Congestive Heart Failure

     Congestive heart failure is a condition in which the heart can no longer pump blood efficiently throughout the body. Due to the inability of the heart to adequately pump blood, blood backs-up into the venous system (the veins of the body where blood is returning from the body to the heart). The blood which backs-up causes "congestion" in these organs.

    This congestion is manifest by peripheral edema (limb swelling, usually in the legs), pulmonary edema (fluid in the lungs, causes coughing, difficulty breathing, shortness of breath), congestive hepatomegaly (liver damage due to backed-up blood in the liver), and jugular venous distention (swelling of the neck veins due to excess blood).

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Immune Surveillance: A Balance Between Pro- and Anti-tumor Immunity

Immune Surveillance: A Balance Between Pro- and Anti-tumor
Immunity

Suzanne Ostrand-Rosenberg
University of Maryland, Department of Biological Sciences, 1000 Hilltop Circle, Baltimore, MD
21250, 410 455-2237 (voice), 410 455-3875 (FAX), < srosenbe@umbc.edu>

Summary
Pre-cancerous and malignant cells can induce an immune response which results in destruction of
transformed and/or malignant cells, a process known as immune surveillance. However, immune
surveillance is not always successful, resulting in “edited” tumors that have escaped immune surveillance. Immunoediting is not simply the absence of anti-tumor immunity, but is due to protumor immunity that blocks anti-tumor adaptive and innate responses, and promotes conditions that favor tumor progression. Several immune pro-tumor effector mechanisms are up-regulated by chronic inflammation, leading to the hypothesis that inflammation promotes carcinogenesis and tumor growth by altering the balance between pro-and anti-tumor immunity, thereby preventing the immune system from rejecting malignant cells, and providing a tumor-friendly environment for progressive disease.

Introduction
The concept that the immune system can be harnessed as a therapeutic agent to treat established tumors (immunotherapy) was first proposed in the early 1900’s by Paul Ehrlich. He suggested that molecules that we now know as antibodies, could deliver toxins directly to cancer cells. Ehrlich’s “magic bullet” strategy was expanded upon in the 1950’s by Burnet and Thomas. They hypothesized that the immune system may also protect against nascent cancers by destroying malignant cells before they developed into detectable tumors, a concept that has become the immune surveillance hypothesis [1,2]. Although enthusiasm for the validity of immunotherapy and immune surveillance waned in the 1970’s, subsequent studies demonstrated that the immune system can protect against tumor onset and be manipulated to reject established tumors. Revival of the immune surveillance hypothesis led to a re-working of the initial concept, to include the concept of “immunoediting.” During immunoediting, the immune system destroys many pre-cancerous and malignant cells; however, some cells escape the immune response and give rise to progressively growing tumors. Immunoediting is thought to continue throughout the life of the tumor so that the phenotype of an established tumor has been directed by the host’s immune response. It has also become apparent that both innate and adaptive immunity have a “dark” side and can promote tumor progression as well as mediate tumor destruction. Not surprisingly, chronic inflammation, which has long been associated with increased tumor risk, is involved in polarizing immunity towards those effectors that facilitate tumor growth. As a result, the immune system has the potential to either promote or  delay tumor onset and progression, and the effectiveness of immune surveillance and the efficacy of immunotherapy depend on the balance between these diametric opposites (Figure 1). After a brief over-view of the observations supporting the concept of immune surveillance, this article will review the cells that mediate pro-and anti-tumor immunity including a discussion of how inflammation polarizes innate and adaptive immunity towards either a protumor or anti-tumor phenotype.

Immune surveillance and immunoediting
Rejuvenation of the concept that the immune system protects against nascent malignant cells
occurred with the demonstration that mice deficient for various components of the adaptive or innate immune systems were more likely to develop some types of tumors, specifically sarcomas as opposed to carcinomas, as compared to immune competent mice, when exposed to carcinogens or transplanted with syngeneic tumor cells. Immune deficiencies included the absence of B cells and αβ or γδ T cells due to deletion of the recombination-activating gene-2 (RAG2) required for immunoglobulin and T cell receptor gene rearrangements, and the absence of interferonγ (IFNγ) or the ability to respond to IFNγ, a key mediator of cellular immunity. Similarly, mice that were knocked-out for perforin, an essential molecule for cell-mediated cytotoxicity used by most effector cells of the innate and adaptive immune systems, or mice deficient for natural killer (NK) or NKT cells, effector cells of the innate immune system, were also more susceptible to spontaneous tumors or had more rapid growth rates of transplanted tumors as compared to wild type or immune competent mice [3,4]. Circumstantial evidence suggests that immune surveillance and immunoediting also occurs in cancer patients. Individuals with hereditary or acquired immunodeficiencies have higher incidences of some types of viral- and carcinogen-associated cancers. Organ transplant patients maintained on immune suppressive drugs are 3–8 fold more likely to develop cancer than
normal controls, although tumors are not randomly distributed in all anatomical locations [1, 2]. In contrast, ovarian, colorectal [5], and melanoma patients whose tumors have high levels of tumor-infiltrating lymphocytes have a better prognosis [1,2]. Collectively, experimental
studies and the clinical observations in patients indicate that the immune system can foil carcinogenesis and mediate regression of established tumor.

CD4+ and CD8+ T lymphocytes               CD4+ and CD8+ T cells are the principal helper and effector cells, respectively, of adaptive cellular immunity, and many immunotherapy strategies are aimed at activating these cells to promote tumor cell destruction and long-term immune memory against recurrence of primary disease or outgrowth of metastases. Type 1 CD4+ T cells (Th1) facilitate tissue destruction and tumor rejection by providing help to cytotoxic CD8+ T cells, while Type 2 CD4+ T cells T (Th2) facilitate antibody production by B cells and polarize immunity away from a beneficial cell-mediated anti-tumor response (Figure 2). CD4+ T regulatory cells (T regs), which are naturally occurring or antigen-induced, promote tumor immunity by blocking the activation of CD8+ cytotoxic T cells. Although additional studies are needed to fully characterize the mechanism(s) by which CD4+ T regs block CD8+ T cell activation, T reg expression of cytotoxic T lymphocyte antigen 4 (CTLA4), an inhibitory signal for T cells, may be involved [6]. As for many pro-tumor mediators, inflammation enhances T reg function since prostaglandin E2 (PGE2) causes differentiation of T regs and increases their immune suppressive activity [7,8]. In addition to their inhibiting CD8+ T cell activation, CD4+ T regs block killing by natural killer cells [9], and thereby down-regulate both adaptive and innate anti-tumor immunity. Although most T regs are CD4+, CD8+ T regs induced by plasmacytoid DC have been identified in ovarian cancer patients [10].  Recently identified CD4+ Th17 cells [11,12], may also promote tumor progression. Th17 cells are induced by IL-23, a cytokine closely related to IL-12 and whose receptor shares the IL-12Rβ1 with IL-12 [13]. Upon activation by IL-23, Th17 cells produce IL-17 which exacerbates inflammation by inducing IL-6, TNFα, G-CSF, and other acute phase proteins [14]. IL-23 itself, has been shown to reduce CD8+ T cell infiltration into tumors, thereby promoting tumor growth [13,15] (Figure 2). Earlier experiments using IL-17-transfected tumor cells were inconclusive as to whether IL-17 promoted tumor growth or tumor rejection [16, 17]. This ambiguity may be explained by a recent study showing that Th17-induced IL-6 blocks CD4+ T regs [18]. Additional experiments are clearly necessary to clarify the roles of IL-23, Th17 cells, IL-17, and regulatory T cells in tumor progression.

B lymphocytes
Tumor-reactive monoclonal antibodies can have significant anti-tumor efficacy when passively administered to cancer patients. In contrast, most cancer vaccines or other therapies that are aimed at inducing tumor-reactive antibodies are largely ineffective in promoting tumor rejection, although there are exceptions [19]. More recent experiments indicate that activated B cells and their soluble products, presumably antibodies, can also facilitate carcinogenesis. Using a transgenic mouse model in which the human keratin 14 promoter drives expression of early region genes of human papilomavirus 16, B cells were shown to promote a chronic inflammatory microenvironment that recruits innate immune cells and factors to the tumor site, thus establishing a stromal environment that supports de novo carcinogenesis. Thus, humoral immunity can enhance malignant transformation by activating the innate immune system [20,21].

Macrophages
Macrophages are part of the innate immune system and play important roles in all aspects of
immunity. They are an exceptionally heterogeneous population of cells. Similar to CD4+ T cells, macrophages can contribute to tumor destruction or facilitate tumor growth and
metastasis, depending on their phenotype (Figure 3).

Macrophages that are “classically activated” by IFNγ and bacterial lipopolysaccharides destroy tumor cells through their production of nitric oxide and type 1 cytokines and chemokines. These macrophages also function as antigen presenting cells to activate cytotoxic CD8+ T [22]. In contrast, macrophages activated through the “alternative” pathway with IL-4, IL-13 and/or TGFβ promote tumor progression by enhancing angiogenesis and producing type 2 cytokines and chemokines [23]). Because of the similarities in cytokine profiles, Mills coined the terminology “M1/M2” after the Th1/Th2 paradigm for classically-activated and alternatively activated macrophages, respectively [24]. This jargon was further developed by Mantovani and colleagues, although they are careful to point out that macrophages are a continuum of phenotypes with M1 and M2 being the polarized extremes [25,26].

Most progressively growing tumors are infiltrated by large numbers of macrophages. These tumor-associated macrophages (TAMS) are a key component of the tumor stroma and are essential for the angiogenesis and matrix remodeling that supports progressively growing
neoplasms. Using a spontaneous mouse mammary tumor model, the transition from premalignant to malignant phenotype was associated with increased blood vessel formation, and that the elimination of TAMS blocked the neoangiogenesis, while early infiltration of TAMS
enhanced angiogenesis [27]. Metastasis is also enhanced by TAMS when they promote the intravasation of tumor cells into local blood vessels, as graphically shown by intravital multiphoton imaging of live mammary tumors in situ [28]. As shown in human ovarian cancer, TAMS also promote tumor progression by blocking the activation of tumor-specific T cells by their expression of B7-H4, a negative regulator of T cell activation [29] Since TAMS promote tumor progression, they are often called M2 macrophages. Gene profiling of TAMS and alternatively-activated peritoneal macrophages (M2) has confirmed that TAMS and M2 macrophages express many of the same molecules; however, TAMS also express some IFN-inducible genes that are characteristic of M1 macrophages, indicating that they are intermediate in the continuum of macrophage phenotypes [30,31].

Natural killer (NK) cells
NK cells are components of the innate immune system that interact with adaptive immunity through their production of cytokines that modulate dendritic cell (DC) and cytotoxic T cell
maturation. They are well recognized for their ability to directly lyse MHC class I-deficient tumor cells through the engagement of their activating receptors and lack of engagement of
their inhibitory receptors. However, a subset of NK cells are also cytotoxic for activated CD8+ T cells [32] and DC [33], and thereby can reduce CD8-mediated anti-tumor immunity. In addition, NK cells have been shown to inhibit DC-mediated antigen presentation through a non-cytotoxic mechanism [34], and elimination of NK cells increases activation of tumor specific CD8+ T cells following immunization [35].

NKT cells
NKT cells, which express both NK and TCR, bridge the innate and adaptive immune systems.
They are usually CD4+ and respond to lipid and glycolipid antigens as presented by nonclassical
MHC class I CD1d molecules. Until recently there was confusion as to whether NKT cells promote tumor rejection or enhance immune surveillance. NKT cells prevent the spread of B16 melanoma metastases and promote immune surveillance in mice treated with the carcinogen 3-methyl-cholanthrene. However, CD1d knockout mice, which lack CD1drestricted NKT cells, reject recurrent fibrosarcomas and are resistant to the 4T1 mammary carcinoma. These apparently conflicting findings were resolved when it was found that type I NKT cells, which express the invariant Vα14Jα18 TCR Vβ chain, mediate tumor rejection, while type II NKT cells, which express a non-Vα14Jα18 TCR Vβ chain, promote tumor growth [36].

Myeloid-derived suppressor cells (MDSC)
MDSC are a morphologically and functionally heterogenous population of cells of myeloid origin that are elevated in almost all patients and experimental mice with cancer [37]. They suppress both innate and adaptive anti-tumor immunity by inhibiting CD8+ and CD4+ T cells,
K and NKT cells, and by blocking DC maturation [38–41]. MDSC suppress T cells through their production of arginase and/or reactive oxygen species (ROS); however, there is variability in which mediator(s) is used depending on the tumor model [38,42,43]. MDSC heterogeneity
is further demonstrated by the requirement for CD80 expression for suppression by some MDSC [44] and the absence of CD80 on other MDSC [45,46]. Likewise, the IL-4Rα is required for the IL-13-induced activation of some MDSC [47]; however, equally suppressive MDSC have been isolated from IL-4R-deficient and wild type mice [40]. Suppression requires MDSC to T cell contact, and for suppression of CD8+ T cells, MDSC nitrate tyrosines of the CD8+ T cells’ TCRs, thereby rendering the T cells incapable of activation by peptide-MHC I complexes of antigen presenting cells [48].

In addition to inhibiting anti-tumor immunity by blocking T cell activation, MDSC also induce CD4+ T regs through an IL-10 and IFNγ-dependent process that is ROS-independent [49]. They also polarize immunity towards a tumor-promoting type 2 phenotype by secreting high levels of IL-10 and shutting down macrophage production of the Type 1 cytokine, IL-12. Macrophages in turn, up-regulate MDSC production of IL-10 further favoring tumor progression [50].

MDSC are similar to other immune system cells in that chronic inflammation heightens their pro-tumor activity. IL-1β and IL-6 increase the accumulation and suppressive activity of MDSC [46,51,52], while reductions in these cytokines reduce MDSC levels [52]. PGE2 is one of the inflammatory inducers of MDSC, since co-cultures of c-kit+ mouse bone marrow stem cells with PGE2 produce immune suppressive Gr1+CD11b+ MDSC [53], and cyclooxygenase-2 (COX-2) produced by human lung cancer cells up-regulates arginase expression in human MDSC [54].

