- Expanded treatment with more algorithms and diagnostic decision trees
- A new feature, Genetic Considerations, describes how new advances affect patient care
- Clinical Guidelines now added throughout, provide evidence-based treatment strategies
- Alternative Medicine...a detailed chapter covers this emerging field
- New Chapter on Late Problems in Patients with Cancer
- New guidelines on Adolescent Health Care
- The latest in Gene Therapy with a new chapter on Screening, Prevention, and Counseling for Genetic Disorders
- New chapter on Infertility and Fertility Control
- Neurobiology of Disease highlights numerous advances made during "The disease of the Brain"
- Late-breaking treatment information on multiple sclerosis, Parkinson's disease, Alzheimer's and more
- A new color atlas of malaria-infected red blood cells
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Chapter 334: Diabetes MellitusDiabetes mellitus, the most common endocrine disease, is characterized by metabolic abnormalities and by long-term complications involving the eyes, kidneys, nerves, and blood vessels. The disorder is not homogeneous, and several distinct diabetic syndromes have been delineated.
The diagnosis of symptomatic diabetes is not difficult. When a patient presents with signs and symptoms attributable to an osmotic diuresis and has hyperglycemia, the diagnosis is unequivocal. There is likewise no disagreement about an asymptomatic patient with persistently elevated fasting plasma glucose concentrations. The problem arises with the asymptomatic patient who for one reason or another is considered to be a potential diabetic but has a normal fasting glucose concentration in plasma. Such patients are often given an oral glucose tolerance test and, if abnormal values are found, are diagnosed as having impaired glucose tolerance or diabetes. There seems to be little question that normal glucose tolerance is strong evidence against the presence of diabetes; the predictive value of an abnormal test is less certain. Much evidence suggests that the standard oral glucose tolerance test overdiagnoses diabetes, probably because a variety of stresses can cause an abnormal response. The operative mechanism is thought to be epinephrine discharge. Epinephrine blocks insulin secretion, stimulates glucagon release, activates glycogen breakdown, and impairs insulin action in target tissues, so that hepatic glucose production is increased and the capacity to dispose of exogenous glucose is impaired. Even anxiety over venipunctures may generate enoughepinephrine to produce an abnormal test. Coexisting illness, inadequate diet, and lack of physical exercise also contribute to false-positive tests.
In an attempt to deal with these problems, the National Diabetes Data Group of the National Institutes of Health in 1979 revised the criteria for the diagnosis of diabetes:
- Fasting (overnight): Venous plasma glucose concentration >7.8 mmol/L (140 mg/dL) on at least two separate occasions.1
- Following ingestion of 75 g of glucose: Venous plasma glucose concentration >11.1 mmol/L (200 mg/dL) at 2 h and on at least one other occasion during the 2-h test; i.e., two values >11.1 mmol/L (200 mg/dL) must be obtained for diagnosis.
If the 2-h value is between 7.8 and 11.1 mmol/L (140 and 200 mg/dL) and one other value during the 2-h test period is equal to or greater than 11.1 mmol/L (200 mg/dL), a diagnosis of "impaired glucose tolerance" is suggested. Persons in this category are at increased risk for the development of fasting hyperglycemia or symptomatic diabetes, but such progression is not predictable in an individual patient.
In 1997, the American Diabetes Association recommended modified criteria for the diagnosis of diabetes mellitus. Please see the update by Jameson, Revised Classification and Criteria for the Diagnosis of Diabetes Mellitus.
A classification of diabetes is given in Table 334-1. The basic categories are those recommended by the National Diabetes Data Group, except for the division into primary and secondary types. Primary implies that no associated disease is present, while in the secondary category, some identifiable condition causes or allows a diabetic syndrome to develop. Insulin dependence in this classification is not equivalent to insulin therapy. Rather, the term means that the patient is at risk for diabetic ketoacidosis (DKA) in the absence of insulin. Many patients classified as non-insulin-dependent require insulin for control of hyperglycemia, although they do not become ketoacidotic if insulin is withdrawn.
The term type 1 diabetes is often used as a synonym for insulin-dependent diabetes mellitus (IDDM), and type 2 diabetes is considered equivalent to non-insulin-dependent diabetes mellitus (NIDDM). This linkage is not ideal, because a subset of patients with apparent non-insulin-dependent diabetes later become fully insulin-dependent and prone to ketoacidosis. These patients are nonobese and usually express HLA antigens associated with susceptibility to insulin-dependent diabetes and have evidence of an immune response to islet cell antigens (see "Pathogenesis," below). For this reason, it has been suggested that the classification shown in Table 334-1 be modified so that the terms insulin-dependent and non-insulin-dependent describe physiologic states (ketoacidosis-prone and ketoacidosis-resistant, respectively), while the terms type 1 and type 2 refer to pathogenetic mechanisms (immune-mediated and non-immune-mediated, respectively). Using such a classification, three major forms of primary diabetes would be recognized: (1) type 1 IDDM, (2) type 1 NIDDM, and (3) type 2 NIDDM. Category 2 is an intermediate stage of autoimmune destruction in which the capacity to produce insulin is sufficient to prevent ketoacidosis but not to maintain normal blood glucose; this variant likely occurs when the autoimmune process begins at an older age and progresses more slowly than usual. It is uncommon when IDDM appears in childhood or early adolescence. A subset of obese people with apparent non-insulin-dependent diabetes can become transiently insulin dependent and develop DKA. Such individuals do not have markers of autoimmunity suggestive of type 1 disease and may not require insulin permanently after recovery from DKA. Presumably, diminution of insulin reserve renders such subjects vulnerable to stress-induced metabolic decompensation and causes transient insulin dependence.
