Introduction to Genetic-Metabolic Disease

We are a set of chemical reactions. The physical basis for life is a series of closely controlled chemical reactions. These reactions govern what we look like, what we are able to eat, and what we are capable of doing. When one of these reactions fails to function, serious consequences to the individual may occur, including failure to develop properly as a fetus, failure to adequately to grow or develop full mental capacity, and failure to live a normal life span.

Each of the chemical reactions in the body is governed by an enzyme that controls the rate of the reaction. The energy of life is provided by controlled oxidation, which is analogous to fire. Obviously, our bodies cannot tolerate open flame. But, through mediation by enzyme-controlled reactions, we are able to "burn" food, and this burning supplies energy and thus allows life to continue.

Each enzyme is itself under the control of a gene that specifies it. Genes are coded within DNA as long strings of the four letters, A T G and C, which represent the chemicals that makeup the DNA molecule. Three of these letters taken together specify one of the twenty amino acids that make up all proteins. The proteins are the molecules that can possess enzymatic activity, as well as provide the structure for the body. Current thinking suggests that humans possess about 25,000 genes. There are more than 25,000 proteins known, so alterations in proteins after they are made from gene information must occur.

Enzymes are encoded by DNA. Within the nucleus of each cell, stretches of DNA called coding regions are transcribed into messenger RNA and then translated into the appropriate protein. An alteration in the sequence of DNA can lead to abnormal construction of a protein, a shortened protein, or an absent protein. Depending on the severity of the error, this process may lead to a defective protein, a protein that is recognized as abnormal by the body and therefore removed, or no protein production at all. Depending on the particular protein involved, the consequences for a person can range from unnoticeable to catastrophic, even leading to spontaneous miscarriage.

Inborn errors of metabolism is the field of genetics devoted to the study of biochemical errors, which involve the many enzyme reactions that control how we metabolize. Basically, all foods are composed of proteins, carbohydrates, or fats. Various inborn errors of metabolism in each of the three groups have been described with potentially severe consequences.

How we inherit errors of metabolism. It is important to remember that one of the basic rules of genetics is that we receive half of our genes from our mother and half of our genes from our father. If we receive a gene that has an abnormality in it from one parent, but the gene from the other parent is intact, then usually this does not lead to an illness. This mode of inheritance is called autosomal recessive, meaning (1) that the defect does not depend upon the sex of the person inheriting it and (2) that persons having only one copy of that defective gene are clinically normal. When both parents are carriers of the same condition, meaning that each parent has one broken copy of a gene and one intact copy, then the chance in each pregnancy for a child to that couple to have the disorder is 25 percent. There is a 50 percent chance that the child will be a carrier like the parents and a 25 percent chance that the child will be normal, with no defective gene for that condition.

Another mode of inheritance is autosomal dominant, which is also sex-independent, but in this case inheriting one copy of the defective gene does result in noticeable illness or deformity. One half of the children of either sex born to a person with this type of disorder will have the gene for that condition.

X-linked disorders are caused by defective genes that normally reside on the X-chromosome. Women have two X chromosomes, whereas men have an X chromosome and a Y chromosome. Carrier females who have a defective gene on one X chromosome but a normal copy on the other X chromosome pass on either one or the other to each child they produce. Since girls receive an X from mother and an X from father, if the father is not a carrier for the condition, then 50% of the female offspring to a carrier mother will be carriers of the condition and 50% of her daughters will be normal. However, when the father donates the Y chromosome, resulting in a male child, 50% of that mother's sons will be affected, because male receives only one X chromosome. Therefore, if she donates her X-chromosome that has the defective gene in it, then the son, having no other X chromosome because he is a male, will display that condition. Half of her sons will be affected and half of her sons will be normal.

It is extremely important to note that when we use words like "normal" and "defective" we remember that all of us are carriers for approximately six genes that, if we have both copies of that gene broken in us, would result in a serious disease. The only difference between normal persons and persons with genetic disorders (or persons who are parents of children with a genetic disorder) is that affected persons know the name of one of the six genes that is broken in their genome. The quality of all our DNA is exactly the same. It is strictly random chance that determines whether we happen to have offspring with a person who is also a carrier for one of the same genes for which we are a carrier.

Inborn errors are rare. Most genetic diseases are quite rare. The inborn errors of metabolism occur with a frequency of about 1/10,000 to 1/300,000 live births. Some of the biochemical disorders with which we deal include conditions known as PKU, galactosemia, or biotinidase deficiency. Most people have never heard of these disorders, and this is understandable because they are so rare. However, all states in the United States screen newborns for certain of these disorders for two reasons: (1) because of the serious consequences if they are not diagnosed early in infancy and (2) because of the potential for near complete correction if appropriate treatment is started in a timely fashion.

Screening for and treatment of inborn errors. Louisiana screens for all three of these inborn errors, and plans are being developed to begin screening all newborns for up to 22 inborn errors of metabolism (using new technology called tandem mass-spectroscopy). Screening begins with a drop of blood collected from the newborn's heel onto filter paper in the nursery, and this blood sample is sent to the State Public Health Laboratory for analysis. Untreated, most of these diseases result in mental retardation or death in the newborn period. With early diagnosis and treatment, good outcomes are possible.

The treatment of inborn errors of metabolism is usually dietary. As noted above, these conditions result from a defect in a gene that affects a chemical reaction. When some chemical reactions in metabolism are inadequate, accumulation of toxic metabolites occurs, causing brain damage or leading to inadequate production of material critical for brain development. For instance, in PKU, the normal amino acid phenylalanine is not converted to tyrosine; this leads to an accumulation of phenylalanine in the blood, producing severe mental retardation. In mothers with PKU, there can be physical defects in her offspring.

PKU was the first disorder of metabolism for which newborn screening was widely applied. When the children are diagnosed in infancy and a low phenylalanine diet is adopted early in the infant's life (ideally in the first two weeks), the child's IQ is normal. Untreated, the children rarely have an IQ greater than 20. Thus it is imperative to detect all such children and to treat them early. The Tulane Hayward Genetics Center is the designated center in Louisiana for treatment of these children. Families of those children confirmed as positive are immediately contacted by a team of specialists, including a geneticist, genetic counselor, and nutritionist, who immediately prescribe a low phenylalanine diet and monitor the infant's progress.

PKU is important to us because it is prevalent in Acadiana. Children from the region are treated with a low phenylalanine diet, and the outcome is uniformly good when the diet is closely followed. Other examples of different diseases with good outcomes may include galactosemia, a disorder of sugar metabolism, and biotinidase deficiency, a disorder of protein metabolism. It is extremely important that every infant born in Louisiana have the simple heel-stick blood test performed. It literally can mean the difference between life and death.

ABOUT THE AUTHOR
Jess G. Thoene, M.D., is Director of the Hayward Genetics Center and Karen Gore Professor of Pediatrics at the Tulane University Health Sciences Center. His major research interest is clinical and biochemical investigation of cystinosis, a lethal disease of lysosomal cystine storage. He has been active in the orphan disease movement, serving as Chairman of the Board of the National Organization for Rare Disorders and Chair of the National Commission on Orphan Diseases.

HOW TO LEARN MORE
Thoene, J. (Ed.) Physician's Guide to Rare Disease (2nd ed.) Montvale, New Jersey: Dowden Press, 1995.

