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The Internist

Title: The Internist - Oct 2010
Date: 01-Oct-2010
Description: COLLEGE OF PHYSICIANS VOL. 10 NO. 2

THE INTERNIST

College of Physicians
Academy of Medicine of Malaysia
COLLEGE OF PHYSICIANS VOL. 10 NO. 2 (FOR MEMBERS ONLY) October 2010

Table of Contents

 

 

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Message from the President

In the fast changing world that we live today, the maxim 'Change is the only constant' is ever so true for medicine. Demography of our society, epidemiology of diseases confronting us, modalities of treatment, and healthcare systems keep moving and changing. So is medical education. What do these all mean to the individual patient, the individual aspirant for and the individual practitioner of the medical profession? Are these changes accessible and affordable to the patient? Are these changes making a real difference, an advance in healthcare to the patient? Do these changes ensure standards of care and standards of medical education and training?, bearing in mind what Bertrand Russell had reminded us, "Change is one thing, progress is another". Further, who drives these changes? 'Need is the mother of invention'. Is it still true in healthcare? Where do professional bodies such as the College of Physicians and the Academy of Medicine sit in in this swirl of change?

This year, the profession gets waken up to a huge cohort of housemen. That number will never be smaller in the years ahead. That in itself may be a good thing; at long last we shall be able to have the necessary number of bodies (of doctors) to put the healthcare agenda of this country on good footing. However, given that they graduate from a hotch-potch of medical schools almost literally around the world, with vast differences in healthcare and educational systems, rationalising and coaching them require some effort and dexterity. Quality does not necessarily will be fulfilled by quantity. Going by current account, a huge effort need be expanded to ensure standards of care and quality of medical practice in this country are kept high and safe.

The College recognises these changes going around us. At its first meeting, the new Council has adopted a number of ways in which the College needs to focus on. The College will organise a series of Saturday morning Teach-ins targeted for the young doctors, trainee doctors, senior medical students as well as general practitioners. These sessions will focus on practical common topics and will be organised in an interactive way, with minimal lectures and maximal workshop style case-centred interactions. Demonstration of clinical signs, discussion on imaging or laboratory results and presentation of real cases would dominate the session. Members and fellows of the College will play a major role as speakers and facilitators. Hopefully these sessions will be held at the Medical Academies Building, close to Hospital Kuala Lumpur. It is expected that the programme will begin soon and we would hope the Ministry of Health to support this initiative while the universities would encourage their senior medical students to participate. Similar programmes would also be carried out from time to time in the states, organised by the College's State Representatives. We would welcome the participation of various colleges of the Academy and the various specialist societies. Through these efforts, the College can be seen by members of our profession and our own members as well as the young generation of doctors as playing an important role in uplifting the standards of care in this country.

Being my first communication, I wish to thank all members who place their confidence in me and the new Council to lead College. I am most appreciative of the efforts of Dr Steven Chow, the immediate Past President, who tried very hard to bring about an appreciation of the relevance of the College to the health profession. I am sure, we all have the best interests of the College and I hope we all would be willing to participate in this huge task of getting the College involved in ensuring high standards of care in this country.

Martin Luther King Jr is famous for his "I dream..." speech. But he also said, "Cowardice asks the question - is it safe? Expediency asks the question - is it politic? Vanity asks the question - is it popular? But conscience asks the question - is it right? And there comes a time when one must take a position that is neither safe, nor politic, nor popular; one must take it because it is right." We shall move together to consolidate the College because not only it is right, but it is the right time and it is the right effort to do so.

 

Professor Dato' Dr Khalid Yusoff
FAMM, FRCP, FRCPE, FACC, FASc
President

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Review Article

Revised Recommendations for HIV Screening of Pregnant Women
Perinatal Counseling and Guidelines Consultation

BACKGROUND
HIV Infection and AIDS in Women and Children

Of the approximately 750,000 AIDS cases reported to CDC through the end of 1999, approximately 129,000 were in women. Approximately 64,000 women were living with AIDS in 1999, a 31% increase from 1996, reflecting improved survival with new combination treatment regimens. However, women with AIDS represent only a fraction of the number of HIV-infected women who need medical and social services. An estimated 120,000-- 160,000 HIV-infected women reside in the United States, 80% of whom are of childbearing age.

Most women with HIV/AIDS in the United States reside in the Northeast and the South. The highest numbers of cases were first observed in the Northeast, but the South has reported the greatest increases in recent years. African-American and Hispanic women are disproportionately affected by the epidemic and account for 80% of AIDS cases reported in U.S. women in 1999. Over time, the proportion of cases in women attributable to injection-drug use has declined, whereas the proportion of cases from heterosexual contact has increased, particularly among young women.

During 1985-1995, approximately 6,000-7,000 HIV-infected women gave birth in the United States each year. During the early 1990s, before perinatal chemoprophylaxis was available, an estimated 1,000-2,000 infants were born with HIV infection annually. By June 2000, a total of 8,027 perinatally acquired AIDS cases were recorded nationwide, most (85%) in African-American and Hispanic children. Before the results of the PACTG 076 trial using prenatal, intrapartum, and postpartum ZDV for perinatal prophylaxis, the risk for mother-to-child transmission ranged from 16% to 25% in studies from North America and Europe, up to 24% in Thailand, and 25-40% in Africa. Worldwide, approximately 600,000 infants each year become infected through mother-tochild transmission of the HIV virus.

In the United States, widespread implementation of the PHS guidelines for universal counseling and testing and perinatal use of ZDV has sharply reduced transmission risk and the number of perinatally acquired HIV infections. By 1995, several cohort studies had documented transmission rates of <11%. During 1996-2000, U.S. studies indicated that transmission rates had declined to 5%- 6% and <1% in women with nondetectable plasma viral loads. During 2000-2001, perinatal transmission rates of <2% have been achieved with combination antenatal antiretroviral drugs or with ZDV combined with cesarean section. Analysis of U.S. perinatal AIDS surveillance data reported through June 2000 indicated a sharp decline in the number of perinatal AIDS cases; this decline was temporally associated with increasing ZDV use among pregnant women aware of their HIV status. To more accurately monitor trends in perinatal HIV transmission and the implementation and impact of perinatal prevention programs (including HIV counseling and testing recommendations), CDC, the Council of State and Territorial Epidemiologists (CSTE), and the American Academy of Pediatrics (AAP) recommended national reporting of perinatal HIV exposure and HIV infection to help identify and target populations where prevention opportunities are missed.

