrast to essential tremor, dystonia is often unilateral, and
triggered by specific activities, such as writing or typing. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?10/46/10984?
source=see_link&amp;anchor=H9#H9\">",
" \"Overview of tremor\", section on 'Essential tremor'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H14\">",
" <span class=\"h2\">",
" Occupational or task-specific dystonia",
" </span>",
" &nbsp;&mdash;&nbsp;Occupational or task-specific dystonia is manifested only
during particular activities. Writer's cramp is the most common form. Other types
of task-specific dystonia include:",
" </p>",
" <p>",
" <ul class=\"bulletCompact-block\">",
" <li>",
" Typist's dystonia",
" </li>",
" <li>",
" Golfer's dystonia (yips)",
" </li>",
" <li>",
" Musician's dystonia",
" </li>",
" </ul>",
" </p>",
" <p>",
" Occupational facial dystonia may manifest as embouchure dystonia, a dystonia
of the lips, jaw, or tongue that affects musicians only during the act of playing
reed or brass instruments, and is absent during other activities such as eating or
speaking [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/33\">",
" 33",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H15\">",
" <span class=\"h3\">",
" Writer's cramp",
" </span>",
" &nbsp;&mdash;&nbsp;Writer's cramp is a focal dystonia elicited by the act of
writing. It appears as an involuntary flexion, extension",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" rotation of the fingers, wrist, and less frequently the elbow and shoulder.
The act of writing requires more effort, and handwriting may become so distorted
that it is no longer legible [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/34\">",
" 34",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H16\">",
" <span class=\"h1\">",
" GENETIC ETIOLOGIES",
" </span>",
" &nbsp;&mdash;&nbsp;There have been many advances in the area of dystonia
genetics, with identification of new genetic loci, increased understanding of
genotype-phenotype interactions, and investigations into the role of the mutant
gene products. Since the discovery of DYT1, the first gene mutation to be cloned,
many additional genetic forms of dystonia have been described (",
" <a class=\"graphic graphic_table graphicRef56658 \" href=\"UTD.htm?
7/8/7310\">",
" table 3",
" </a>",
" ) [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/35,36\">",
" 35,36",
" </a>",
" ].",
" </p>",
" <p>",
" Some of the more common",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" important types of dystonia related to gene mutations are described in greater
detail below.",
" </p>",
" <p class=\"headingAnchor\" id=\"H17\">",
" <span class=\"h2\">",
" DYT1 dystonia",
" </span>",
" &nbsp;&mdash;&nbsp;Many patients with hereditary dystonia have DYT1 dystonia,
which is caused by a mutation in the TOR1A gene that encodes torsinA, an ATP-
binding protein [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/37\">",
" 37",
" </a>",
" ]. A three-base pair deletion results in loss of a glutamic acid residue in
the C-terminal region of the torsinA protein [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/38\">",
" 38",
" </a>",
" ].",
" </p>",
" <p>",
" DYT1 dystonia typically begins in childhood with limb onset, followed by
progression to generalized dystonia. However, the phenotypic spectrum of DYT1
dystonia is broad, and late onset can occur. In one study with 176 TOR1A carriers,
the mean age at onset was 17.6 years, with a range from three to 70 years [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/4\">",
" 4",
" </a>",
" ].",
" </p>",
" <p>",
" DYT1 dystonia accounts for approximately 40 to 65 percent of early onset
primary dystonia in non-Jewish populations and 90 percent of early onset limb
dystonia in the Ashkenazi Jewish population [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/39\">",
" 39",
" </a>",
" ]. Inheritance is autosomal dominant, but penetrance is reduced approximately
30 to 40 percent [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/5\">",
" 5",
" </a>",
" ]. Thus, most mutation carriers do not express clinically apparent disease.",
" </p>",
" <p>",
" The pathogenic mechanism for DYT1 dystonia is uncertain. The primary
abnormality is a mutation in the DYT1 protein product, torsinA [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/40\">",
" 40",
" </a>",
" ]. Although the function of torsinA is not known, it is associated with the
endoplasmic reticulum and nuclear envelope, and has been hypothesized to play an
important role in protein folding. Mutant torsinA also demonstrates perinuclear
staining and forms distinct globular inclusions that contain vesicular monoamine
transporter 2 (VMAT2). Since VMAT2 plays an important role in the exocytosis of
monoamines in neurons, it may be that mutant torsinA may interfere with VMAT2
expression and dopamine release.",
" </p>",
" <p class=\"headingAnchor\" id=\"H18\">",
" <span class=\"h2\">",
" DYT6 and other primary dystonias",
" </span>",
" &nbsp;&mdash;&nbsp;The genetics of late onset focal and segmental dystonia
have been more difficult to delineate than early onset DYT1 dystonia (",
" <a class=\"graphic graphic_table graphicRef56658 \" href=\"UTD.htm?