Measuring Health: an Introduction

An Emerging New Era in Measurement StandardsBefore the French Revolution, every town in France had its own system of weights and measures. The French were dissatisfied with the many different ways of measuring grain, liquid volume, distance, and land area, and their grievances set the stage for the development of the metric system.
Today, every health care provider has its own system for measuring health, functioning, customer satisfaction, and employee skill levels, just as every school and test publisher has its own system of measures for assessing learning. Much of the general dissatisfaction with the quality of health care and education and with our inability to improve that quality, can be traced to the lack of general measurement standards. Fortunately, measurement quality is improving rapidly in a number of areas of health care.
Quanitites and AmountsContrary to what is usually assumed, 75 years of research show that it is possible to measure health, and the capacity to function at work, in school, and at home, just as rigorously and scientifically as height, weight, time, or temperature are measured. Anyone who has ever bought fruits and vegetables in a grocery store can understand how measurement should always work. The basic point follows from the fact that we do not buy apples, for instance, according to the number of apples a shopper puts in a bag. Instead, the purchase price of a bag of a particular kind of apple is set by how much the apples weigh. The individual apples vary in size. A person with seven small apples in a bag would not expect to pay as much as they would for seven large apples, given that the apples are of the same kind and quality.
So we recognize that amounts of apples are not strictly related to numbers of apples. Fair trade depends on finding a way of measuring amounts of apple that stays constant across different groups of apples that naturally vary in size. International standards organizations work with weight scale manufacturers to make sure that the same amount of weight gives the same numeric reading, within an acceptable range of error, no matter which brand scale is used, no matter what is being weighed, and no matter who is using the scale.
Unfortunately, there are no international standards organizations yet working with test and survey publishers to see whether health and learning can be measured so that the same
Unless demand for more convenient and scientific measurement in health care and education grows, the supply of it is not likely to increase. The basic messages we want to convey are that
(1) health and learning outcomes can be quantified in units of measurement as rigorous as units of height, weight, time, and temperature;
(2) health and learning outcome measures can be made as familiar and widely available as measures of height, weight, time, and temperature; and
(3) the LSU Health Sciences Center and its Health Care Services Division are international leaders in the development and use of these measures.
The remainder of this article will address each of these three points in turn.
Measuring QuantitiesTo measure scientifically, researchers have to show, via experiments, that the variable of interest, such as health, learning, or satisfaction with services, adds up in the same way numbers do. The measurement of length, for instance, can be accomplished by placing a block of wood end-to-end with itself as many times as is needed to span a distance. Because we are counting the repetitions of a single block of wood, we know that every repetition is in fact one more of the same thing. The difference between 1 and 2 repetitions is the same amount of difference as that obtained between 3 and 4, between 112 and 113, or between any other pair of adjacent whole numbers. In order to measure, it is vitally important that researchers establish via experimental tests that the thing to be measured add up the same way the numbers used to represent it do.
Unfortunately, these experimental tests are rarely done. Because experimental evidence is not gathered, we do not really know whether many of the things we want to measure are actually quantitative. We therefore also do not know exactly what many of our tests and surveys actually measure. Finally, the lack of experimentally-calibrated instruments forces us to have different numerical scoring schemes for each different instrument, when what we need are different brand instruments for each different thing we want to measure, and which all measure in a uniform reference standard metric.
Different brand instruments should provide measures that indicate constant amounts of what is measured. It would be okay for the instruments to express those amounts in different numeric units, in the same way that inches and centimeters both indicate the same amount of length. A better system would be to have all instruments measuring one particular variable (physical functioning, for instance) do so in the same numeric unit. Research shows that different existing physical functioning instruments can in fact measure in the same unit even though they each phrase the questions on their instruments in slightly different ways.
Health and learning are not, of course, as easily measured as length, weight, time, or temperature. However, when data are evaluated, on the basis of which responses are most likely to occur (and measurement error is accounted for) health and learning data patterns are often found to meet the mathematical requirements for quite precise measurement. To obtain these kind of data, however, we must pay considerably more attention to both the design of tests, performance assessments, and surveys, as well as to the ways in which they are used.
As mentioned above, we have deeply ingrained cultural assumptions about the appropriate use of instruments, and these assumptions guide us toward producing high quality data in the measurement of height, for instance. Our lack of similar cultural expectations for the appropriate use of tests and surveys prevents us from gathering high quality data on health and learning, and it also prevents us from achieving the same kind of mathematical rigor and practical convenience that we enjoy with other kinds of instruments.
Access to Measures
Over the last 70 years, a wide variety of instruments for measuring health and learning have been shown to meet mathematically rigorous scaling requirements. And when these requirements are met, we see (1) that different brands of instruments intended to measure the same thing often actually do and (2) that the different brands of instruments could measure the same things in the same numeric units.
Now, instead of asking whether the blocks are longer than the distance from the origin to the mark on the ruler, we are asking people to answer questions that will tell us something about the amount of health, daily functionality, or learning they possess. When different brands of instruments are properly calibrated, they will measure constant, invariant amounts of the variable, even if they express those amounts with different numbers.
So why don't we have well known and widely available units of measurement expressing constant amounts of each of the key variables important to better understanding and managing health and learning? The answer to that question lies in another set of deeply ingrained cultural assumptions that we bring to bear when we think about and try to do measurement.
This set of assumptions has to do with the very ancient idea that the world is already quantitative in and of itself before we do anything to measure it. Even though instrument calibration is a very exacting process, and even though billions of dollars are spent on instrument development and maintenance every year, we seem to think that measuring units happen by themselves somehow, that they are so firmly a part of the world around us that we don't have to do anything to make them a part of our lives.
In the last 50 years, these assumptions have been challenged by work in the history, philosophy, and social studies of science, though the challenges have had little impact on measurement practice. The facts remain, however, that measurement, as the science of metrology, begins by calibrating individual instruments and that it progresses toward the quantitative coordination of different brands of instruments, so that users anywhere can tell when they are obtaining reasonable results and when they are not.
It is often said that a field of study is scientific to the extent that it is mathematical, but it is a mistake to think that the use of numbers automatically makes a field mathematical. A better way to think of the matter stems from the realization that a field is mathematical only to the extent that researchers working within it all share a common quantitative language in which they think about and act on the variables of interest. Without rigorously calibrated instruments and widely disseminated units of measurement, the common quantitative language does not exist.
Measurement at LSU Health Sciences Center and its HCSDThe LSU Health Sciences Center and its Health Care Services Division (HCSD) are taking steps toward both rigorously calibrating health surveys and educational tests, and toward coordinating instruments' units of measurement, by bringing together researchers and practitioners in various fields to educate them about the new possibilities and to help them take the first steps toward more rigorous and more convenient measurement.
A variety of tests and surveys intended for use in graduate medical education, hospital management, and health care research have been successfully calibrated over the last seven years. The disciplinary areas involved have included public health, preventive medicine, internal medicine, graduate medical education, pathology, genetics, and nursing. Measures have focused on matters such as chronic disease management (primarily diabetes and asthma), patient satisfaction, general health status, pain, obesity, and calibrating the human genome. The long term goals are to be able to demonstrate that rigorously quantitative units of measurement for each of these variables can be constructed, and to implement these units on a wide scale, putting instruments that provide the needed information into the hands of patients and providers at the point of care.
Diabetes management is one area in which improved measurement is being addressed. In 1994 in Louisiana, there were 115,508 diagnosed diabetes cases. Based on current LSUHSC-HCSD statistics, the HCSD hospitals are caring for about 17% of these cases (or about 20,000 persons). The incidence of diabetes in Louisiana far exceeds that of the rest of the nation. Recent statistics show that there are 33.4 diabetes cases per 100,000 persons in Louisiana, whereas there are about 21.8 cases per 100,000 persons in the U. S. as a whole.
The cost of diabetes accounts for 15% of all US health care expenditures. Based on American Diabetes Association (ADA) data, in 1992, the direct (medical care) and indirect (lost productivity) cost of diabetes in Louisiana was about $1,616,000,000 (1.6 billion dollars). In 1997, approximately 20,000 patients with diabetes were seen in the LSU hospitals and outpatient clinics with about 2,300 admissions for associated conditions. The average length of hospital stay for these 2,300 admissions was 8.8 days with a cost of about $900 per inpatient day.
Our Diabetes Disease Management Program is intended to address several needs. First, we need to help people with diabetes normalize their blood sugars. To do that, we need to implement systematic methods of education and provide the needed tools for glucose monitoring. We also need to continuously improve our diabetes care processes, patient-care giver relationships, use of resources, and clinical outcomes through research and education. Systems for doing so have either been put in place or are being designed.
The diabetes program is a disease management treatment program in which uninsured persons with diabetes are seen by physicians in the LSUHSC hospitals' outpatient clinics, tested and confirmed to have diabetes, placed on standard of care treatment drug therapy in accordance with ADA guidelines, and monitored for short and long term glycemic control and long term end organ complications.
Research suggests that a comprehensive outpatient care program for diabetes, with the institution of clearly defined ADA guidelines, can reduce hospitalization by 47%, reduce length of stay by 71%, reduce amputations by 50%, reduce the incidence of heart disease by 43%, and reduce kidney disease requiring dialysis by 43%.
The ADA has devised a set of recommended diabetes treatment processes and outcomes, with suggestions as to the minimum acceptable percentages of patients receiving the treatments and achieving the outcomes. Hospitals with percentages above the ADA minimums are eligible for certification in a Provider Recognition Program (PRP).
In the year 2000, the HCSD as a whole achieved PRP levels on three out of seven indicators. In a comparison with the performance of hospitals participating in nine different national health plans, the HCSD hospitals and patients achieved the same or better percentages on seven of eight indicators. The quality of diabetes care being provided to Louisiana's uninsured thus can stand comparison with diabetes care being provided anywhere in the nation. As the goals of improved measurement and disease management become better integrated, the quality of life for persons with diabetes will continue to improve.
Anyone interested in learning more about improved measurement or disease management are invited to contact the authors at the addresses below.
Contact InformationWilliam P. Fisher, Jr., Ph.D.Professor of ResearchPublic Health & Preventive MedicineLSU Health Sciences Center1600 Canal Street, Suite 1123New Orleans, LA 70112504-568-8083 (Office)504-568-6905 (Fax)http://www.medschool.lsuhsc.edu/genetics/Faculty/William_Fisher.html wfishe@lsuhsc.edu
Lauren Haygood, R.N., M.S.N., C.N.A.RN Health Care Program ConsultantLSUHSC - HCSD8550 United Plaza, suite 400Baton Rouge, LA 70809(225) 922-0747 (Office 1)(337) 262-1849 (Office 2)
How to Learn MoreIntroductory and advanced courses on measurement theory and practice are taught at LSUHSC regularly. In April 2000, the Tenth International Objective Measurement Workshops (IOMW) were held at the LSU Health Science Center's Medical Education Building, and the Eleventh IOMW was held in New Orleans in April 2002.
Anyone interested in learning more about measurement or disease management is invited to consult the following resources.
A highly readable introduction to the basic measurement issues is provided by the book, Applying the Rasch model: fundamental measurement in the human sciences, by T. Bond and C. Fox (Mahwah, NJ: Lawrence Erlbaum Associates, 2001).
Information on measurement-related books, technical papers, professional associations, scientific journals, videos, software, conferences, seminars, consultants, a discussion list, and the full text of Rasch Measurement Transactions is available at http://www.winsteps.com.
A comprehensive, general clearinghouse on disease management information is available at http://www2.umdnj.edu/omcweb/1998/diseasemanagement.htm.