Despite the declines, cases of perinatal HIV transmission continue to occur, largely because of missed opportunities for prevention, particularly among women who lack prenatal care or who are not being offered voluntary HIV counseling and testing during pregnancy. The estimated 280-370 infants born with HIV infection each year represent populations in which prevention efforts are impeded by lack of timely HIV testing and treatment of pregnant women. Of 329 children with perinatally acquired AIDS born during 1995-1996, a total of 112 (34%) were born to mothers not tested for HIV before the child's birth and 67 (20%) to mothers for whom the time of testing was not known.

Dynamics of Perinatal HIV Transmission

Perinatal transmission can occur during pregnancy (intrauterine), during labor and delivery (intrapartum), or after delivery through breast-feeding (postpartum). In the absence of breast-feeding, intrauterine transmission accounts for 25%-40% of infection, and 60%-75% of transmission occurs during labor and delivery. Among women who breast-feed, approximately 20%-25% of perinatal infections are believed to be associated with intrauterine transmission, 60%-70% with intrapartum transmission or very early breast-feeding, and 10%-15% with later postpartum transmission through breast-feeding. In a randomized trial of formula feeding versus breast-feeding, approximately 44% of HIV infection was attributed to breast-feeding. In breast-feeding populations, a shift toward an increasing proportion of transmission related to breast-feeding is likely to occur as a consequence of successful preventive interventions directed at late prenatal and intrapartum transmission.

Intrapartum transmission can occur during labor through maternal-fetal exchange of blood or during delivery by contact of the infant's skin or mucous membranes with infected blood or other maternal secretions. Several studies have indicated that most infections transmitted through breast-feeding probably occurred during the first few weeks to months of life. Risk factors during breast-feeding include viral load in breast milk, subclinical or clinical mastitis, breast abscesses, and maternal seroconversion during the lactation period.

Several risk factors are associated with perinatal HIV transmission. Clinical factors that increase the likelihood of transmission include immunologically or clinically advanced HIV disease in the mother, high plasma viral load, maternal injection-drug use during pregnancy, preterm delivery, nonreceipt of the PACTG 076 regimen, and breast-feeding. No link has been established between perinatal HIV transmission and maternal age, race/ethnicity, or history of having a previously infected child.

Obstetric factors also influence HIV transmission risk. The risk for perinatal trans-mission increases per hour duration of membrane rupture after controlling for other risk factors. Delivery >4 hours after the rupture of the fetal membranes can double the risk for HIV transmission. Maternal infection with another sexually transmitted disease (STD) during pregnancy and certain obstetrical procedures can also increase risk. Chorioamnionitis (i.e., uterine infection) has been associated with an increased risk for HIV transmission.

Most of these risk factors were identified before the recommended use of ZDV to prevent perinatal HIV transmission. Their effects are unknown now that most pregnant women infected with HIV are receiving ZDV chemoprophylaxis to prevent mother-to- child transmission, as well as combination therapy for their own health. Because of the sharp reductions in perinatal HIV transmission associated with effective antiretroviral interventions, factors that interfere with women or their infants receiving ZDV treatment (e.g., barriers to prenatal care, lack of HIV testing for some pregnant women) are increasingly important.

Prevention of Perinatal Transmission

The birth of every perinatally HIV-infected infant is a sentinel health event signaling either a missed prevention opportunity or, more rarely, a failure of prophylaxis. An opportunity is missed whenever a woman of childbearing age is unaware of her HIV status or her risk for HIV or when an HIV-infected pregnant woman a) does not receive prenatal care, b) is not offered HIV testing, c) is unable to obtain HIV testing, d) is not offered chemoprophylaxis, e) is unable to obtain chemoprophylaxis, or f) does not complete the chemoprophylaxis regimen. Prophylaxis failures occur when an infant becomes infected despite chemoprophylaxis and other preventive interventions. Each of these missed opportunities or failures deserves attention from service providers and prevention programs.

Early Prenatal Care

Maximum reduction of perinatal transmission depends on preventing HIV infection in women or identifying HIV infection before pregnancy or as early as possible during pregnancy. Diagnosis allows a woman to receive effective antiretroviral therapies for her own health and preventive drugs (e.g., ZDV) to improve the chances that her infant will be born free of infection. Early knowledge of maternal HIV status is also important for decisions regarding obstetrical management. Achieving these goals requires increased access to and use of prenatal care.

Four states that conducted enhanced HIV surveillance reported that during 1993-1996, approximately 15% of HIV-infected pregnant women in the United States received no prenatal care, compared with only 2% of women in the general population. HIVinfected women who used illicit drugs during pregnancy were at the highest risk for not receiving prenatal care - 35% compared with 6% for HIV-infected women who were not drug users. During 1997--1998, the HIV transmission rate among women in New York State was 17.5% (30/171) among those with no prenatal care, 16.2% (23/142) among those with 1-2 prenatal visits, and 8.0% (90/1,124) among those with >3 prenatal visits, indicating the importance of prenatal care in providing services that prevent perinatal transmission.

Offer and Acceptance of HIV Testing

Most women who have given birth since the 1995 PHS guidelines have received information or counseling regarding HIV infection and have been offered testing. This has occurred independently of state-to-state variations in application of recommended practices, type of prenatal health-care provider, type of patient insurance, or maternal demographic characteristics. A 14-state study of HIV counseling and testing data for 1996-1997 reported that the proportion of pregnant women voluntarily tested for HIV was 58%- -81%. Women most likely to receive HIV counseling and testing during pregnancy were those who were African-American, had less than a high school education, were aged <25 years, received care in public rather than private health-care settings, and were Medicaid beneficiaries.

When offered, most women (approximately 70% in most settings) will accept HIV testing. In a multicity study of prenatal clinic patients, 74%-95% of participants accepted HIV testing. Reasons most commonly cited for acceptance were a) belief that knowledge of positive HIV serostatus during pregnancy (and subsequent chemoprophylaxis) can be beneficial to both mother and infant and b) strong provider endorsement for prenatal HIV testing. The most common reasons for declining the test were no perceived risk, administrative scheduling difficulties, history of previous testing, and lack of provider endorsement.

