Prenatal Genetic Screening and Diagnosis

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Presented by: Jane Cheuh, MD
Director, Prenatal Diagnosis and Therapy
Stanford University Medical Center
March 21, 2013

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Prenatal screening, including ultrasounds and blood tests, gives pregnant women an important heads-up on possible birth defects and allow women to make decisions about their pregnancy.  The most common test is for Down syndrome (trisomy 21), a condition in which an extra chromosome causes delays in the child’s mental and physical development. It affects about 1 in every 800 babies born in the United States.

Down syndrome and other chromosomal abnormalities are tested by chorionic villus sampling (CVS), which is done when the pregnancy is at 10 to 14 weeks. CVS involves taking a small sample of cells through the cervix. The main advantage of CVS is that it can be done earlier than an amniocentesis, which is generally done between 15 and 20 weeks.

Twenty years ago, the procedure was associated with a very small risk of miscarriage (1 percent) compared to amniocentesis (.5 percent), although the risk today is minimal when performed by an experienced physician, said Jane Chueh, MD, a clinical professor of maternal fetal medicine who practices at Stanford Hospital and at Packard Children’s Hospital. Dr. Chueh spoke at a presentation sponsored by the Stanford Hospital Health Library.

Prenatal screening should be done by women over age 35, since the risk of a chromosomal anomaly tends to be higher in older mothers. However since most mothers are under age 35, the majority of Down syndrome cases occur in younger women, so she advocates that all women should be screened early in their pregnancy.

“Age is only one factor,” she said. “Age 35 is an arbitrary number and is no longer the threshold for screening.”

Dr. Chueh said the average risk of Down syndrome for women age 35 is 1 in 380,, which is considered moderate. In comparison, the risk is 1 in 11 (high) in women age 49 or older; and is 1 in 667 (low risk) in 20-year-old women. First and second trimester screening tests are available through the state of California State. If the results show high risk, the state will pay for subsequent diagnostic testing

First Trimester Tests
Several tests are offered during the first trimester. A prenatal test called a nuchal fold scan, or NT, uses ultrasound to measure the space in the tissue at the back of the developing fetus’ neck. A fetus with an abnormality tends to accumulate more fluid at the back of the neck during the first trimester, causing the space to be larger than average. The NT scan must be done between 11.5 and 14 weeks of pregnancy. The result is combined with concurrent tests for PAPP-A (pregnancy-associated plasma protein A and free beta hCG.

“Increased NT is associated with chromosomal abnormalities, cardiac problems, and other fetal anomalies,” Dr. Chueh said. “But timing is important. Being off by even one day can throw it off, and if it’s done too early we may need to redraw blood or re-measure another day”

“Screening is not the same as a diagnosis. It’s important to realize that there are certain algorithms for these tests that consider detection rates and the chance of a false positive. Testing positive means there is a possibility of Down, but the test is not definitive,” she said.

Second Trimester Tests
Second trimester screenings, which are generally integrated with the first series of tests,  include a quad marker screen, a blood test for increased risk of Down syndrome and neural tube defects such as spina bifida. The quad screen is done between 15 and 20 weeks of pregnancy and can detect about 80 percent of fetuses affected by Down syndrome.

Ultrasounds may also detect soft markers which, while not necessarily an anomaly, may increase the statistical chances of chromosomal abnormalities. These markers include an enlarged nuchal fold, echogenic bowel, and short humerus or femur bones. Often these markers have no real impact on risk if the patient has a low risk to begin with, said Dr. Chueh, and may soon become obsolete with the advent of cell free DNA screening on maternal blood.

The Future of Screenings
While current diagnostic tests such as amniocentesis and CVS are reliable and readily available, they are invasive and carry a slight risk of miscarriage. The goal, said Dr. Chueh, is to identify a technique for noninvasive and accurate diagnosis.

That goal is closer, thanks to a new finding that assesses fetal DNA circulating in the mother’s blood. Minute amounts of free-floating DNA (CfDNA) from fragments of the placenta appear to increase with gestational age and completely disappear 48 hours after birth. Physicians are able to look at the DNA sequences of certain chromosomes and match them up to determine if the fetus is normal. If the counts run less or more than normal, there is a possibility of an  anomaly. Several companies now offer cfDNA tests.