Testing DNA

Introduction

DNA testing involves a set of procedures in which DNA (the genetic material) extracted from a patient's cells (usually from a blood sample) is tested in the laboratory for changes. Although these DNA changes are usually suspects for causing a disease, DNA testing can also be used to gather other information important for proper healthcare.
DNA is a very large molecule composed of two closely entwined strings of small molecules. Diseases arise from mutations (Greek for changes) in the DNA. A mutation causes one or more of the small molecules to be missing or altered in one or both strings. When the mutation involves only one of the small molecules, techniques for finding the alteration are very laborious, because there are three billion of the small molecules in each person's DNA. At the other extreme, some mutations involve such large segments of DNA that they are visible under the microscope. There are numerous laboratory tricks and techniques used to detect the smaller mutations.
Most DNA tests are tests for constitutional mutations. That type of mutation is inherited, so it is present at the moment of conception and therefore occurs in all cells in the body. Any readily available source of living cells can be tested. Most commonly, blood cells are used. The blood is drawn from a vein into a glass Vacutainer tube containing a preservative, such as liquid EDTA or acid-citrate solution. The blood specimen is usually drawn at a local laboratory and mailed to a reference laboratory. The reference laboratory usually waits until it receives many specimens and then processes them all at once in order to conserve labor and chemicals. After the test is completed, the report is returned to the local laboratory.
In some diseases, the mutation is focal, which means that it is present only in certain body cells (tissues). An example of a focal mutation is a mutation that causes a tumor. The DNA change that causes a tumor only occurs in cells that make up the tumor and not in other cells of the body. In this case, additional steps are required in the testing process. A biopsy (piece) of the tissue must be obtained surgically. Simple liquid solutions may not suffice for preservation of this tissue, so more exotic mechanisms can be required such as freezing in liquid nitrogen. This makes mailing difficult. The added steps make the process expensive.
When is DNA testing needed? There are several reasons, or indications, why DNA testing of an individual or a family may be needed.
DNA testing for accurate diagnosis. Medically, ensuring the accuracy of a disease diagnosis is the most important reason for DNA testing, because many diseases can occur in a form that is difficult to recognize. In other cases, different diseases may be so similar that it is difficult to decide which is present. It is important to be certain about a diagnosis in order to choose the correct treatment. Prognosis, or knowledge about what problems the disease will cause in the future, is also important. Finally, there are different genetic mechanisms of disease that may cause the disease to occur in different relatives or children.
DNA testing to prevent or delay disease. Sometimes there are indications for DNA testing when no disease is present. In a family in which a genetic disease is known to exist, DNA testing may be able to identify which relatives may get the disease. In some groups, particular genetic diseases are so common that testing might be done on everybody. This type of testing is of greatest value if there is some form of intervention that might either prevent the disease or delay its onset. This intervention could be a lifestyle change, medication, or surgery.
Even if there is no intervention available, testing of this type can identify persons whose children could be affected. In these cases, there may be a prenatal DNA test that can determine if a fetus is affected by the disease. Preimplantation DNA testing can be done on early embryos resulting from in vitro fertilization in order to select those that are free from a particular serious genetic disease. Because many additional procedures are required, however, preimplantation testing is expensive and is not usually covered by insurance.
A carrier is a person who does not have a particular genetic disease but who can pass the genetic mutation that causes the disease to his or her children. Carrier testing can be offered (1) to individuals who have family members with a genetic disease, (2) to family members of an identified carrier, and (3) to members of groups known to have a higher carrier rate for a particular disease. Carrier testing identifies persons who have a mutation for a disease inherited in an autosomal recessive or X-linked recessive manner. Although the mutation does not cause the disease in carriers, it confers a high risk of transmitting the disease to their children. Carrier testing helps parents understand these risks and make informed decisions.
Social and Legal Indications for DNA testing. There are also legal and social indications for DNA testing. If paternity is uncertain, DNA testing can identify the biological father. This can be important in determining responsibility for financial support and for the legalities of inheritance. When family history is absent or inadequate, DNA testing can determine if specific genetic diseases exist in children who are available for adoption. Certain genetic diseases may appear identical to those produced by alleged malpractice, and DNA testing can exonerate the accused physician. The same is true for product liability defenses.
Organ Transplantation. DNA zygosity testing can be used to identify a donor for organ transplant. (Identical, or monozygotic, twins are logically the best donors). DNA banking is offered by some of the same laboratories that perform DNA testing. DNA banking involves extracting DNA from cells and freezing or refrigerating it for future testing. DNA is stable even outside of cells and therefore can be stored for years. DNA banking may be offered to terminally ill patients with a known or suspected genetic disease, persons with a genetic disorder for which no testing is yet available, or persons who do not presently wish to pursue available testing but would like to reserve the option for the future.
How much does DNA testing cost? Costs for DNA testing can range from reasonable to exorbitant. For easy-to-detect constitutional mutations, the cost is approximately the same as for hormone tests - $200, more or less, per test. Difficult tests and tests for focal mutations can cost thousands of dollars. Most insurers cover only the less expensive tests. The "turnaround time" or the time from specimen collection to reporting is usually a matter of weeks or months.
Are there problems associated with DNA testing? Interpretation of the DNA testing report is usually straightforward but may require some knowledge of genetics and disease processes. Because different mutations in different locations in DNA can produce essentially identical diseases, the mutational repertoire of most genetic diseases can present problems. Also, most DNA tests are exquisitely specific: A test for a one mutation may miss a different mutation in the same gene. This problem has led to the saying, "Absence of proof is not proof of absence." Hence, DNA testing is sometimes a gamble.
Testing for some genetic diseases requires linkage analysis. Instead of searching for the exact mutation that causes a disease, linkage is based on testing for harmless mutations that surround the area of DNA in which the disease-causing mutation occurs. Linkage analysis can detect disease-causing mutations of any type, but the testing of several relatives is required to accurately determine the area of DNA with the mutation. This is costly and carries risks of infringement of privacy, including disclosure of non-paternity. In addition, the body's normal process of safely exchanging similar parts of DNA molecules (called crossing over) during the production of sperm and egg cells in the parent can, simply by chance, interfere with the accuracy of the analysis of a child's DNA. Again, linkage analysis is a gamble, but a much more expensive one because of the requirement of testing for several mutations in several people.
ConclusionMany authorities feel that there is a bright future in DNA testing because a large number of individual mutation tests can be programmed into a single computer chip. This promises both increased ease of testing and increased accuracy. However, there is still a hurdle to overcome in that many genetic diseases are rare and so demand may not be high. In this hazy future, techniques to test for all mutations in all genes may be required to overcome that hurdle and make DNA testing more generally applicable.
At present, DNA tests are available for about 400 disease-causing genes. However, that number includes numerous cases in which the same or very similar diseases are caused by different genes, so the actual number of genetic diseases for which a DNA test is available is much lower. For example, there are DNA tests for 12 different genes that cause the disease called epidemolysis bullosa. There are clinical differences in the forms of the disease, so a physician does not necessarily have to order all 12 tests. All of the different forms of all genetics diseases are described at the website, Online Mendelian Inheritance in Man (OMIM), which is accessed at http://www3.ncbi.nlm.nih.gov/Omim/.
Large national referral laboratories (like LabCorp and the Mayo Clinic) offer the most frequently used tests and may already be on contract with a local laboratory. In all, there are about 400 certified laboratories that provide clinical DNA testing. (These laboratories should not to be confused with research testing laboratories from which results are not certified and are not necessarily released to the doctor or patient). At present, there is no print edition of a guide to the laboratories and tests. An online list is available to healthcare providers, who must register and receive a password: http://www.genetests.org/.
About the AuthorThe late Dr. Thurmon was Professor of Pediatrics and the Director of the Medical Genetics Section at the LSU School of Medicine in Shreveport. His teaching, service and research in Louisiana span over 30 years. His research involved genes of folic acid metabolism and of spastic paraplegia, population genetics, and computer programming for clinical genetics. His book, A Comprehensive Primer on Medical Genetics was published in 1999 by Parthenon Publishing Group, New York.