Although most providers agreed that all women should be tested for HIV, some offered testing only to women whom they considered at risk for infection). Risk-based testing approaches identified fewer HIV-infected women than routine voluntary testing of all pregnant women and also decreases in effectiveness as more women are infected through heterosexual contact without knowing their partner's HIV risk status.

Receipt of ZDV Chemoprophylaxis

The primary strategy to prevent perinatal transmission (in addition to avoidance of breast-feeding) is antiretroviral chemoprophylaxis using ZDV, now often part of a combined antiretroviral therapy regimen that reduces viral load as low as possible near the time of delivery. In the PACTG 076 protocol, chemoprophylaxis consisted of three components: ZDV administered orally to the mother during the second and third trimesters of pregnancy, intravenous administration of ZDV to the mother during labor and delivery, and administration of oral ZDV to the infant during the first 6 weeks of life.

Data from several sources demonstrated rapid implementation of the recommendations for ZDV prophylaxis by health-care providers and use of ZDV by HIV-infected pregnant women. One study analyzed approximately 6,800 perinatally exposed and infected children born during 1993-1998 in 32 states that reported HIV infection. Among those whose mothers were tested for HIV before or at birth of the infant, the percentage of infants receiving any component of the recommended ZDV regimen increased from 37% in 1994 to approximately 85% during 1996-1998. In a supplemental study of women diagnosed before delivery in four states, the proportion offered prenatal ZDV increased from 27% in 1993 to 85% in 1996, the proportion offered intrapartum ZDV increased from 5% to 75%, and the proportion offered neonatal ZDV increased from 5% to 76%. Fewer than 5% of women refused ZDV.

Abbreviated Antiretroviral Regimens

Given the complexity and cost of the PACTG 076 regimen, particularly for the developing world, other effective strategies to reduce the risk for perinatal HIV transmission have been identified. Results of randomized clinical trials in developing countries and observational data from the United States indicated that abbreviated perinatal antiretroviral regimens, regimens that begin as late as the onset of labor, and possibly antiretroviral chemoprophylaxis given only to the newborn are effective in reducing the risk for perinatal transmission.

Abbreviated antiretroviral regimens have also proved effective in reducing the risk for transmission in resource-poor countries. In nonbreast-feeding women, a short antepartum/intrapartum regimen of ZDV reduced transmission by 50%; a similar regimen in breast-feeding populations was also effective, although efficacy was lower. Two other intrapartum/postpartum antiretroviral regimens were effective in reducing transmission in clinical trials among breast-feeding African women. One regimen was nevirapine given as a single dose to the woman in labor and to the infant at age 48 hours, and the other was ZDV plus lamivudine (3TC) given orally intrapartum and to the infant and mother for 1 week postpartum. Observational data and animal studies indicated that newborn prophylaxis alone offered some protection. Updated recommendations for use of these regimens in the United States, including for pregnant women who do not receive health care until near the time of delivery are available at the HIV/AIDS Treatment Information Service (ATIS) website at <http://www.hivatis.org>.

Other Strategies to Prevent Perinatal Transmission

Reducing exposure of the infant to maternal blood and secretions during the intrapartum period can prevent perinatal HIV transmission. Cesarean delivery performed before onset of labor and membrane rupture lowers the risk for HIV transmission compared with vaginal delivery in certain populations of women. Cesarean delivery resulted in a 50% reduction in perinatal HIV transmission overall among HIV-infected women who had cesarean deliveries compared with women delivering vaginally. A randomized clinical trial in Europe demonstrated a benefit of elective cesarean section before onset of labor for both untreated HIV-infected women and infected women on antiretroviral therapy. However, cesarean delivery is associated with greater morbidity than vaginal delivery among both HIV-infected and noninfected women. In 1999 and 2000, the American College of Obstetricians and Gynecologists (ACOG) recommended offering scheduled cesarean delivery at 38 weeks gestation to reduce the risk for vertical transmission of HIV infection. Other intrapartum interventions alone (e.g., vaginal disinfection during labor and cleansing of the newborn) have not proven effective.

Follow-Up Care for Infected Women and Perinatally Exposed Infants

Providing mothers and their infants with ongoing HIV-related care can maximize the benefits of prevention interventions. The medical care of HIV-infected women is a complicated task requiring use of potent combinations of antiretroviral drugs, monitoring of viral load and drug resistance, treatment and prophylaxis of opportunistic infections, and monitoring of immune status. In addition to conditions (e.g., Pneumocystis carinii pneumonia [PCP]) for which all immunocompromised HIVinfected persons are at risk, women experience specific manifestations of HIV disease (e.g., aggressive pelvic inflammatory disease and persistent and difficult-to-treat vaginal yeast infections requiring frequent screening and treatment). HIV-infected women are also at increased risk for cervical dysplasia, which can result in cancer. With early detection and appropriate treatment, many of these complications can be prevented and treated. Improved health outcomes resulting from advances in HIV management and treatment depend not only on access to medical care but also on access to prevention and psychosocial support services. In the United States, most mothers and children with HIV/AIDS live in areas where poverty, illicit drug use, poor housing, and limited access to and use of medical care and social services add to the challenges of HIV disease. Women with HIV infection often have difficulty gaining access to health care and frequently are responsible for caring for children and other family members who might also be HIV-infected. They often lack social support and face other challenges that could interfere with their ability to gain access to and adhere to complicated treatment regimens. The complex medical and social problems of families affected by HIV are best managed by multidisciplinary case-management teams that integrate specialty medical care with prevention, psychosocial, and other HIV-related services (see Revised Guidelines for HIV Counseling, Testing, and Referral).

Postnatal evaluation of infants at risk for HIV infection that begins immediately after birth is the key to early diagnosis and optimal medical management of infected children. PCP is the most common opportunistic infection in children with AIDS and is often fatal. Because PCP occurs most often in perinatally infected children at ages 3-6 months, effective prevention requires that children born to HIV-infected mothers be identified promptly, preferably through maternal testing, so that PCP prophylactic therapy can be initiated at age 6 weeks. In 1995, CDC published revised guidelines recommending PCP prophylaxis for all perinatally exposed infants at ages 4-6 weeks until their infection status was determined. Perinatal screening can identify HIVexposed infants early, making it possible to follow infected children closely and promptly diagnose other potentially treatable, HIVrelated conditions (e.g., severe bacterial infections). This also allows antiretroviral treatment to be initiated as soon as indicated to prevent morbidity, prolong survival, and reduce the need for hospitalization.