The advantages to this approach over traditional screening tests are numerous, said Dr. Chueh, including a shorter wait time for results, a single blood draw, and an earlier window of opportunity for screening. Integrated first and second trimester screening results are available after six weeks and have a 90 percent detection rate; cfDNA tests have a 99.4 percent detection rate and take one to two weeks. They are also automated, which make them more consistent and less time-consuming.

There is a downside, however, she added. These tests are still new and are more expensive than standard tests, which are covered by the state. They test for only a few conditions and have a higher failure rate in which the tests are not able to get a result.

“The success of cell free DNA has opened up renewed interest in noninvasive prenatal diagnosis. The next step is finding intact fetal cells in maternal blood with no invasive procedure to the pregnancy,” Dr. Chueh says. “We are looking for strategies that are faster, cheaper, and more comprehensive than current screening tests, but more studies are needed.”

About the Speaker
Dr. Chueh is a clinical professor of obstetrics and gynecology and the director of Prenatal Diagnosis and Therapy in the Division of Maternal Fetal Medicine. She received her MD from the University of California, San Diego, did her internship and residency at University of Washington Medical Center, and did a fellowship at University of California, San Francisco. She is Board Certified in Maternal and Fetal Medicine and in Obstetrics and Gynecology by the American Board of Obstetrics and Gynecology.

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Celiac Disease

Posted By SHL Librarian

Presented by: Nielsen Fernandez-Becker, MD, PhD
Instructor, Gastroenterology
Stanford University Medical Center
March 11, 2010

Lecture Overview:

  • Celiac disease is a digestive condition caused by eating gluten, which is found in wheat, barley, or rye. It affects the small intestine’s ability to absorb nutrients.
  • Its cause is unknown and may be a combination of genetic, environmental, and immune system factors.
  • Diagnosis may involve a blood test, intestinal biopsy, and a dietary assessment while still consuming gluten products.
  • The only effective treatment is to remove gluten from the diet.

Celiac disease is a digestive condition triggered by eating gluten, which is found in foods containing wheat, barley, or rye. These ingredients cause an immune reaction in the small intestine, damaging its surface in a way that interferes with the absorption of important nutrients. Over time, this decreased absorption can cause vitamin deficiencies that affect the brain, nervous system, bones, liver, and other organs.

About 2 million people in the United State have the disease-one in 133 individuals. That number increases to one in 22 people when there is a first-degree family member with celiac disease. Though common, its symptoms can mimic other conditions, such as irritable bowel syndrome, gastric ulcers, Crohn’s disease, infections, or anemia.

There is no one cause of celiac disease, though two specific genes have been associated with the condition. One or the other of these genes-DQ2 and DQ8-are present in more than 95 percent of celiac disease patients, although they also appear in 20 to 30 percent of the population who show no symptoms.

“Having one of these genes does not necessarily mean you will have celiac disease but that you may be at a higher risk,” said Nielsen Fernandez-Becker, MD, PhD, at a presentation sponsored by the Stanford Health Library. “It’s a combination of genetics, an immune system defect, and the environment-in this case exposure to gluten,”

The small intestine is lined with tiny, hair-like projections called villi that absorb vitamins, minerals, and other nutrients. Normally, villi look like a plush carpet inside the small intestine; celiac disease can be patchy, like a mosaic pattern, with scalloping of the intestinal lining, nodules, and ulceration.

Initial symptoms can range from abdominal pain to diarrhea, vomiting, constipation, and weight loss. In time, due to the loss of calcium and Vitamin D, patients may suffer from bone disease, fatigue, anemia, arthritis, rashes, and other complaints. Because of its wide range of symptoms, there are five different classifications of celiac disease, from classic conditions to no response to treatment despite a positive blood test.

Diagnosis often involves a blood test to measure certain immune system antibodies involved in modification of gluten peptides; high levels aid in the diagnosis of the disease. Intestinal biopsy is the “gold standard” to confirm a diagnosis. A trial of a diet containing gluten in patients who have been abstinent can also be used to confirm a diagnosis.

“Celiac can sometimes be tricky to diagnose because its symptoms can be non-specific. We often use a variety of tests before we can be certain its celiac disease. To diagnose accurately, the person must be consuming gluten,” said Fernandez-Becker. “Once gluten is out of the diet the intestine begins to heal, making it difficult to detect the disease in someone on a gluten-free diet.”

The only effective treatment for celiac disease is to remove gluten from the diet-that means no pasta, crackers, bread, or beer. There are also “hidden sources” of gluten: It can be used in soy sauce, vinegar, processed foods, and even some shampoos and lotions. Even a small amount of gluten is enough to cause symptoms and complications, she said, so read labels carefully.