7/8/7310\">",
" table 3",
" </a>",
" ). Many late onset cases are likely to have a hereditary component [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/41-43\">",
" 41-43",
" </a>",
" ]. In most patients with late onset dystonia, DYT1 testing is not recommended
unless there a family history of early onset dystonia.",
" </p>",
" <p>",
" DYT6 was initially described in Amish-Mennonite families and characterized as
an early-onset, cranial-cervical dystonia with autosomal dominant inheritance and a
penetrance of 60 percent [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/44,45\">",
" 44,45",
" </a>",
" ]. Mutations responsible for DYT6 dystonia in the THAP1 gene on chromosome 8
were discovered as founder mutations in the Amish-Mennonite families [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/45,46\">",
" 45,46",
" </a>",
" ]. Involvement of cranial muscles, leading to disabling dysarthria or
dysphonia, was thought to be characteristic of DYT6 dystonia.",
" </p>",
" <p>",
" Subsequent investigations of patients with non-DYT1, familial, early onset,
generalized dystonia showed that there were additional mutations in the THAP1 gene
besides those reported in the Amish-Mennonite families [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/47,48\">",
" 47,48",
" </a>",
" ]. These additional THAP1 mutations were found in 25 percent of the families
studied [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/47\">",
" 47",
" </a>",
" ], suggesting that THAP1 mutations (DYT6) could be responsible for a
substantial proportion of familial non-DYT1 early-onset primary dystonia in
patients of European descent, including those of German, Irish, and Italian
ancestry. In another study that screened over 1200 subjects with dystonia and 600
controls, a mutation in THAP1 was found in 18 affected subjects and one
asymptomatic carrier from 16 families with primary dystonia, and in one normal
control [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/49\">",
" 49",
" </a>",
" ]. The phenotype of the patients with THAP1 dystonia was highly variable, with
age of onset ranging from 8 to 69 years (mean 48 years), and with site of onset
predominantly cervical and laryngeal. The dystonia remained focal in 15 of 18
patients (83 percent).",
" </p>",
" <p>",
" THAP1 encodes for a transcription regulating protein that modulates other
target genes, including the TOR1A gene associated with DYT1 dystonia [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/50,51\">",
" 50,51",
" </a>",
" ]. Genetic studies in humans and animals have shown that the wild-type THAP1
protein binds to the TOR1A gene promoter region and represses the expression of
torsinA, while pathophysiologic DYT6 mutations of THAP1 abolish the interaction
between THAP1 protein and the TOR1A promoter, leading to decreased repression of
TOR1A [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/50,51\">",
" 50,51",
" </a>",
" ]. Thus, these findings suggest a common molecular pathway linking DYT1 and
DYT6.",
" </p>",
" <p>",
" Other genetic forms of focal",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" segmental dystonia (",
" <a class=\"graphic graphic_table graphicRef56658 \" href=\"UTD.htm?
7/8/7310\">",
" table 3",
" </a>",
" ) have also been reported (eg, DYT4, DYT7, DYT13) [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/52-55\">",
" 52-55",
" </a>",
" ]. Cohort analysis suggests an autosomal dominant inheritance with variable
penetrance. Although these families are rare, additional gene loci are certain to
be identified in the future.",
" </p>",
" <p class=\"headingAnchor\" id=\"H19\">",
" <span class=\"h2\">",
" Dopa-responsive dystonia",
" </span>",
" &nbsp;&mdash;&nbsp;Dopa-responsive dystonia (DRD) manifests primarily as a
focal dystonia with onset in early childhood [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/56-59\">",
" 56-59",
" </a>",
" ]. Parkinsonism, including rigidity and bradykinesia, may be present at onset
or develop during the course of untreated disease. Often, children with DRD
experience a long delay in diagnosis [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/60\">",
" 60",
" </a>",
" ] or are initially misdiagnosed as having a primary dystonia or cerebral palsy
[",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/61,62\">",
" 61,62",
" </a>",
" ].",
" </p>",
" <p>",
" In the original description of DRD, the investigators observed a diurnal
fluctuation in symptoms, which worsened over the course of a day and improved
following sleep [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/56\">",
" 56",
" </a>",
" ]. However, this diurnal fluctuation may not be present in all patients with
DRD [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/63\">",
" 63",
" </a>",
" ].",
" </p>",
" <p>",
" The hallmark of DRD is a clinically significant, sustained response to
levodopa. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?11/52/12105?
source=see_link\">",
" \"Treatment of dystonia\"",
" </a>",
" .)",
" </p>",
" <p>",
" The most frequent form of DRD is autosomal dominant DYT5 dystonia caused by a
mutation in the guanosine triphosphate (GTP) cyclohydrolase 1 gene (GCH1) [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/64\">",
" 64",
" </a>",
" ]. The GTP cyclohydrolase 1 protein encoded by this gene is involved in the
biosynthesis of tetrahydrobiopterin, which is a cofactor for tyrosine hydroxylase,
the rate-limiting enzyme in the synthesis of dopamine. It is also a cofactor for
phenylalanine and tryptophan hydroxylase. Numerous mutations of the GCH1 gene can
cause DRD, making gene testing difficult.",
" </p>",
" <p>",
" An autosomal recessive form of DRD (Segawa syndrome) is caused by mutation in
the tyrosine hydroxylase gene [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/65-67\">",
" 65-67",
" </a>",
" ]. Other rare entities that can present with a phenotype of DRD include
mutations in the sepiapterin reductase gene (SPR gene) and the 6-pyruvoyl-
tetrahydropterin synthase gene (PTS gene) [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/68,69\">",
" 68,69",
" </a>",
" ].",
" </p>",
" <p>",
" In the clinical setting, the most practical and useful diagnostic test for DRD
is a markedly positive response to a trial of levodopa, slowly increased to doses
of 600 to 1,000 mg daily. However, a positive response to levodopa does not
differentiate DRD from juvenile onset Parkinson disease. Typically, patients with
DRD will have a sustained benefit from low doses of levodopa without developing
motor fluctuations and dyskinesia, in contrast to juvenile Parkinson disease, in
which these motor complications are a frequent occurrence.",
" </p>",
" <p>",
" Other proposed diagnostic methods for DRD include assessment of
tetrahydrobiopterin and neopterin in the cerebrospinal fluid, and the
phenylalanine-loading test [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/70,71\">",
" 70,71",
" </a>",
" ]. However, most clinicians rely on confirmation with levodopa and do not
undertake more extensive laboratory testing. Genetic testing for GCH1 is available,
although there are many mutations that may give rise to the disorder [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/72\">",
" 72",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H20\">",
" <span class=\"h2\">",
" Myoclonus-dystonia",
" </span>",
" &nbsp;&mdash;&nbsp;Myoclonus-dystonia is a genetically heterogeneous autosomal
dominant movement disorder characterized by myoclonic jerks primarily affecting the
neck, arms, and axial muscles, combined with variable features of dystonia. Onset
is typically in the second decade. The dystonia may be mild, and may improve
dramatically after alcohol intake. At least two genetic loci have been identified
(DYT11, DYT15).",
" </p>",
" <p>",
" Myoclonus-dystonia is discussed in detail separately. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?7/32/7689?