Follow-up of infants, both infected and uninfected, who are exposed to antiretroviral drugs is critical to identifying potential short- and long-term toxicities. Data on the risks of antiretroviral drugs during pregnancy are summarized and updated regularly.

Laboratory Testing Considerations

Testing of women before or during pregnancy is typically conducted according to the standard protocol for detection of antibody to HIV. For women with unknown HIV status during active labor, antiretroviral treatment can still be effective when given during labor and delivery, followed by treatment of the newborn. This expedited intervention requires the use of rapid diagnostic testing during labor or rapid return of results from standard testing.

Standard Testing Protocol

The HIV testing algorithm recommended by PHS consists of initial screening with an FDA-licensed enzyme immunoassay (EIA) followed by confirmatory testing of repeatedly reactive EIAs with an FDA-licensed supplemental test (e.g., Western blot). Although each test is highly sensitive and specific, using both increases the accuracy of results.

Indeterminate Western blot results can be caused by either incomplete antibody response to HIV in samples from infected persons or nonspecific reactions in samples from uninfected persons. Incomplete antibody responses that produce negative or indeterminate results on Western blot tests can occur among persons recently infected with HIV who have low levels of detectable antibodies (i.e., seroconversion), persons who have endstage HIV disease, and perinatally exposed but uninfected infants who are seroreverting (i.e., losing maternal antibody). Nonspecific reactions producing indeterminate results in uninfected persons have occurred more frequently among pregnant or parous women than among other persons. No large-scale studies have been conducted to estimate the prevalence of indeterminate test results in pregnant women. However, a survey of 1,044,944 neonatal dried-blood specimens tested by EIA for maternally acquired HIV-1 antibody indicated a relatively low rate of indeterminate Western blot results (<1 in 4,000 specimens tested by EIA). Overall, 2,845 Western blots were performed.

False-positive Western blot results (especially those with a majority of bands) are rare. For example, in a study that used a sensitive culture technique to test approximately 290,000 blood donors , no false-positive Western blot results were detected (75). In a study of the frequency of false-positive diagnoses among military applicants from a low-prevalence population (i.e., <1.5 infections/1,000 population), one false-positive result was detected among 135,187 persons tested.

An HIV test should be considered positive only after screening and confirmatory tests are reactive. A confirmed positive test result indicates that a person has been infected with HIV. False-positive results when both screening and confirmatory tests are reactive are rare. However, the possibility of a mislabeled sample or laboratory error must be considered, especially for a client with no identifiable risk for HIV infection. HIV vaccine-induced antibodies may be detected by current tests and may cause a false-positive result. Persons whose test results are HIV-positive and who are identified as vaccine trial participants should be encouraged to contact or return to their trial site or an associated trial site for HIV counseling, testing, and referral (CTR) services.

Incorrect HIV test results occur primarily because of specimenhandling errors, laboratory errors, or failure to follow the recommended testing algorithm. However, patients might report incorrect test results because they misunderstood previous test results or misperceived that they were infected. Although these occurrences are rare, increased testing of pregnant women will result in additional indeterminate, false-positive, and incorrect results. Because of the significance of an HIV-positive test result, its impact on a woman's reproductive decisions, and the resulting need to consider HIV therapeutic drugs for both a pregnant woman and her infant, previous guidelines have emphasized that HIV test results must be obtained and interpreted correctly. In some circumstances, correct interpretation might require consideration of not only additional testing but also the woman's clinical condition and history of possible exposure to HIV.

Diagnosis of HIV Infection in Newborns

The standard antibody assays used for older children and adults are less useful for diagnosis of infection in children aged <18 months. Nearly all infants born to HIV-infected mothers passively acquire maternal antibody and, in some cases, will test antibody positive until age 18 months regardless of whether they are infected. Definitive diagnosis of HIV infection in early infancy requires other assays, including nucleic acid amplification (e.g., polymerase chain reaction [PCR]) or viral culture. HIV infection is diagnosed by two positive assays (PCR or viral culture) on two separate specimens. Infant HIV testing should be done as soon after birth as possible so appropriate treatment interventions can be implemented quickly.

RECOMMENDATIONS

The following revised recommendations for HIV screening ofpregnant women are based on scientific and clinical advances inpreventing perinatally acquired HIV and caring for HIV-infectedwomen, recommendations from IOM, consultations withspecialists in the field, and public opinion. They reflect the need foruniversal HIV testing of all pregnant women and simplification ofthe pretest process so that operational procedures do not impedewomen from benefitting from proven measures to preventperinatal transmission and from other advances in the care andtreatment of HIV disease. Although universal testing isrecommended, testing should remain a voluntary decision by thepregnant woman.

Education and Prevention Counseling of Pregnant Women Regarding HIV

When the pretest process is simplified to providing essential information, the value of prevention counseling should not be lost. For some women, the prenatal care period could be an ideal opportunity for HIV prevention and subsequent behavior change to reduce risk for acquiring HIV infection. Thus, the following steps are recommended:

  • Information regarding HIV and assessment of risks for HIVinfection (i.e., risk screening) should be provided to all pregnantwomen as part of routine health education. Reluctance toprovide HIV prevention counseling should never be a barrier toHIV testing. Similarly, a focus on increased HIV testing shouldnot be a barrier to providing effective HIV preventioncounseling for persons determined to be at increased risk foracquiring or transmitting HIV (see Revised Guidelines for HIVCounseling, Testing, and Referral).
  • Pregnant women found to have behaviors that place them athigh risk for acquiring HIV infection (e.g., multiple sex partners,current diagnosis or history of STDs, exchange of sex for moneyor drugs, substance abuse) or who want more intensive clientcenteredHIV prevention counseling should be provided with orreferred to HIV risk-reduction services (e.g., drug treatment, STDtreatment, HIV centers with personnel trained in HIVcounseling).

Recommendations for HIV-Infected Pregnant Women

  • HIV-infected pregnant women should receive HIV preventioncounseling as recommended (see Revised Guidelines for HIVCounseling, Testing, and Referral). This counseling shouldinclude discussion of the risk for perinatal HIV transmission,ways to reduce this risk, and the prognosis for infants whobecome infected. HIV-infected pregnant women should also betold the clinical implications of a positive HIV antibody testresult and the need for and benefit of HIV-related medical andother early intervention services, including how to access theseservices.
  • HIV-infected pregnant women should be counseled regardingantiretroviral therapy during pregnancy to improve their healthand prevent perinatal transmission. Medical care andmanagement of HIV-infected persons, especially pregnantwomen, can be complicated because of the need forcombination therapy with multiple drugs, management ofcommon side effects, careful monitoring of viral load and drugresistance, prophylaxis for and treatment of opportunisticinfections, and monitoring of immune status. Health-careproviders who are not experienced in the care of pregnant HIVinfectedwomen are encouraged to obtain referral for specialtycare from providers who are knowledgeable in this area.