“It’s difficult to follow this kind of diet, because gluten is often a hidden ingredient,” said Fernandez-Becker. “Patients benefit from seeing a specialist to evaluate what they’re eating. It involves a lifelong lifestyle change.”

She suggests that celiac patients keep products clearly marked and separate in the pantry to avoid cross contamination. Many people check directly, and regularly, with manufacturers to see if a product contains gluten. Once gluten is eliminated, inflammation in the small intestine will begin to subside, usually within several weeks, and many people notice improvement in just a few days.

About the Speaker
Nielsen Q. Fernandez-Becker is an instructor in gastroenterology and is Board Certified by the American Board of Internal Medicine. She received her medical education at Albert Einstein College of Medicine in New York, did her residency and internship at Massachusetts General Hospital, and completed her fellowship at Beth Israel Deaconess Medical Center. She joined Stanford in 2009.

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Inflammatory Bowel Disease

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Presented by: Shamita Shah, MD
Clinical Assistant Professor, Gastroenterology
Clinical Director, Stanford Inflammatory Bowel Disease Program
Stanford University Medical Center
February 24, 2010

Lecture Overview:

  • Ulcerative colitis and Crohn’s disease are chronic inflammatory disorders of the gastrointestinal tract known as inflammatory bowel disease (IBD).
  • Its cause is unknown and may be a combination of genetic, environmental, and immune system factors.
  • Treatment is designed to induce a rapid response and maintain remission.
  •  Management of symptoms is individualized for each patient, and compliance to medical treatment is essential.

Inflammatory bowel disease (IBD) refers to two chronic diseases that cause inflammation of the intestines: ulcerative colitis and Crohn’s disease. Although the diseases have some features in common, there are some important differences.

It’s estimated that as many as 2 million Americans have inflammatory bowel disease, with 10,000 news cases reported each year. The disease occurs most frequently in young people, age 20 to 30, and may also occur in middle-aged adults, age 50 to 60. It is most common in the industrialized nations of Western Europe and North America; however as nations in Asia, Africa, and South America become more “Westernized”, more cases of IBD are being reported.

“While there’s no test to predict who might develop IBD, people with a family history are 30 to 100 times more likely to develop the condition,” said Shamita Shah, MD, the clinical director of the IBD program at Stanford, who spoke at a presentation sponsored by the Stanford Health Library. “A genetic predisposition coupled with environmental triggers can cause a dysregulation of the immune system, and that imbalance can trigger chronic inflammation.”

Two Different Conditions
Ulcerative colitis is an inflammatory disease in which the lining of the large intestine becomes inflamed, starting in the rectum and then working its way up through the colon.  Symptoms may include bloody diarrhea, rectal bleeding, weight loss and fever.

Crohn’s disease causes inflammation that extends much deeper into the layers of the intestinal wall and tends to involve the entire bowel wall, whereas ulcerative colitis affects only the lining of the bowel. It may affect any part of the gastrointestinal system, from the mouth to the anus. Symptoms may include non-bloody diarrhea, weight loss, abdominal pain, fatigue, and fevers.

Triggers can range from infection to antibiotics, stress, diet, and nonsteroid anti-inflammatory drugs (NSAIDs). Both disorders can be painful, debilitating, and lead to sometimes life-threatening complications.

The two conditions have different characteristics and physicians need to conduct a thorough evaluation to diagnose the disease, which may include endoscopy, tissue biopsy, imaging (X-ray, MRI, or CT), blood and stool tests. “It’s very important to get an accurate diagnosis since some infections can mimic IBD,” said Shah. “Tests can also make sure that there are no complications such as abscess, fistula, or narrowing of the intestine.”

Evaluation for other manifestations of IBD outside of the intestine is also very important because the disease can also affect the eye, skin, joints, liver, and other organs.

Individualized Treatment
“Treatment is designed to induce a rapid response and maintain remission. The goal is to achieve and maintain mucosal healing, avoiding complications and hospitalizations, and improving quality of life,” Shah said.

Physicians can prescribe a variety of medications, including anti-inflammatories such as steroids, and oral or topical mesalamine agents, biologics, and immunomodulators. Some drugs are used to induce remission (induction) and others to maintain remission (maintenance).  For example, steroids are helpful for getting inflammation under control initially but should only be used in the short term and should never be stopped abruptly, she said. Immunomodulators take time to work so they are used for maintenance rather than induction therapy. These medications often have side effects which should be discussed with your physician.

