JULY 2011 VOL 1, NO. 1 JOURNAL Vol 1 No. 1... · 2012-01-05 · Vol. 1, No. 1, July 2011 Official Journal of the Bangladesh Institute of Research & Rehabilitation of Diabetes, Endocrine

VOL 1, NO. 1JULY 2011

Vol. 1, No. 1, July 2011

Official Journal of the Bangladesh Institute of Research & Rehabilitation of Diabetes,Endocrine and Metabolic Disorders (BIRDEM)

122, Kazi Nazrul Islam AvenueDhaka-1000, Bangladesh

EDITORIAL BOARD ADVISORY BOARD

Chairperson:Prof. Nazmun Nahar

Editor in Chief:Prof. Zafar Ahmed Latif

Executive Editor:Prof. Khwaja Nazimuddin

Editor:Prof. Mohammad Omar FaruqProf. Rahima BegumProf. AKM MohibullahProf. AKM Nur Nobi ChowdhuryProf. Md. Faruque PathanProf. Arup Ratan ChowdhuryProf. Md. Anisur RahmanProf. Jalaluddin Ashraful HaqueProf. Md. Hazrat AliProf. Abdullah Al AminDr. Shahidul Alam KhanProf. Tahmina BegumProf. Amirul HaqueProf. Mirza Mahbubul HasanProf. Zaheer Al AminProf. Abu Saleh MohiuddinProf. Reza Bin ZaidProf. Nazma Afroze

Assistant Editors:Dr. Nirmalendu Bikash BhowmikDr. SM AshrafuzzamanDr. Sarwar IqbalDr. Shamsad JahanDr. Md. Mahbubul HassanDr. Fauzia MohsinDr. Mamunur RashidDr. ASM Areef Ahsan

The Journal of BIRDEM is a peerreviewed Journal. It is publishedtwice (January and July) in ayear. It accepts original article,review articles and case reports.Complimentary copies of thejournal are sent to libraries of allmedical and other relevantacademic institutions in thecountry and selected institutionsabroad.

While every effort is alwaysmade by the Editorial Board andthe members of the JournalCommittee to avoid inaccurate ormisleading informationappearing in the Journal ofBIRDEM, information within theindividual article are theresponsibility of its author(s).The Journal of BIRDEM, itsEditorial Board and JournalCommittee accept no liabilitywhatsoever for the consequencesof any such inaccurate andmisleading information, opinionor statement.

Prof. A K Azad KhanProf. A R KhanProf. Mirza Mazharul IslamProf. A H Sydur RahmanProf. T A ChowdhuryProf. Hajera MahtabProf. Maj. Gen. (Rtd.) Ziauddin AhmedProf. ASQ Md. SadequeProf. Subhagata ChoudhuryProf. Humayun Kabir ChowdhuryProf. Mohammad AliProf. Kishwar AzadProf. Liaquat Ali

Prof. Khwaja Nazim UddinOn behalf of BIRDEM

ADDRESS OF CORESPONDENCEExecutive Editor: BIRDEM MEDICAL JOURNAL, BIRDEM, ROOM-1116

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(Birdem Med J 2011; 1(1)

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BIRDEM MEDICAL JOURNAL

Vol. 1, No. 1, Page 1-58 July 2011

EDITORIAL

ORIGINAL ARTICLES

REVIEW ARTICLES

CASE REPORTS

CONTENTS

BIRDEM NEWS

NAME OF THE REVEWERS OF ARTICLES IN THIS ISSUE

FROM THE DESK OF THE EXECUTIVE EDITOR

56

58

57

BIRDEM: Inception and evolution. 1Dengue: A Seasonal fever (Moushumi jar)

Clinical and Biochemical Assessment of Hypogonadism in Type 2 Diabetic Men 3Talukder SK, Afsana F, Latif ZA, Pathan F, Ashrafuzzaman SM, Khan SJ, Habib SH, Saha SThe Incidence, Predisposing Factors, Complications and Outcome of Preeclampsia in Diabetic Pregnancy 10Jesmin S, Jahan S, Khan MI, Sultana N, Jerin J, Habib SH, Paul DClinical Spectrum and Management of Diabetic Ketoacidosis: Experience in A Tertiary Care Hospital 15Rahim MA, Uddin KN, Zaman S, Musa AKM, Rahman MR, Hossain MD, Ahmed AKMS, Ahmed JU,Samad T, Haque HF, Dewan P, Sarker RSC, Dastidar SPrevalence of Metabolic Syndrome among Obese Children and Adolescents 21Mohsin F, Baki A, Nahar J, Akhtar S, Begum T, Azad K, Nahar N