Although pregnancy is not an adequate reason to defer therapy for HIV infection, unique considerations exist regarding use of antiretroviral drugs during pregnancy, including the potential need to alter dosing because of physiologic changes associated with pregnancy, the potential for adverse short- or long-term effects on the fetus and infant, and the effectiveness in reducing the risk for perinatal transmission.

  • Obstetric providers should adhere to best obstetric practices,including offering scheduled cesarean section at 38 weeks toreduce risk for perinatal HIV transmission.
  • HIV-infected pregnant women should receive informationregarding all reproductive options. Reproductive counselingshould be nondirective. Health-care providers should be awareof the complex concerns that HIV-infected women mustconsider when making decisions regarding their reproductiveoptions and should be supportive of any decision.
  • To eliminate the risk for postnatal transmission, HIV-infectedwomen in the United States should not breast-feed. Supportservices for use of appropriate breast milk substitutes should beprovided when necessary. UNAIDS and World HealthOrganization recommendations for HIV and breast-feedingshould be followed in international settings.
  • To optimize medical management, positive and negative HIVtest results should be available to a woman's health-careprovider and included on her confidential medical records andthose of her infant. After informing the mother, maternalhealth-care providers should notify the pediatric-care providersof the impending birth of an HIV-exposed infant and anyanticipated complications. If HIV is first diagnosed in the infant,health-care providers should discuss the implications for themother's health and help her obtain care. Women should alsobe encouraged to have their other children tested for HIV.Children can be infected with HIV for many years beforecomplications occur. Providers are encouraged to buildsupportive health-care relationships that promote discussion ofpertinent health information. Confidential HIV-relatedinformation should be disclosed or shared only in accordancewith prevailing legal requirements.
  • After receiving their test results, HIV-infected pregnant womenshould receive counseling, including assessment of the potentialfor negative effects (e.g., discrimination, domestic violence,psychological difficulties). Counseling should also includeinformation on how to minimize these consequences, assistancein identifying supportive persons in their own social networks,and referral to appropriate psychological, social, and legal services. HIV-infected women should be counseled regardingthe risk for transmission to others and ways to decrease thisrisk. They also should be told that discrimination based onHIV status or AIDS in housing, employment, state programs,and public accommodations (including physicians' officesand hospitals) is illegal.
  • Health-care providers should thoroughly assess theprevention service needs of HIV-infected women (e.g.,substance abuse, STD treatment, partner referral, or familyplanning services) and develop a plan to promote access toand use of these services (see Revised Guidelines for HIVCounseling, Testing, and Referral).
  • Health-care providers should follow the Public Health ServiceTask Force recommendations for using antiretroviral drugs totreat pregnant HIV-1 infected women and reduce perinatalHIV-1 transmission in the United States, which addresstreating pregnant women who do not receive health careuntil near the time of delivery. These recommendations areavailable at the HIV/AIDS Treatment Information Service(ATIS) website at <http://www.hivatis.org> .

Recommendations for Postpartum Follow-Up of Infected Women and Perinatally Exposed Children

  • HIV-infected women should receive ongoing HIV-relatedmedical care, including immune-function monitoring,recommended therapy, and prophylaxis for and treatment of opportunistic infections and other HIV-related conditions.HIV-infected women should receive gynecologic care,including regular Pap smears, reproductive counseling,information on how to prevent sexual and drug-relatedtransmission of HIV, and treatment of gynecologic conditionsaccording to published recommendations. Obstetricalproviders should ensure that HIV-infected women areintroduced or referred to another provider to continue theircare after pregnancy.
  • HIV-infected women (or their children's guardians) should beinformed of the importance of follow-up for their children.Children whose HIV infection status is unknown require earlydiagnostic testing and prophylactic therapy to prevent PCPpending determination of their status.
    • Infected children require follow-up care to determine theneed for prophylactic therapy and antiretroviral treatmentand to monitor disorders in growth and development thatoften occur before age 24 months.
    • Uninfected children who are exposed to antiretroviraltherapy should be assessed for potential short- and longtermside effects.
  • Identification of an HIV-infected mother indicates that herfamily needs or will need medical and social services as herdisease progresses. Thus, health-care providers should ensurethat referrals to services address the needs of the entire family.

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Medico-legal Issues
from Dr. Steven E. Lerner & Associates*

Musculoskeletal and rheumatic complaints account forapproximately 15% of the patients seen by primary carephysicians. These complaints include muscle pain andweakness, regional pain syndrome such as back or neck pain,rheumatoid arthritis, gout, ankylosing spondylitis and lupuserythematosus among others. Rheumatologists are specialists inthe diagnosis and management of musculoskeletal disordershaving completed three years of training in the broad field ofinternal medicine and a two year fellowship in rheumatology.

Rheumatoid arthritis is a systemic disorder characterized by femalepredominance. It is persistent, symmetric and may be associatedwith systemic features such as fatigue, weight loss and anemia. 70- 80% of patients with rheumatoid arthritis are positive withrheumatoid factor (an antibody against IgM). Most patients alsohave an elevated sedimentation rate.

Medications are useful in managing inflammation associated withrheumatoid arthritis. The first compounds employed are eithersalicylates or other nonsteroidal anti-inflammatory drugs. Thesemedications exert their anti-inflammatory action by modifyingprostaglandin metabolism. They are used as initial therapies. Allshare common toxicities including stomach upset, liver functionabnormality, renal dysfunction and fluid retention. About 1 - 2%of people who take aspirin or other nonsteroidal antiinflammatorydrugs may have peptic ulceration.

In those patients who cannot be managed with aspirin or othernonsteroidal anti-inflammatory drugs, medications such as goldeninjections, Plaquenil, penicillamine and Methotrexate areemployed in an attempt to modify the course of the disease.

Gold:
Gold is a remittive agent that can prevent disease progression. It is generally given by injection but can be taken orally. It has some common toxicities including skin and mucous membrane problems. About 1% of patients get kidney or blood problems related to gold injections and/or oral ingestion.