There are several secondary forms of diabetes. Pancreatic disease, particularly chronic pancreatitis in alcoholics, is a common cause. Destruction of the beta cell mass is the etiologic mechanism. Hormonal causes include pheochromocytoma, acromegaly, Cushing's syndrome, and administration of steroid hormones. "Stress hyperglycemia," associated with severe burns, acute myocardial infarctions, and other life-threatening illnesses, is due to endogenous release of glucagon and catecholamines. Hormonal hyperglycemia results from varying combinations of impairment of insulin release and induction of insulin resistance. A large number of drugs can lead to impaired glucose tolerance or hyperglycemia. Hyperglycemia and even ketoacidosis can be due to quantitative or qualitative defects in the insulin receptor or to antibodies directed against it. The mechanism is essentially pure insulin resistance. Genetic syndromes associated with impaired glucose tolerance or hyperglycemia include the lipodystrophies, myotonic dystrophy, and ataxia-telangiectasia. The final category, other, is poorly defined and is meant to include any condition that does not fit elsewhere in the etiologic scheme. The appearance of abnormal carbohydrate metabolism in association with any of these secondary causes does not necessarily indicate the presence of underlying diabetes, although, in some cases, mild, asymptomatic primary diabetes is made overt by the secondary illness.
The prevalence of diabetes is difficult to determine because various standards, many no longer acceptable, have been used in diagnosis. If fasting hyperglycemia is the diagnostic standard, the prevalence in the United States is probably 1 to 2 percent. Using data from the National Health Interview Surveys, an estimate of 3.1 percent was made in 1993; the National Diabetes Data Group, using the response to a 75-g oral glucose tolerance test as the diagnostic criterion, estimated the prevalence of diabetes at 6.6 percent, with 11.2 percent of the population having impaired glucose tolerance. These figures are almost certainly too high. Most subjects who are diagnosed as having impaired glucose tolerance or diabetes on the basis of oral glucose tolerance testing never develop fasting hyperglycemia or symptomatic diabetes when followed longitudinally. For example, in a massive screening program (more than 300,000 subjects) carried out in Cleveland, Ohio, only 31 percent of persons who had 2-h glucose values of 10 mmol/L (180 mg/dL) or higher in the glucose tolerance test progressed to overt diabetes after 5 years. Other studies confirm the imprecision of oral glucose challenges in predicting or diagnosing diabeteshence the estimates of 1 to 2 percent prevalence used here. Similar conclusions have been reached in Sweden, where the prevalence is around 1.5 percent. Estimates for IDDM are more reliable than for the NIDDM because most patients are diagnosed after the abrupt appearance of symptoms. In England, the prevalence of the type 1 disorder is estimated to be 0.22 percent by age 16, and a study in the United States suggested a prevalence of 0.26 percent by age 20. If the prevalence of diabetes is about 2 percent, it follows that NIDDM is seven to eight times more common than IDDM. The ratio of the frequency of IDDM to that of NIDDM varies with age, being higher if a young population is studied and lower in the older age range. The cited prevalences are for populations as a whole. Certain subsets have different rates. For example, more than 40 percent of Pima Indians in the United States have type 2 NIDDM.
The fact that persons with asymptomatic, undiagnosed diabetes occasionally develop complications despite the absence of fasting hyperglycemia has led to suggestions that large-scale screening with glucose tolerance tests be instituted. For the reasons given above, this course seems unwise...
Table of ContentsPart I: Introduction to Clinical Medicine. Part II: Cardinal Manifestations and Presentation of Disease. Part III: Genetics and Disease. Part IV: Clinical Pharmacology. Part V: Nutrition. Part VI: Oncology and Hematology. Part VII: Infectious Diseases. Part VIII: Disorders of the Cardiovascular System. Appendix A: Laboratory Values of Clinical Importance.
An Interview with Eugene Braunwald, M.D.
Barnes & Noble.com: How long have you been editing Harrison's and how is it possible to coordinate and organize such a vast amount of material for a new edition?