Cancers of the Lung and Pancreas in Acadiana

In 1975 and 1976,the National Cancer Institute first published maps of the United States showing regional death rates for specific types of cancer in each of the 50 states for the time period 1950-1969. Separate volumes were prepared for mortality in Whites and "Nonwhites." In Louisiana, the nonwhite population for the 20-year period 1950-69 was overwhelmingly Black/African American. Therefore, these ethnic/racial groups will be referred to broadly as White and Black. These so-called "cancer maps" highlighted parts of the U.S. where the death rates for specific cancers were unusually high or low and served to stimulate grant funding to test hypotheses about factors that might be related to elevated death rates in certain places.
The cancer maps graphically displayed high death rates for cancer of the lung in south Louisiana primarily among men, both Whites and Blacks. High death rates for cancer of the pancreas in White and Black men and White women in parts of south Louisiana were also noted. The maps themselves have been updated over time, and examples are shown below for cancer of the pancreas in White men and women for 1970-80.
The most recent maps can be found on the website for the National Cancer Institute at http://www.nci.nih.gov.
Following publication of the first set of maps, the National Cancer Institute issued a call for research to study risk factors for these cancers that might explain the high rates in particular geographic areas. Louisiana State University School of Medicine was funded to conduct three case-control studies, including one on cancer of the lung and a study of cancer of the pancreas in the early 1980s. The two studies yielded important information about these cancers and have stimulated additional research by Louisiana scientists and scientists elsewhere. The findings of these studies will be briefly discussed and subsequent and on-going research will follow.
Consistent with the findings of others, the relative importance of cigarette smoking in the risk of lung cancer in Louisiana cannot be overemphasized. The lung cancer study included interviews with 1253 lung cancer cases and 1274 matched controls. Approximately 98% of all male lung cancer cases were current or former smokers, as were 94% and 88% of the Black and White female cases, respectively. A 12 to 25-fold increased risk of lung cancer was observed among smokers in Louisiana compared to non-smokers, depending on the number of years smoked and the amount. Non-filter smokers had double the risk of smokers of filter cigarettes. Persons who started to smoke before the age of 16 had three times the lung cancer risk of those who began smoking after age 20. This study was the first U.S. study to find an increased risk of lung cancer in non-smokers exposed to the smoke of others (also called passive smoke, environmental tobacco smoke, or ETS). Many other studies throughout the world have subsequently confirmed a small but significant increased risk in ETS-exposed non-smokers. A follow-up study of lung cancer in non-smokers conducted by these LSU researchers in the mid-1980's to early 1990's found a two-fold increase of lung cancer in non-smokers with a family history of lung cancer.
Diet was examined as a risk factor for lung cancer in Louisiana. Low intake of fruits and vegetables was found to increase lung cancer risk, as did low dietary intake of vitamin C and all types of carotenes combined. This study was one of the earliest studies to report this "protective effect" of fruits and vegetables, and this finding has been consistently confirmed all over the world. The specific components of fruits and vegetables responsible for this reduced risk have not been clearly determined. Fruits and vegetables contain vitamins such as vitamin C and folate, beta-carotene and other carotenoids, minerals, fiber and phytochemicals or non-nutrient substances contained in food. Whether it is one or more of these components or the full "package" that decreases the risk of lung cancer and other epithelial cancers, the message is clear that five or more daily servings of fruits and vegetables is important to a healthy lifestyle.
Occupation was examined in this study, and Louisiana men employed in forestry occupations, particularly sawmill workers, were found to be at increased risk of lung cancer. Consistent with this finding was an increased risk in persons who reported occupational exposure to wood dust. Subsequent studies in other geographic areas have also found an increased risk of lung cancer associated with wood dust exposure. A two-fold increased risk of lung cancer was also found for occupational exposure to mineral oil mist.
The pancreatic cancer study also conducted in the early 1980's included 363 persons with pancreatic cancer and 363 matched controls -- persons of similar age, sex, and race without pancreatic cancer. In this study, several findings suggested a role of inherited susceptibility. A two-fold increased risk of pancreatic cancer was found among persons reporting Acadian ancestry. An almost two-fold increased risk of pancreatic cancer was observed in persons reporting a family history of any cancer, increasing to a five-fold increased risk in persons with a family history of pancreatic cancer. It should be noted, however, that families often share not only genes but also a common environment and lifestyle, so this familial risk may represent either an inherited susceptibility or similar exposures or both.
Cigarette smoking is a risk factor for pancreatic cancer, one of the few well-documented risk factors. However, the smoking-associated risk of pancreatic cancer is much smaller than that for cancer of the lung. A two-fold increased risk of cancer of the pancreas was found in this study for cigarette smokers.
The relationship of diet to pancreatic cancer risk in Louisiana was examined in detail. Significant increases in pancreatic cancer risk were found among persons who consumed large amounts of pork and processed meats and large amounts of rice, breads and cereals. The level of risk tended to increase with increasing amounts of pork products and dairy products consumed by men; among women, risks increased with increasing consumption of seafood. This is called a "dose-response." In others words, the higher the "dose" the greater the "response" or, in this case, risk. As in the lung cancer study, frequent consumption of fruits was "protective"; that is, persons with low intake had about double the risk of those with higher consumption. Neither alcohol nor coffee was associated with risk.
Employment in professional and managerial occupations and sugarcane farmers had significantly increased risks, between one and a half and two-fold. And a doubling of risk was seen in persons who lived in rural areas compared to urban areas. The risks associated with both rural residence and with each of the dietary factors were more apparent in persons reporting Acadian ancestry, suggesting a possible gene-environment interaction.
Since these studies were completed, the epidemiologists at LSU School of Medicine have continued to study these and other cancers common in the Louisiana population. The earlier studies were entirely based on responses to questions asked by interviewers in structured questionnaires. More recently, scientific and technological advances have allowed researchers to address the issue of susceptibility to specific exposures. Individuals with equal exposure to the same carcinogen differ in their biologic response. Inherited mutations in genes, such as the "breast cancer genes" BRCA1 and BRCA2, are relatively rare and account for only about 15% of all breast cancers. Other individual differences in common genetic traits responsible for how a person handles (activates or detoxifies) carcinogens now appear to be important determinants of risk. Wide differences in these traits have been documented between individuals, and differences in the distribution of these traits have also been found among different racial/ethnic groups. The latter may account for some of the differences in cancer risk observed in different racial and ethnic groups, in addition to differences in lifestyle and other exposures.
Two epidemiological studies by researchers at L.S.U. are currently in progress, one of lung cancer in southeast Louisiana funded by the Environmental Protection Agency and one of pancreatic cancer in the Lafayette/Acadiana region funded by the Louisiana Board of Regents. Each study seeks to address risks associated with environmental and lifestyle exposures as well as risks associated with differences in genetic traits responsible for the activation or detoxification of substances believed to be important in risks of these two cancers.
For cancer of the lung, our primary interest is in several genes responsible for metabolizing "polycyclic aromatic hydrocarbons" (PAH). These compounds are found in cigarettes are also produced in certain industrial settings, and are believed to be important contributors to risk. We will examine whether any of these genetic traits responsible for handling PAH increases risk of lung cancer and whether certain exposures only increase risk in persons with traits that make them unusually susceptible.
Some chemicals in a group of compounds called N-nitrosamines are carcinogenic and have been shown to cause pancreatic cancer in laboratory animals. Their role in human pancreatic cancer is unclear at this time. Nitrosamines and other related compounds have been found in pork products and cigarette smoke, each of which has been shown to increase risk of pancreatic cancer in our earlier Louisiana study. Further, vitamin C, found in fruits and associated with a lower risk of pancreatic cancer, can inhibit the formation of N-nitrosamines. In our recently initiated study of pancreatic cancer in Acadiana, we will focus on genetic differences in several genes responsible for activating and detoxifying N-nitrosamines. We will also study the role of other potential carcinogens that may be related to our earlier study.
Contact Information: efonth@lsuhsc.edu
How to Learn More: http://www.cancer.org
Fontham ETH, Haenszel W, Pickle LW, et al. Dietary vitamins A and C and lung cancer risk in Louisiana. Cancer 62:2267-2273, 1988.
Falk RT, Pickle LW, Fontham ETH, et al. Lifestyle and pancreatic cancer in Louisiana: a case-control study. Am J Epidemiol 128:324-336, 1988.
Fontham ETH, Correa P, Reynolds, P et al. Environmental tobacco smoke and lung cancer in nonsmoking women: a multicenter study. JAMA 271 (22): 1752-1759, 1994.
Wu AH, Fontham ETH, Reynolds, et al. Family history of lung cancer and risk of lung cancer among lifetime nonsmoking women in the United States. Am J Epidemiol 143 (6):535-542, 1996.
Heath C and Fontham ETH. Cancer Etiology. In, The American Cancer Society's Clinical Oncology. Lenhard RE et al Editors. Blackwell Science Inc., Maiden MA, pp. 37-54, 2000.

Exercising When You Have Diabetes

Lowering Blood Sugar through Physical Activity

Exercise can do more than help you lose weight. It can increase circulation, decrease stress, and reduce the risk for heart disease and strokes by lowering blood pressure and cholesterol. Getting some exercise is recommended for overall health. For people with diabetes, exercise can do even more. It can help keep blood glucose levels in range, and can go a long way towards preventing the complications associated with diabetes.

Type 1

Type 1 diabetes can be a balancing act when it comes to exercise. People diagnosed with Type 1 produce no insulin, or very little, in response to eating. They must take insulin in some form everyday in order to live. Blood glucose levels are dependent upon carbohydrates eaten, insulin administration and activity level.

• Insulin and Diabetes

Exercise can lower blood glucose levels during exercise and also after the exercise is finished. This can result in hypoglycemia. People with Type 1 need to check their blood glucose before, during and after exercise, and also bring a few carbohydrate snacks with them in case their blood sugar drops.