Careful monitoring of gold therapy is very important in patients with rheumatoid arthritis. During the duration of the therapy complete blood counts, platelet counts and urinalyses must be done at the time of each injection. After a prolonged period of time without toxicity monitoring may be done every other injection. If severe blood reactions and/or kidney problems develop then medication should be discontinued.

Plaquenil:
Plaquenil or hydroxychloroquine is an anti-malarial agent with
anti-inflammatory properties in rheumatoid arthritis. Like gold it
is used in those patients who fail to respond to a conservative
regimen including rest, salicylates and/or other nonsteroidal antiinflammatory
drugs. These are given orally. Ophthalmologic
monitoring is necessary to check for visual loss at an early
reversible stage. Patients should be seen by their eye doctors a
minimum of once a year. This therapy should be discontinued if
any eye problems are related to the medication.

Penicillamine:
Penicillamine has been shown in controlled studies to be effectivein reducing inflammatory arthritis such as rheumatoid arthritis. Itis given orally. Like gold it may be associated with a variety ofproblems including skin and mucous membrane problems, blooddisorders and/or kidney problems. It must be carefully monitored.Complete blood counts, platelet counts and urinalyses should bedone monthly for the first six months of therapy and every othermonth thereafter. Laboratory data is essential to permit earlydetection of problems with the blood and/or kidneys.

Corticosteroids:
Corticosteroids are among the most potent of the antiinflammatoryagents. However they have a high incidence oftoxicity and may not change the course of rheumatoid arthritis.They should only be used in patients with activie synovitis in manyjoints. These medications are useful in incapacitatingconstitutional symptoms such as fever, anemia, wieght loss,neuropathy and vasculitis (blood vessel inflammation).

Prednisone:
Prednisone is the preferred agent because of its cost and lowpotential for fluid retention. Tablets are available in 1 mg and 5mg dosages. All patients should be educated about the side effectsof corticosteroids. Informed consent is most inportant in their use.

Methotrexate:
Methotrexate is a new usage of a very old medication. In generalit is given by "modified pulse" with 3 to 9 tablets administeredweekly. Methotrexate should only be given by those physicianswho are knowledgeable and experienced in its usage. The use ofMethotrexate involves periodic monitoring for toxicity. Monitoringshould include complete blood counts with differential and plateletcounts. It should also involve liver and renal function tests.Patients who are at increased risk for impaired Methotrexateelimination (i.e., patients with kidney problems) should bemonitored more frequently.

Methotrexate may be associated with a variety of problemsincluding liver toxicity, lung problems, mouth ulcers, stomachpain, etc. Liver biopsies may be necessary if there is a questionabout the degree of Methotrexate liver toxicity and continuation ofthis drug.

Rheumatoid arthritis is a manageable disorder is patients who aretreated by rheumatologists and/or experienced internal medicinephysicians. With proper education, exercise and medicationsmany patients may expect to lead fairly normal lives. The goals oftreatment are to maintain joint function and to prevent deformity.Medications are available for this purpose. However, they must beused by physicians who are knowledgeable about their use andemploy the proper monitoring techniques.

Physicians who use these medications in patients with rheumatoidarthritis must be aware of the strong possibility of serious sideeffects. All the ramifications of treatment should be duscussed withthe patient prior to initiation of these medications. Patients usingthese medications should be under constant physician supervision.

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Case Report

An African male with cough, haemoptysis, weight loss and hypercalcaemia: TB or not TB?
A.F. Al-Mobeireek*, M. Arafah**, N. Siddiqui*
*Dept of Medicine, **Dept of Pathology, College of Medicine, King Saud University, Riyadh, Saudi Arabia

Case history

A 60-yr-old Sudanese male was referred to the University Hospital,Riyadh, Saudi Arabia, with the chief complaints of chronic coughproductive of scanty sputum and occasional haemoptysis,anorexia and weight loss for 9 months. The patient was extensivelyinvestigated in other hospitals and was treated as a pulmonarytuberculosis (TB) patient on the basis of lymphocytic pleural fluidcytology and the finding of granuloma on pleural biopsy. Hecontinued to get worse, despite receiving four anti-TB drugs for theprevious 4 months.

The patient's course was complicated by hypercalcaemia, whichfailed to respond to steroids and saline diuresis and requiredcalcitonin. He also developed right-sided pneumothorax, whichrequired prolonged thoracostomy drainage. He was a nonsmokerand worked as a painter.

On physical examination, the patient was cachectic, depressed andhad finger clubbing. Furthermore, he had findings consistent withright pleural effusion.

A summary of investigations is shown in table 1. An initial chestradiograph is shown in figure 1. Selected images of computed chesttomography (CT) are shown in figure 2. In addition, the patientunderwent a CT-guided lung biopsy, which is shown in figure 3.

Interpretation
Chest radiography

The chest radiograph (fig. 1) shows a consolidation and a pleural effusion on the right as well as a small effusion on the left. Computed tomography

The chest CTs (figs. 2a and b) show a consolidation with an air bronchogram, pleural effusion, pneumothorax and chest tube on the right side, and mediastinal lymphadenopathy with calcification. Site of the bronchopleural fistula can be seen in the periphery of the right lung in figure 2a.

Histological examination

The histopathology of the lung biopsy (fig. 3) showed marked expansion of the interstitium, with dense infiltration by lymphocytes and ill-defined noncaseating epithelioid granulomas.

The infiltrate was extending to the subendothelium of the smallvascular walls, with no luminal involvement. Necrosis was absent.Cytologically, there was a mixture of small-to-medium sizedlymphocytes with plasmacytoid appearance. There were a fewlarge cells with vesicular nuclei and small prominent nucleoli.Many mature plasma cells with Russell bodies were also noted.Epithelioid cells constituted small and ill-defined granulomas.Most lymphocytes stained positively with B-cell marker (CD20) byimmunohistochemical analysis. A few CD3 positive T-cells werealso present. Immunohistochemical analyses for demonstration oflight chain restriction were not conclusive. CD30 was negative.Review of the pleural biopsy (done previously in the referringhospital) showed similar cellular infiltrate with many ill-definedepithelioid granulomas and areas of dense fibrosis withcalcifications.