Conclusions
The immune system has the capacity to either block tumor development and deter established
tumors, or to promote carcinogenesis, tumor progression, and metastasis. Which of these
conditions prevails depends on the balance between the pro- and anti-tumor mediators of both innate and adaptive immunity. Presumably, there are unifying mechanisms that orchestrate
immunity towards tumor promotion vs. tumor destruction. Since many of the tumor-promoting
elements of the immune system are induced by, or themselves cause, inflammation, chronic inflammation may be a key process that polarizes immunity towards a tumor-promoting phenotype [55]. Accordingly, chronic inflammation would produce an immune suppressive, tumor-friendly environment that would negate immune surveillance and be permissive for carcinogenesis. As tumor growth progressed and tumors themselves produced proinflammatory molecules, innate and adaptive immunity would be further polarized towards a tumor-promoting phenotype, creating an ideal environment for further tumor growth and metastasis (Figure 4). Chronic inflammation has long been associated with increased risk of tumor onset and progression, and is known to enhance angiogenesis and tissue remodeling, and promote protein and DNA damage through oxidative stress, processes that are integral to tumor progression [55–57]. By polarizing immunity towards a tumor-promoting phenotype, inflammation not only promotes the genetic and histological changes that facilitate carcinogenesis, but it also deters immune surveillance, thereby functioning as both an initiator and a protector for neoplastic cells.

Acknowledgments
The author’s laboratory is supported by National Institute of Health grants R01CA118550 and R01CA84232, and Susan G. Komen Foundation for the Cure BCTR0503885.

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53•. Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S. Prostaglandin E2 promotes tumor
progression by inducing myeloid-derived suppressor cells. Cancer Res 2007;67:4507–4513. [PubMed: 17483367]Using a mouse mammary tumor, this paper from the author’s laboratory demonstrated that the inflammatory agent PGE2 induces the differentiation of myeloid-derived suppressor cells from bone marrow stem cells and that tumor progression is delayed in mice that are deficient for the E-prostanoid receptor 2 for PGE2. This paper, together with ref. #54, provide direct evidence that induction of this important population of suppressor cells that is found in most cancer patients and experimental animals with tumors, is directly regulated by inflammation.
54•. Rodriguez PC, Hernandez CP, Quiceno D, Dubinett SM, Zabaleta J, Ochoa JB, Gilbert J, Ochoa AC. Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma. J Exp Med 2005;202:931–939. [PubMed: 16186186]This paper demonstrated that a mouse lung tumor produces COX-2 which up-regulates the immunosuppressive enzyme arginase I in myeloid-derived suppressor cells via the E-prostanoid receptor 4, thereby promoting immune suppression.                                            55•. Karin M, Greten FR. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 2005;5:749–759. [PubMed: 16175180]This comprehensive review article describes the studies demonstrating a linkage between infection, inflammation, and cancer, and proposed that NF-κB is a key regulatory molecule in inflammation-induced tumor progression.
It also reviews the various immune mediators that are activated by inflammation.
56. Balkwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 2005;7:211–217. [PubMed: 15766659]
57. de Visser KE, Eichten A, Coussens LM. Paradoxical roles of the immune system during cancer
development. Nat Rev Cancer 2006;6:24–37. [PubMed: 16397525]

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Guidelines for Chronic Kidney Disease

KDOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification Figures Tables Acronyms and abbreviations KDOQI advisory board members Work group and evidence review team membership and support group Foreword Part 1. Executive Summary Part 2. Background Part 3. Chronic kidney disease as a public health problem Part 4. Definition and classification of stages of chronic kidney disease * Guideline 1. Definition and Stages of Chronic Kidney Disease * Guideline 2. Evaluation and Treatment * Guideline 3. Individuals at Increased Risk of Chronic Kidney Disease

Part 5. Evaluation of laboratory measurements for clinical assessment of kidney disease * Guideline 4. Estimation of GFR * Guideline 5. Assessment of Proteinuria * Guideline 6. Markers of Chronic Kidney Disease Other Than Proteinuria Part 6. Association of level of GFR with complications in adults * Guideline 7. Association of Level of GFR With Hypertension * Guideline 8. Association of Level of GFR With Anemia * Guideline 9. Association of Level of GFR With Nutritional Status * Guideline 10. Association of Level of GFR With Bone Disease and Disorders of Calcium and Phosphorus Metabolism * Guideline 11. Association of Level of GFR With Neuropathy * Guideline 12. Association of Level of GFR With Indices of Functioning and Well-Being Part 7. Stratification of risk for progression of kidney disease and development of cardiovascular disease * Guideline 13. Factors Associated With Loss of Kidney Function in Chronic Kidney Disease * Guideline 14. Association of Chronic Kidney Disease With Diabetic Complications * Guideline 15. Association of Chronic Kidney Disease With Cardiovascular Disease Part 8. Recommendations for clinical performance measures Part 9. Approach to chronic kidney disease using these guidelines Part 10. Appendices * Appendix 1. Methods for Review of Articles * Appendix 2. Kidney Function and Associated Conditions in the United States: Methods and Findings From the Third National Health and Nutrition Examination Survey (1988 to 1994) * Appendix 3. Methodological Aspects of Evaluating Equations to Predict GFR and Calculations Using 24-Hour Urine Samples Part 11. Work group members Part 12. Acknowledgements Bibliography Disclaimer

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cause of hyponatremia

Major causes of hyponatremia

Disorders in which ADH levels are elevated
• Effective circulating volume depletion
• True volume depletion—vomiting, diarrhea, bleeding, urinary loss
• Congestive heart failure and cirrhosis
• Thiazide diuretics
• Syndrome of inappropriate ADH secretion
• Hormonal changes: adrenal insufficiency, hypothyroidism, and pregnancy

Disorders in which ADH may be appropriately suppressed
• Advanced renal failure
• Primary polydipsia
• Beer drinkers’ potomania

Pseudohyponatremia
• High plasma osmolality: hyperglycemia or mannitol
• Normal plasma osmolality: hyperlipidemia, glycine solutions, and hyperproteinemia

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dengue fever

Dengue Fever

Author: Daniel D Price, MD, Director of Ultrasound Fellowship, Department of Emergency Medicine, Highland General Hospital, Alameda County Medical Center
Coauthor(s): Sharon R Wilson, MD, Assistant Professor of Emergency Medicine, Department of Emergency Medicine, University of California at Davis Medical Center
Contributor Information and Disclosures
Updated: Jan 31, 2008

Introduction

Background
Dengue has been called the most important mosquito-transmitted viral disease in terms of morbidity and mortality. Dengue fever is a benign acute febrile syndrome occurring in tropical regions. In a small proportion of cases, the virus causes increased vascular permeability that leads to a bleeding diathesis or disseminated intravascular coagulation (DIC) known as dengue hemorrhagic fever (DHF). Secondary infection by a different dengue virus serotype has been confirmed as an important risk factor for the development of DHF. In 20-30% of DHF cases, the patient develops shock, known as the dengue shock syndrome (DSS). Worldwide, children younger than 15 years comprise 90% of DHF subjects; however, in the Americas, DHF occurs in both adults and children.
Dengue is a homonym for the African ki denga pepo, which appeared in English literature during an 1827-28 Caribbean outbreak. The first definite clinical report of dengue is attributed to Benjamin Rush in 1789, but the viral etiology and its mode of transmission via mosquitos were not established until the early 20th century.


Pathophysiology
Dengue viral infections frequently are not apparent. Classic dengue primarily occurs in nonimmune, nonindigenous adults and children. Symptoms begin after a 5- to 10-day incubation period. DHF/DSS usually occurs during a second dengue infection in persons with preexisting actively or passively (maternally) acquired immunity to a heterologous dengue virus serotype. Illness begins abruptly with a minor stage of 2-4 days' duration followed by rapid deterioration. Increased vascular permeability, bleeding, and possible DIC may be mediated by circulating dengue antigen-antibody complexes, activation of complement, and release of vasoactive amines. In the process of immune elimination of infected cells, proteases and lymphokines may be released and activate complement coagulation cascades and vascular permeability factors.
Frequency
United States
Between 1990 and 1992, reports of 10 imported cases of dengue fever were published. While still rare, this is a dramatic increase from 1 case reported during the period from 1987 to 1989; this probably results from increases in air travel and an exotic vector that has adapted to cold climates. Cases along the Texas-Mexico border have been cited recently.
International
Dengue virus causes about 100 million cases of acute febrile disease annually, including more than 500,000 reported cases of DHF/DSS. Currently, dengue is endemic in 112 countries. The world's largest known epidemic of DHF/DSS occurred in Cuba in 1981, with more than 116,000 persons hospitalized and as many as 11,000 cases reported in a single day. Current outbreaks can be monitored via the ProMed listserve by contacting owner-promed@promedmail.org.
Mortality/Morbidity
• Treated DHF/DSS is associated with a 3% mortality rate.
• Untreated DHF/DSS is associated with a 50% mortality rate.
Race
Ethnicity is nonspecific, but the disease's distribution is geographically determined. Fewer cases have been reported in the black population than in other races.
Sex
No predilection is known; however, fewer cases of DHF/DSS have been reported in men than in women.
Age
All ages are susceptible. In endemic areas, a high prevalence of immunity in adults may limit outbreaks to children.
Clinical
History
• Fever
o Abrupt onset, rising to 39.5-41.4°C
o Accompanied by frontal or retro-orbital headache
o Lasts 1-7 days, then defervesces for 1-2 days
o Biphasic, recurring with second rash but not as high
• Rash
o Initial rash transient, generalized, macular, and blanching; occurs in first 1-2 days of fever
o Second rash occurring within 1-2 days of defervescence, lasting 1-5 days
o Second rash morbilliform, maculopapular, sparing palms and soles
o Occasionally desquamates
• Bone pain
o Absent in dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS)
o After onset of fever
o Increases in severity
o Not associated with fractures
o May last several weeks
o Most common in legs, joints, and lumbar spine
• Miscellaneous symptoms
o Nausea and vomiting
o Cutaneous hyperesthesia
o Taste aberrations
o Anorexia
o Abdominal pain (severe in DHF/DSS)
Physical
• Fever
• Signs of intravascular volume depletion
o Hypotension with narrowed pulse pressure
• Hemorrhagic manifestations
o Positive tourniquet test
o Petechiae, purpura, epistaxis, gum bleeding, GI bleeding, menorrhagia
• Rash
• Hepatomegaly (inconsistent)
• Generalized lymphadenopathy
Causes
• Dengue virus types 1-4
o Aedes aegypti mosquito vector
o Human-mosquito-human cycle
o Found in tropical regions, especially Southeast Asia
Differential Diagnoses
Hepatitis
Tick-Borne Diseases, Rocky Mountain Spotted Fever

Malaria
Yellow Fever

Meningitis

Pediatrics, Bacteremia and Sepsis

Pediatrics, Meningitis and Encephalitis

Other Problems to Be Considered
Leptospirosis
Rickettsioses
River viruses
Scrub typhus
Typhoid
Viral infections (eg, influenza, chikungunya, Mayaro fever, Rift Valley fever, West Nile, Sindbis, and Ross River)
Workup
Laboratory Studies
• Isolation of virus in serum and detection of immunoglobulins (IgM and IgG) by enzyme-linked immunosorbent assay (ELISA) antibody capture, monoclonal antibody, or hemagglutination
• Complete blood count
o Hemoconcentration (hematocrit increased 20%)
o Thrombocytopenia (platelet count <100 x 109/L)
o Leukopenia
• Chemistry panel
o Electrolyte imbalances
o Acidemia
o Elevated BUN
• Liver function tests
o Elevated transaminases
o Hypoproteinemia
• Guaiac test for occult blood in stool
• DIC panel, as indicated
Imaging Studies
• Chest radiography
o Bronchopneumonia
o Pleural effusion
• Head CT scan without contrast
o For altered level of consciousness
o Intracranial bleeding
o Cerebral edema
Other Tests
• Electrocardiography
o Nonspecific changes may be effects of fever, electrolyte disturbances, tachycardia, or medications.
o Usefulness of these changes as a marker of cardiac involvement is unclear.
Treatment
Prehospital Care
• Initiate supportive therapy
o Intravenous (IV) crystalloids, as needed to keep systolic blood pressure above 90 mm Hg
o O2, empirically
Emergency Department Care
• Supportive therapy
o IV access, O2, and monitoring are helpful.
o IV crystalloids may be necessary for hypotension; central line may be needed.
o Correct electrolyte abnormalities and acidemia.
• Implement therapy for DIC if indicated.
• Corticosteroids are not helpful.
• No antiviral therapy is available.
Consultations
• Infectious disease
• Travel clinic, if available
Medication
No specific medications are indicated for direct treatment of the dengue virus infection.
Follow-up
Further Inpatient Care
• Admit to ICU if hypotensive or in DIC, otherwise admit to medicine ward.
o Patient may require a central line.
o Patient may require an arterial line.
o Patient may require blood components.
Deterrence/Prevention
• Reduce A aegypti vector populations.
• Reduce exposure to A aegypti.
o Use insect repellent.
o Sleep under a mosquito net in affected areas.
o Wear protective clothing.
• Vaccines against all 4 serotypes are currently under development. While this is challenging due to the complex immune response, vaccines may ultimately be the most effective control strategy, since vector control programs have been largely unsuccessful and of only short-term local benefit.
Complications
• Complications are rare but may include the following:
o Brain damage from prolonged shock or intracranial hemorrhage
o Myocarditis
o Encephalopathy
o Liver failure
Prognosis
• Morens states that the rapid clinical response to aggressive fluids and electrolytes in even moribund children with DHF/DSS "is among the most dramatic events in clinical medicine." Treated promptly, children in shock and coma can wake up and return to near normalcy within hours.
• Convalescence may be prolonged, with weakness and mental depression.
• Continued bone pain, bradycardia, and premature ventricular contractions (PVCs) are common.
• Survival is related directly to early hospitalization and aggressive supportive care.
• Dengue fever is not contagious through person-to-person contact.
Patient Education
• See Deterrence/Prevention section.
Miscellaneous
Medicolegal Pitfalls
• Failure to admit patients for aggressive supportive therapy
• Failure to rule out other possible illnesses and specific therapies
Special Concerns
• Pediatric deaths associated with dengue viral infection most commonly occur in infants younger than 1 year.