• Hypoglycemia
• 5 Good Reasons to Check Your Blood Sugar

With careful monitoring of blood glucose, a person with Type 1 can learn what their individual response is to exercise and how many carbs to take in and how much insulin to use. A good guideline to follow is to eat 15 to 30 gm of carbohydrate snack every 30 to 60 minutes during exercise or if glucose levels are 100 mg/dl or less. Avoid exercise if fasting glucose levels are greater than 250 mg/dl, especially if ketosis is present. Ketosis changes the acidity of the blood and can damage kidneys and the liver.

• Type 1 Diabetes

Type 2

People diagnosed with Type 2 diabetes usually have something called "insulin resistance." This means that their bodies still produce insulin, but it's not as effective at lowering blood glucose any more. Sometimes the insulin receptors aren't as sensitive, and sometimes the pancreas just doesn't make as much insulin as it used to. This insulin resistance is usually associated with increased fat and decreased muscle mass. Muscle cells use insulin much more efficiently than fat cells do, so building more muscle and reducing fat helps the body use the insulin that is produced thereby lowering overall blood glucose levels.

• Type 2 Diabetes

Pre-diabetes

People who are overweight and sedentary are at risk for developing pre-diabetes, which can be a precursor to Type 2. Prediabetes is diagnosed when fasting plasma glucose (FPG) is greater than 100 mg/dl but less than 126 mg/dl, or greater than 140 mg/dl but less than 200 mg/dl during an oral glucose tolerance test (OGTT). The danger of Type 2 can be delayed or possibly even prevented if lifestyle changes include weight loss and increased physical activity.

• What is Pre-Diabetes?

How To Begin

Aim for 30 minutes of moderate activity five days a week. There are lots of different kinds of exercise. Try some of these or come up with your own:

• Walking, biking, hiking, or dancing
• Exercise videos and DVD's at home
• Classes at the local Y such as yoga, tai chi, or pilates
• Team sports like volleyball, martial arts, basketball, raquetball
• Winter sports like cross country skiing, snowshoeing, or mall walking

Diabetes : Lose Weight with Free On-line Diet Tools

Losing just 5% to 7% of your total body weight can lower your risk of developing type 2 diabetes. If you already have diabetes, keeping your weight down is essential for optimum diabetes management. It can seem like the warnings about obesity and health risks are everywhere. But how do you get started on the road to better health? How do you keep track of fat grams and carbohydrates, as well as calories in and calories out? There are free on-line tools to help you on your way.

• Calorie-Count.com - offers free weight loss tools such as food logs, activity logs, nutritional information on many different foods including restaurant meals and fast food, and an active, supportive community to help you organize your weight loss. There are a few unique features also:
  • The "walkthrough" is an automated demo which literally "walks" you through the website so that you can fully utilize all the features.
  • The recipe analyzer allows you to enter your own recipes and figures out the nutritional facts for you.

• The National Heart, Lung and Blood Institute (NHLBI) offers an interactive Menu Planner.
• The Menu Planner helps you figure out your total calories, fat grams, and carbs for the day and let's you know whether you've stayed within your limits. The site also can help you calculate your BMI. The site offers lots of information about good nutrition and calorie requirements, too.

• FitDay.com Free Diet and Weight Loss Journal - offers a free online diet tool that includes a large data base of different kinds of food including many name brands. It breaks down calories, carbs, fat grams, and more and figures out serving sizes. It also show your progress with pie charts and line graphs, while keeping track of exercise and goals. You may also journal about your feelings at FitDay as you journey towards your weight loss goals.

• My-Calorie-Counter.com - allows you to enter your food, meal by meal and gives calorie counts, fat grams, carbs, sodium and other information. It also has a variety of tools such as a BMI calculator, body fat calculator, activity and exercise list, and a weight loss ticker.

Ebola virus

Ebola is a virus-caused disease limited to parts of Africa. Within a week, a raised rash, often hemorrhagic (bleeding), spreads over the body. Bleeding from the mucous membranes is typical causing apparent bleeding from the mouth, nose, eyes and rectum.

A.D.A.M., Inc. is accredited by URAC, also known as the American Accreditation HealthCare Commission (www.urac.org). URAC's accreditation program is the first of its kind, requiring compliance with 53 standards of quality and accountability, verified by independent audit. A.D.A.M. is among the first to achieve this important distinction for online health information and services. Learn more about A.D.A.M.'s editorial process. A.D.A.M. is also a founding member of Hi-Ethics (www.hiethics.com) and subscribes to the principles of the Health on the Net Foundation (www.hon.ch).

The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. A licensed physician should be consulted for diagnosis and treatment of any and all medical conditions. Call 911 for all medical emergencies. Links to other sites are provided for information only -- they do not constitute endorsements of those other sites. Copyright 2004 A.D.A.M., Inc. Any duplication or distribution of the information contained herein is strictly prohibited.

All Vaccines For All Positive People Should Get

Vaccines are given to stimulate the body's immune response in order to produce antibodies that will protect against certain illnesses. These vaccines are those most commonly given to people living with HIV and AIDS.

• Flu
• Hepatitis A
• Hepatitis B
• Pneaumovax <>
  
• Tetanus
• Twinrix <>
  
• HPV <>
  

Your Guide to the HPV Vaccine

The New Vaccine that Protects Women from HPV

What is Human Papillomavirus?

Human Papillomavirus (HPV) is a very common virus that spreads by way of sexual contact. Most often, HPV is harmless, causing few symptoms and going away without any residual effects. However, there are some types of HPV that can infect a woman's cervix, causing cells of the cervix to change, which can in some cases lead to cervical cancer, a cancer that kills almost 4,000 women each year in the United States alone.
In addition to cervical cancer, HPV infection can also cause genital warts, a highly contagious, sexually-transmitted disease characterized by clusters of lumps around the genital and anal areas. In women, the warts can spread to the inner walls of the vagina, the uterus, the cervix and the anus.

Facts About the HPV Vaccine

The HPV vaccine is the first vaccine approved by the FDA that prevents infection by four types of HPV. These four types account for 70 percent of all cervical cancers and 90 percent of all genital warts.

How is the Vaccine Given?
The vaccine is given in a series of three injections over a six-month period. Women who become pregnant after starting the series should wait until after the delivery of their baby before finishing the vaccine series.

Who Should Get the Vaccine?
The purpose of the new HPV vaccine is to prevent infection with HPV. To do this, vaccination is ideally given before a woman becomes sexually active. To that end, experts recommend that all girls 11 and 12 years old receive the vaccine. The vaccine can be given to girls as young as nine years of age. Girls 13 to 26 should receive the vaccine if they have not completed the series previously or are not yet sexually active. There is not enough clinical data available for the FDA to approve the vaccine for women older than 26 years.

Why is the Vaccine Given to Such Young Girls?
The vaccine is targeted to girls nine to 13 because there is a higher probability that girls that age are not yet sexually active. Girls that are already sexually active have in most cases been exposed to at least one and in some case as many as four of the HPV types covered by the vaccine. For them, HPV infection has already occurred and the vaccine would be of limited benefit.

What About Boys and Pregnant Women? Should They Be Vaccinated?
As of now, the vaccine should not be given to boys or pregnant women. The benefits to boys and the effects on the unborn have not been studied enough to endorse vaccination in those populations. That's not to say the vaccine will never be recommended for them, but for now the vaccine is limited to young girls nine to 26.

How Much Does the Vaccine Cost?
The current cost of the HPV vaccine is about $120 per dose or $360 for the series. Some commercial insurance companies cover the cost of recommended vaccines along with the cost administration. Keep in mind, however, that it may take some time for the vaccine to get listed on formularies and lists of covered services. There are also federally funded programs that will assist with the cost of the vaccine. One such program is the Vaccines for Children Program that provides free vaccines to children in need.

Treatment for Cancer of the penis (penile cancer)

The type of treatment that you are given will depend on a number of things, including the position and size of the cancer, whether or not it has spread, the grade of the cancer, and your general health.

The treatments used for penile cancer include surgery, radiotherapy and chemotherapy. Surgical techniques have advanced recently, and it is usually possible to either preserve the penis or perform a reconstruction.

Men with cancer of the penis should be treated in a specialist cancer centre.

Surgery

Small, surface cancers that have not spread are treated by removing only the affected area. The cancer can be removed with conventional surgery, using laser or by freezing (cryotherapy). Cryotherapy is carried out with a cold probe, which freezes and kills the cancer cells.

If the cancer is affecting only the foreskin, it may be possible to treat it with circumcision alone.

All the above treatments can usually be given to you as an outpatient. They may be done under local or general anaesthetic, depending on individual circumstances.

Wide local excision If the cancer has spread over a wider area, you will need to have an operation known as a wide local excision. This means removing the cancer with a border of healthy tissue around it. This border of healthy tissue is important as it reduces the risk of the cancer coming back in the future. The operation is done under general anaesthetic and will involve a short stay in hospital.

Removing the penis (penectomy) This may be advised if the cancer is large and is covering a large area of the penis. Amputation may be partial (where part of the penis is removed) or total (removal of the whole penis). The operation most suitable for you depends on the position of the tumour. If the tumour is near the base of the penis, total amputation may be the only option.