Diagnosis: "Primary pulmonary lymphoma (B-cell)"
Hospital course

The patient received the first cycle of chemotherapy, which resulted in stabilisation of his clinical condition over the following month. The patient decided to travel back to his home country to complete his treatment there. There was no further follow-up.

Discussion

Although TB is endemic in the patient's geographical location andthe clinical picture is compatible with TB (includinghypercalcaemia, a definite microbiological or histological proofwas lacking. Granulomas without acid-fast bacilli or positivemycobacterial culture are not specific; a variety of infectious andnoninfectious causes may be responsible (table 2). The patient'scondition worsened despite antituberculous therapy. Otherdiagnoses that can cause chronic pulmonary infiltrates andhypercalcaemia that should be considered in this setting includesarcoidosis, malignancy (including lymphoma), multiplemyeloma, and amyloidosis.

A diagnosis of sarcoidosis is supported by the presence ofgranulomas, hypercalcaemia, hypergammaglobulinaemia and anegative tuberculin test. All these features were present in thepatient, except that he also had pleural effusion, which is unusualfor sarcoidosis. He was also given steroids, without clinicalimprovement.

The presence of elevated erythrocyte sedimenta<1?show=[fo]>tionrate, anaemia, hyperproteinaemia, hypercalcaemia and renalinsufficiency should also raise the possibility of multiple myeloma.This diagnosis is ruled out, however, by the negative bone marrow,the polyclonal nature of the gammopathy and the absence ofBence-Jones protein in the urine. Secondary amyloidosis,complicating his chronic pulmonary disease, may be consideredbecause of the hypergammaglobulinaemia, hepatomegaly andrenal insufficiency. Again, this is unlikely because of the relativelyshort period of his illness, the negative rectal biopsy and theradiological picture.

Carcinomatosis with hypercalcaemia is another consideration, butthere was no evidence clinically or radiologically pointing to aprimary tumour, and multiple organ biopsies were negative. Inaddition, many other conditions can cause pulmonary granuloma(not necessarily associated with hypercalcaemia), but there was noclinical or laboratory evidence to support any of these (table 2).

This leaves primary pulmonary lymphoma (PPL) for consideration,taking into account the histological picture and the lack ofevidence of lymphoma elsewhere. PPL is not common, representing3.6% of extranodal non-Hodgkin's lymphomas (NHL). Severalhistopathological subtypes of PPL have been described. The fourmost distinct entities are: pulmonary lymphoma of B-cellphenotype and of low-grade malignancy, B-cell lymphoma ofhigh-grade malignancy, peripheral T-cell NHL, and lymphomatoidgranulomatosis, whose clonal characterisation is sometimesdifficult to confirm.

The most common types of low-grade B-cell PPL are welldifferentiatedlymphomas that originate from the mucosaassociatedlymphoid tissue (low-grade MALT lymphoma). Thetypical site of MALT lymphoma in humans is the gastrointestinaltract. It has also been described in conjunctiva, salivary, thyroidand thymus glands. Most maltomas arise in the setting of anautoimmune disease or chronic antigenic stimulation.Involvement of the lung was described by Addis et al. in 1988.Pulmonary maltomas are most often indolent and remainlocalised in the lung for long periods.

Epithelioid granulomas are known to be seen in pulmonarylymphoma. In one study, they were observed in 20% of 54 cases oflow-grade malignant lymphoma. Their presence may beresponsible for an erroneous diagnosis of TB in a small biopsyspecimen, and their presence in conjunction with diffuse denselymphoid infiltrate should be interpreted cautiously. Severalancillary methods (e.g. genetic analysis, multiparametric flowcytometry and gene amplification pattern) can be applied whenworking with small biopsies and cytological samples.

In conclusion, lymphoproliferative diseases affecting the lungoccur over a broad clinicopathological spectrum. Pulmonarylymphoma can mimic many diseases and should be considered inthe differential diagnosis. Diagnosis can be difficult, as it requiresadequate tissue sampling and a skilled pathologist. The presence ofgranulomas should not lead to the erroneous diagnosis ofgranulomatous diseases, particularly in the prescence of clonallymphoplasmacytic infilterate, and if the clinicopathologicalsetting is not typical.

Acknowledgements

The authors are grateful to A. Rikabi for reviewing the manuscript.

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Infection disease update / Self Assessment

Drug-resistant Streptococcus Pneumoniae Disease

Clinical Features Pneumonia, bacteremia, otitis media (OM), meningitis, peritonitis and sinusitis
Etiologic Agent Streptococcus pneumoniae. Resistant to one or more commonly used antibiotics. Seven sero-types (6A, 6B, 9V, 14, 19A,19F, and 23F) account for most DRSP.
Streptococcus pneumoniae. Resistant to one or more commonly used antibiotics. Seven sero-types (6A, 6B, 9V, 14, 19A,19F, and 23F) accounted for most DRSP before the introduction of 7-valent pneumococcal conjugate vaccine(PCV7, Prevnar®, Wyeth) in the U.S. in 2000). Most antibiotic resistance today is found in serotype 19A.
Incidence Until 2000, S. pneumoniae infections caused 60,000 cases of invasive disease each year and up to 40% of these werecaused by pneumococci non-susceptible to at least one drug. These figures have decreased substantially followingthe introduction of the pneumococcal conjugate vaccine for children. In the year 2006, there were 41,400 cases ofinvasive pneumococcal disease. Of these, 38% were caused by pneumococci non-susceptible to at least one drugand 15% were due to a strain non-susceptible to 3 or more drugs. Prevalence of DRSP shows geographic variation.
Sequelae Death occurs in 14% of hospitalized adults with invasive disease. Neurologic sequelae occur in meningitis patients. Hearing impairment can result from recurrent otitis media. Resistance has led to treatment failures.
Costs DRSP is associated with increased costs due to use of antimicrobial agents, recurrent disease, surveillance, education, and new antimicrobial drug development.
Transmission Person-to-person.
Risk Groups Persons who attend or work at child-care centers and persons who recently used antimicrobial agents are at increased risk for infection with DRSP.
Surveillance CDC sponsors active, population-based surveillance in ten states. Laboratory-based reporting of DRSP has been mandated in several states. Several private-sector systems also track DRSP.
Trends The new pneumococcal conjugate vaccine is preventing many infections due to drug-resistant pneumococci. Outbreaks of DRSP have been reported in nursing homes, institutions for HIV-infected persons, and child-care centers.
Challenges Widespread overuse of antimicrobial agents and the spread of resistant strains has contributed to emergingresistance. The 23-valent vaccine is underused. Supplies of the new conjugate vaccine for children are inadequate.Some clinical laboratories have not adopted standard methods (NCCLS guidelines) for identifying and defining DRSP.
Opportunities Campaigns for more judicious use of antibiotics and use of the new conjugate vaccine may slow or reverseemerging drug resistance. Prevention of infections could improve through expanded use of 23-valentpolysaccharide vaccine and the new conjugate vaccine. Among children 5 years of age, the conjugate vaccine elicitsprotection against ~80% of invasive pneumococcal isolates that are not susceptible to penicillin.