source=see_link&amp;anchor=H15#H15\">",
" \"Classification and evaluation of myoclonus\", section on 'Myoclonus-
dystonia'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H21\">",
" <span class=\"h2\">",
" Dystonia plus parkinsonism",
" </span>",
" &nbsp;&mdash;&nbsp;Other genetic forms of dystonia combine features of
dystonia with parkinsonism.",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" X-linked dystonia-parkinsonism (DYT3), also known as Lubag dystonia, is
characterized by progressive dystonia, often accompanied by parkinsonism. This
disorder mainly affects Filipino men in their fifth decade, but woman can also be
affected [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/73\">",
" 73",
" </a>",
" ]. Prominent pathologic findings include pronounced atrophy of the caudate
and putamen. The disorder is poorly responsive to medication and patients usually
survive for only 10 to 12 years. However, a case series found that the clinical
course is much more benign in women [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/74\">",
" 74",
" </a>",
" ]. The responsible mutation involves the TATA-binding protein-associated
factor 1 gene (TAF1 gene) on chromosome Xq13.1 [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/75,76\">",
" 75,76",
" </a>",
" ].",
" </li>",
" <li>",
" Rapid onset dystonia-parkinsonism (DYT12) is an autosomal dominant disorder
in which dystonia, parkinsonism, prominent dysarthria and dysphagia emerge and
evolve over a period of hours to weeks. Onset occurs in adolescence and early
adulthood. The disorder is linked to chromosome 19q13 and six missense mutations in
the ATP1A3 gene that encodes the",
" <span class=\"nowrap\">",
" Na+/K+",
" </span>",
" -ATPase alpha3 subunit have been described [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/77\">",
" 77",
" </a>",
" ]. Genetic testing for the ATP1A3 gene is recommended when abrupt onset,
rostrocaudal gradient and prominent bulbar findings are present [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/78\">",
" 78",
" </a>",
" ]. Despite reduced cerebrospinal homovanillic acid levels, this syndrome
responds poorly to dopaminergic agents.",
" </li>",
" <li>",
" Early onset dystonia-parkinsonism (DYT16) is an apparently autosomal
recessive disorder characterized by early onset of focal dystonia followed by rapid
spread of symptoms [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/79\">",
" 79",
" </a>",
" ]. Parkinsonism is variably present, and was observed in four of the
original seven cases [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/79\">",
" 79",
" </a>",
" ]. The syndrome does not respond to levodopa or high-dose anticholinergic
treatment. Early onset dystonia-parkinsonism is linked to a mutation in the PRKRA
gene on chromosome 2q31.3 [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/79,80\">",
" 79,80",
" </a>",
" ].",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H22\">",
" <span class=\"h2\">",
" Paroxysmal dyskinesia with dystonia",
" </span>",
" &nbsp;&mdash;&nbsp;Several rare genetic forms of dystonia are characterized by
paroxysmal dyskinesia (",
" <a class=\"graphic graphic_table graphicRef56658 \" href=\"UTD.htm?
7/8/7310\">",
" table 3",
" </a>",
" ):",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Paroxysmal nonkinesigenic dyskinesia (PNKD) is characterized by spontaneous
episodes of dystonia",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" choreoathetosis not triggered by exercise or activity. Alcohol, coffee, tea,
fatigue, stress, or excitement may be precipitating factors. Episodes last minutes
to hours and recur two or three times a month. One type of PNKD (DYT8) is caused by
mutations in the myofibrillogenesis 1 regulator gene (MR1 gene) on chromosome 2q35
[",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/81,82\">",
" 81,82",
" </a>",
" ]. Another maps to chromosome 2q31 [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/83\">",
" 83",
" </a>",
" ].",
" </li>",
" <li>",
" Paroxysmal choreoathetosis with episodic spasticity and ataxia (DYT9)
manifests with episodes of dystonia, diplopia, and paresthesia [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/84,85\">",
" 84,85",
" </a>",
" ]. Exercise, emotional stress, sleep deprivation, and alcohol consumption
may be precipitating factors. Some patients have a spastic paraparesis. DYT9 maps
to chromosome 1p [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/85\">",
" 85",
" </a>",
" ].",
" </li>",
" <li>",
" Paroxysmal kinesigenic choreoathetosis, also known as paroxysmal kinesigenic
dyskinesia, is characterized by episodic choreoathetosis and dystonia brought on by
voluntary movement [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/84,86\">",
" 84,86",
" </a>",
" ]. The disorder is genetically heterogeneous; episodic kinesigenic
dyskinesia 1 is caused by mutations in the PRRT2 gene on chromosome 16p11.2 [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/87-91\">",
" 87-91",
" </a>",
" ], and episodic kinesigenic dyskinesia 2 maps to chromosome 16q13-q22.1 [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/92\">",
" 92",
" </a>",
" ]. A third locus does not link to chromosome 16 [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/93\">",
" 93",
" </a>",
" ].",
" </li>",
" <li>",
" Paroxysmal exertion-induced dyskinesia is an autosomal dominant disorder
with reduced penetrance that begins in childhood with dyskinesia and dystonia
induced by prolonged exertion (eg, &ge;15 minutes), fasting and stress [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/94-96\">",
" 94-96",
" </a>",
" ]. Associated features include absence",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" partial complex seizures. Affected members of one family also had hemolytic
anemia [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/97\">",
" 97",
" </a>",
" ]. The condition is linked to mutation or deletion of the SLC2A1 gene on
chromosome 1p35-p31.3 that encodes the GLUT1 facilitated glucose transporter [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/97\">",
" 97",
" </a>",
" ].",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H23\">",
" <span class=\"h1\">",
" PATHOGENESIS",
" </span>",
" &nbsp;&mdash;&nbsp;There are no consistent neuropathologic findings in primary
dystonia [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/98-102\">",
" 98-102",
" </a>",
" ]. The lack of cell degeneration suggests that primary dystonia is a dynamic
disorder, arising from abnormal cell function.",
" </p>",
" <p>",
" The anatomic localization and specific neurotransmitter defects of dystonia
have also been elusive. In patients with hemidystonia, lesions of the basal ganglia
on head CT or neuropathologic examination were associated with contralateral
dystonia [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/103\">",
" 103",
" </a>",
" ]. Neuroimaging studies with positron emission tomography (PET) and functional
MRI have shown that dystonia can be associated with abnormal activity in multiple
regions of the brain, including motor cortex, supplementary motor areas,
cerebellum, and basal ganglia [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/104,105\">",