The surgeon may also remove lymph nodes from the groin if there is evidence that cancer cells have spread to these nodes, or a possibility that they may have.

Reconstructive surgery It is often possible to have a penis reconstructed after amputation. This requires another operation. The techniques that may be used include taking skin and muscle from your arm, and using this to make a new penis. Sometimes it is also possible for surgeons to reconnect some of the nerves, to provide sensation and the necessary blood flow to allow the reconstructed penis to become erect. This type of surgery is carried out by surgeons who have specialist experience, and you may need to travel to a specialist hospital to have the surgery done.

Radiotherapy

treats cancer using high-energy rays to destroy cancer cells, while doing as little harm as possible to healthy cells. It can be used before or after surgery. Radiotherapy may also be given to treat symptoms, such as pain, if the cancer has spread to other parts of the body, like the bones.

External radiotherapy is normally given as a series of short daily treatments in the hospital's radiotherapy department. High-energy x-rays are directed from a machine at the area of the cancer. The treatments are usually given from Monday to Friday, with a rest at the weekend. Each treatment takes 10–15 minutes. The number of treatments will depend on the type and size of the cancer, but the whole course of treatment for early cancer will usually last for up to six weeks. Your doctor will discuss the treatment and possible side effects with you.

Before each session of radiotherapy, the radiographer will position you carefully on the couch and make sure that you are comfortable. During your treatment you will be left alone in the room, but you will be able to talk to the radiographer who will be watching you carefully from the next room.

Radiotherapy is not painful, but you do have to lie still for a few minutes while your treatment is being given. The treatment will not make you radioactive and it is perfectly safe for you to be with other people, including children, after your treatment.

Radioactive implants Radiotherapy can be given using a radioactive implant. This is also known as brachytherapy. Under a general anaesthetic, small radioactive wires are very carefully positioned in the affected area of the penis. The wires stay in place for about 4–5 days and are then removed. This method of treatment is usually used for smaller cancers on the end of the penis (the glans). While the implant is in place, you need to stay in an isolated room in the hospital so that other people are not exposed unnecessarily to the radiation.

Side effects of radiotherapy

There are sometimes side effects from radiotherapy treatment to the penis. Towards the end of your treatment, the skin on your penis can become sore and may break down. Long-term, radiotherapy can cause thickening and stiffening of healthy tissues (fibrosis). In some men, this can result in narrowing of the tube that carries urine through the penis (the urethra) and so can cause difficulty in passing urine. If narrowing of the urethra does develop, it can usually be relieved by an operation to stretch (dilate) the area. This is done by passing a tube into the urethra and is performed under a general anaesthetic.

Chemotherapy

is the use of anti-cancer (cytotoxic) drugs to destroy cancer cells. It can be one drug or several drugs used together. It is not commonly used to treat cancer of the penis. Chemotherapy cream may sometimes be used to treat very small, early cancers that are confined to the foreskin and end of the penis (glans).

Chemotherapy may also be given as tablets, or by injection, into a vein for more advanced cancer. It may be given along with surgery or radiotherapy (or both).

Mesothelioma

Mesothelioma is a form of cancer that is almost always caused by previous exposure to asbestos. in this disease, malignant cells develop in the mesohelium, a protective lining that covers most of the body's internal organs. it's most common site is the pleura(outer lining of the lungs and chest cavity), but it may also occur in the peritoneum (the lining of the abdominal cavity) or the percardium (a sac that surrounds the heart).
most people who develop mesothelioma have worked on jobs where they inhaled asbestos particles, or have been exposed to asbestos dust and fibre in other ways, such as by washing the clothes of a family member who worked with asbestos, or by home renovation using asbestos cement products. there is no association between mesothelioma and smoking.

Signs and symptoms
Symptoms of mesothelioma may not appear until 20 to 50 years after exposure to asbestos. Shortness of breath, cough, and pain in the chest due to an accumulation of fluid in the pleural space are often symptoms of pleural mesothelioma.
Symptoms of peritoneal mesothelioma include weight loss and cachexia, abdominal swelling and pain due to ascites (a buildup of fluid in the abdominal cavity). Other symptoms of peritoneal mesothelioma may include bowel obstruction, blood clotting abnormalities, anemia, and fever. if the cancer has spread beyong the mesothelium to other parts of the body, symptoms may include pain, trouble swallowing, or swelling of the neck or face.
These symptoms may be caused by mesothelioma or by other, less serious conditions.

Mesothelioma that affects the pleura can cause these signs and symptoms:

• chest wall pain
• pleural effusion, or fluid surrounding the lung
• shortness of breath
• wheezing, hoarseness, or cough

In severe cases, the person may have many tumor masses. The individual may develop a pneumothorax, or collapse of the lung. The disease may metastasize, or spread, to other parts of the body.

Tumors that affect the abdominal cavity often do not cause symptoms until they are at a late stage. Symptoms include:

• abdominal pain
• ascites, or an abnormal buildup of fluid in the abdomen
• a mass in the abdomen
• problems with bowel function
• weight loss

In severe cases of the disease, the following signs and symptoms may be present:

• blood clots in the veins, which may cause thrombophlebitis
• disseminated intravascular coagulation, a disorder causing severe bleeding in many body organs
• jaundice, or yellowing of the eyes and skin
• low blood sugar level
• pleural effusion
• pulmonary emboli, or blood clots in the arteries of the lungs
• severe ascites

A mesothelioma does not usually spread to the bone, brain, or adrenal glands. Pleural tumors are usually found only on one side of the lungs.

Treatment for Anal Cancer

The main types of treatment used for anal cancer are a combination of radiotherapy and chemotherapy, which may be given at the same time (concurrently) or following one another. This combination of treatment is usually very successful. If radiotherapy and chemotherapy are given at the same time, the side effects can be worse.

Surgery may be used, but it is not often the first choice of treatment for anal cancer.
HIV and treatment

People who have a lowered immunity because of HIV, as well as having anal cancer may get more side effects during and after treatment. As a result, the amount of radiotherapy and dosages of chemotherapy may be reduced. Your specialist can give you more information.
Radiotherapy

High-energy rays are used to destroy cancer cells, while doing as little harm as possible to normal cells. The treatment is often given for a few minutes each weekday for several weeks.

During the treatment period you may have changes in your bowel function such as diarrhoea, or passing wind: these side effects can sometimes be reduced by avoiding particular foods. Towards the end of the treatment period you may have blistering and soreness of the skin around the anal area, and possibly in the groin areas too. Extreme tiredness, or fatigue, is also a common side effect of radiotherapy for anal cancer.

These side effects usually decrease gradually once the treatment has ended, but it may take some months for skin changes to go back to normal. A small proportion of people find that their bowel function is permanently altered. It is important to discuss this with your doctor as it is often possible to find ways of reducing any problems. Your doctor or a dietitian at the hospital can give you further advice.

Other potential side effects that can occur after radiotherapy for anal cancer include narrowing of the vagina (vaginal stenosis), and vaginal dryness. To help prevent this, women will be asked to use a vaginal dilator with a lubricating jelly to keep the vaginal walls open and supple. Some women may also need to use lubricating jelly during sexual intercourse.

Infertility can also be a side effect of radiotherapy. If you are concerned about your risks of being infertile following treatment, it is a good idea to discuss this issue with your specialist before starting.
Chemotherapy

Chemotherapy is the use of anti-cancer (cytotoxic) drugs to destroy cancer cells. The chemotherapy drugs are usually given by injection into a vein (intravenously). They can temporarily reduce the number of normal cells in your blood. When your blood count is low you are more likely to get an infection and you may tire very easily. During chemotherapy your blood will be tested regularly and, if necessary, you may be given antibiotics to treat any infection. Blood transfusions may be given if you become anaemic due to chemotherapy.

Other side effects may include feeling sick (nausea) and vomiting. Some chemotherapy drugs can also make your mouth sore and cause small mouth ulcers. Regular mouthwashes are important and your nurse will show you how to use these properly. If you don’t feel like eating meals, you can supplement your diet with nutritious drinks or soups. A wide range of drinks is available and you can buy them at most chemists. You can ask your doctor to refer you to a dietitian for advice about your diet.
Surgery

Surgery may be used if initial treatment does not completely get rid of the cancer, or if there are signs that your cancer has returned. There are two main types of surgery: local resection and abdominoperineal resection.

Local resection This may be used for small tumours on the outside of the anus. This operation only removes the area of the anus containing the cancer cells. The anal sphincter is not usually affected, and so normal bowel function is maintained for most people.

Abdominoperineal resection This is the removal of the anus and rectum. This operation requires a permanent colostomy, which involves diverting the open end of the bowel on to the surface of the abdomen (tummy area), to allow faeces to be passed out of the body into a colostomy bag. The opening on the abdominal wall is known as a stoma.

Although the idea of a colostomy is initially frightening and distressing for many people, most people find that they adapt over time and can return to normal activities. You will be able to get support and advice from the stoma nurse in your hospital. We can send you information about having a colostomy.

Anal cancer

The anus is the name for the muscular area at the very end of the large bowel. It is the muscle which opens and closes to control bowel movements, and is where the bowel opens to the outside of the body. This muscle is also called a sphincter.