Surgery may be required in advanced cases of ulcerative colitis, when no other treatment helps. “The beauty is, once you remove the part affected part of your colon affected by ulcerative colitis, you’re cured,” said Shah. “That’s not the case in Crohn’s disease: Surgery is not curative and the disease may recur.”

Adherence to treatment, a healthy diet, bone density tests to assess for osteopenia and osteoporosis after prolonged steroid use, and routine vaccinations are essential in staying healthy with IBD.

“It’s important to individualize therapy and understand the disease,” said Shah.  “Ongoing research is improving our understanding and new therapies continue to be developed.”

About the Speaker
Shamita Shah, MD, is a clinical assistant professor of medicine (gastroenterology) and the clinical director of Stanford’s Inflammatory Bowel Disease Program. She is board certified in internal medicine and gastroenterology.  A specialist in Crohn’s disease and inflammatory bowel disease, Shah has a clinical and research focus in treating severe colitis, applying novel diagnostic tools,and preventing post-operative recurrence. Shah joined Stanford in 2008 after completing a fellowship in inflammatory bowel diseases at the University of Chicago.

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Cancer Awareness Series: New Successes in Colorectal Cancer Treatments and Outcomes

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Presented by: George Fisher, MD, PhD
Associate Professor, Oncology

Uri Ladabaum, MD, MS
Associate Professor, Gastroenterology

Hanlee Ji, MD, PhD
Assistant Professor, Oncology

Samuel Strober, MD
Professor, Immunology and Rheumatology

March 24, 2011

Lecture Overview:

Colorectal cancer (CRC) is the third most common cancer in the United States and is the country’s second leading cause of cancer death (behind lung cancer)

“We are working to raise awareness of the disease and to celebrate the  successes we have had with colorectal cancer,” said George Fisher, MD, PhD, an associate professor of oncology, who spoke at a presentation sponsored by the Stanford Cancer Center and the Stanford Health Library. “Our strongest advocates are the people who have been touched by the disease who can help us engage others and build a community dedicated to the elimination of colorectal cancer.”

Colorectal cancer can develop from an atypical growth called a polyp. There are two types of polyps: hyperplastic, which have a very small chance of developing into cancer, and adenomatous, the source of nine out of 10 cases of CRC.

At least half the cases could be prevented with regular screening since early detection is crucial to successful treatment. Colorectal cancer’s mortality rate has declined steadily in recent years, aided by a public awareness of the importance of screening for prevention and early detection, as well as significant improvements in treatment.

“Advances are being made, but until we can create screening systems for all people at risk, we will continue to deal with advanced disease. We are improving our therapies and looking for a cure so that colorectal cancer is gone forever. The challenge can be met if we are able to put all the pieces together,” said Dr. Fisher. “That’s the advantage of an academic medical center like Stanford, where we can combine the multidisciplinary expertise of scientists in different specialties together with clinicians working directly patients.”

Patients benefit from teams made up of surgeons, radiologists, gastroenterologists, and radiation oncologists, he said, as well as experts in peripheral specialties like interventional radiology and genetics, who discuss treatment plans for each individual. “This approach is of enormous value because it allows us to provide care that is both seamless and cutting-edge,” he said. Research is integrated into patient care and includes investigations into cancer stem cells, vaccines, and cancer genomics.

Dr. Fisher also advocated for community involvement to support research in pivotal areas, including investigations to:

  • identify biomarkers to aid in early diagnosis and therapy follow-up
  • study the genes involved in colon cancer
  • refine prevention and therapeutic trials
  • educate individuals and families
  • encourage lifestyle changes to eliminate avoidable risk factors like smoking and obesity
  • promote early screening and develop strategies for early diagnosis
  • improve treatments through targeted therapies and genomics

Genetics and Screening
While we do not know the cause of colorectal cancer, it’s most likely related to genetic changes from external influences in our cellular DNA. Risk factors include age (most cases appear in people over age 50), a diet high in red or processed meat, lack of physical activity, obesity, smoking and alcohol use, and health conditions like diabetes.

“Why screen? To find and remove polyps before they can develop into cancer and to identify cancer at an early stage when treatments are most effective,” said Uri Ladabaum, MD, MS, a professor of gastroenterology, who spoke on Screening and the Role of Genetic Evaluation.