" 104,105",
" </a>",
" ].",
" </p>",
" <p>",
" Data from electrophysiologic testing (eg, blink reflex recovery) and
functional imaging studies suggest that the pathophysiology of dystonia, in
particular the task specific dystonias, may arise from a decrease of central
inhibitory mechanisms, an increase of plasticity, or an impairment in sensory
function [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/3,106\">",
" 3,106",
" </a>",
" ].",
" </p>",
" <p>",
" Direct microelectrode recordings obtained in patients with dystonia during
electrode implantation for deep brain stimulation have shown alterations in mean
discharge rates, somatosensory responsiveness, and altered patterns of neuronal
activity in the globus pallidus [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/107\">",
" 107",
" </a>",
" ]. These recordings have given rise to new constructs for diagrams of the
basal ganglia and its involvement in dystonia, in which the modulating influences
within the basal ganglia change with activity, reflecting the movement-dependent
nature of dystonia.",
" </p>",
" <p>",
" The underlying neurochemistry of dystonia is not known, but dopaminergic and
cholinergic neurotransmitter systems may be involved.",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Abnormal dopaminergic activity in the basal ganglia is indirectly suggested
by extrapolation from observations that dopamine receptor antagonism can cause
acute and chronic dystonic symptoms (eg, oculogyric crisis and tardive dystonia)
and that dystonia is often associated with Parkinson disease, a disorder with
marked dopamine depletion. The co-occurrence of parkinsonism and dystonia in dopa-
responsive dystonia further implicates a role for dopamine in the pathogenesis of
dystonia.",
" </li>",
" <li>",
" Cholinergic mechanisms are suggested by the success of anticholinergic
therapy, mainly in children with dystonia [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/108\">",
" 108",
" </a>",
" ].",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H24\">",
" <span class=\"h1\">",
" DIAGNOSIS",
" </span>",
" &nbsp;&mdash;&nbsp;The diagnosis of dystonia is based mainly upon clinical
features, although the diagnostic laboratory can provide supportive evidence. In
the absence of specific diagnostic tests, expert observation by a movement disorder
specialist is suggested to confirm the diagnosis of dystonia in cases where there
is uncertainty or confusion [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/109,110\">",
" 109,110",
" </a>",
" ].",
" </p>",
" <p>",
" Primary dystonia is separated from secondary dystonia by the absence of
additional neurologic abnormalities and the lack of possible acquired cause (",
" <a class=\"graphic graphic_table graphicRef70065 \" href=\"UTD.htm?
28/4/28747\">",
" table 4",
" </a>",
" ).",
" </p>",
" <p>",
" As noted earlier, the age and anatomic distribution of dystonia at onset are
important clinical clues for diagnosis. Atypical presentations (eg, a child with
onset of dystonia in the neck or face, or an adult with onset in the leg, or an
adult who develops generalized dystonia) indicate the need to evaluate for an
underlying cause. (See",
" <a class=\"local\" href=\"#H5\">",
" 'Clinical features'",
" </a>",
" above.)",
" </p>",
" <p>",
" Laboratory testing in primary dystonia is of minimal usefulness, but essential
in the evaluation of secondary dystonia, or dystonia with atypical features.",
" </p>",
" <p class=\"headingAnchor\" id=\"H25\">",
" <span class=\"h2\">",
" Levodopa trial",
" </span>",
" &nbsp;&mdash;&nbsp;Patients with focal or generalized dystonia of unknown
etiology should have a trial of levodopa (eg,",
" <a class=\"drug drug_general\" href=\"UTD.htm?35/36/36423?source=see_link\">",
" carbidopa-levodopa",
" </a>",
" <span class=\"nowrap\">",
" 25/100",
" </span>",
" mg three times daily) to confirm or exclude the diagnosis of dopa-responsive
dystonia. (See",
" <a class=\"local\" href=\"#H19\">",
" 'Dopa-responsive dystonia'",
" </a>",
" above.)",
" </p>",
" <p class=\"headingAnchor\" id=\"H26\">",
" <span class=\"h2\">",
" Genetic testing",
" </span>",
" &nbsp;&mdash;&nbsp;In patients with early onset dystonia, or those with late
onset who have an affected relative with early onset dystonia, DYT1 gene testing is
indicated with appropriate genetic counseling [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/4,110\">",
" 4,110",
" </a>",
" ]. (See",
" <a class=\"local\" href=\"#H17\">",
" 'DYT1 dystonia'",
" </a>",
" above.)",
" </p>",
" <p>",
" Molecular genetic testing is possible but NOT widely available for dopa-
responsive dystonia (DYT5), myoclonus-dystonia (DYT11), rapid-onset dystonia-
parkinsonism (DYT12), and deafness-dystonia-optic neuronopathy syndrome [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/111\">",
" 111",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H27\">",
" <span class=\"h2\">",
" Laboratory evaluation",
" </span>",
" &nbsp;&mdash;&nbsp;The assessment of atypical",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" secondary dystonia is extensive [",
" <a class=\"abstract\" href=\"UTD.htm?0/60/970/abstract/6\">",
" 6",
" </a>",
" ]. Laboratory evaluations and brain imaging should be obtained and
appropriately directed. When there is clinical suspicion for secondary or
heredodegenerative dystonia, we suggest obtaining the following studies:",
" </p>",
" <p>",
" <ul class=\"bulletCompact-block\">",
" <li>",
" CT or MRI of brain (basal ganglia calcifications or necrosis and other
abnormalities)",
" </li>",
" <li>",
" Complete blood count",
" </li>",
" <li>",
" Electrolytes",
" </li>",
" <li>",
" Renal and liver function tests",
" </li>",
" <li>",
" Antinuclear antibodies",
" </li>",
" <li>",
" Ceruloplasmin, serum copper, and 24-hour urinary copper (for Wilson
disease)",
" </li>",
" <li>",
" Erythrocyte sedimentation rate",
" </li>",
" <li>",
" Rapid plasma reagent",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"PATIENT_INFORMATION\">",
" <span class=\"h1\">",
" INFORMATION FOR PATIENTS",
" </span>",
" &nbsp;&mdash;&nbsp;UpToDate offers two types of patient education materials,
&ldquo;The Basics&rdquo; and &ldquo;Beyond the Basics.&rdquo; The Basics patient
education pieces are written in plain language, at the 5",
" ^{",
" th",
"}",
" to 6",
" ^{",
" th",
"}",
" grade reading level, and they answer the four or five key questions a patient
might have about a given condition. These articles are best for patients who want a
general overview and who prefer short, easy-to-read materials. Beyond the Basics
patient education pieces are longer, more sophisticated, and more detailed. These
articles are written at the 10",
" ^{",
" th",
"}",
" to 12",
" ^{",
" th",
"}",
" grade reading level and are best for patients who want in-depth information
and are comfortable with some medical jargon.",
" </p>",
" <p>",
" Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also
locate patient education articles on a variety of subjects by searching on
&ldquo;patient info&rdquo; and the keyword(s) of interest.)",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Basics topics (see",
" <a class=\"medical medical_basics\" href=\"UTD.htm?34/2/34849?