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Systemic lupus erythematosus

Systemic lupus erythematosus
Jessica J Manson* and Anisur Rahman
Address: Centre for Rheumatology Research, Windeyer Building, University College London,46 Cleveland Street, London W1T 4JF, UK
Email: Jessica J Manson* - j.manson@ucl.ac.uk; Anisur Rahman - anisur.rahman@ucl.ac.uk

Abstract
Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease, which is autoimmune in origin and is characterized by the presence of autoantibodies directed against nuclear antigens. It is a multi-system disease, and patients can present in vastly different ways. Prevalence varies with ethnicity, but is estimated to be about 1 per 1000 overall with a female to male ratio of 10:1. The clinical heterogeneity of this disease mirrors its complex aetiopathogenesis, which highlights the importance of genetic factors and individual susceptibility to environmental factors. SLE can affect every organ in the body. The most common manifestations include rash, arthritis and fatigue. At the more severe end of the spectrum, SLE can cause nephritis, neurological problems, anaemia and
thrombocytopaenia. Over 90% of patients with SLE have positive anti-nuclear antibodies (ANA). Significant titres are accepted to be of 1:80 or greater. SLE is a relapsing and remitting disease, and treatment aims are threefold: managing acute periods of potentially life-threatening ill health, minimizing the risk of flares during periods of relative stability, and controlling the less lifethreatening, but often incapacitating day to day symptoms. Hydroxychloroquine and non-steroidal anti-inflammatory drugs are used for milder disease; corticosteroids and immunosuppressive therapies are generally reserved for major organ involvement; anti-CD20 monoclonal antibody is now used in patients with severe disease who has not responded to conventional treatments. Despite enormous improvements in prognosis since the introduction of corticosteroids and immunosuppressive drugs, SLE continues to have a significant impact on the mortality and morbidity of those affected.
Disease name and synonyms

Systemic lupus erythematosus Lupus
Definition/Diagnostic criteria
Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease which is autoimmune in origin, and characterized by the presence of autoantibodies directed against nuclear antigens. It is, by definition, a multi-system disease, and patients can present in vastly different ways. Classification criteria have been developed, in part in an attempt to keep the patient group as homogeneous as possible for research purposes. These criteria (Table 1), which are published by the American College of Rheumatology (ACR), were revised in 1982 [1] and combine clinical signs and symptoms with abnormalities detected in blood tests such as a positive anti-nuclear antibody or thrombocytopaenia. They were further updated in 1997 [2] to reflect a greater under- standing of the role of antiphospholipid antibodies in patients with SLE.
Epidemiology
SLE is up to 10 times more common in women than men, and typically has a predilection for women in their childbearing years [3]. Reliable data about the prevalence of SLE are difficult to come by. Variable methods for data collection and inconsistency regarding case definition contribute to this problem, but it is clear that the statistics vary with ethnicity. The overall prevalence is estimated to be about 1 per 1000. A study from Birmingham, UK, found the prevalence to be 27.7/100,000 in the general population, but nearly 9 times higher in Afro-Caribbean females [4]. Data from a national health survey in the USA found the self-reported prevalence of SLE (defined as having been given a diagnosis of SLE by a physician) to be 241/100,000 [5]. Recognizing that this may well be an over-estimate, combining self-reporting with evidence of a current prescription for anti-malarials, corticosteroids, or other immunosuppressive medications reduced this figure to 53.6/100,000 [5].
Aetiology/Pathogenesis
The clinical heterogeneity of this disease is mirrored by its complex aetiopathogenesis (reviewed in [6]). Twin studies initially indicated the importance of genetic factors, and genome screening has highlighted a number of potential loci of interest [7]. In the susceptible individual, disease may result from a variety of environmental triggers including exposure to sunlight, drugs and infections, particularly with Epstein-Barr virus. Even within one patient, lupus flares can result from different precipitants at different times. Despite extensive work, the precise pathological mechanisms of SLE are still not fully understood. The majority of patients have elevated levels of autoantibodies, directed
in particular against nuclear components such as nucleosomes, DNA and histones, and it is generally accepted that at least some of these have a directly pathogenic role, either by precipitating as immune complexes in target organs or by cross-reacting with other functionally relevant antigens. The presence and persistence of these autoantibodies indicate an abnormality in tolerance, which results from a combination of abnormal handling of autoantigens following apoptosis, and deranged function of T and B lymphocytes.
Differential diagnosis
The list of possible differential diagnoses is broad, and will vary with the presentation of each case. The non-specific clinical features of widespread pain and fatigue mean that in some cases fibromyalgia and other chronic pain syndromes may be appropriate differentials. Indeed, it is important to note that fibromyalgia and SLE can co-exist in the same patient. A number of patients will present with a cluster of features suggestive of an autoimmune rheumatic disease, though at initial presentation the final diagnosis appears unclear. A proportion of these "undifferentiated" patients will go on to develop full blown SLE, or other diseases such as systemic sclerosis. Some malignancies, particularly lymphoma and leukaemia, which are relevant to this age-group, can present with a similar clinical picture. Similarly, there is significant overlap with the presentation of some infections, notably,
Table 1: Diagnostic criteria of SLE. Adapted from Tan et al, 1982 [1]. A person is said to have SLE if he/she meets any 4 of these 11
criteria simultaneously or in succession
Criterion Definition/examples
1. Malar rash Fixed erythema over the malar eminences, tending to spare the
nasolabial folds
2. Discoid rash Erythematosus raised patches, may scar
3. Photosensitivity Skin rash as a result of unusual reaction to sunlight
4. Oral ulcers Usually painless
5. Arthritis Non-erosive: Jaccoud's arthropathy
6. Serositis a) Pleuritis – pleuritic pain, pleural rub, pleural effusion b) Pericarditis –
ECG changes, rub, pericardial effusion
7. Renal disorder a) Proteinuria (> 3+ or 0.5 g/day) b) Cellular casts in urine
8. Neurological disorder a) Seizures b) Psychosis
9. Haematological disorder a) Haemolytic anaemia b) Leukopaenia c) Lymphopaenia d)
Thrombocytopaenia
10. Immunological disorder a) Anti-DNA antibodies b) Anti-Sm antibodies c) Anti-phospholipid antibodies
11. Anti-nuclear antibody Exclude drug causes tuberculosis, HIV/AIDS and bacterial endocarditis. In view of the immunosuppressive nature of the required drugs, it is clearly crucial to exclude underlying infection before starting treatment for SLE.
The acutely ill patient
Even when the diagnosis of SLE has been established, the acutely ill patient must be thoroughly assessed before the illness is presumed to be due to a flare of their lupus. Since both SLE itself and the drugs used to treat it can cause immunosuppression, sepsis is common and may present in atypical ways. Thus, the physician must remain vigilant in looking for infection. In addition, the possibility of catastrophic antiphospholipid syndrome should be considered. We are becoming increasingly aware of this rare, but devastating association. A recent paper [8] describes a series of 80 such patients. The occlusion of multiple small vessels results in multi-organ failure, and mortality was reported to be 48% in this group.
Clinical manifestations
The clinical features of SLE are diverse and will be discussed by system as much as possible, and where appropriate, each section will refer to a review for more information. Quoted frequencies of each disease manifestation come from a prospective European study which followed 1000 patients with SLE over 10 years [3].
Constitutional symptoms such as fatigue, weight loss and fever are not life threatening, but have a significant impact on quality of life. Patients with SLE describe overwhelming
fatigue and unsatisfying sleep, though the extent to which this tiredness relates directly to lupus disease activity remains controversial [9].
Renal disease affects about 30% of patients with SLE, and remains the most dangerous, life-threatening complication. Patients who will develop lupus nephritis most commonly
do so within the first few years of their disease. As renal involvement is often asymptomatic, particularly initially, regular urinalysis and blood pressure monitoring is
crucial. Renal involvement is characterized by proteinuria (> 0.5 g/24 hours), and/or red cell casts, and early referral for renal biopsy is generally advocated. The histological classification of lupus nephritis has recently been updated [10]. Table 3 shows the revised classification criteria, developed under the auspices of the International Society of Nephrology and the Renal Pathology Society. Lupus nephritis classes I-V describe mesangial (I, II), proliferative (III, IV) or membranous (V) lesions, and each biopsy may have features of more than one class of disease. Classes III and IV are subdivided further depending on the activity or chronicity of the abnormalities seen. Class VI is reserved for widespread sclerotic disease. The renal biopsy findings are used to assess prognosis and guide management. Response to treatment can be assessed using serial urine protein/creatinine ratios, in addition to other more general measures of disease activity (see below).
Neuropsychiatric lupus (NPSLE) is seen in about 20% of cases. NPSLE is often a difficult diagnosis to make. Not only are there 19 different clinical manifestations as described by the American College of Rheumatology [11] (Table 3), but there is also no single, simple diagnostic test. In many cases, a brain biopsy would be the only definitive test, and this is rarely performed. The clinical features vary from central nervous system disease causing headache and seizures, or psychiatric diagnoses including
Table 2: The revised classification of glomerulonephritis in SLE [10]
Class I Minimal mesangial lupus nephritis Normal on light microscopy. Mesangial immune deposits on immunofluorescence
Class II Mesangial proliferative lupus nephritis Mesangial hypercellularity or matrix expansion, with mesangial immune deposits on
immunofluorescence
Class III Focal lupus nephritis Glomerulonephritis involving < 50% of glomeruli, typically with sub-endothelial immune deposits.
Class IV Diffuse lupus nephritis Glomerulonephritis involving > 50% of glomeruli, typically with sub-endothelial immune deposits. Can be
segmental or global.
Class V Membranous lupus nephritis Global or segmental sub-epithelial immune deposits
Class VI Advanced sclerotic lupus nephritis > 90% of glomeruli globally sclerosed without residual activity
Table 3: Neuropsychiatric syndromes seen in systemic lupus
erythematosus [11]
Central nervous system Peripheral nervous system
Aseptic meningitis Acute inflammatory polyneuropathy
Cerebrovascular disease Autonomic disorder
Demyelinating syndrome Mononeuropathy (single or multiplex)
Headache Myasthenia gravis
Movement disorder Cranial neuropathy
Myelopathy Plexopathy
Seizure disorders Polyneuropathy
Acute confusional state
Anxiety disorder
Cognitive dysfunction
Mood disorder
Psychosis
depression and psychosis, to peripheral nervous system involvement causing neuropathy.
The investigations of choice will vary with the presentation. Central nervous system disease usually warrants magnetic resonance imaging (MRI) of brain or spinal cord, and examination of the cerebrospinal fluid where appropriate. It must be remembered, however, that normal investigations, and lack of evidence of disease activity in another system, do not rule out the diagnosis of NPSLE – in a recent study of MRI in patients with NPSLE, 34% had normal brain scans [12]. This included patients with focal disease clinically. Interestingly, only one of the 85 patients included in this study proceeded to brain biopsy, which is probably indicative of generally accepted practice. The frequency of musculoskeletal disease in SLE means that rheumatologists often make the initial diagnosis. Arthralgia and myalgia occur in most patients. The classical "Jaccoud's arthropathy" although not causing a destructive arthritis, can result in significant deformity and functional impairment. A rheumatoid-like arthritis is seen more rarely, sometimes associated with a positive rheumatoid factor. Similarly, an overlap with myositis also occurs.
Skin involvement in lupus is also very common. In addition to the classic malar and discoid rashes, more generalized photosensitivity is often present, and furthermore sun exposure is known to trigger systemic disease flares. Alopecia can be scarring when associated with discoid lesions, or more diffuse, often fluctuating with disease activity. Recurrent crops of mouth ulcers are also a feature of active disease. Other oral manifestations include dryness as a result of secondary Sjogren's syndrome, and these patients also experience dryness of the eyes and vagina.
Haematological features include normocytic normochromic anaemia, thrombocytopaenia (sometimes, but not always associated with antiphospholipid antibodies) and leukopaenia. Severe haematological disease can occur, but this is relatively rare [13].
Pleuritis , causing chest pain, cough and breathlessness, is the most common pulmonary manifestation of SLE [14]. Although pleuritic symptoms may relate directly to active lupus, pulmonary embolism must always be considered, particularly in those who have antiphospholipid antibodies. Pleural effusions are usually exudates, have low levels of complement, and test positive for anti-nuclear antibodies (ANA). Infections are common, and any parenchymal lesion must be treated as infectious until proven otherwise. Rarer complications include interstitial lung disease and pulmonary hypertension (both more common in systemic sclerosis) and pulmonary haemorrhage.
Gastrointestinal involvement [15] most commonly results in non-specific abdominal pain and dyspepsia though it can be unclear whether such pain results from the illness itself or from drug side-effects. Hepatosplenomegaly can come and go with disease activity. Mesenteric vasculitis is very rare, but can be life-threatening, especially if it leads to perforation, and may only be diagnosed at laparotomy. SLE is associated with a variety of vascular manifestations. Raynaud's phenomenon, causing the classical triphasic colour change, was seen in 16% of patients in the European study[3]. Abnormalities in the micro vasculature are also thought to account for the association with livedo reticularis. Arterial and venous thrombosis affected up to 10% of the cohort, particularly in association with the secondary antiphospholipid syndrome. In the last decade, it has become clear that patients with SLE are at increased risk of atherosclerosis. Chronic inflammation and the use of corticosteroids contribute to this risk, and have led rheumatologists to treat SLE as an independent risk factor for stroke and myocardial infarction, much as an endocrinologist might regard the risk associated with diabetes. Ward [16] showed that in women between 18 and 44 years of age, those with SLE were twice as likely to develop a myocardial infarction or stroke, and nearly 4 times as likely to present with heart failure. Screening for cardiac disease with echocardiography (ECHO) has established that asymptomatic valvular lesions are common. In addition, pericarditis and pericardial effusions are common though myocardial disease is relatively rare.
Laboratory findings
Over 90% of patients with SLE have positive anti-nuclear antibodies (ANA). Significant titres are accepted to be of 1:80 or greater. ANA although sensitive, is far from specific for SLE. A positive ANA is also seen in many other illnesses including systemic sclerosis and polymyositis, as well as some chronic infections. All patients should be screened for extractable nuclear antigens (ENA). Different ENAs are associated with different disease manifestations – for instance, anti-Sm is associated with renal involvement, and anti-Ro with secondary Sjogren's syndrome. Antibodies to double-stranded DNA (dsDNA), and more recently to nucleosomes (though this test is not commonly available in most routine labs) are more specific for SLE, and anti-dsDNA titres are also predictive of renal involvement. Typically, a disease flare is accompanied by a rising titre of dsDNA antibodies and erythrocyte sedimentation rate (ESR), and falling complement and lymphocyte count. The C-reactive protein (CRP), unlike the ESR, does not usually rise with disease activity unless there is arthritis or serositis, and a raised CRP in a patient with SLE must always make you consider infection.
Treatment
SLE is a relapsing and remitting disease, and treatment aims are threefold: managing acute periods of potentially life-threatening ill health, minimizing the risk of flares during periods of relative stability, and controlling the less life-threatening, but often incapacitating day to day symptoms. Our limited understanding of the precise pathogenesis of SLE means that the majority of treatments are still broadly immunosuppressive in action, and hence carry asignificant risk of adverse effects. At the milder end of the spectrum, hydroxychloroquine is commonly used. This is effective for skin disease, joint pain and fatigue. Non-steroidal anti-inflammatory drugs are also useful for arthralgia and arthritis, though more aggressive treatment with methotrexate may be required. Low dose oral steroids or intramuscular injections of depot steroid preparations are sometimes used for mild disease, but immunosuppressive therapies and high dose steroids are generally reserved for major organ involvement. Lupus nephritis remains the complication which carries with it the biggest risk of death or long-term morbidity. Treatment of renal disease (Cochrane review [17]) was standardized by the National Institute of Health guidelines [18] published in 1992. Combining high dose corticosteroids with cyclophosphamide was the gold standard in the management of proliferative lupus nephritis for many years. Although efficacious, this regimen is limited
by significant toxicity. Both agents are immunosuppressive. In addition, corticosteroids are associated with a whole host of adverse effects including osteoporosis and weight gain, and cyclophosphamide can cause haemorrhagic cystitis and infertility. More recently, the classic regimen of monthly boluses of 1g cyclophosphamide for 6 months, followed by once every three months for the next 2 years, has been modified by some groups, who instead advocate the use of "low-dose" cyclophosphamide (6 fortnightly pulses of 500 mg). The so-called Euro-lupus trial, published in 2002, showed that the use of this lower dose regimen has better outcomes in terms of infertility risk, with no deleterious impact on renal disease [19]. Following remission induction, azathioprine is commonly used for maintenance therapy. Mycophenolate mofetil [20] has been added to the repertoire of drugs used for the treatment of lupus nephritis. This is now used commonly as maintenance therapy following cyclophosphamide, and its use in the induction phase has been adopted in some centres. Similarly, immunosuppressive treatments, such as cyclophosphamide and azathioprine, are also used for central nervous system involvement and rarely, serositis and haematological disease. Furthermore, persistent autoimmune thrombocytopenia sometimes requires immunoglobulin. In an attempt to improve management, biological therapies are being developed, which target specific cells or molecules within the abnormally functioning immune system. For example, the depletion of B cells using rituximab, an anti-CD20 monoclonal antibody previously used in the treatment of B cell lymphomas, is now being used in patients with severe disease which has not responded to conventional treatments [21].
Prognosis
Despite significant advances in treatment over the last decade, SLE still caries a significant risk of mortality and long term morbidity. A European study of 1000 patients with SLE, demonstrated a 10 year survival probability of 92% overall, reduced to 88% in those who presented with nephropathy [3]. Mean age at death was 44, but varied widely from 18–81 years. Cause of death varies with disease duration. In one cohort [22]), renal lupus accounted for the biggest number of deaths in those with less than 5 years of disease, whereas vascular disease was the most important factor in the group who died later in the disease course.As mentioned previously, we are becoming increasingly aware of the impact that premature atherosclerosis is having on the long term prognosis of lupus patients who survive the early years of illness. As we develop better immune targeted therapies, optimizing the management of these longer term complications will become increasingly important.
References
1. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ: The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982, 25:1271-1277.
2. Hochberg MC: Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997, 40:1725.
3. Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, Lavilla P, Mejia JC, Aydintug AO, Chwalinska-Sadowska H, de Ramon E, Fernandez- Nebro A, Galeazzi M, Valen M, Mathieu A, Houssiau F, Caro N, Alba P, Ramos-Casals M, Ingelmo M, Hughes GR, European Working Partyon Systemic Lupus Erythematosus: Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore) 2003, 82:299-308.
4. Johnson AE, Gordon C, Palmer RG, Bacon PA: The prevalence and incidence of systemic lupus erythematosus in Birmingham, England. Relationship to ethnicity and country of birth. Arthritis Rheum 1995, 38:551-558.
5. Ward MM: Prevalence of physician-diagnosed systemic lupus erythematosus in the United States: results from the third national health and nutrition examination survey. J Womens Health (Larchmt) 2004, 13:713-718.
6. Manson JJ, Isenberg DA: The pathogenesis of systemic lupus erythematosus. Neth J Med 2003, 61:343-346.
7. Nath SK, Kilpatrick J, Harley JB: Genetics of human systemic lupus erythematosus: the emerging picture. Curr Opin Immunol 2004, 16:794-800.
8. Asherson RA, Cervera R, Piette JC, Shoenfeld Y, Espinosa G, Petri MA, Lim E, Lau TC, Gurjal A, Jedryka-Goral A, Chwalinska-Sadowska H, Dibner RJ, Rojas-Rodriguez J, Garcia-Carrasco M, Grandone JT, Parke AL, Barbosa P, Vasconcelos C, Ramos-Casals M, Font J, Ingelmo M: Catastrophic antiphospholipid syndrome: clues to the pathogenesis from a series of 80 patients. Medicine (Baltimore) 2001, 80:355-377.
9. Tench CM, McCurdie I, White PD, D'Cruz DP: The prevalence and associations of fatigue in systemic lupus erythematosus. Rheumatology (Oxford) 2000, 39:1249-1254.
10. Weening JJ, D'Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, Balow JE, Bruijn JA, Cook T, Ferrario F, Fogo AB, Ginzler EM, Hebert L, Hill G, Hill P, Jennette JC, Kong NC, Lesavre P, Lockshin M, Looi LM, Makino H, Moura LA, Nagata M: The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 2004, 15:241-250.
11. The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 1999, 42:599-608.
12. Jennings JE, Sundgren PC, Attwood J, McCune J, Maly P: Value of MRI of the brain in patients with systemic lupus erythematosus and neurologic disturbance. Neuroradiology 2004, 46:15-21.
13. Sultan SM, Begum S, Isenberg DA: Prevalence, patterns of disease and outcome in patients with systemic lupus erythematosus who develop severe haematological problems. Rheumatology (Oxford) 2003, 42:230-234.
14. Paran D, Fireman E, Elkayam O: Pulmonary disease in systemic lupus erythematosus and the antiphospholpid syndrome. Autoimmun Rev 2004, 3:70-75.
15. Sultan SM, Ioannou Y, Isenberg DA: A review of gastrointestinal manifestations of systemic lupus erythematosus. Rheumatology (Oxford) 1999, 38:917-932.
16. Ward MM: Premature morbidity from cardiovascular and cerebrovascular diseases in women with systemic lupus erythematosus. Arthritis Rheum 1999, 42:338-346.
17. Flanc RS, Roberts MA, Strippoli GF, Chadban SJ, Kerr PG, Atkins RC: Treatment for lupus nephritis. Cochrane Database Syst Rev:CD002922.
18. Boumpas DT, Austin HA 3rd, Vaughn EM, Klippel JH, Steinberg AD, Yarboro CH, Balow JE: Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet 1992, 340:741-745.
19. Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, Garrido Ed, Ede R, Danieli MG, Abramovicz D, Blockmans D, Mathieu A, Direskeneli H, Galeazzi M, Gul A, Levy Y, Petera P, Popovic R, Petrovic R, Sinico RA, Cattaneo R, Font J, Depresseux G, Cosyns JP, Cervera R: Immunosuppressive therapy in lupus nephritis: the Euro- Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum 2002, 46:2121-1231.
20. Chan TM, Li FK, Tang CS, Wong RW, Fang GX, Ji YL, Lau CS, Wong AK, Tong MK, Chan KW, Lai KN: Efficacy of Mycophenolate Mofetil in Patients with Diffuse Proliferative Lupus Nephritis. N Engl J Med 2000, 343:1156-1162.
21. Leandro MJ, Edwards JC, Cambridge G, Ehrenstein MR, Isenberg DA: An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis Rheum 2002, 46:2673-2677.
22. Moss KE, Ioannou Y, Sultan SM, Haq I, Isenberg DA: Outcome of a cohort of 300 patients with systemic lupus erythematosus attending a dedicated clinic for over two decades. Ann Rheum Dis 2002, 61:409-413.