The lifetime risk for developing colorectal cancer is one in 18 for men, and one in 20 for women. In most cases, physicians cannot identify a specific risk. In fact, in about 75-85 percent of cases, there is no genetic cause for the disease. Only between 10 and 30 percent of cases are clustered within a family, pointing to a genetic, or hereditary, root.

“When there is a family history of colorectal cancer, the risk is higher based on the number the relatives and the age they had it,” he said. “The younger the age, the greater the risk. But even when older, a first-degree relative (a parent or sibling) can elevate the risk.”

For example, a person with no family history of CRC has a 5 percent chance of developing the disease. The chance is 10 percent for a person with one family member with CRC and three times higher with two family members. Risk is also elevated when a person has an inflammatory bowel disease such as Crohn’s or ulcerative colitis. Irritable bowel is not a risk factor, he said.

Lynch syndrome, or hereditary nonpolyposis colorectal cancer (HNPCC), is a rare inherited condition that increases the risk and early onset of colon cancer. If a parent has the gene mutation for Lynch, each child has a 50 percent greater chance of inheriting the defective gene and an 80 percent chance of developing cancer over their lifetime, said Dr. Ladabaum. However if the gene mutation is identified, colonoscopies can remove polyps before cancer develops and significantly decrease the risk.

Genetic testing for inherited conditions like Lynch syndrome can help identify who is at an elevated risk so screenings can be scheduled more frequently and at a younger age.

“The point of screening is to reduce risk—to find the precursors of cancer and remove them. It’s not just early detection, it’s also prevention,” he said. “We remove the adenomas before symptoms develop, when the condition is most treatable.”

Adults with average risk should start screening at age 50 and repeat the test every 10 years. A person with a relative who developed symptoms after age 60 should start screening at age 40 and return every 10 years; a person with a relative who developed symptoms under age 60 should be screened at age 40, or 10 years before the relative’s onset, and return every five years.

“We’ve progressed from one-size-fits-all screening protocols to the ability to tailor tests for individual risk,” said Dr. Ladabaum. “Intensive screening can dramatically reduce the incidence of CRC and its mortality rate.”

Analyzing Cancer Genomes
Deoxyribonucleic acid (DNA) is the chemical compound that encodes your genetic blueprint—the instructions your cells need to develop and function. A complete set of DNA is called the genome.

Throughout your life, DNA can make mistakes during cell replication. Most of these genetic glitches are harmless, but once in a while a mutation causes damage that pushes a cell to becoming cancerous. Through a process called sequencing, scientists have created vast databases of the genomic mutations found in several cancers, including CRC.

“Through a combination of technology, computational analysis, and DNA  sequencing, we know more about the genetic factors of colorectal cancer than any other cancer,” said Hanlee Ji, MD, an assistant professor of medicine (oncology), who discussed Personalized Colon Cancer Medicine through Analyzing Cancer Genomics.  “There’s a new era in personalized cancer treatment, based on the analysis of the genes in tumor cells.”

DNA sequencing allows scientists to identify mutations, cellular variations, and other genomic anomalies that contribute to cancer development. They can then home in on likely suspects, and these mutations can then be used to identify targets for therapy and to anticipate how a patient will respond.

Dr. Ji predicts that as technology continues to improve, genomic applications will be more fully integrated into a diagnostic setting. Assessing the genome will allow physicians to determine the risk of developing CRC, track the possibility of metastasis, and predict patient response. This process is accelerated at Stanford by the close proximity of scientists to clinicians who are working together in a back-and-forth dynamic called translational medicine.

“It used to take months to deal with the amount of data contained in a cell genome, and now it’s possible to isolate a tumor and potentially sequence an entire cancer genome in weeks,” he said. “There is no comparison as to what we could do and what we can do now. Next-generation gene sequencing will cause a major change in how we look at genomics. Diagnostic solutions will allow personalized medicine to become a reality.”

Vaccine Strategies
“The purpose of cancer vaccines is to elicit a more powerful immunity in the patient,” said Samuel Strober, MD, a professor of immunology and rheumatology. “However, tumor-specific antigens have been hard to find, and many immune agents now in use target healthy cells as well as the cancerous cells.”

Dr. Strober spoke about the challenge of developing ways to attack a tumor without affecting normal cells. One promising option may be the development of a cancer vaccine. Last year the U.S. Food and Drug Administration approved the first anti-cancer vaccine: a patient-specific dendritic-cell vaccine for use against advanced prostate cancer.