source=see_link\">",
" \"Patient information: Dystonia (The Basics)\"",
" </a>",
" )",
" </li>",
" <li>",
" Beyond the Basics topics (see",
" <a class=\"medical medical_basics\" href=\"UTD.htm?21/8/21633?
source=see_link\">",
" \"Patient information: Spasmodic dysphonia (The Basics)\"",
" </a>",
" )",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H28\">",
" <span class=\"h1\">",
" SUMMARY AND RECOMMENDATIONS",
" </span>",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Dystonia is a movement disorder characterized by involuntary, sustained
muscle contractions that result in twisting and repetitive movements or abnormal
postures. (See",
" <a class=\"local\" href=\"#H1\">",
" 'Introduction and definition'",
" </a>",
" above.)",
" </li>",
" <li>",
" Dystonia is classified by anatomic distribution, age of onset, and etiology
(",
" <a class=\"graphic graphic_table graphicRef59278 \" href=\"UTD.htm?
38/52/39755\">",
" table 1",
" </a>",
" ) (see",
" <a class=\"local\" href=\"#H2\">",
" 'Classification'",
" </a>",
" above):",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"hyphen-block\">",
" <li>",
" Dystonia may be classified anatomically as focal (involving a single body
area), segmental (involving contiguous body areas), generalized (involving at least
one leg, the trunk, and another body area), multifocal (involving two or more
noncontiguous body areas), and hemidystonia (involving one side of the body).",
" </li>",
" <li>",
" Early onset dystonia presents in childhood or young adulthood (before age
26). It most often begins with symptoms in the limbs, typically the leg. It spreads
to other body areas to become generalized in over 50 percent of patients. Late
onset dystonia (age 26 or older) most frequently begins in the neck, arm, or face
and tends to remain focal or segmental.",
" </li>",
" <li>",
" Classification by etiology (",
" <a class=\"graphic graphic_table graphicRef59044 \" href=\"UTD.htm?
33/63/34813\">",
" table 2",
" </a>",
" ) broadly separates the spectrum of dystonia into two main categories,
primary and secondary. Primary dystonia presents with signs related solely to
dystonia. Secondary dystonia is associated with additional neurologic abnormalities
and usually arises from a specific underlying condition.",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" The prevalence of dystonia is estimated to be between 2 to 7500 per million
people, depending on the populations assessed and the methods of ascertainment.
Focal dystonia is approximately 10 times more frequent than generalized dystonia.
(See",
" <a class=\"local\" href=\"#H4\">",
" 'Epidemiology'",
" </a>",
" above.)",
" </li>",
" <li>",
" The clinical features of dystonia vary according to anatomic location, age
of onset, and etiology. Early onset dystonia usually begins in a leg, often as
intorsion of the foot. Spread from one leg to other body areas occurs in
approximately 50 to 90 percent of children, usually within five years of onset.
Late onset primary focal dystonia may involve different body areas. Common",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" important types of focal dystonia include (see",
" <a class=\"local\" href=\"#H5\">",
" 'Clinical features'",
" </a>",
" above):",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"hyphen-block\">",
" <li>",
" Cervical dystonia (see",
" <a class=\"local\" href=\"#H8\">",
" 'Cervical dystonia'",
" </a>",
" above)",
" </li>",
" <li>",
" Blepharospasm (see",
" <a class=\"local\" href=\"#H9\">",
" 'Blepharospasm'",
" </a>",
" above)",
" </li>",
" <li>",
" Oromandibular dystonia and facial dystonia (see",
" <a class=\"local\" href=\"#H10\">",
" 'Oromandibular dystonia and facial dystonia'",
" </a>",
" above)",
" </li>",
" <li>",
" Spasmodic dysphonia (see",
" <a class=\"local\" href=\"#H11\">",
" 'Spasmodic dysphonia'",
" </a>",
" above)",
" </li>",
" <li>",
" Arm dystonia (see",
" <a class=\"local\" href=\"#H13\">",
" 'Arm dystonia'",
" </a>",
" above)",
" </li>",
" <li>",
" Occupational or task-specific dystonia such writer's cramp (see",
" <a class=\"local\" href=\"#H14\">",
" 'Occupational or task-specific dystonia'",
" </a>",
" above and",
" <a class=\"local\" href=\"#H15\">",
" 'Writer's cramp'",
" </a>",
" above)",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" There are numerous genetic causes of dystonia (",
" <a class=\"graphic graphic_table graphicRef56658 \" href=\"UTD.htm?