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Heart Attack

What is a heart attack?

A heart attack (also known as a myocardial infarction) is the death of heart muscle from the sudden blockage of a coronary artery by a blood clot. Coronary arteries are blood vessels that supply the heart muscle with blood and oxygen. Blockage of a coronary artery deprives the heart muscle of blood and oxygen, causing injury to the heart muscle. Injury to the heart muscle causes chest pain and chest pressure sensation. If blood flow is not restored to the heart muscle within 20 to 40 minutes, irreversible death of the heart muscle will begin to occur. Muscle continues to die for six to eight hours at which time the heart attack usually is "complete." The dead heart muscle is eventually replaced by scar tissue.

Approximately one million Americans suffer a heart attack each year. Four hundred thousand of them die as a result of their heart attack.

What causes a heart attack?


Atherosclerosis

Atherosclerosis is a gradual process by which plaques (collections) of cholesterol are deposited in the walls of arteries. Cholesterol plaques cause hardening of the arterial walls and narrowing of the inner channel (lumen) of the artery. Arteries that are narrowed by atherosclerosis cannot deliver enough blood to maintain normal function of the parts of the body they supply. For example, atherosclerosis of the arteries in the legs causes reduced blood flow to the legs. Reduced blood flow to the legs can lead to pain in the legs while walking or exercising, leg ulcers, or a delay in the healing of wounds to the legs. Atherosclerosis of the arteries that furnish blood to the brain can lead to vascular dementia (mental deterioration due to gradual death of brain tissue over many years) or stroke (sudden death of brain tissue).

In many people, atherosclerosis can remain silent (causing no symptoms or health problems) for years or decades. Atherosclerosis can begin as early as the teenage years, but symptoms or health problems usually do not arise until later in adulthood when the arterial narrowing becomes severe. Smoking cigarettes, high blood pressure, elevated cholesterol, and diabetes mellitus can accelerate atherosclerosis and lead to the earlier onset of symptoms and complications, particularly in those people who have a family history of early atherosclerosis.

Coronary atherosclerosis (or coronary artery disease) refers to the atherosclerosis that causes hardening and narrowing of the coronary arteries. Diseases caused by the reduced blood supply to the heart muscle from coronary atherosclerosis are called coronary heart diseases (CHD). Coronary heart diseases include heart attacks, sudden unexpected death, chest pain (angina), abnormal heart rhythms, and heart failure due to weakening of the heart muscle.

Atherosclerosis and angina pectoris

Angina pectoris (also referred to as angina) is chest pain or pressure that occurs when the blood and oxygen supply to the heart muscle cannot keep up with the needs of the muscle. When coronary arteries are narrowed by more than 50 to 70 percent, the arteries may not be able to increase the supply of blood to the heart muscle during exercise or other periods of high demand for oxygen. An insufficient supply of oxygen to the heart muscle causes angina. Angina that occurs with exercise or exertion is called exertional angina. In some patients, especially diabetics, the progressive decrease in blood flow to the heart may occur without any pain or with just shortness of breath or unusually early fatigue.

Exertional angina usually feels like a pressure, heaviness, squeezing, or aching across the chest. This pain may travel to the neck, jaw, arms, back, or even the teeth, and may be accompanied by shortness of breath, nausea, or a cold sweat. Exertional angina typically lasts from one to 15 minutes and is relieved by rest or by taking nitroglycerin by placing a tablet under the tongue. Both resting and nitroglycerin decrease the heart muscle's demand for oxygen, thus relieving angina. Exertional angina may be the first warning sign of advanced coronary artery disease. Chest pains that just last a few seconds rarely are due to coronary artery disease.

Angina also can occur at rest. Angina at rest more commonly indicates that a coronary artery has narrowed to such a critical degree that the heart is not receiving enough oxygen even at rest. Angina at rest infrequently may be due to spasm of a coronary artery (a condition called Prinzmetal's or variant angina). Unlike a heart attack, there is no permanent muscle damage with either exertional or rest angina.

Atherosclerosis and heart attack

Occasionally the surface of a cholesterol plaque in a coronary artery may rupture, and a blood clot forms on the surface of the plaque. The clot blocks the flow of blood through the artery and results in a heart attack (see picture below). The cause of rupture that leads to the formation of a clot is largely unknown, but contributing factors may include cigarette smoking or other nicotine exposure, elevated LDL cholesterol, elevated levels of blood catecholamines (adrenaline), high blood pressure, and other mechanical and biochemical forces.

Unlike exertional or rest angina, heart muscle dies during a heart attack and loss of the muscle is permanent, unless blood flow can be promptly restored, usually within one to six hours.

Heart Attack illustration - Myocardial Infarction

While heart attacks can occur at any time, more heart attacks occur between 4:00 A.M. and 10:00 A.M. because of the higher blood levels of adrenaline released from the adrenal glands during the morning hours. Increased adrenaline, as previously discussed, may contribute to rupture of cholesterol plaques.

Approximately 50% of patients who develop heart attacks have warning symptoms such as exertional angina or rest angina prior to their heart attacks, but these symptoms may be mild and discounted.

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New Joint Statement Streamlines Definition of Metabolic Syndrome

October 8, 2009 (Brussels, Belgium) — A new joint statement from a number of professional organizations has identified specific criteria for the clinical diagnosis of the metabolic syndrome, tightening up the definition, which previously differed from one organization to the next [1].

The statement, published online October 5, 2009 in Circulation, includes the participation of the International Diabetes Federation (IDF), the National Heart, Lung, and Blood Institute (NHLBI), the World Heart Federation, the International Atherosclerosis Society, and the American Heart Association (AHA) and is an attempt to eliminate some of the confusion regarding how to identify patients with the syndrome.

"This paper represents an attempt to make the definition global," Dr Robert Eckel (University of Colorado, Denver), one of the authors of the new report, told heartwire . "The IDF definition and the [National Cholesterol Education Program Adult Treatment Panel] ATP III definition have been the two that have been utilized most frequently, and now the different organizations--the IDF, the International Atherosclerosis Society, the NHLBI, and the AHA--have all signed on to a single definition. I think that's a step forward in terms of not continuing to confuse people who are working in this field."

Specifically, the new metabolic-syndrome definition streamlines previous differences related to abdominal obesity as defined by measurements in waist circumference. Substantial disparities existed between the previous IDF and the ATP III definitions of what constituted an excessively large waist circumference, by as much as 8 cm between the two groups, but these have been amended. Now, the criteria for elevated waist circumference are based on population- and country-specific definitions, which, although streamlined, do leave some work to be done, said Eckel.