Dr. Eugene Braunwald: I have been an editor of Harrison's for ten editions (the 6th through the 15th) and editor-in-chief for the 11th and 15th editions. I first became an editor in 1967.
The workload is quite heavy. It is about half-time for one year every edition, i.e. every three and a half years. During the other two and a half years there is a constant "drumbeat" of work, approximately 10 percent to 20 percent effort, especially now that the editors also have responsibility for Harrison's On-Line.
The "long" editorial meeting of the Harrison's editors was begun by Tinsley Harrison with the first edition and is one of the keys to the book's success. The editors (and their families) meet at a beautiful location for eight to ten days and immerse themselves totally in planning the table of contents and selecting authors for the next edition. Although each editor has specific areas of responsibility (mine are the cardiovascular, respiratory and renal systems), the table of contents is the responsibility of the entire group. The intense interplay among the editors during this "long" meeting also assures an integrated approach to the book, the avoidance of overlap and of contradictions. The camaraderie among the editors in this setting enhances frank discussion, critique, and constructive criticism.
A key task in editing a large multi-authored text is to develop a forward-looking table of contents and to identify outstanding authors who are true authorities in their field and have a track record for delivering their work on time.
B&N.com: This edition has more than 90 new chapters. How do the number of changes in this edition compare to previous revisions, and what changes do you personally think were the most important?
EB: The changes introduced into the 15th edition represent the largest changes made in any edition since I joined the book. These changes have resulted from two influences: a) the dramatic impact of the advances in genetics and of molecular biology on all aspects of clinical internal medicine. These developments have to be made understandable to the practicing physician. b) The emergence of evidence-based medicine as a foundation for clinical practice. This translates into practice guidelines, algorithms, and crisp descriptions of diagnostic and therapeutic strategies. In addition, a modern textbook must also point the physician to principles of cost-effective care.
B&N.com: Harrison's 15th has a detailed chapter on Alternative Medicine for the first time. Why was this included?
EB: During the planning meeting for the 15th edition, the editors debated at great length about whether or not to add a chapter on Alternative Medicine. Since this approach is used so widely today, we decided that we must include it. To me "alternative medicine" is quite appropriate as long as its effectiveness and safety have been established by rigorous evidence. We don't always have to understand how a therapy works as long as we are confident that it does work.
B&N.com: Harrison's is the No. 1 bestselling medicine text in the world. Why do you think it is the preferred reference? What do you think makes it stand out?
EB: I think the book is so well received because it possesses several features:
a) Harrison's can be trusted. The editors are international authorities, and they author many of the chapters themselves. They recruit truly authoritative authors. In addition, all of the sections and individual chapters are carefully reviewed -- line by line -- by the editors and then systematically reviewed by outside experts and special consultants to assure accuracy and clarity.
b) The "whole is greater than the sum of the parts". The book is an integrated effort. Duplication and contradiction are kept to an absolute minimum.
c) Harrison's integrates basic science and pathophysiology with clinical medicine. The front of the book summarizes the science underlying clinical practice and describes the cardinal manifestations of disease. Patients present with symptoms such as chest pain, fever, or dizziness, not with myocardial infarction, gram negative septicemia, or a cerebellar tumor. Therefore, we deem it essential to describe how to approach patients with these symptoms in one portion of the book, and the diseases themselves in another, with appropriate cross-referencing. This approach seems obvious, but it is unique to Harrison's among major medical textbooks. It was Tinsley Harrison's idea, and we have continued it through 15 editions.
d) Harrison's is complete and is packed with an enormous quantity of information that has been carefully considered, sifted, and integrated.
e) Harrison's is current. In addition to being on an accelerated publication schedule, the most recent developments are added in the proof stage. Now, with Harrison's On-Line, key developments are added on a daily basis.
f) The editors are all distinguished physician-scientist-administrators, but they have a deep commitment to the excellence of the book. It is a labor of love.
B&N.com: Could you tell us a bit about your background? What are your special interests? And are there any other books you've recently read that you would like to recommend?
EB: I received my M.D. from New York University and trained at Mt. Sinai, Columbia, and Johns Hopkins. I have served as chief of Cardiology at the National Institutes of Health, and Chief of Medicine at the University of California, San Diego and at the Brigham and Women's Hospital, Harvard Medical School.
My professional life has always consisted of research in and practice of cardiology, teaching of internal medicine, administration and, of course, editing. I am editor of Heart Disease and the Atlas of Heart Disease (a 12-volume series); and I am co-editor, with Lee Goldman, of Primary Cardiology.
I enjoy reading history and biography. I have recently completed the new two-volume biography of Adolph Hitler by Ian Kershaw, Hitler: 1889-1935 Hubris and Hitler: 1936-1945 Nemesis. Although the story is gruesome, it teaches the reader the terrible danger of getting on a slippery slope. My principal avocation is classical music, and I listen to CDs at least 15 hours a week and always when editing Harrison's.