7/8/7310\">",
" table 3",
" </a>",
" ) (see",
" <a class=\"local\" href=\"#H16\">",
" 'Genetic etiologies'",
" </a>",
" above):",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"hyphen-block\">",
" <li>",
" DYT1 primary dystonia is caused by a mutation in the TOR1A gene. Other
genetic types of primary dystonia include DYT4, DYT6, DYT7, and DYT13 (see",
" <a class=\"local\" href=\"#H17\">",
" 'DYT1 dystonia'",
" </a>",
" above and",
" <a class=\"local\" href=\"#H18\">",
" 'DYT6 and other primary dystonias'",
" </a>",
" above)",
" </li>",
" <li>",
" Dopa-responsive dystonia manifests primarily as a focal dystonia with onset
in early childhood. The most frequent form of DRD is autosomal dominant DYT5
dystonia with a mutation in the GCH1 gene (see",
" <a class=\"local\" href=\"#H19\">",
" 'Dopa-responsive dystonia'",
" </a>",
" above)",
" </li>",
" <li>",
" Myoclonus-dystonia (DYT11, DYT15) is an autosomal dominant movement disorder
characterized by alcohol-sensitive myoclonic jerks, primarily affecting the arms
and axial muscles, combined with variable features of dystonia (see",
" <a class=\"local\" href=\"#H20\">",
" 'Myoclonus-dystonia'",
" </a>",
" above)",
" </li>",
" <li>",
" Genetic forms of dystonia with parkinsonism include X-linked dystonia-
parkinsonism (DYT3), rapid onset dystonia-parkinsonism (DYT12), and early onset
dystonia-parkinsonism (DYT16) (see",
" <a class=\"local\" href=\"#H21\">",
" 'Dystonia plus parkinsonism'",
" </a>",
" above)",
" </li>",
" <li>",
" Several rare genetic forms of dystonia are characterized by paroxysmal
dyskinesia (DYT8, DYT9, DYT10) (see",
" <a class=\"local\" href=\"#H22\">",
" 'Paroxysmal dyskinesia with dystonia'",
" </a>",
" above)",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" The pathogenesis of most forms of primary dystonia is largely unknown. There
are no consistent neuropathologic features, suggesting that dystonia occurs because
of cellular dysfunction. Multiple brain areas may be involved, including basal
ganglia, motor cortex, supplementary motor areas, and cerebellum. Postulated
mechanisms include a decrease of inhibition, an increase of plasticity, or
impairment in sensory function. Abnormalities in dopaminergic and cholinergic
neurotransmitter systems may play a role. (See",
" <a class=\"local\" href=\"#H23\">",
" 'Pathogenesis'",
" </a>",
" above.)",
" </li>",
" <li>",
" The diagnosis of dystonia is mainly clinical. Expert observation by a
movement disorder specialist is suggested to confirm the diagnosis of dystonia in
cases where there is uncertainty or confusion (",
" <a class=\"graphic graphic_table graphicRef70065 \" href=\"UTD.htm?
28/4/28747\">",
" table 4",
" </a>",
" ). Atypical presentations",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" suspicion for secondary etiologies should prompt further investigations
(see",
" <a class=\"local\" href=\"#H24\">",
" 'Diagnosis'",
" </a>",
" above).",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"hyphen-block\">",
" <li>",
" For patients with focal or generalized dystonia of unknown etiology, we
recommend a trial of levodopa (eg,",
" <a class=\"drug drug_general\" href=\"UTD.htm?35/36/36423?
source=see_link\">",
" carbidopa-levodopa",
" </a>",
" <span class=\"nowrap\">",
" 25/100",
" </span>",
" mg three times daily, slowly increased to total levodopa doses of 600 to
1,000 mg daily) to confirm or exclude the diagnosis of dopa-responsive dystonia.",
" </li>",
" <li>",
" For patients with early onset dystonia, or those with late onset who have an
affected relative with early onset dystonia, we suggest TOR1A genetic testing for
DYT1 dystonia.",
" </li>",
" </ul>",
" </p>",
" </div>",
" <div id=\"topicAgreement\">",
" Use of UpToDate is subject to the",
" <a class=\"licenseLink\" href=\"./license\" id=\"sla_in_page\"
target=\"_blank\">",
" Subscription and License Agreement",
" </a>",
" .",
" </div>",
" <div class=\"headingAnchor\" id=\"references\">",
" <h1>",
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" </h1>",
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" Evidente VG, Nolte D, Niemann S, et al. Phenotypic and molecular analyses of
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" de Carvalho Aguiar P, Sweadner KJ, Penniston JT, et al. Mutations in the
Na+/K+ -ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia
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2007; 130:828.",
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" <a class=\"nounderline abstract\" href=\"UTD.htm?0/60/970/abstract/79\">",
" Camargos S, Scholz S, Sim&oacute;n-S&aacute;nchez J, et al. DYT16, a novel
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mutation in the stress-response protein PRKRA. Lancet Neurol 2008; 7:207.",
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" Seibler P, Djarmati A, Langpap B, et al. A heterozygous frameshift mutation
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choreoathetosis locus maps to chromosome 16p11.2-q12.1. Am J Hum Genet 1999;
65:1688.",
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mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat Genet 2011;
43:1252.",
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cause of paroxysmal kinesigenic dyskinesia in the European population. Neurology
2012; 79:170.",
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" van Vliet R, Breedveld G, de Rijk-van Andel J, et al. PRRT2 phenotypes and
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" Spacey SD, Valente EM, Wali GM, et al. Genetic and clinical heterogeneity in
paroxysmal kinesigenic dyskinesia: evidence for a third EKD gene. Mov Disord 2002;
17:717.",
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induced dyskinesia and benign epilepsy: a clinical and neurophysiological study of
an uncommon disorder. Neurol Sci 2000; 21:165.",
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" Vitek JL. Pathophysiology of dystonia: a neuronal model. Mov Disord 2002; 17
Suppl 3:S49.",
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" Pisani A, Bernardi G, Ding J, Surmeier DJ. Re-emergence of striatal
cholinergic interneurons in movement disorders. Trends Neurosci 2007; 30:545.",
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" Logroscino G, Livrea P, Anaclerio D, et al. Agreement among neurologists on
the clinical diagnosis of dystonia at different body sites. J Neurol Neurosurg
Psychiatry 2003; 74:348.",
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" Albanese A, Barnes MP, Bhatia KP, et al. A systematic review on the
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" </ol>",
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" <h1>",
" TOPIC OUTLINE",
" </h1>",
" <div id=\"outline\">",
" <ul>",
" <li>",
" <a class=\"sr_button\" href=\"#H28\" id=\"summRecButton\">",
" <span>",
" SUMMARY &amp; RECOMMENDATIONS",
" </span>",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H1\">",
" INTRODUCTION AND DEFINITION",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H2\">",
" CLASSIFICATION",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H3\">",
" Age of onset and anatomic distribution",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H4\">",
" EPIDEMIOLOGY",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H5\">",
" CLINICAL FEATURES",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H6\">",
" Early onset primary dystonia",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H7\">",
" Late onset primary dystonia",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H8\">",
" Cervical dystonia",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H9\">",
" Blepharospasm",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H10\">",
" Oromandibular dystonia and facial dystonia",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H11\">",
" Spasmodic dysphonia",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H12\">",
" Vocal tremor",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H13\">",