There are two fundamental concepts behind vaccines. One is prophylactic—to prevent the disease from occurring. The Human Papillomavirus vaccine (HPV) works by causing the body to make antibodies that recognize and fight the virus cells before they develop. HPV is a cause of cervical cancer and genital warts.

The other type of vaccine is therapeutic— stimulating the immune system response to home in on existing cancer cells.

Current cancer treatments—radiation and chemotherapy—are non-specific: They destroy healthy as well as malignant cells and can cause severe side-effects. Dr. Strober has been looking at ways to harness the immune system to develop precisely targeted therapies that home in on just the tumor cells.

His research involves using T-cells, a type of white blood cell that protects the body from infection by responding to antigens presented to T-cells by dendritic cells. Antigens stimulate the T-cells to produce proteins that can kill or slow the growth of a foreign invader or a tumor.

Dr. Strober’s laboratory has been developing ways to stimulate immunity to tumors in animal models of primary and metastatic tumors that involve three steps:

  • The primary tumor is treated with focused, high doses of radiation to kill the cancer cells. The few cells remaining are made more apparent to the immune system as foreign. The scientists take dendritic cells and insert them into the tumor to activate a T-cell response. The T-cells, which have now been trained to recognize tumor antigens, are collected and stored.
  • Animals are treated with additional irradiation and/or chemotherapy to kill metastatic tumor cells and to promote expansion of T-cells that will be injected.
  • The T-cells are injected into the blood. Because they have been conditioned to recognize the cancer antigen, they go straight to the tumor and destroy remaining tumor cells.

All three steps are required for the system to work, said Dr. Strober. Using all three steps resulted in a cure in eight of 11 animals, and when a second tumor was introduced, the immune system prevented its growth. “The animal was immunized,” he said, “and 80 percent survived more than six months.”

The process showed that advanced tumors can be treated with the three-step strategy, and Dr. Strober and his team are working with clinicians to develop protocols for human clinical trials. “We hope to have trials in place by the end of 2011,” he said.

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Chronic Pancreatitis: Diagnosis and Management

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Presented by: Walter G. Park, MD, MS
Instructor, Gastroenterology and Hepatology
Stanford University Medical Center
October 13, 2011

Unlike acute pancreatitis—a sudden inflammation of the pancreas—chronic pancreatitis is a long-term condition that alters the organ’s normal structure and function, and can cause persistent, debilitating pain.

The pancreas is a gland located directly behind the stomach, and close to the spine, that serves two primary functions: to produce insulin, a hormone needed to regulate glucose metabolism, and to make digestive enzymes that help absorb nutrients in the food you eat.

It is estimated that in Western Europe and North America, chronic pancreatitis is diagnosed in three to nine people in 100,000. While not common, chronic pancreatitis has a significant effect on quality of life and economic productivity, says Walter G. Park, MD, MS, an instructor of gastroenterology and hepatology, at a presentation sponsored by the Stanford Health Library.

One large-scale study showed that only 40 percent of patients with the condition could work, and 16 percent were disabled. The disease also affects social life, personal relationships, and daily activities. It is most prevalent in middle-aged men (70-90 percent are male).

Causes and Symptoms
The most common cause is long-term heavy alcohol abuse, which is believed to account for approximately 70 percent of all cases. But since only about 10 percent of alcoholics develop chronic pancreatitis, Dr. Park said drinking is probably only a trigger for people with an underlying vulnerability rather than a direct cause.

Other possible causes include nicotine; cancer or cysts that may create anatomical obstructions; high triglyceride levels; and certain medications, but about 20 percent of all cases are from unknown (idiopathic) origins. (New studies point to changes in these statistics: 44 percent from alcohol, 29 percent idiopathic, and 27 percent from other causes.)

Symptoms range from severe abdominal pain to nausea, weight loss, and eventual diarrhea and malnutrition. Many develop diabetes because the pancreas is no longer able to produce insulin properly. A doctor may suspect the disease because of the patient’s symptoms, history of repeated acute pancreatitis flare-ups, or alcohol abuse.

Under a microscope, a tissue sample will show cell atrophy, chronic inflammation, scar tissue, and/or ductal changes, but there currently is no safe and reliable way to get the tissue, said Dr. Park. “We do not have a way to acquire a tissue sample without the risk of surgery.” he said. “That means we need to rely on other means to make a diagnosis.”