"The problem that still exists is that regional differences around the world may be substantial in terms of what waist circumference confers additional risk for heart disease and diabetes," he said. "The new definition relies on different geographic regions, or different countries, to drill down into their own databases in terms of relating waist circumference to risk." Eckel noted that the IDF previously considered elevations in waist circumference mandatory when defining metabolic syndrome, although the ATP III did not. Now, waist circumference is just one of five criteria that physicians can use when diagnosing the metabolic syndrome. Patients with three of the five criteria--including elevated waist circumference, elevated triglycerides, reduced HDL-cholesterol levels, elevated blood pressure, and elevated fasting-glucose levels--are considered to have the syndrome.


Criteria for Clinical Diagnosis of the Metabolic Syndrome

Measure Categorical cut points
Elevated waist circumference Population- and country-specific definitions
Elevated triglycerides (drug treatment for elevated triglycerides is an alternate indicator) >150 mg/dL
Reduced HDL cholesterol (drug treatment for reduced HDL cholesterol is an alternate indicator) <40 mg/dL for males and <50 mg/dL for females
Elevated blood pressure (drug treatment for elevated blood pressure is an alternate indicator) Systolic >130 mm Hg and/or diastolic >85 mm Hg
Elevated fasting glucose (drug treatment for elevated glucose is an alternate indicator) >100 mg/dL

Notably absent from the joint statement is the American Diabetes Association. As reported by heartwire , there are unresolved scientific issues between the ADA and other associations, including the AHA, regarding the metabolic syndrome. Specifically, the ADA, as well as the European Association for the Study of Diabetes (EASD), objected to the manner in which the metabolic syndrome was characterized as a risk factor for heart disease or diabetes, arguing that there was no need to diagnose a patient with the syndrome because emphasis should be placed on aggressively treating the individual risk factors. In 2005, the ADA and EASD issued their own joint statement calling for a critical appraisal of the metabolic syndrome, its designation as a syndrome, and its clinical utility.

To heartwire , Eckel said the IDF, AHA, NHLBI, and others began working on the new metabolic syndrome definition in 2008 and that they simply went ahead without ADA participation. He stressed the metabolic syndrome is not a disease but simply a clustering of risk factors. The original intention of identifying the syndrome was simply to draw clinicians' and the public's attention to the importance of a high-quality lifestyle, and the metabolic syndrome is never meant to be used as a predictor of heart disease or diabetes risk.

References
Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome. A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009; 120:1640-1645.

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Diabetes Mellitus, Type 2 - A Review

Scott R Votey, MD, Assistant Dean for Graduate Medical Education, Professor of Medicine/Emergency Medicine, David Geffen School of Medicine at UCLA, UCLA Medical Center
Anne L Peters, MD, CDE, Director of Clinical Diabetes Programs, Professor, Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, California, Los Angeles County/University of Southern California Medical Center

Introduction
Background
Diabetes mellitus is a chronic disease that requires long-term medical attention both to limit the development of its devastating complications and to manage them when they do occur. It is a disproportionately expensive disease; in 2002, the per-capita cost of healthcare was $13,243 for people with diabetes, while it was $2560 for those without diabetes.



This article focuses on the ED evaluation and treatment of the acute and chronic complications of diabetes other than those directly associated with hypoglycemia and severe metabolic disturbances such as diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS). (Please see Hypoglycemia, Diabetic Ketoacidosis, and Hyperosmolar Hyperglycemic Nonketotic Coma for more information on these disorders.)


Pathophysiology
The 2 basic types of diabetes mellitus are type 1 and type 2. Type 1 diabetes mellitus is reviewed more fully in a separate eMedicine article (see Diabetes Mellitus, Type 1 - A Review).

Type 2 diabetes mellitus was once called adult-onset diabetes. Now, because of the epidemic of obesity and inactivity in children, type 2 diabetes mellitus is occurring at younger and younger ages. Although type 2 diabetes mellitus typically affects individuals older than 40 years, it has been diagnosed in children as young as 2 years of age who have a family history of diabetes.

Type 2 diabetes is characterized by peripheral insulin resistance with an insulin-secretory defect that varies in severity. For type 2 diabetes mellitus to develop, both defects must exist: all overweight individuals have insulin resistance, but only those with an inability to increase beta-cell production of insulin develop diabetes. In the progression from normal glucose tolerance to abnormal glucose tolerance, postprandial glucose levels first increase. Eventually, fasting hyperglycemia develops as inhibition of hepatic gluconeogenesis declines.

About 90% of patients who develop type 2 diabetes mellitus are obese. Because patients with type 2 diabetes mellitus retain the ability to secrete some endogenous insulin, those who are taking insulin generally do not develop DKA if it is stopped. Therefore, they are considered to require insulin but not to depend on insulin. Moreover, patients with type 2 diabetes mellitus often do not need treatment with oral antidiabetic medication or insulin if they lose weight or stop eating.

Maturity-onset diabetes of the young (MODY) is a form of type 2 diabetes mellitus that affects many generations in the same family with an onset in individuals younger than 25 years. Several types exist. Some of the genes responsible can be detected by using commercially available assays.
Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. GDM is a complication in approximately 4% of all pregnancies in the United States, though the rates may be 1-14% depending on the population studied. Untreated GDM can lead to fetal macrosomia, hypoglycemia, hypocalcemia, and hyperbilirubinemia. In addition, mothers with GDM have increased rates of cesarean delivery and chronic hypertension. To screen for GDM, a 50-g glucose screening test should be done at 24-28 weeks of gestation. This is followed by a 100-g, 3-hour oral glucose tolerance test if the patient's plasma glucose concentration at 1 hour after screening is greater than 140 mg/dL.


Frequency
United States
In 2005, people with diabetes were estimated to account for 7% of the US population, or approximately 20.8 million people. Of these 20.8 million people, 14.6 million have a diagnosis of diabetes, and diabetes is undiagnosed in another 6.2 million. Approximately 10% have type 1 diabetes, and the rest have type 2. Additionally, an estimated 54 million people have pre-diabetes. Pre-diabetes, as defined by the American Diabetes Association, is that state in which blood glucose levels are higher than normal but not high enough to be diagnosed as diabetes.


Mortality/Morbidity
The morbidity and mortality associated with diabetes are related to the short- and long-term complications. Complications include the following:

Hypoglycemia and hyperglycemia
Increased risk of infections
Microvascular complications (eg, retinopathy, nephropathy)
Neuropathic complications
Macrovascular disease (eg, coronary artery disease, stroke)
Diabetes is the major cause of blindness in adults aged 20-74 years, as well as the leading cause of nontraumatic lower-extremity amputation and end-stage renal disease (ESRD).


Race
Type 2 diabetes mellitus is more prevalent among Hispanics, Native Americans, African Americans, and Asians/Pacific Islanders than in non-Hispanic whites.


Sex
The incidence is essentially equal in women and men in all populations.


Age
Type 2 diabetes mellitus is becoming increasingly common because people are living longer, and the prevalence of diabetes increases with age.
It is also seen more frequently now than before in young people, in association with the rising prevalence of childhood obesity.
Although type 2 diabetes mellitus still occurs most commonly in adults aged 40 years or older, the incidence of disease is increasing more rapidly in adolescents and young adults than in other age groups.
Clinical
History
Correctly determining whether a patient has type 1 or type 2 diabetes is important because patients with type 1 diabetes are dependent on a continuous source of exogenous insulin and carbohydrates for survival. Patients with type 2 diabetes may not need treatment for hyperglycemia during periods of fasting or decreased oral intake. A patient whose diabetes is controlled with diet or an oral antidiabetic agent clearly has type 2 diabetes. A lean patient who has had diabetes since childhood, who has always been dependent on insulin, or who has a history of DKA almost certainly has type 1 diabetes.

Distinguishing the type of diabetes can be difficult in (1) patients who are treated with insulin and are young but clinically appear to have type 2 diabetes and (2) older patients with late onset of diabetes who nonetheless take insulin and seem to share characteristics of patients with type 1 diabetes. (This latter group is now said to have latent autoimmune diabetes of the adult [LADA]). When in doubt, treat the patient with insulin and closely monitor his or her glucose levels. Some adolescents or young adults, mostly Hispanic or African American patients, who present as with classic DKA are subsequently found to have type 2 diabetes.

Many patients with type 2 diabetes are asymptomatic, and their disease is undiagnosed for many years. Studies suggest that the typical patient with new-onset type 2 diabetes has had diabetes for at least 4-7 years before it is diagnosed. Among patients with type 2 diabetes, 25% are believed to have retinopathy; 9%, neuropathy; and 8%, nephropathy at the time of diagnosis.

Pre-diabetes often precedes overt type 2 diabetes. Pre-diabetes is defined by a fasting blood glucose level of 100-125 mg/dL or a 2-hour post oral glucose tolerance test (OGTT) glucose level of 140-200 mg/dL. Patients who have pre-diabetes have an increased risk for macrovascular disease as well as diabetes.

Often confused with pre-diabetes is the metabolic syndrome (also called syndrome X or the insulin-resistance syndrome). Metabolic syndrome, thought to be due to insulin resistance, can occur in patients with overtly normal glucose tolerance, prediabetes, or diabetes. It is characterized by central obesity, then by dyslipidemia. Hypertension is a common feature. Eventually, clinically apparent insulin resistance develops. Unfortunately, insulin resistance is not measured clinically, except in research settings. An elevated fasting blood glucose level is the first indication of insulin resistance, but fasting insulin levels are generally increased long before this occurs. Measurement of fasting insulin levels are not yet recommended for the diagnosis of insulin resistance. An effort to standardize insulin assays is underway and may allow for the use of fasting insulin levels to diagnose insulin resistance in the future.

See Workup for more information on diagnosis of diabetes. See Diabetes Mellitus, Type 1 - A Review for more information on the symptomatic patient with diabetes.

During history taking, inquire about the type and duration of the patient's diabetes and about the care the patient is receiving for diabetes.

Type and estimated duration of diabetes: This information helps to determine if the patient is insulin dependent. The diagnosis is based on history, therapy, and clinical judgment, as described above.
Diabetes care: Inquire about the patient's current treatment of diabetes and about his or her usual blood glucose levels based on self-monitoring and/or recent measurements of hemoglobin A1C (A 1C , an indicator of long-term glucose control).
A focused diabetes history should include the following questions:

Is the patient's diabetes generally well controlled (with near-normal blood sugar levels)? Patients with poorly controlled blood glucose levels heal more slowly and are at increased risk for infection and other complications.
Does the patient have severe hypoglycemic reactions? If the patient has episodes of severe hypoglycemia and therefore is at risk for losing consciousness, this possibility must be addressed, especially if the patient drives.
Does the patient have peripheral neuropathy?
Does the patient have any unrecognized foot ulcers or lesions that need treatment?
Does the patient have diabetic nephropathy that might alter use of medications or intravenous radiographic contrast material?
Does the patient have macrovascular disease, such as coronary artery disease (CAD), that should be considered in the ED?
As circumstances dictate, additional questions may be warranted.

Diabetes care
What is the patient's diet? Does he or she use oral antidiabetic agents, insulin, or both? If so, what are the doses and frequencies of the medications?
Does the patient self-monitor his or her glucose levels? If yes, what is the frequency and the usual range of values at each time of day?
When was the patient's A 1C level last measured? What was it?
Does the patient adhere to a specific diet or exercise regularly?
Hyperglycemia: Ask about polyuria, polydipsia, nocturia, weight loss, and fatigue.
Hypoglycemia
Does patient have episodes of hypoglycemia? Are these episodes explicable? Are these episodes mild or severe?
Does the patient require the assistance of another person for treatment?
When and how often do these episodes occur? How does the patient treat them?
Does the patient have hypoglycemia unawareness (ie, does the patient lack the adrenergic warning signs of hypoglycemia)? Hypoglycemia unawareness indicates an increased risk of subsequent episodes of hypoglycemia.
Microvascular complications
Retinopathy: When was the patient's last dilated eye examination? What were the results? Any recent deterioration in vision?
Nephropathy: Does the patient have known kidney disease? What were the results and dates of the last measurements of urine protein and serum creatinine levels? If urine protein has been negative to trace, has a microalbumin-to-creatinine ratio been assessed within the past year?
Neuropathy: Does the patient have any history of neuropathy or symptoms of peripheral neuropathy or autonomic neuropathy (including impotence if the patient is male)?
Macrovascular complications
Hypertension: Does the patient have hypertension (defined as a BP of >130/80 mm Hg)? What medications are taken?
CAD: Does the patient have CAD? Does the patient have a family history of CAD?
Peripheral vascular disease: Does the patient have symptoms of claudication or a history of vascular bypass?
Cerebrovascular disease: Has the patient had a stroke or transient ischemic attack?
Hyperlipidemia: What are the patient's most recent lipid levels? Is the patient taking lipid-lowering medication?
Diabetic foot disease: Does the patient have a history of foot ulcers or amputations? Are any foot ulcers present?
Infections: Are frequent infections a problem? At what site?
Physical
A diabetes-focused examination includes vital signs, funduscopic examination, limited vascular and neurologic examinations, and a foot assessment. Other organ systems should be examined as indicated by the patient's clinical situation.