" Arm dystonia",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H14\">",
" Occupational or task-specific dystonia",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" <a class=\"outlineLink\" href=\"#H15\">",
" - Writer's cramp",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H16\">",
" GENETIC ETIOLOGIES",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H17\">",
" DYT1 dystonia",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H18\">",
" DYT6 and other primary dystonias",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H19\">",
" Dopa-responsive dystonia",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H20\">",
" Myoclonus-dystonia",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H21\">",
" Dystonia plus parkinsonism",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H22\">",
" Paroxysmal dyskinesia with dystonia",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H23\">",
" PATHOGENESIS",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H24\">",
" DIAGNOSIS",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H25\">",
" Levodopa trial",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H26\">",
" Genetic testing",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H27\">",
" Laboratory evaluation",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#PATIENT_INFORMATION\">",
" INFORMATION FOR PATIENTS",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H28\">",
" SUMMARY AND RECOMMENDATIONS",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a href=\"#references\">",
" REFERENCES",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" <div class=\"openRelatedGraphics\" id=\"NEURO/4886\" rel=\"outline_link\">",
" GRAPHICS",
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" View All",
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" </h1>",
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" TABLES",
" </a>",
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" <a class=\"graphic graphic_table\" href=\"UTD.htm?38/52/39755\" title=\"table
1\">",
" Classification dystonia",
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" </li>",
" <li class=\"bulletItem\">",
" <a class=\"graphic graphic_table\" href=\"UTD.htm?33/63/34813\" title=\"table
2\">",
" Etiology dystonia",
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" </li>",
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" <a class=\"graphic graphic_table\" href=\"UTD.htm?7/8/7310\" title=\"table
3\">",
" Genetic forms dystonia",
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" </li>",
" <li class=\"bulletItem\">",
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4\">",
" Features primary dystonia",
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" <h1>",
" RELATED TOPICS",
" </h1>",
" <div id=\"relatedTopics\">",
" <ul>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_review\" href=\"UTD.htm?7/32/7689?
source=related_link\">",
" Classification and evaluation of myoclonus",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_review\" href=\"UTD.htm?10/46/10984?
source=related_link\">",
" Overview of tremor",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_basics\" href=\"UTD.htm?34/2/34849?
source=related_link\">",
" Patient information: Dystonia (The Basics)",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_basics\" href=\"UTD.htm?21/8/21633?
source=related_link\">",
" Patient information: Spasmodic dysphonia (The Basics)",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_review\" href=\"UTD.htm?11/52/12105?
source=related_link\">",
" Treatment of dystonia",
" </a>",
" </li>",
" </ul>",
" </div>",
" </div>"].join("\n");
var title_f0_60_971="Risk factors surgery obstructive jaundice";
var content_f0_60_971=[" <div id=\"graphicsToolbar\">",
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" &copy;2013 UpToDate",
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" <div class=\"graphic\">",
" <div class=\"figure\">",
" <div class=\"ttl\">",
" Risk factors for morbidity and mortality in patients with obstructive jaundice
undergoing surgery",
" </div>",
" <div class=\"cntnt\">",
" <table cellspacing=\"0\">",
" <tbody>",
" <tr>",
" <td>",
" Azotemia",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Cholangitis",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Hematocrit &lt; 30 percent",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Hypoalbulminemia",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Malignant cause of biliary obstruction",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Serum bilirubin level &gt; 11 mg/dL (188 &micro;mol/liter)",
" </td>",
" </tr>",
" </tbody>",
" </table>",
" </div>",
" <div class=\"lgnd\">",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Reproduced with permission from Friedman LS. The risk of surgery in patients
with liver disease. Hepatology 1999; 29:1617. Copyright &copy; 1999 Elsevier
Science.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
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var outline_f0_60_971=null;
var title_f0_60_972="Motor automatisms";
var content_f0_60_972=[" <div id=\"graphicsToolbar\">",
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" &copy;2013 UpToDate",
" ^{",
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"}",
" </div>",
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title=\"Print this page\"/>",
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=PEDS
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title=\"Print this page\">",
" Print",
" </a>",
" <a class=\"etacLink\" href=\"#\">",
" <img alt=\"Email graphic(s)\" src=\"./../images/icn_email.myextg\"
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" Email",
" </a>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\">",
" <div class=\"ttl\">",
" Motor automatisms in Neonatal seizures",
" </div>",
" <div class=\"cntnt\">",
" <table cellspacing=\"0\">",
" <tbody>",
" <tr>",
" <td class=\"subtitle1_single\">",
" Ocular signs",
" </td>",
" </tr>",
" <tr>",
" <td colspan=\"1\">",
" Random and roving eye movements or nystagmus (distinct from tonic eye
deviation)",
" </td>",
" </tr>",
" <tr>",
" <td colspan=\"1\">",
" May be provoked or intensified by tactile stimulation",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Presumed pathophysiology: nonepileptic",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle1_single\">",
" Oral-buccal-lingual movements",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Sucking, chewing, tongue protrusions",
" </td>",
" </tr>",
" <tr>",
" <td colspan=\"1\">",
" May be provoked or intensified by stimulation",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Presumed pathophysiology: nonepileptic",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle1_single\">",
" Progression movements",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Rowing or swimming movements",
" </td>",
" </tr>",
" <tr>",
" <td colspan=\"1\">",
" Pedaling or bicycling movements of the legs",
" </td>",
" </tr>",
" <tr>",
" <td colspan=\"1\">",
" May be provoked or intensified by stimulation",
" </td>",
" </tr>",
" <tr>",
" <td colspan=\"1\">",
" May be suppressed by restraint or repositioning",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Presumed pathophysiology: nonepileptic",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle1_single\">",
" Complex purposeless movements",
" </td>",
" </tr>",
" <tr>",
" <td colspan=\"1\">",
" Sudden arousal with transient increased random activity of limbs",
" </td>",
" </tr>",
" <tr>",
" <td colspan=\"1\">",
" May be provoked or intensified by stimulation",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Presumed pathophysiology: nonepileptic",
" </td>",
" </tr>",
" </tbody>",
" </table>",
" </div>",
" <div class=\"lgnd\">",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Adapted with permission from: Mizrahi, EM, Kellaway, P. Diagnosis and
Management of Neonatal Seizures. Lippincott-Raven, Philadelphia 1998. p.181.