The most common type of anal cancer is squamous cell. Other rarer types are basal cell, adenocarcinoma and melanoma. This information deals with the treatment of squamous cell carcinoma.

Diagram showing the position of the anus

Causes of anal cancer

Cancer of the anus is rare. Less than 400 people are diagnosed with this type of cancer each year in the UK. It is slightly more common in women than in men. As with most cancers the cause of anal cancer is unknown.

Signs and symptoms

The most common symptoms of anal cancer are bleeding from the rectum and pain. Some people develop small firm lumps which may be confused with piles (haemorrhoids). Other symptoms include discomfort, itching and a discharge of mucous (a jelly-like substance) from the anus. Faecal incontinence (a reduced ability to control bowel function) may also occur. Anal cancer can appear as an ulcerated area and may spread to the skin of the buttocks.

It is known that anal cancer is more common in gay men. It is also more likely to develop in people who have had a particular virus infection called the human papilloma virus (HPV). The risk of having HPV increases with the number of sexual partners you have. Anal cancer is also more common in people who have a lowered immunity due to medical conditions, such as HIV. Cigarette smoking may also increase a person’s risk of developing anal cancer.

How it is diagnosed

Usually you begin by seeing your GP who will examine you and refer you to a specialist in bowel conditions (gastroenterologist). The doctor at the hospital will take your full medical history, do a physical examination and take blood samples to check your general health. Before the doctor can make a firm diagnosis of anal cancer a number of tests will have to be done.

Rectal examination This is also sometimes known as a PR examination and is where the doctor examines your back passage with a gloved finger.

Biopsy A small sample of cells is taken from the tumour so that it can be examined under a microscope. Usually this involves using either a special biopsy device (known as a punch biopsy) or the doctor can cut a small piece away from the tumour (known as an incisional biopsy). This can be done under local or general anaesthetic.

X-rays These may be taken to show if there has been any spread of the cancer.

Ultrasound scan This is a simple scan that uses sound waves to form a picture of the inside of the abdomen. These scans are done in the hospital's scanning department. Once you are lying comfortably on your back, a gel is spread onto your abdomen. A small device is then rubbed over the area. The sound waves are converted into a picture using a computer. The test is completely painless and takes 15–20 minutes.

You may also have an ultrasound scan known as an endoanal ultrasound. For this scan a small probe is passed into the rectum, which can show the size and extent of the tumour.

CT (computerised tomography) scan This is a more sophisticated type of x-ray which builds up a three-dimensional picture of the inside of the body. The scan is painless but takes longer than an x-ray (10–30 minutes). It may be used to identify the exact site of the tumour or to check for any spread of the cancer. Most people who have a CT scan are given a drink or injection to allow particular areas to be seen more clearly. Before having the injection or drink, it is important to tell the person doing this test if you are allergic to iodine or have asthma.

MRI (magnetic resonance imaging) scan This test is similar to a CT scan, but uses magnetic fields instead of x-rays to form a series of cross-sectional pictures of inside the body. During the scan you will be asked to lie very still on the couch inside a metal cylinder. You will usually be given an injection to allow the pictures to be seen more clearly.

The test can take about 30 minutes and is completely painless, although the machine is quite noisy. If you don’t like enclosed spaces you may find the machine claustrophobic. You will be given earplugs or headphones and you can usually take someone with you into the room to keep you company. A two-way intercom enables you to talk with the people controlling the scanner.

Staging

The 'stage' of a cancer is a term used to describe its size and whether it has spread beyond its original site. Knowing the particular type and the stage of the cancer helps the doctors to decide on the most appropriate treatment.

Cancer can spread in the body, either in the bloodstream or through the lymphatic system. The lymphatic system is part of the body’s defence against infection and disease. The system is made up of a network of lymph glands (also known as lymph nodes) that are linked by fine ducts containing lymph fluid.
Your doctors will usually check the nearby lymph nodes when staging your cancer.

• Stage 1 The cancer only affects the anus and is smaller than 2cm in size. It has not begun to spread into the sphincter muscle.
• Stage 2 The cancer is bigger than 2cm in size but has not spread into nearby lymph nodes or to other parts of the body.
• Stage 3A The cancer has spread to the lymph nodes close to the rectum, or to nearby organs such as the bladder or vagina.
• Stage 3B The cancer has either spread to the lymph nodes in the groin and pelvis, or to the lymph nodes close to the anus as well as nearby organs, such as the bladder or vagina.
• Stage 4 The cancer has spread to lymph nodes in the abdomen or to other parts of the body, such as the liver.

A different staging system called the TNM staging system is sometimes used instead of the number system described.

• T describes the size of the tumour and whether it has spread into nearby organs.
• N describes whether the cancer has spread to the lymph nodes.
• M describes whether the cancer has spread to another part of the body, such as the liver (secondary or metastatic cancer).

Although this system is more complex, it can give more precise information about the tumour stage.

If the cancer comes back after initial treatment, this is known as recurrent cancer.

Grading

Grading refers to the appearance of the cancer cells under the microscope and gives an idea of how quickly the cancer may develop. Low-grade means that the cancer cells look very like normal cells. They are usually slow-growing and are less likely to spread. In high-grade tumours the cells look very abnormal, are likely to grow more quickly and are more likely to spread.

Treatment for Bile duct cancer (cholangiocarcinoma)

The type of treatment that you are given will depend on a number of factors, including your general health, the position and size of the cancer in the bile duct and whether the cancer has spread beyond the bile duct.

Surgery

Surgery may be used to remove the cancer if it has not spread beyond the bile duct. It is not always possible to carry out surgery, as bile duct cancer is in a difficult position and it may be impossible to remove the cancer completely. The decision about whether surgery is possible or not depends on the results of the tests described above. If surgery is recommended then you will be referred to a surgeon with a special interest in this rare cancer.

There are different operations depending upon how big the cancer is and whether it has begun to spread into nearby tissues.

Removal of the bile ducts If the cancer is small and contained within the ducts, then just the bile ducts containing the cancer are removed and the remaining ducts in the liver are joined to the small bowel, allowing the bile to flow again.

Partial liver resection If the cancer has begun to spread into the liver, the affected part of the liver is removed, along with the bile ducts.

Whipple's If the cancer is larger and has spread into nearby structures, then the bile ducts, part of the stomach, part of the duodenum (small bowel), the pancreas, gall bladder and the surrounding lymph nodes are all removed.

After your operation you may stay in an intensive-care ward for the first couple of days. You will then be moved to a general ward until you recover. Most people need to be in hospital for up to two weeks after this type of operation.

Bypass surgery Sometimes it isn't possible to remove the tumour and other procedures may be performed to relieve the blockage and allow the bile to go into the intestine. The jaundice will then clear up.

The surgical method of dealing with blockage (obstruction) of the bile duct involves joining the gall bladder (or the bile duct) to part of your small bowel (the duodenum or jejunum). This bypasses the blocked part of the bile duct and allows the bile to flow from the liver into the intestine. This operation is called a cholecysto-jejunostomy or cholecysto-duodenostomy if the gall bladder is used. It is called a hepatico-jejunostomy if the bile duct is used.

Another type of operation may be necessary if the duodenum is also blocked. This is called a gastrojejunostomy and involves connecting a piece of the small bowel (the jejunum) to the stomach to bypass the duodenum. This will stop the persistent vomiting that can occasionally happen if the cancer blocks the duodenum.

Stent insertion

There are two ways in which it may be possible to relieve jaundice without a surgical operation. These use the ERCP or PTC procedures described below.

The ERCP method involves the insertion of a tube, called a stent into the blocked bile duct. The stent is about as thick as a ball-point pen refill and about 5–10cm long (2–4 inches). The stent clears a passage through the bile duct to allow the bile to drain away. The preparation and procedure is the same as for ERCP described above. By looking at the x-ray image the doctor will be able to see the narrowing in the bile duct. The narrowing can be stretched using dilators (small inflatable balloons), and the stent can then be inserted through the endoscope to enable the bile to drain.

The tube usually needs to be replaced every three to four months to prevent it becoming blocked. If the tube does block, recurrent high temperatures and/or return of the jaundice will occur. It is important to tell your specialist about these symptoms as early as possible. Antibiotic treatment may be needed and your specialist may advise that the stent is exchanged for a new one. This procedure can be done relatively easily for most people.

During the PTC method, the procedure and the preparation you will need is as described in the section about PTC. A temporary wire is passed to the area of blockage and the stent is guided along the wire. Sometimes a drainage tube (catheter) is left in the bile duct. One end of the catheter is in the bile duct and the other lies outside the body connected to a bag, which collects the bile. This is to help with the insertion of the stent or, sometimes, to enable x-rays to be taken to check the position of the stent after it has been put in place. It is usually left in for a few days. Once the catheter is removed the hole heals over within two days. You will be given antibiotics before and after the procedure to help prevent any infection. It is likely that you will stay in hospital for a few days.

Sometimes, if the bile duct cannot be opened easily from the small intestine during ERCP, a combination of ERCP and PTC may be used.