Assessment of vital signs
Is the patient hypertensive or hypotensive? Orthostatic vital signs may be useful in assessing volume status and in suggesting the presence of an autonomic neuropathy.
If the respiratory rate and pattern suggest Kussmaul respiration, DKA must be considered immediately, and appropriate tests ordered.
Funduscopic examination
The funduscopic examination should include a careful view of the retina, including both the optic disc and the macula.
If hemorrhages or exudates are seen, the patient should be referred to an ophthalmologist as soon as possible. Examiners who are not ophthalmologists tend to underestimate the severity of retinopathy, especially if the patients' pupils are not dilated.
Foot examination
The dorsalis pedis and posterior tibialis pulses should be palpated and their presence or absence noted. This is particularly important in patients who have foot infections because poor lower-extremity blood flow can delay healing and increase the risk of amputation.
Documenting lower-extremity sensory neuropathy is useful in patients who present with foot ulcers because decreased sensation limits the patient's ability to protect the feet and ankles. This can be assessed with a monofilament, or more readily by assessment of reflexes, position, and vibration sensation.
If peripheral neuropathy is found, the patient should be made aware that foot care (including daily foot examination) is very important for the prevention of foot ulcers and lower-extremity amputation.
Causes
The major risk factors for type 2 diabetes mellitus are the following:

Age - Older than 45 years (though, as noted above, type 2 diabetes mellitus is occurring with increasing frequency in young individuals)
Obesity - Weight greater than 120% of desirable body weight (true for approximately 90% of patients with type 2 diabetes mellitus)
Family history of type 2 diabetes in a first-degree relative (eg, parent or sibling)
Hispanic, Native American, African American, Asian American, or Pacific Islander descent
History of previous impaired glucose tolerance (IGT) or impaired fasting glucose (IFG)
Hypertension (>140/90 mm Hg) or dyslipidemia (high-density lipoprotein [HDL] cholesterol level <40>150 mg/dL)
History of GDM or of delivering a baby with a birth weight of >9 lb
Polycystic ovarian syndrome (which results in insulin resistance)
Differential Diagnoses
Diabetes Mellitus, Type 1 - A Review
Diabetic Ketoacidosis
Hyperosmolar Hyperglycemic Nonketotic Coma
Hypoglycemia


Workup
Laboratory Studies
A fingerstick glucose test is appropriate in the ED for virtually all patients with diabetes. All other laboratory studies should be individualized to the clinical situation.
In patients who present with symptoms of uncontrolled diabetes (eg, polyuria, polydipsia, nocturia, fatigue, weight loss) with a confirmatory random plasma glucose level of >200 mg/dL, diabetes can be diagnosed.
In asymptomatic patients whose random serum glucose level suggests diabetes (>140 mg/dL), a fasting plasma glucose (FPG) concentration should be measured. The oral glucose tolerance test no longer is recommended for the routine diagnosis of diabetes.
An FPG level of >126 mg/dL on 2 separate occasions is diagnostic for diabetes.
An FPG level of 100-125 mg/dL is considered impaired IFG.
An FPG level of <100>1 ng/dL in a patient who has had diabetes for more than 1-2 years is suggestive of type 2 diabetes (ie, residual beta-cell function).
Autoantibodies can be useful in differentiating between type 1 diabetes and type 2 diabetes.
Islet-cell autoantibodies (IA2) are present in children with new-onset type 1 diabetes but not type 2 diabetes. These antibodies are positive for approximately 6 months after diagnosis.
Anti-GAD65 antibodies are present in 80% of adult patients with new-onset type 1 diabetes (known as latent autoimmune diabetes of the adult [LADA]). These antibodies remain positive over time.
Other Tests
A glucose tolerance test usually is not necessary, except when GDM or IGT is being diagnosed.
Treatment
Emergency Department Care
The ED care of patients with type 2 diabetes requires attention to both the patient's glycemic control and any of the numerous complications of diabetes the patient may have.

New-onset diabetes
Most patients with diabetes have type 2, and most of those are asymptomatic at diagnosis. Initial treatment of these patients is a trial of medical nutrition therapy (MNT, diet therapy) plus metformin. Therefore, if an asymptomatic patient is incidentally found to have an elevated blood glucose level in the ED, the patient's primary care provider can perform follow-up. Patients with mild symptoms of poorly controlled and previously undiagnosed diabetes can usually be treated on an outpatient basis.
The treatment of markedly symptomatic patients with newly discovered type 2 diabetes and glucose levels greater than 400 mg/dL is controversial. If close follow-up can be arranged, maximal doses of a sulfonylurea agent can be started, and they can be treated on an outpatient basis. Patients generally feel better in 1-2 days, and in a week, their blood glucose levels are markedly lower. The sulfonylurea dose can be tapered as they comply with MNT and metformin is added; in some, diabetes can be controlled with diet alone. Patients who cannot drink adequate amounts of fluid, those with serious coexisting medical conditions (eg, myocardial infarction [MI], systemic infection), and those without reliable follow-up should generally be hospitalized to start therapy. Alternately, insulin therapy can be initiated and doses adjusted in either an inpatient setting or an outpatient setting.
Abnormalities caused by hyperglycemia
Acute hyperglycemia, even when not associated with DKA or hyperglycemic hyperosmolar nonketotic syndrome (HNKS), is harmful for a number of reasons. If the blood glucose level exceeds the renal threshold for glucose, an osmotic diuresis ensues, with loss of glucose, electrolytes, and water. Hyperglycemia impairs leukocyte function through a variety of mechanisms. Patients with diabetes have an increased rate of wound infection, and hyperglycemia may impair wound healing.
In patients with known type 2 diabetes that is poorly controlled, no absolute level of blood glucose elevation requires admission to the hospital or administration of insulin in the ED. If the patient is severely symptomatic or if the precipitating cause of hyperglycemia cannot be treated adequately in the ED, the patient may need to be admitted. In general, lowering the patient's blood glucose level in the ED does not correct the underlying cause and has no long-term effects on the patient's blood glucose levels. Therefore, a plan for lowering and monitoring the patients' glucose levels is needed. Adequacy of follow-up is extremely important. Whether insulin is given in the ED is of less consequence and can be decided on an individual basis.
Hyperglycemia during medical illness and surgery
Serious medical illness and surgery produce a state of increased insulin resistance. Hyperglycemia can occur, even in patients who do not have diabetes, because of stress-induced insulin resistance plus the use of dextrose-containing intravenous fluids. Increases in glucagon, catecholamines, cortisol, and growth hormone levels antagonize the effects of insulin, and the alpha-adrenergic effect of increased catecholamine levels inhibits insulin secretion. Counterregulatory hormones also directly increase hepatic gluconeogenesis.
Increasing evidence shows the benefits of treatment of hyperglycemia in severely ill patients with or without preexisting diabetes. In ICU patients, in patients before and after coronary artery bypass grafting (CABG), and in those with an acute MI, morbidity and mortality are reduced when they receive glucose-insulin-potassium infusion (GIK infusion) designed to maintain glucose levels in the reference range. Many hospitals are implementing GIK-infusion protocols for patients in ICU, surgical ICU, and critical care unit (CCU) settings.
Treatment regimens must be modified for patients not requiring an ICU setting to compensate for both decreased caloric intake and increased physiologic stress. Blood glucose levels of 100-150 mg/dL should be maintained in medical and surgical patients with diabetes for the following reasons:
To prevent electrolyte abnormalities and volume depletion secondary to osmotic diuresis
To prevent the impairment of leukocyte function that occurs when blood glucose levels are elevated
To prevent the impairment of wound healing that occurs when blood glucose levels are elevated
Cardiovascular disease (CVD) or renal dysfunction increases surgical morbidity and mortality in patients with or without diabetes, and diabetic autonomic neuropathy increases the risk of cardiovascular instability. The ED clinician caring for the patient with diabetes who requires emergency surgery must notify the surgeon and the anesthesiologist of the patient's condition, consult medical specialists when appropriate, and promptly initiate a thorough medical evaluation to avoid delaying surgery.
Infections in general
Infections cause considerable morbidity and mortality in patients with diabetes. Infections may precipitate metabolic derangements and, conversely, the metabolic derangements of diabetes may facilitate infection.
A few infections, such as malignant otitis externa, rhinocerebral mucormycosis, and emphysematous pyelonephritis, occur almost exclusively in patients with diabetes. Infections, such as staphylococcal sepsis, occur more frequently and result in greater mortality in patients with diabetes than in others. Infections such as pneumococcal pneumonia affect patients with diabetes and others the same.
Hyperglycemia and acidemia exacerbate impairments in humoral immunity and polymorphonuclear leukocyte and lymphocyte functions but are substantially, if not entirely, reversed when pH and blood glucose levels return to normal. Although the exact level above which leukocyte function is impaired is not defined, in vitro evidence suggests that glucose levels greater than 200 mg/dL impair leukocytic function.
Patients with long-standing diabetes tend to have microvascular and macrovascular disease with resulting poor tissue perfusion and increased risk of infection. The ability of the skin to act as a barrier to infection may be compromised when the diminished sensation of diabetic neuropathy results in unnoticed injury.
Ear, nose, and throat infections
Two head and neck infections that are associated with high rates of morbidity and mortality are malignant otitis externa and rhinocerebral mucormycosis; these are seen almost exclusively in patients with diabetes.
Malignant or necrotizing otitis externa principally occurs in patients with diabetes who are older than 35 years and is almost always due to Pseudomonas aeruginosa.
Infection starts in the external auditory canal and spreads to adjacent soft tissue, cartilage, and bone. Patients typically present with severe ear pain and otorrhea. Although they often have preexisting otitis externa, progression to invasive disease is usually rapid.
Examination of the auditory canal may reveal granulation tissue, but spread of infection to the pinna, preauricular tissue, and mastoid often makes the diagnosis apparent. Involvement of the cranial nerves, particularly the facial nerve, is common; when infection extends to the meninges, it is often lethal.
CT helps define the extent of disease.
Prompt surgical consultation is mandatory for malignant otitis externa because surgical debridement is often an essential part of therapy. Intravenous antipseudomonal antibiotics should be started immediately in patients with invasive disease. Patients with diabetes with severe otitis externa but no evidence of invasive disease can be treated with an otic antibiotic drop and oral ciprofloxacin; they require close follow-up.
Mucormycosis collectively refers to infections caused by various ubiquitous molds. Invasive disease occurs in patients with poorly controlled diabetes, especially with DKA. Organisms colonize the nose and paranasal sinuses, spreading to adjacent tissues by invading blood vessels and causing soft tissue necrosis and bony erosion.
Patients usually present with periorbital or perinasal pain, swelling, and induration. Bloody nasal discharge may be present. Involvement of the orbits, with lid swelling, proptosis, and diplopia, is common.
The nasal turbinates may appear dusky red or frankly necrotic. Black necrotic tissue is an important visual clue. The infection may invade the cranial vault through the cribriform plate, resulting in cerebral abscess, cavernous sinus thrombosis, or thrombosis of the internal carotid artery.
Wet smears of necrotic tissue often reveal broad hyphae and distinguish mucormycosis from severe facial cellulitis. CT helps delineate the extent of disease.
Treatment consists of controlling the predisposing hyperglycemia and acidemia, administering intravenous amphotericin B, and immediate surgical debridement. Until the diagnosis is confirmed, antistaphylococcal antibiotic therapy is appropriate.
Urinary tract infections
Patients with diabetes have increased risk of cystitis and, more important, of serious upper urinary tract infection. Intrarenal bacterial infection should be considered in the differential diagnosis of any patient with diabetes who presents with flank or abdominal pain.
The treatment of cystitis is essentially the same as that in patients without diabetes, except that longer courses of therapy are generally recommended (eg, 7 d for uncomplicated cystitis). Individuals with a neurogenic bladder due to diabetic neuropathy may not empty their bladder well and may require urologic referral. Sulfonamide antibiotics can cause hypoglycemia in patients taking sulfonylurea agents by displacing the sulfonylurea agents from their binding sites and increasing their hypoglycemic effect.
Treatment of pyelonephritis does not differ for patients with diabetes, but a lower threshold for hospital admission is appropriate. First, pyelonephritis makes control of diabetes more difficult by causing insulin resistance; in addition, nausea may limit the patient's ability to maintain normal hydration. The ensuing hyperglycemia further compromises their immune response. Second, patients with diabetes are more susceptible than others to the complications of pyelonephritis (eg, renal abscess, emphysematous pyelonephritis, renal papillary necrosis, gram-negative sepsis).
More than 70% of cases of emphysematous pyelonephritis occurred in patients with diabetes. Emphysematous pyelonephritis is an uncommon necrotizing renal infection caused by Escherichia coli, Klebsiella pneumoniae, or other organisms capable of fermenting glucose to carbon dioxide. The presentation is usually similar to that of uncomplicated pyelonephritis, and the diagnosis is established by identifying renal gas on plain radiography or sonography. Surgery is indicated at diagnosis.
Skin and soft tissue infections
Sensory neuropathy, atherosclerotic vascular disease, and hyperglycemia all predispose patients with diabetes to skin and soft tissue infections. These can affect any skin surface but most commonly involve the feet.
Blood glucose levels greater than 250 mg/dL significantly increase a patient's risk of soft tissue infection.
Cellulitis; lymphangitis; and, most ominously, staphylococcal sepsis can complicate even the smallest wound. Minor wound infections and cellulitis are typically caused by Staphylococcus aureus or hemolytic streptococci. Treatment with a penicillinase-resistant synthetic penicillin or a first-generation cephalosporin has been effective for the outpatient treatment of minor infections, but the increasing prevalence of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) must now be considered when selecting an antibiotic. Patients with diabetes do not appear to have a higher prevalence of CA-MRSA than comparable patients without diabetes.
Outpatient treatment of minor infections is appropriate for patients who are reliable, who monitor their blood glucose, and who have access to close follow-up.
Necrotizing infections of the skin, subcutaneous tissues, fascia, or muscle can also complicate wounds and particularly cutaneous ulcers. These infections are typically polymicrobial, involving group A streptococci, enterococci, S aureus, Enterobacteriaceae, and various anaerobes. Radiographs of any spreading soft tissue infection in a patient with diabetes should be obtained to look for the soft tissue gas that characterizes necrosis. Surgical debridement is necessary for necrotizing infections. Gram stains and surface cultures are not helpful; antibiotic coverage should reflect the range of potential pathogens.
Osteomyelitis
Contiguous spread of a polymicrobial infection from a skin ulcer to adjacent bone is common in patients with diabetes.
In one study, osteomyelitis was found in the bone under 68% of diabetic foot ulcers, and findings on physical examination and plain radiographs did not help in diagnosing one half of the cases. Unfortunately, these diagnostic modalities are often the only ones available in the ED, and the diagnosis might be suspected but not established. MRI, if available on an emergent basis, has better sensitivity and specificity in diagnosing osteomyelitis.
If osteomyelitis is apparent on radiography or physical examination (eg, if the wounds are deep enough to expose tendons or bone), the patient should be admitted for intravenous antibiotics. If osteomyelitis is suspected but the soft tissue infection or metabolic disturbances do not warrant admission, the patient can be discharged for outpatient workup.
Other infections
Although cholecystitis is probably no more common in patients with diabetes than in the general population, severe fulminating infection, especially with gas-forming organisms, is more common. The early clinical manifestations of emphysematous cholecystitis are indistinguishable from those of usual cholecystitis. The diagnosis can be made by finding gas in the gallbladder lumen, wall, or surrounding tissues. Even with immediate surgery, the rate of mortality is high. Clostridial species are found in more than 50% of cases.
The incidence of staphylococcal and K pneumoniae infections is greater in people with diabetes than people without diabetes.
Diabetes is a risk factor for reactivation of tuberculosis.
Cryptococcal infections and coccidioidomycoses are more virulent in patients with diabetes than in others.
Ophthalmologic complications
Diabetes can affect the lens, vitreous, and retina, causing visual symptoms that may prompt the patient to come to the ED. Visual blurring may develop acutely as the lens changes shape with marked changes in blood glucose concentrations. This effect, which is caused by osmotic fluxes of water into and out of the lens, usually occurs as hyperglycemia increases, but it also may be seen when high glucose levels are lowered rapidly. In either case, recovery to baseline visual acuity can take up to a month, and some patients are almost completely unable to read small print or do close work during this period.
Patients with diabetes also tend to develop senile cataracts sooner than persons without diabetes, though this is not related to the degree of glycemic control.
Whether patients develop diabetic retinopathy depends on the duration of their diabetes and on the level of glycemic control maintained. Because the diagnosis of type 2 diabetes often is delayed, 20% of these patients have some degree of retinopathy at diagnosis. The following are the 5 stages in the progression of diabetic retinopathy:
Dilation of the retinal venules and formation of retinal capillary microaneurysms
Increased vascular permeability
Vascular occlusion and retinal ischemia
Proliferation of new blood vessels on the surface of the retina
Hemorrhage and contraction of the fibrovascular proliferation and the vitreous
The first 2 stages of diabetic retinopathy are known as background or nonproliferative retinopathy.
Initially, the retinal venules dilate, then microaneurysms, (tiny red dots on the retina that cause no visual impairment) appear.
As the microaneurysms or retinal capillaries become more permeable, and hard exudates appear, reflecting the leakage of plasma. Rupture of intraretinal capillaries results in hemorrhage. If a superficial capillary ruptures, a flame-shaped hemorrhage appears.
Hard exudates are often found in partial or complete rings (circinate pattern), which usually include multiple microaneurysms. These rings usually mark an area of edematous retina.
The patient may not notice a change in visual acuity unless the center of the macula is involved. Macular edema can cause visual loss; therefore, all patients with suspected macular edema must be referred to an ophthalmologist for evaluation and possible laser therapy. Laser therapy is effective in decreasing macular edema and preserving vision but is less effective in restoring lost vision.
Preproliferative and proliferative diabetic retinopathy are the next stages in the progression of the disease. Cotton-wool spots can be seen in preproliferative retinopathy. These represent retinal microinfarcts caused by capillary occlusion and appear as patches that range from off-white to gray and have poorly defined margins.
Proliferative retinopathy is characterized by neovascularization, or the development of networks of fragile new vessels that often are seen on the optic disc or along the main vascular arcades. The vessels undergo cycles of proliferation and regression. During proliferation, fibrous adhesions develop between the vessels and the vitreous. Subsequent contraction of the adhesions can result in traction on the retina and retinal detachment. Contraction also tears the new vessels, which hemorrhage into the vitreous. Patients may notice a small hemorrhage, which appears as a floater, though a large hemorrhage may result in marked visual loss.
Patients with preproliferative or proliferative retinopathy must immediately be referred for ophthalmologic evaluation because laser therapy can be effective in this condition, especially before actual hemorrhage occurs. Patients with retinal hemorrhage should be advised to limit their activity and to keep their head upright (even while sleeping) so that the blood settles to the inferior portion of the retina, minimizing obscuration of their central vision.
Patients with active proliferative diabetic retinopathy are at increased risk of retinal hemorrhage if they receive thrombolytic therapy; therefore, this condition is a relative contraindication to the use of thrombolytic agents.
Nephropathy
Patients with type 2 diabetes account for most patients with diabetes with ESRD. All patients with diabetes should be considered to have the potential for renal impairment unless proven otherwise. Therefore, extreme care should be exercised when using any nephrotoxic agent in a patient with diabetes.
The use of contrast media can precipitate acute renal failure in patients with underlying diabetic nephropathy. Caution should be used when contrast-enhanced studies are being considered in patients with diabetes with a creatinine level greater than 2 mg/dL; such studies should absolutely be avoided in patients with a creatinine level greater than 3 mg/dL. Although most recover within 10 days, some develop irreversible renal failure. Patients with diabetes who must undergo such studies should be well hydrated before, during, and after the study, and their renal function should be carefully monitored. A better solution is to seek equivalent clinical information by using an alternative study that does not require the use of contrast material (eg, sonography, noncontrast CT, MRI).
Potentially nephrotoxic drugs should be avoided whenever possible. Renally excreted or potentially nephrotoxic drugs should be given at reduced dosage as appropriate to the patient's serum creatinine level.
Because chronically elevated blood pressure contributes to the decline in renal function, hypertensive patients with diabetes must be referred for long-term management of the blood pressure. If antihypertensive therapy is started in the ED, an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) are recommended because these agents decrease proteinuria and slow decline in renal function independent of their effect on blood pressure. ACE inhibitors and ARBs tend to increase the serum potassium level and therefore should be used with caution in patients with renal insufficiency or elevated serum potassium levels.
Neuropathy
Of the many types of peripheral and autonomic diabetic neuropathy, distal symmetric sensorimotor polyneuropathy (in a glove-and-stocking distribution) is the most frequent. Besides causing pain in its early stages, this type of neuropathy eventually results in the loss of peripheral sensation. The combination of decreased sensation and peripheral arterial insufficiency often leads to foot ulceration and eventual amputation.
Acute-onset mononeuropathies in diabetes include acute cranial mononeuropathies, mononeuropathy multiplex, focal lesions of the brachial or lumbosacral plexus, and radiculopathies. Of the cranial neuropathies, the third cranial nerve (oculomotor) is most commonly affected, followed by the sixth nerve (abducens) and the fourth nerve (trochlear). Patients can present with diplopia and eye pain.
In diabetic third-nerve palsy, the pupil is usually spared, whereas in third-nerve palsy due to intracranial aneurysm or tumor, the pupil is affected in 80-90% of cases.
Consideration of nondiabetic causes of cranial nerve palsies is important because 42% are due to causes other than diabetes. Therefore, evaluation should include nonenhanced and contrast-enhanced CT or, preferably, MRI. Neurologic consultation is recommended. Acute cranial-nerve mononeuropathies usually resolve in 2-9 months. Acute thrombosis or ischemia of the blood vessels supplying the structure involved is thought to cause these neuropathies.
Autonomic dysfunction can involve any part of the sympathetic or parasympathetic chains and produce myriad manifestations. Patients likely to seek care in the ED are those with diabetic gastroparesis and vomiting, severe diarrhea, bladder dysfunction and urinary retention, or symptomatic orthostatic hypotension.
Treatment of gastroparesis is symptomatic, and symptoms tend to wax and wane. Patients with gastroparesis may benefit from metoclopramide or erythromycin. Before these therapies are started, the degree of dehydration and metabolic imbalance must be assessed, and other serious causes of vomiting must be excluded. In severe cases, gastric pacing has been used.
Patients with disabling orthostatic hypotension may be treated with salt tablets, support stockings, or fludrocortisone.
Alleviating the functional abnormalities associated with the autonomic neuropathy is often difficult and frustrating and requires a long-term treatment plan with input from all of the patient's healthcare team.
Diabetic foot disease
About 50-70% of all nontraumatic lower-extremity amputations occur in patients with diabetes. The insensate, poorly perfused foot is at risk for ulcers from pressure necrosis or inflammation from repeated skin stress and unnoticed minor trauma. These can evolve into cellulitis, osteomyelitis, or nonclostridial gangrene and end in amputation.
Patients with diabetes who present with wounds, infections, or ulcers of the foot should be treated intensively. In addition to appropriate use of antibiotics, avoidance of further trauma to the healing foot is mandatory. This can be achieved by immobilization in a boot and/or using crutches, a wheelchair, or bed rest. Patients should be treated by a podiatrist or an orthopedist with experience in the care of diabetic foot disease. If bone or tendon is visible, osteomyelitis is present, and hospitalization for intravenous antibiotics is often necessary. Many patients need a vascular evaluation in conjunction with local treatment of the foot ulcer because a revascularization procedure may be required to provide adequate blood flow for wound healing.
Because curing ulcers and foot infections is difficult, their prevention is extremely important. At one clinic, the rate of amputation was halved after patients were required to remove their shoes and socks at every visit. ED clinicians can facilitate this practice by briefly inspecting the feet of each patient with diabetes and by educating them about the need for proper foot care. Patients with distal sensory neuropathy to pinprick or light touch, decreased peripheral pulses, moderate-to-severe onychomycosis, or impending skin breakdown should be referred to a podiatrist.
Macrovascular disease
This is the leading cause of death in patients with diabetes, causing 75% of deaths in this group but approximately 35% of deaths in people without diabetes. Diabetes increases the risk of myocardial infarction (MI) 2-fold in men and 4-fold in women, and many patients have other risk factors for MI as well. The risk of stroke in patients with diabetes is double that of people without diabetes, and the risk of peripheral vascular disease is 4 times that of people without diabetes. Subtle differences in the pathophysiology of atherosclerosis in patients with diabetes result in both earlier development and a more malignant course. Therefore, lipid abnormalities must be treated aggressively to lower the risk of serious atherosclerosis. Findings suggest that statin therapy should be started in all patients with type 2 diabetes, regardless of their lipid levels, to lower their risk of CVD.
Hypertension, which also increases the risk of atherosclerosis, is twice as common in patients with type 2 diabetes as in persons without diabetes. In patients with diabetes, hypertension must be treated aggressively to lower their risk of serious atherosclerosis. ACE inhibitors and angiotensin II–receptor blockers (ARBs) may also reduce CVD risk independent of its effects on blood pressure. Many advocate their use, in addition to statins, in most patients with type 2 diabetes.
Patients with diabetes may have an increased incidence of silent ischemia. However, silent ischemia is common in many patients with CAD, and the apparently increased incidence may be because patients with diabetes are more likely than others to have CAD to begin with. Nevertheless, an ECG is prudent in patients with diabetes and a serious illness or who present with generalized weakness, malaise, or other nonspecific symptoms that are not expected to be due to myocardial ischemia.
Diastolic dysfunction is common in patients with diabetes and should be considered in the patient with symptoms of congestive heart failure and a normal ejection fraction.
Medication
Target glucose levels