Copyright &copy; 1998 Lippincott Williams &amp; Wilkins.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
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var title_f0_60_973="Classification of epileptic seizures";
var content_f0_60_973=[" <div id=\"graphicsToolbar\">",
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" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\">",
" <div class=\"ttl\">",
" International classification of epileptic seizures",
" </div>",
" <div class=\"cntnt\">",
" <table cellspacing=\"0\">",
" <tr>",
" <td class=\"subtitle1_single\">",
" Partial (focal, local) seizures",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle2_single\">",
" Simple partial seizures (conciousness not impaired)",
" </td>",
" </tr>",
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" With motor symptoms",
" </td>",
" </tr>",
" <tr>",
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" Focal motor without march",
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" <tr>",
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" Versive",
" </td>",
" </tr>",
" <tr>",
" <td class=\"sublist2\">",
" Postural",
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" </tr>",
" <tr>",
" <td class=\"sublist2\">",
" Phonatory (vocalization or arrest of speech)",
" </td>",
" </tr>",
" <tr>",
" <td class=\"sublist2_start\">",
" With somatosensory or special sensory symptoms",
" </td>",
" </tr>",
" <tr>",
" <td class=\"sublist2\">",
" Somatosensory",
" </td>",
" </tr>",
" <tr>",
" <td class=\"sublist2\">",
" Visual",
" </td>",
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" Auditory",
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" <td class=\"sublist2\">",
" Vertiginous",
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" </tr>",
" <tr>",
" <td class=\"indent1\">",
" With autonomic symptoms or signs (including epigastric, pallor, sweating,
etc)",
" </td>",
" </tr>",
" <tr>",
" <td class=\"sublist2_start\">",
" With psychic symptoms (disturbance of higher cerebral function). Usually
occur with impairment of consciousness and classified as complex partial.",
" </td>",
" </tr>",
" <tr>",
" <td class=\"sublist2\">",
" Dysphasic",
" </td>",
" </tr>",
" <tr>",
" <td class=\"sublist2\">",
" Cognitive (eg, distortions of time sense)",
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" </tr>",
" <tr>",
" <td class=\"sublist2\">",
" Dysmnesic (eg, deja-vu)",
" </td>",
" </tr>",
" <tr>",
" <td class=\"sublist2\">",
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" <tr>",
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" <tr>",
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" Complex partial (with impairment of consciousness)",
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" </tr>",
" <tr>",
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" Simple partial onset followed by impairment of consciousness",
" </td>",
" </tr>",
" <tr>",
" <td class=\"sublist2_start\">",
" Impairment of consciousness at onset",
" </td>",
" </tr>",
" <tr>",
" <td class=\"sublist2\">",
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" </td>",
" </tr>",
" <tr>",
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" With automatisms",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle2_single\">",
" Partial seizures (simple or complex) evolving to secondarily generalized
seizures",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle1_single\">",
" Generalized seizures",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle2_single\">",
" Nonconvulsive (absence)",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Typical (3/sec spike and slow wave complexes on EEG)",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Atypical (&lt;3/sec spike and slow wave complexes on EEG)",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle2_single\">",
" Convulsive",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Myoclonic seizures",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Clonic seizures",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Tonic seizures",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Tonic-clonic seizures",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Atonic (\"drop attacks\")",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle1_single\">",
" Unclassified seizure",
" </td>",
" </tr>",
" </table>",
" </div>",
" <div class=\"lgnd\">",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Adapted from Commission on Classification and Terminology of the
International League against Epilepsy, Epilepsia 1981; 22:489.",
" </div>",
" </div>",
" </div>",
" </div>",
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var title_f0_60_974="Electrolyte patterns PFTs";
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"}",
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" <div class=\"graphic\">",
" <div class=\"figure\" style=\"width: 504px\">",
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" The characteristic electrolyte secretory concentration patterns observed in
pancreatic fluid in response to secretin administration",
" </div>",
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" </div>",
" <div class=\"lgnd\">",
" Sodium and potassium are maintained at stable concentrations and isotonic to
plasma. There is a gradual rise in bicarbonate concentration to a peak of
approximately 120 mEq/L. Chloride exhibits a reciprocal decrease in
concentration.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Courtesy of Cleveland Clinic Foundation.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var script_f0_60_974=[""].join("\n");
var outline_f0_60_974=null;
var title_f0_60_975="Evaluation intractable hiccups";
var content_f0_60_975=[" <div id=\"graphicsToolbar\">",
" <div id=\"graphicsCopy\">",
" &copy;2013 UpToDate",
" ^{",
" &reg;",
"}",
" </div>",
" <div id=\"graphicsLinks\">",
" <a href=\"?imageKey=PC
%2F79155&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=1\" onclick=\"\">",
" <img alt=\"Print this page\" src=\"./../images/icn_print.myextg\"
title=\"Print this page\"/>",
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=PC
%2F79155&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=1\" onclick=\"\"
title=\"Print this page\">",
" Print",
" </a>",
" <a class=\"etacLink\" href=\"#\">",
" <img alt=\"Email graphic(s)\" src=\"./../images/icn_email.myextg\"
title=\"Email graphic(s)\"/>",
" </a>",
" <a class=\"icontxt textLink etacLink\" href=\"#\" title=\"Email graphic(s)\">",
" Email",
" </a>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\" style=\"width: 486px\">",
" <div class=\"ttl\">",
" Diagnostic evaluation of persistent or intractable hiccups",
" </div>",
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" </div>",
" <div class=\"lgnd\">",
" <div class=\"footnotes\">",
" CXR: chest x-ray; sx: symptoms; ENT: ear, nose, and throat; LP: lumbar
puncture; LFTs: liver function tests.",
" </div>",
" <div class=\"reference\">",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var script_f0_60_975=[""].join("\n");
var outline_f0_60_975=null;