Diagnosis and Management
Structural tests, such as a CT or MRI scan, can show physical damage to the pancreas, but not until the disease is relatively advanced. An endoscopic ultrasound or a magnetic resonance cholangiopancreatography (MRCP) test are now used as a noninvasive approach to looking for common features of the disease. Functional tests are used to stimulate hormones and measure the organ’s ability to respond. Blood tests may also be used to check the blood glucose levels, which may be elevated.

“In terms of managing the disease, the key problem is debilitating pain,” said Dr. Park. “But we also need to address malnutrition, diabetes, and other complications.”

The pain associated with chronic pancreatitis may be a result of a plumbing problem, an obstruction of pancreatic secreted fluid causing a buildup of pressure and reduced blood flow. Surgery can be used to open the duct, but 25 to 50 percent of patients still have pain after surgery, he said. The pain could also be a wiring problem, caused by the inflammation of nerves that alters the biology of the pancreas and eventually changes the perception of pain.

While pain is a key symptom of chronic pancreatitis, the use of opiate-type pain medications should be minimized because the condition is long term and there are many side effects with long-time usage of these drugs, he said. Instead, medications may include antioxidants, like selenium, vitamin E, vitamin C, or beta carotene; selective serotonin re-uptake inhibitors (SSRIs); anticonvulsants; or neuropathic medications that help to alter the perception of pain.

Other tools include enzyme replacement therapy and endoscopic treatment to drain fluid or remove stones. “For some select patients, surgery may be an option,” said Dr. Park, such as a procedure to remove a ductal obstruction or to remove the most damaged part of the gland.

Multidisciplinary Care
Dr. Park works closely with a variety of other specialists to help treat pain, minimize other complications, and maintain quality of life. He collaborates with experts from the Stanford Pain Center, as well as surgeons, radiologists, and advanced endoscopists.

He also works with nutritionists to help patients manage their diet and to track them for signs of nutrient deficiencies. “Malnutrition can show up 10 to 15 years into the disease,” he said. “Patients need to be reminded to stop drinking, smoking and to modify their diet.”

People with chronic pancreatitis should keep a diet log to track their food intake. They need to eat more calories using a low-fat diet and maintain their metabolism by eating four to six small meals a day. Supplements like Ensure and medium-chain triglycerides like coconut oil and palm kernel oil are also recommended.

About the Speaker
Walter Park, MD, MS, is an instructor of medicine (gastroenterology and hepatology), with a particular interest in the diagnosis and management of acute and chronic pancreatitis. He received his medical degree at Johns Hopkins School of Medicine and completed his residency in internal medicine and a fellowship at Stanford, where he also received an MS in health services research. He is Board Certified in internal medicine and in gastroenterology by the American Board of Internal Medicine.

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Celiac Disease and Gluten Associated Disorders

Posted By SHL Librarian

Presented by: Nielsen Fernandez-Becker, MD, PhD
Clinical Assistant Professor, Gastroenterology and Hepatology
May 5, 2016

Celiac disease is a chronic inflammatory disease of the gastrointestinal tract that is triggered by eating gluten, the protein found in wheat, rye, and barley. When people with celiac disease eat gluten, their body mounts an an immune response that results in destruction of the villi, small finger-like projections that line the small intestine. The damaged villi are not able to absorb nutrients properly, which over time can cause vitamin deficiencies that lead to systemic complications such as bone disease, fatigue, anemia, arthritis, and other problems.

Celiac disease was first noted by Areatus of Cappadocia in the second century, who described the symptoms as koiliakos, meaning abdominal. In the late 1880s Samuel Gee first linked the condition with diet, and 70 years later Dutch pediatrician Willem Dicke made the diet connection directly to wheat protein. More recent research identified specific antibodies that cause the immune reaction and identified genes that put people at higher risk for developing the disease.

“We are only seeing the tip of the iceberg in terms of diagnosing celiac disease,” said Nielsen Fernandez-Becker, MD, PhD, a clinical assistant professor of gastroenterology and hepatology, who spoke at a presentation sponsored by the Stanford Health Library. “Like other complex diseases, it is due to a combination of various factors, including genetics, a malfunction of the innate and adaptive immune systems, and the environment.”

Common Condition
Celiac disease affects about 3 million people in the United States—about 1 percent of the population. Two genes—DQ2 and DQ8—have been associated in 99.9 percent of people with the condition: While carrying one of these genes puts an individual at risk of developing celiac disease, it does not mean the individual will definitively develop the disease. In fact, about 30 percent of the population have one or the other of these genes, but only 4 percent of that group goes on to develop celiac.