Chronic hyperglycemia is associated with an increased risk of microvascular complications, as shown in the Diabetes Control and Complications Trial (DCCT) in individuals with type 1 diabetes and the United Kingdom Prospective Diabetes Study (UKPDS) in people with type 2 diabetes. In the DCCT, intensive therapy to maintain normal blood glucose levels greatly reduced the development and progression of retinopathy, microalbuminuria, and neuropathy over 7 years.
The ongoing Epidemiology of Diabetes Interventions and Complications Study (EDIC), an observational study that continues to follow the patients previously enrolled in the DCCT, demonstrates that benefit has continued since the DCCT trial ended in 1993. Intensive therapy was not associated with increased mortality or incidence of major macrovascular events and did not decrease the quality of life, though it did increase the likelihood of severe hypoglycemic episodes. Furthermore, in the EDIC study, a long-term follow-up of the DCCT, over time those who had been in the intensively treated group had a reduction in the risk of CVD compared with those in the conventionally treated group.

In the UKPDS, more than 5000 patients with type 2 diabetes were followed up for up to 15 years. Those in the intensely treated group had a significantly lower rate of progression of microvascular complications than that of those receiving standard care. Rates of macrovascular disease were not altered except in the metformin-monotherapy arm in obese individuals, in which the risk of MI was significantly decreased. Moreover, severe hypoglycemia occurred less often than it did in patients with type 1 diabetes in the DCCT.

Kooy et al found an improved body weight, glycemic control, and insulin requirements when metformin was added to insulin in type 2 diabetes mellitus. No improvement of an aggregate of microvascular and macrovascular morbidity and mortality was observed; however, risk reduction of macrovascular disease was evident after a follow-up period of 4.3 years. Because of these sustained beneficial effects, it is important to support the policy to continue metformin treatment after the introduction of insulin in type 2 diabetes mellitus unless contraindicated.1
The goal of oral antidiabetic therapy is to lower blood glucose levels to near-normal (preprandial levels of 90-130 mg/dL and A1C levels <7%)>20 mg given in divided doses bid; Glucotrol XL not to exceed 20 mg/d PO
Start at 2.5 mg/d PO for elderly patients and patients with hepatic or renal disease; may start at higher doses in patients with severe hyperglycemia or symptoms, if home glucose monitoring and close follow-up can be arranged

Pediatric
Not established

Interactions
Numerous possible, few clinically significant; sulfonamides may enhance hypoglycemic effect

Contraindications
Documented hypersensitivity; DKA; type 1 diabetes mellitus

Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Caution in hepatic or renal impairment; cardiovascular disorders may occur; other risk factors are older age, malnutrition, and irregular eating (if prolonged or recurrent, consider admission); may cause rash, nausea, vomiting, leukopenia, agranulocytosis, aplastic anemia (rare), intrahepatic cholestasis (rare), disulfiramlike reaction, flushing, headache, and SIADH causing hyponatremia

Glyburide (DiaBeta, Micronase, PresTab, Glynase)
Second-generation sulfonylurea agent; increases insulin secretion from pancreatic beta cells.

Dosing
Adult
5 mg/d PO initially in untreated, symptomatic patients; not to exceed 20 mg/d PO
Start 2.5 mg/d PO for elderly patients and patients with hepatic or renal disease; may start at <20>1.5 mg/dL (men) or >1.4 mg/dL (women); hepatic dysfunction; acute or chronic acidosis; local or systemic tissue hypoxia; excessive alcohol intake; drug therapy for CHF

Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions
Fatal lactic acidosis if given with contraindication (rare without contraindication); discontinue before IV contrast enhancement, do not restart until creatinine level normal; withhold in acute hypoxia; check renal function regularly and discontinue if abnormal; adverse effects (including GI, especially diarrhea [30%]), may cause discontinuation (5%)


Thiazolidinediones
Thiazolidinedione derivatives improve glycemic control by improving insulin sensitivity. These drugs are selective agonists for peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Activation of PPAR-gamma receptors regulates insulin-responsive gene transcription involved in glucose production, transport, and utilization, thereby reducing blood glucose concentrations and hyperinsulinemia. Must be taken about 12-16 weeks to achieve maximal effect. These agents are used as monotherapy or with sulfonylurea, metformin, meglitinide, or insulin.
The US Food and Drug Administration issued an alert to patients and health care professionals on May 21, 2007, of rosiglitazone potentially causing an increased risk of myocardial infarction (MI) and heart-related deaths following the online publication of a meta-analysis (See rosiglitazone).
In the RECORD trial, cardiovascular outcomes were assessed after adding rosiglitazone to metformin or sulfonylurea regimens for type 2 diabetes mellitus.4 The study was a multicenter, open-label trial that included 4447 patients with mean HbA1c of 7.9%. Follow-up of the 2 combinations took place over 5-7 years. No difference was observed between the 2 groups for cardiovascular death, myocardial infarction, and stroke. Sixty-one patients who received rosiglitazone experienced heart failure that caused either hospital admission or death compared with 29 patients in the active control group (hazard ratio [HR] 2.10, 1.35-3.27 risk difference per 1000 person-years 2.6, 2.2-4.1).
Noncardiovascular adverse effects included increased upper and distal lower limb fracture rates, particularly in women. At 5 years, mean HbA1c was lower in the rosiglitazone group compared with the active control group. Results of the RECORD study found that use of rosiglitazone for type 2 diabetes mellitus increases risk of heart failure. Additionally, the risk for select fractures is increased, particularly in women.
Troglitazone (Rezulin), another thiazolidinedione, was voluntarily withdrawn from the market by the manufacturer on March 21, 2000, following concerns about its hepatic toxicity.