Radiotherapy

is occasionally used. Radiotherapy treats cancer by using high-energy x-rays to destroy cancer cells while doing as little harm as possible to normal cells. It may be given either externally from a radiotherapy machine, or internally by placing radioactive material close to the tumour.

Chemotherapy

is the use of anti-cancer (cytotoxic) drugs to destroy the cancer cells. They work by disrupting the growth of cancer cells. Occasionally, chemotherapy may be given in combination with radiotherapy for cancers that cannot be removed surgically. Researchers are still looking into how effective chemotherapy is for the treatment of bile duct cancer.

Photodynamic Therapy (PDT)

uses a combination of laser light of a specific wavelength and a light-sensitive drug to destroy cancer cells. In bile duct cancer it is used to help relieve symptoms.

The light-sensitive drug (a photosensitising agent) is injected into a vein. It circulates in the bloodstream and enters cells throughout the body. The drug enters more cancer cells than healthy cells. It does not do anything until it is exposed to laser light of a particular wavelength. When a laser is shone on to the cancer, the drug becomes active and destroys the cancer cells.

Bile duct cancer

Cancers of the bile duct are rare in the Western world. There are approximately 600 new cholangiocarcinomas diagnosed each year in the UK.

The bile ducts are the tubes connecting the liver and gall bladder to the small intestine (small bowel). Bile is a fluid made by the liver and stored in the gall bladder. Its main function is to break down fats during their digestion in the small bowel. In people who have had their gall bladder removed, bile flows directly into the small intestine. The bile ducts and gall bladder are known as the biliary system.

Diagram showing the position of the bile duct

Cancer is classified according to the type of cell from which it starts. Cancer of the biliary system almost always starts in a type of tissue called glandular tissue and is then known as adenocarcinoma.

If the cancer starts in the part of the bile ducts contained within the liver it is known as intra-hepatic. If it starts in the area of the bile ducts outside the liver it is known as extra-hepatic. This information concentrates mainly on extra-hepatic bile duct cancers. Intra-hepatic bile duct cancers may be treated like primary liver cancer.

Causes of bile duct cancer

The cause of most bile duct cancers is unknown but they are more likely to occur in people who are born with (congenital) abnormalities of the bile ducts such as choledochal cysts. People who have a chronic inflammatory bowel condition, known as ulcerative colitis, are also at an increased risk of developing this type of cancer.

In Africa and Asia, infection with a parasite known as the liver fluke is thought to cause a large number of bile duct cancers. Bile duct cancer, like other cancers, is not infectious and cannot be passed on to other people.

Signs and symptoms

If cancer develops in the bile ducts it may block the flow of bile from the liver to the intestine. This causes the bile to flow back into the blood and body tissues, and leads to the skin and whites of the eyes becoming yellow (known as jaundice). The urine also becomes a dark yellow colour and stools (bowel motions) are pale. The skin may become itchy. Mild discomfort in the abdomen, loss of appetite, high temperatures (fevers) and weight loss may also occur.

These symptoms can be caused by many things other than bile duct cancer, but any jaundice or any symptoms which get worse or last for a few weeks should always be checked by your doctor.

How it is diagnosed

Usually you begin by seeing your GP, who will examine you. They will refer you to a hospital specialist for any tests that may be necessary and for expert advice and treatment. The doctor at the hospital will take your full medical history, do a physical examination and take blood samples to check your general health and your liver is working properly.

The following tests are commonly used to diagnose bile duct cancer:

Ultrasound scan Sound waves are used to make up a picture of the bile ducts and surrounding organs. These scans are done in the hospital's scanning department. You will be asked not to eat, and to drink clear fluids only (nothing fizzy or milky) for 4–6 hours before the scan. Once you are lying comfortably on your back, a gel is spread onto your abdomen. A small device, like a microphone, is then rubbed over the area. The sound waves are converted into a picture using a computer. The test is completely painless and takes 15–20 minutes.

CT (computerised tomography) scan A CT scan takes a series of x-rays which are fed into a computer to build up a detailed picture of your bile ducts and surrounding organs. On the day of the scan you will be asked not to eat or drink anything for at least four hours before your appointment. You will be given a special liquid to drink an hour before the test and again immediately before the scan. The liquid shows up on x-ray to ensure that a clear picture is obtained.

Once you are comfortably positioned on your back on the couch, the scan can be taken. About half-way through the scan a special dye will be injected into a vein to show up the blood vessels. This may make you feel warm or ‘flushed’ for up to half an hour. The test itself is completely painless, but it will mean that you have to lie still for about 10–30 minutes. If you had little to drink before the scan, you may be advised to drink plenty afterwards to make up for this.

MRI (magnetic resonance imaging) scan This test is similar to a CT scan, but uses magnetism instead of x-rays to build up cross-sectional pictures of your body. During the test you will be asked to lie very still on a couch inside a large metal cylinder which is open at both ends. The whole test may take up to an hour. It can be slightly uncomfortable and some people feel a bit claustrophobic during the scan, which is also very noisy. You will be given earplugs or headphones to wear. A two-way intercom enables you to talk with the people controlling the scanner.

ERCP (endoscopic retrograde cholangio-pancreatography) This is a procedure by which an x-ray picture of the pancreatic duct and of the bile duct can be taken. It may also be used to unblock the bile duct if necessary.

You will be asked not to eat or drink anything for about six hours before the test so that the stomach and duodenum (first part of the small bowel) are empty. You will be given an injection to make you relax (a sedative) and a local anaesthetic spray will be used to numb your throat. The doctor will then pass a thin flexible tube known as an endoscope through your mouth into your stomach and into the duodenum just beyond it. Looking down the endoscope, the doctor can find the opening through which the bile duct and the duct of the pancreas drain into the duodenum. A dye which can be seen on x-ray can be injected into these ducts and the doctor will be able to see whether there is any abnormality or any blockage in the ducts.

If there is a blockage it may be possible for the doctor to insert a small tube known as a stent. You may have some discomfort during this procedure; if you do, it is important that you let your doctor know. You will be given antibiotics beforehand (to help prevent any infection) and will probably stay in hospital for one night afterwards.

PTC (percutaneous transhepatic cholangiography) This is another procedure by which your doctor can obtain an x-ray picture of the bile duct. You will be asked not to eat or drink anything for about six hours before the test and will be given a sedative as for the ERCP.

An area on the right side of your abdomen will be numbed with a local anaesthetic (an injection) and a thin needle will be passed into the liver through the skin. A dye will be injected through the needle into the bile duct within the liver. X-rays will then be taken to see if there is any abnormality or blockage of the duct.

You may feel some discomfort as the needle enters the liver. You will be given antibiotics before and after this procedure (to help prevent infection) and you will stay in hospital for at least one night afterwards.

Angiography As the bile duct is very close to the major blood vessels of the liver, a test called an angiogram may be done. The angiogram can check whether the blood vessels are affected by the tumour.

A fine tube is inserted into an artery in your groin and a dye is injected through the tube. The dye circulates in the arteries to make them show up on x-ray. An angiogram is carried out in a room within the x-ray department. Sometimes an MRI scan can be used to show up the blood vessels of the liver and then an angiogram will not be necessary.

Biopsy The results of the previous tests may make your doctor strongly suspect a diagnosis of cancer of the bile duct, but the only way to be sure of the diagnosis is to take some cells or a small piece of tissue from the affected area of the bile duct to look at under a microscope. This is called a biopsy and may be carried out during an ERCP or PTC.

A fine needle is passed into the tumour through the skin after the area has been numbed using a local anaesthetic injection. CT or ultrasound may be used at the same time, to make sure that the biopsy is taken from the right place.

Endoscopic ultrasound scan (EUS) This scan is similar to an ERCP but involves an ultrasound probe being passed down the endoscope to take an ultrasound scan of the pancreas and surrounding structures.

Staging

The stage of a cancer is a term used to describe its size and whether it has spread beyond its original site. Knowing the particular type and the stage of the cancer helps the doctors to decide on the most appropriate treatment.

Cancer can spread in the body, either in the blood stream or through the lymphatic system. The lymphatic system is part of the body’s defence against infection and disease. The system is made up of a network of lymph glands (also known as lymph nodes) that are linked by fine ducts containing lymph fluid. Your doctors will usually look at the lymph nodes close to the biliary system in order to find the stage of your cancer.

• Stage 1A The cancer is contained within the bile duct.
• Stage 1B The cancer has spread through the wall of the bile duct but has not spread into nearby lymph nodes or other structures.
• Stage 2A The cancer has spread into the liver, pancreas or gall bladder or to the nearby blood vessels, but not the lymph nodes.
• Stage 2B The cancer has spread into nearby lymph nodes.
• Stage 3 The cancer is affecting the main blood vessels that take blood to and from the liver, or it has spread into the small or large bowel, the stomach or the abdominal wall. Lymph nodes in the abdomen may also be affected.
• Stage 4 The cancer has spread to distant parts of the body such as the lungs.

If the cancer comes back after initial treatment, this is known as recurrent cancer.

Grading

Grading refers to the appearance of the cancer cells under the microscope and gives an idea of how quickly the cancer may develop. Low-grade means that the cancer cells look very like normal cells; they are usually slow-growing and are less likely to spread. In high-grade tumours the cells look very abnormal, are likely to grow more quickly and are more likely to spread.