SELF ASSESSMENT

13 year old boy was brought to casualty by his parents in a drowsy state. Earlier in the afternoon, the teachernoted that he was walking aimlessly in class and did not respond when he was questioned.There was nointense exercise prior to the abnormal behaviour.His mother has type 2 diabetes and she is takingglibenclamide.He gave a history of being bullied in school.

Dextrostix in casualty was 1.3mmol/L and he regained consciousness after dextrose infusion. He was fasted overnight and developed another episode of hypoglycaemia the next morning.

Blood results taken the next morning:
Fasting insulin: 91IU/ml ( <11 )
Glucose: 2mmol/L

1. List 2 differential diagnosis.
2. What is the classic test to confirm the diagnosis?
3. What is the final diagnosis?

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Medical Updates

COPD
Janice Charles, Helena Britt, Salma Fahridin

Keywords: pulmonary disease, chronic obstructive

From April 2008 to March 2009 in BEACH (Bettering theEvaluation and Care of Health) data, chronic obstructivepulmonary disease (COPD) was managed by generalpractitioners at a rate of 8 per 1000 encounters, which suggestsit is managed about 923 000 times per year nationally. Theprevalence of COPD in the population attending generalpractice is 2.6%. 1

The BEACH data confirmed that patients managed for COPDwere were significantly more likely than average to be male.Male patients were managed for COPD at a rate of 10 per 1000encounters, significantly higher than the rate for females (7 per1000). They were also more likely to be older than the averagegeneral practice patient; three quarters of COPD patients wereaged 65 years or more. Chronic obstructive pulmonary diseasewas managed at a rate of 21 per 1000 encounters with patientsin that age group (Figure 1)

Consultations of COPD patients took place less often thanusual in the surgery. As would be expected with these olderpatients, consultations at residential aged care facilities (RACF)or the patient’s home were recorded at four times the BEACHaverage (Figure 1).

Management of COPD
There were 116 medications prescribed, advised or supplied for every 100 COPD problems managed (Table 1). The most common were inhaled tiotropium, which accounted for more than one-quarter of these medications, salbutamol (one in 5) and fluticasone/salmeterol. Prednisolone was less common.

Clinical treatment and procedures provided by the GP for COPD were recorded at a significantly lower than average rate (25 per 100 COPD problems compared with 33 per 100 total problems managed). Counselling or advice about smoking accounted for one-quarter of the clinical treatments, and the performing of respiratory function tests accounted for more than half of the procedures.

Referals were given at a rate of 6 per 100 COPD problems which was significantly lower than average. The majority of referrals were to respiratory physicians. Imaging tests were ordered at the usual rate, with the most common being chest X-rays. The ordering of pathology tests was rare for COPD with only five recorded per 100 COPD problems managed. The pathology test ordered most frequently was full blood count.

Authors
Janice Charles, Helena Britt and Salma Fahridin, Australian GP Statistics & Classification Centre, University of Sydney, New South Wales.

Conflict of interest: none declared.

Acknowledgments
The authors thank the GP participants in the BEACH programand all members of the BEACH team. Financial contributors toBEACH in 2008 and 2009: Australian Government Departmentof Health and Ageing; Australian Institute of Health andWelfare; National Prescribing Service; AstraZeneca Pty Ltd(Australia); Janssen-Cilag Pty Ltd; Merck, Sharp and Dohme(Australia) Pty Ltd; Pfizer Australia; Abbott Australasia; Sanofi-Aventis Australia Pty Ltd; Wyeth Australia Pty Ltd.

Reference

  1. Knox SA, Harrison CM, Britt HC, Henderson JV. Estimating prevalence of common chronic morbidities in Australia. Med J Aust 2008; 189:66- 70.

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Answers

Self Assessment

  1. a) Insulinoma
    b) Factitious hypoglycaemia
  2. 72-hour fast
    A suggested protocol for 72 –hour fast at local setting in view of the laboratory cost.
    • Date the onset of the fast as the time of the last food intake.
    • Allow the patient to drink calorie-free and caffeine-free beverages.
    • Ensure that the patient is active during waking hours.
    • Collect blood specimens for measurement of plasma glucose every six hours ,insulin and C-peptide at the start and end of test
      Because of possible delays in the availability of the results of plasma glucose testing, a bedside reflectance meter may have to be used to measure blood glucose . However, the decision to end the fast should not be made on the basis of a fingerstick blood glucose value.
    • End the fast when the plasma glucose concentration is less than 2.5 mmol/L, the patient has symptoms or signs of hypoglycemia or 72 hours have elapsed.

  3. Factitious hypoglycaemia most likely secondary to sulfonylurea ingestion.

Discussion

The 72 hour fast in this patient was normal. During the fast he did not have any hypoglycaemic symptoms and plasma glucose concentration of less than 2.5mmol/L was not attained.

Hypoglycaemia associated with insulin excess is often caused by either insulinoma or sulfonylurea administration. Features of patients that should cause one to think of factitious hypoglycaemia include health care professionals, patients with relatives who have diabetes mellitus as in this patient.

Factitial hypoglycemia caused by sulfonylurea drugs biochemically mimics the insulinoma response since these drugs stimulate insulin and C-peptide secretion. Normal subjects have complete suppression of serum insulin and C-peptide when hypoglycemia is induced by a non-insulin-mediated mechanism. In contrast, patients with insulinoma and sulfonylurea-induced hypoglycemia can have serum insulin and C-peptide values above or within the normalovernight fasting range. These ranges, however, are too high for the low serum glucose concentration. Short of an admission by the patient of self-administration of a sulfonylurea, the only convincing biochemical finding that confirms the diagnosis is detection of sulfonylurea in the serum .The sulfonylurea may be detected in plasma or urine by high-performance liquid chromatography or mass spectroscopy.

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