Pioglitazone (Actos)
Insulin sensitizer; decreases hepatic glucose output and increases insulin-dependent glucose use in skeletal muscle and possibly liver and adipose tissue.

Dosing
Adult
15 or 30 mg PO qd; may increase prn; not to exceed 45 mg/d; maximal effect may not be achieved for up to 12 wk

Pediatric
Not established

Interactions
With insulin or oral hypoglycemics (eg, sulfonylureas) may increase risk of hypoglycemia

Contraindications
Documented hypersensitivity; active liver disease, ALT level >2.5 times upper limits of normal; DKA; type 1 diabetes mellitus; congestive heart failure

Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Caution in patients with edema; may worsen macular edema; may decrease hemoglobin, hematocrit, and WBC counts (dilution); effects on lipids neutral or beneficial (decreased triglyceride, increased HDL levels); may increase risk for distal fractures in women

Rosiglitazone (Avandia)
Insulin sensitizer; major effect in stimulating glucose uptake in skeletal muscle and adipose tissue. Lowers plasma insulin levels. Used to treat type 2 diabetes mellitus with insulin resistance.

Dosing
Adult
4-8 mg/d PO or divided bid

Pediatric
Not established

Interactions
With insulin or oral hypoglycemics (eg, sulfonylureas) may increase risk of hypoglycemia

Contraindications
Documented hypersensitivity; active liver disease, ALT level >2.5 times upper limits of normal; DKA; type 1 diabetes mellitus; congestive heart failure

Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Caution in edema; may worsen macular edema; may decrease hemoglobin, hematocrit, and WBC counts (dilution); may increase HDL cholesterol, neutral effect on triglycerides; may increase risk for distal fractures in women
The US Food and Drug Administration issued an alert to patients and health care professionals on May 21, 2007, of rosiglitazone potentially causing an increased risk of myocardial infarction (MI) and heart-related deaths following the online publication of a meta-analysis. A large-scale phase III trial (RECORD) is currently underway that is specifically designed to study cardiovascular outcomes of rosiglitazone.
For more information, see FDA's Safety Alert on Avandia. The online published meta-analysis entitled "Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes" can be viewed at The New England Journal of Medicine. Additionally, responses to the controversy can be viewed at the Heartwire news (theheart.org from WebMD) including the following articles: (1) Rosiglitazone increases MI and CV death in meta-analysis, (2) The rosiglitazone aftermath: Legitimate concerns or hype? and (3) RECORD interim analysis of rosiglitazone safety: No clear-cut answers. Also see, the FDA's Information for Health Care Professionals updated August 14, 2007.


Dipeptidyl Peptidase IV (DPP-4) Inhibitors
These agents block the action of DPP-4, which is known to degrade glucagon-like peptide 1 (GLP-1), thereby increasing its concentrations. The levels of GLP-1 achieved enhance glucose-dependent insulin secretion and suppress elevated glucagon secretion.

Sitagliptin (Januvia)
Indicated for monotherapy or combined with metformin or a thiazolidinedione.

Dosing
Adult
100 mg PO qd
CrCl >30 to <50>3 d) to maintenance dose of 120 mcg; premeal insulin dose is decreased by 50% when pramlintide is started, but the basal insulin dose is usually unchanged; after target dose of pramlintide is achieved, optimize insulin dose to maintain glycemic control

Pediatric
Not established

Interactions
May delay absorption of concomitant oral drug (administer other drug 1 h before or 2 h after)

Contraindications
Documented hypersensitivity to pramlintide, components, or metacresol; gastroparesis; hypoglycemia unawareness; drugs that slow gastric emptying (eg, anticholinergics, eg, atropine) or that slow intestinal nutrient absorption (eg, alpha-glucosidase)

Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Increases risk of insulin-induced severe hypoglycemia, especially with type 1 diabetes mellitus or gastroparesis, rare in patients with type 2 diabetes mellitus; common adverse effects are GI complaints, especially nausea (decreased when dose increased gradually); always use separate insulin syringe to measure and administer, do not mix in same syringe (insulin alters pharmacokinetics); redness, swelling, or itching at injection site; do not administer without major meal (>250 cal or 30 g carbohydrates)


Alpha-glucosidase Inhibitors
These agents inhibit action of alpha-glucosidase (carbohydrate digestion), delaying and attenuating postprandial blood glucose peaks. Undigested sugars are delivered to the colon, where they are converted into short-chain fatty acids, methane, carbon dioxide, and hydrogen.

Alpha-glucosidase inhibitors (AGIs) do not increase insulin levels or inhibit lactase; their major effect is to lower postprandial glucose levels (lesser effect on fasting levels). They do not cause weight gain and may restore ovulation in anovulation due to insulin resistance. AGIs are not commonly used in the United States, but they are more commonly used in other countries.

Alone, AGIs do not cause hypoglycemia. Less than 2% is absorbed as active drug. They are used as monotherapy or with sulfonylurea, TZD, metformin, or insulin. Take with food to minimize GI effects.

Acarbose (Precose)
Delays hydrolysis of ingested complex carbohydrates and disaccharides and absorption of glucose. Inhibits metabolism of sucrose to glucose and fructose.

Dosing
Adult
25 mg PO tid ac initially with first bite of food; adjust q4-8wk based on 1-h postprandial glucose levels and tolerance; may increase dose prn, not to exceed 100 mg PO tid

Pediatric
Not established

Interactions
Hypoglycemia with insulin or sulfonylurea agents (give glucose as dextrose, as absorption of long-chain carbohydrates is delayed); may decrease absorption and bioavailability of digoxin, propranolol, and ranitidine; digestive enzymes (eg, amylase, pancreatin) may reduce effects

Contraindications
Documented hypersensitivity; DKA; cirrhosis; IBD; colonic ulceration; serum creatinine level >2 mg/dL; elevated liver enzyme levels; partial or predisposition to intestinal obstruction

Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions
GI effects (eg, flatulence, diarrhea, abdominal discomfort) common, especially with metformin (17% discontinue); systemic accumulation at high doses and in renal dysfunction, with possible drug-induced hepatitis

Miglitol (Glyset)
Delays glucose absorption in small intestine; diminishes postprandial hyperglycemia.

Dosing
Adult
25 mg PO tid ac initially with first bite of food; increase to 50 mg tid after 4-8 wk; may increase prn; not to exceed 100 mg PO tid

Pediatric
Not established

Interactions
Hypoglycemia with insulin or sulfonylurea agents (give glucose as dextrose, as absorption of long-chain carbohydrates is delayed); may decrease absorption and bioavailability of digoxin, propranolol, and ranitidine; digestive enzymes (eg, amylase, pancreatin) may reduce effects

Contraindications
Documented hypersensitivity; DKA; colonic ulceration; partial or predisposition to intestinal obstruction; IBD

Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions
May cause GI symptoms; not recommended in significant renal dysfunction


Follow-up
Further Inpatient Care
Inpatient care generally is warranted only for the management of major acute complications such as severe recurrent hypoglycemia, major infections, or HHS.
Further Outpatient Care
Although a few of the complications require hospitalization, type 2 diabetes mellitus can usually be managed on an outpatient basis.
Deterrence/Prevention
Moderation in diet, weight loss, and exercise are all important deterrents of type 2 diabetes mellitus. The ADA suggests that metformin can be used to help prevent the progression of prediabetes to diabetes.
Risk for vascular complications and cardiovascular mortality in patients with diabetes mellitus is increased by poor glucose control. Loimaala et al evaluated the efficacy of a long-term exercise training program on metabolic control and arterial stiffness in patients with type 2 diabetes mellitus. The study showed that long-term endurance and strength training was effective and resulted in improved metabolic control of diabetes mellitus compared with standard treatment; however, significant cardiovascular risk reduction and conduit arterial elasticity did not improve.5
Complications
The complications of diabetes include hypoglycemia and hyperglycemia, increased risk of infections, microvascular complications (ie, retinopathy, nephropathy), neuropathic complications, and macrovascular disease.
Diabetes is the major cause of blindness in adults aged 20-74 years.
Diabetes is the leading cause of nontraumatic lower-extremity amputation and ESRD.
For a detailed discussion of complications, see Emergency Department Care.
Prognosis
Patients with diabetes have a lifelong challenge to achieve and maintain blood glucose levels as close to the reference range as possible. With appropriate glycemic control, the risk of microvascular and neuropathic complications is decreased markedly. In addition, if hypertension and hyperlipidemia are treated aggressively, the risk of macrovascular complications decreases as well.
These benefits are weighed against the risk of hypoglycemia and the short-term costs of providing high-quality preventive care. Studies have shown cost savings due to a reduction in acute diabetes-related complications within 1-3 years after starting effective preventive care.
With each healthcare system encounter, patients with diabetes should be educated about and encouraged to follow an appropriate treatment plan. Providers must ensure that the care for each patient with diabetes includes all necessary laboratory tests, examinations (eg, foot and neurologic examinations), and referrals to specialists (eg, ophthalmologist, podiatrist).
Patient Education
For excellent patient education resources, see eMedicine's Diabetes Center. Also, visit eMedicine's patient education article Diabetes.
Miscellaneous
Medicolegal Pitfalls
Overtreatment or undertreatment of hypoglycemia such as premature discharge of a patient who develops hypoglycemia due to long-acting insulin
After an episode of severe hypoglycemia, patients should be discharged home with a prescription for glucagon.
If the hypoglycemia resulted in a loss of consciousness while driving, patients with diabetes should be educated about how to drive safely with their condition. In many states, a loss of consciousness while driving must be reported to the state department of motor vehicles, though if a patient has a monitored treatment plan for their diabetes, this notification may not be required.
Failure to treat the blood glucose levels of patients with wounds or active infections when levels are greater than 200 mg/dL
Underestimation of the severity of diabetic retinopathy on funduscopic examination because of a failure to dilate the pupils or the failure to urgently refer any patient with lesions near the macula to an ophthalmologist
Failure to provide adequate hydration to patients with mild diabetic nephropathy before contrast material is given may precipitate acute renal failure
Failure to examine the patient's feet and failure to detect small ulcers or underestimating their seriousness
Failure to consider myocardial ischemia in patients with nonspecific symptoms
Special Concerns
Pregnancy
MNT is the treatment of choice for GDM. If diet fails, the treatment is insulin.
In the past, oral antidiabetic agents were considered contraindicated in pregnancy. Glyburide is safe and effective in the treatment of GDM. Evidence suggests that metformin may be safe and effective in pregnancy as well. Studies are underway to assess their role in pregnant patients with increased insulin resistance.
Because patient education and ongoing glycemic control are essential to optimize fetal outcomes, consultation and specific follow-up are imperative.
Childhood diabetes: Although the predominant form of diabetes in children is type 1, type 2 diabetes also may occur in children.
References
[Best Evidence] Kooy A, de Jager J, Lehert P, Bets D, Wulffelé MG, Donker AJ, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med. Mar 23 2009;169(6):616-25. [Medline].

Agency for Healthcare Research and Quality. Comparative Effectiveness and Safety of Oral Diabetes Medications for Adults With Type 2 Diabetes. AHRQ: Agency for Healthcare Research and Quality. Available at http://effectivehealthcare.ahrq.gov/healthInfo.cfm?infotype=rr&ProcessID=6&DocID=40. Accessed January 27, 2009.

US Food and Drug Administration. Early Communication About Safety of Lantus (insulin Glargine). July 1, 2009. [Full Text].

[Best Evidence] Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet. Jun 20 2009;373(9681):2125-35. [Medline].

[Best Evidence] Loimaala A, Groundstroem K, Rinne M, Nenonen A, Huhtala H, Parkkari J, et al. Effect of long-term endurance and strength training on metabolic control and arterial elasticity in patients with type 2 diabetes mellitus. Am J Cardiol. Apr 1 2009;103(7):972-7. [Medline].

American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. Jan 2007;30 Suppl 1:S42-7. [Medline]. [Full Text].

American Diabetes Association. Standards of medical care in diabetes--2007. Diabetes Care. Jan 2007;30 Suppl 1:S4-S41. [Medline]. [Full Text].

Cefalu WT, Waldman S, Ryder S. Pharmacotherapy for the treatment of patients with type 2 diabetes mellitus: rationale and specific agents. Clin Pharmacol Ther. May 2007;81(5):636-49. [Medline].

Centers for Disease Control and Prevention. National Diabetes Fact Sheet. United States. 2005. Available at http://www.cdc.gov/diabetes/pubs/general.htm.

DCCT Group. The Diabetes Control and Complications Trial Research Group: the effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. Sep 30 1993;329(14):977-86. [Medline].

Frank RN. Diabetic retinopathy. N Engl J Med. Jan 1 2004;350(1):48-58. [Medline].

Jawa A, Kcomt J, Fonseca VA. Diabetic nephropathy and retinopathy. Med Clin North Am. Jul 2004;88(4):1001-36, xi. [Medline].

Lipsky BA, Berendt AR, Deery HG, Embil JM, Joseph WS, Karchmer AW, et al. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis. Oct 1 2004;39(7):885-910. [Medline].

Mokabberi R, Ravakhah K. Emphysematous urinary tract infections: diagnosis, treatment and survival (case review series). Am J Med Sci. Feb 2007;333(2):111-6. [Medline].

Peters AL, Davidson MB, Schriger DL, Hasselblad V. A clinical approach for the diagnosis of diabetes mellitus: an analysis using glycosylated hemoglobin levels. Meta-analysis Research Group on the Diagnosis of Diabetes Using Glycated Hemoglobin Levels. JAMA. Oct 16 1996;276(15):1246-52. [Medline].

Turner R, Cull C, Holman R. United Kingdom Prospective Diabetes Study 17: a 9-year update of a randomized, controlled trial on the effect of improved metabolic control on complications in non-insulin-dependent diabetes mellitus. Ann Intern Med. Jan 1 1996;124(1 Pt 2):136-45. [Medline].

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