The 20 or more feet of the small intestine are lined with tiny, finger-like projections called villi that absorb vitamins, minerals, and other nutrients. Gliadin, the toxic component of gluten in celiac disease patients, binds special immune cells called antigen-presenting cells (APC) via HLA molecules. This causes the activation of the body’s T cells and the inflammatory response that damages the intestinal mucosa.

“In a sense, the immune cells think the gliadin is a pathogen,” said Dr. Fernandez-Becker. “It’s like friendly fire. Every time the immune response is activated, it causes damage to the small intestine. In time, the villi are destroyed.”

Normally the intestinal lining, or mucosa, looks velvety, like a plush carpet inside the small intestine. Celiac disease corrodes the lining so it becomes smooth, with scalloping, nodules and fissures. With continued inflammation, additional problems can arise, including osteoporosis, anemia, malnutrition, liver abnormalities, and cancer.

Signs and symptoms of celiac disease may range from mild abdominal discomfort to severe diarrhea and bloating. It is possible to have celiac disease without any symptoms or to have a refractory condition that prevails despite no exposure to gluten. Some doctors may monitor these people carefully or introduce a no-gluten diet as a preventive measure, Dr. Fernandez-Becker said. The disease is often misdiagnosed since its symptoms can be non-specific and similar to other disorders, such as irritable bowel syndrome.

Diagnosis and Treatment
Other conditions that mimic celiac include gluten sensitivity, which causes similar symptoms but does not cause damage to the small intestine, and wheat allergy, caused by a specific immune response to a particular antibody (IgE) in food. Neither of these conditions is considered an autoimmune disorder nor do they involve an identified genetic marker. Adopting a gluten free diet will not provide an accurate diagnosis since all three conditions will improve with gluten exclusion.

There are two steps to confirm whether you have celiac disease. Screening involves a blood test to measure certain immune system antibodies. The most common is called a tTG-IgA test, which accurately identifies the disease in more than 90 percent of cases. If test results suggest celiac disease, an endoscopic exam can check for changes in the small intestine to confirm the diagnosis.

“You must be on a diet containing gluten when undergoing these tests,” Dr. Fernandez-Becker said. “If you have stopped eating gluten it may make the diagnosis very difficult, and gluten may need to be reintroduced to clarify the diagnosis. You need to have an accurate diagnosis because of the long-term complications of the disease, even if you feel better without gluten.”

Diet Changes
There is no cure for celiac disease: The only effective treatment is to remove gluten from the diet. Once gluten is eliminated, inflammation in the small intestine typically begins to subside fairly quickly, but it may take many months for mucosa to heal completely.

A gluten-free diet means no wheat-containing beer, pasta, bread, or crackers are allowed. There are also “hidden sources” of gluten, such as soy sauce, vinegar, processed foods, and even toothpaste and medication. Even a small amount of gluten is enough to cause symptoms and complications, so read labels carefully. Quinoa, corn, millet, wild rice, soy, grits and tapioca are still okay to eat.

Patients benefit from seeing an experienced dietician for guidance on following a gluten-free diet long-term, which involves a lifelong lifestyle change. Studies found that patients who do not respond to diet changes either were still exposed to gluten (35 percent), had an overlapping condition of irritable bowel syndrome (25 percent), or had another condition (10 percent), including bacterial overgrowth, colitis, lactose deficiency, or refractory celiac disease.

Researchers are studying the basic biology of the triggers to celiac, clarifying the role of T cells and the small intestine’s epithelial cells, and tracing what factors causes only some people with the DQ2 or DQ8 gene to develop celiac. Once promising trial involves using a peptide that breaks down gluten into components so small they do not induce an immune response; another is looking at a molecule that tightens connections between intestinal cells to prevent gluten from coming into contact with immune cells. There also are efforts under way to develop a vaccine to suppress immune response to gluten.

In the meantime, Dr. Fernandez-Becker suggested patients follow CELIAC guidelines: Consultations; Education; Lifelong adherence; Identify and treat deficiencies; Advocacy access; and Continuous long-term following.

About the Speaker
Nielsen Q. Fernandez-Becker is a clinical assistant professor of gastroenterology who specializes in celiac disease. She received her medical education at Albert Einstein College of Medicine in New York, did her residency and internship at Massachusetts General Hospital, and completed her fellowship at Beth Israel Deaconess Medical Center. She joined Stanford in 2009.

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