Overview on Obesity - A Review 26Ashrafuzzaman SMExtensively Drug-Resistant (XDR) Tuberculosis: A Review 30Ahmed JU, Musa AKM, Hossain D, Rahim MA, Shaheen AKM, Uddin KN

A Case Report On Peripartum Cardiomyopathy 37Safder AMB, Mir SA, Miah BM, Tamanna RJ, Mohibullah AKMKawasaki Disease - A Rare Presentation in a Bangladeshi Infant- A Case Report 43Akhter S, Islam SMS, Islam N, Baki A, Ahmed A, Nahar J, Zabeen B, Mohsen F, Nahar N Surgical Management of Calcific Metamorphosis of Pulp: A Case Report 46Kulsum U, Farzana FGranulomatous Hepatitis: A Rare Case Report 51Amin AA, Mondal SK, Ullah ME

IMAGES IN MEDICAL PRACTICE

LETTERS TO THE EDITOR 55

54

EDITORIAL

Diabetic association of Bangladesh(DAB) is the symbolof a success story of the devoted visionary- late nationalprofessor Dr. Md Ibrahim, starting in 1956.BIRDEM(Bangladesh Institute of Research & Rehabilitation inDiabetes, Endocrine and Metabolic disorders). Thoughan icon,it is one of the seven enterprises of - DAB, nowBADAS-(Bangladesh Diabetic Samity).

It was started in a semi permanent space of 35.5 sqmeters at Segun Bagicha, Dhaka with one man and twoto three associates. From the day of inception it has threethemes - to serve diabetic and related patients, a goodlaboratory service and authentic research, which arestill continuing.

In 1957 DAB had 39 registered patients. Now BIRDEMhas around 500000 registered patients (Diabetics-4,34,753, IGT- 37,860, GDM-641) .The hospital firststarted with only 18 beds in 1957. Now BIRDEMgeneral hospital has become a multidisciplinary tertiarycare hospital with 600 bed including 110 free bedswhere treatment is provided 100% free of cost, to keepthe motto of Prof. Ibrahim that “no diabetic should dieunfed, unemployed, untreated even if he is poor”. It isthe best referral centre of the country for care of patientswith diabetes mellitus, it’s complications and comorbidities.

In 1980 BIRDEM was shifted from Segun Bagicha tothe present Shahbagh complex. Initially the OPD startedin 3 storied building and the hospital moved to this sitein 1984. Subsequently through successive revised plansand extension it came to the present state of 16 storiedcomplex through generous support of differentgovernment. In 1982 it was recognized as WHOcollaboration centre for developing community orientedservices, education, training and research for preventionand control of diabetes mellitus.Starting in 1987, BIRDEM Academy has produced somany (Ph.D, MS, MD, M.Phill) experts who are servingboth nationally and internationally. It has been running18 regular postgraduate courses, certificate courses forgraduate diabetes practitioners (DLP), Emergency

BIRDEM: Inception & Evolution

health care( BLS ,ACLS).It also run diabetic educatorcourse and nursing update course.

The hospital is equipped with modern facilities forhaemodialysis and organ transplants. So far 89successful living related donor kidney transplants andtwo successful liver transplants have been done atBIRDEM.

It also has a state of the art ICU service, a Special carebaby unit (SCABU) and Physiotherapy centres. It has24 hr emergency service for all disciplines of medicalsciences with available laboratory services.

BIRDEM has the largest OPD facilities for diabetics inthe world, handling 3000 patients everyday on average.It also has OPD treatment follow up fascilities for bothdiabetics and non diabetics patients in supraspecialitiesof Pediatrics, surgery, Gynae and Obstetrics andMedicine. It has specialized infertility centre, foot carecentre and day care centre for Gastroenterology,haemato-oncology. It also runs Obesity clinic, PCOSclinic, Rheumatology clinic and liver clinic. Recently ithas expanded it’s facility by opening BIRDEM-2 atSegun Bagicha with help of the Ministry for Womenand Children Affairs, exclusively for women andchildren.

To encourage learning, BIRDEM library is open for 14hours everyday and has a wide array of books,magazines, journals, periodicals and internet browsingand printing facilities.

Other facilities like the auditorium, canteen, mosqueall are within the premises.

BIRDEM is run by formidable service rule. Eachemployee has his own ID number and health card, allof them enjoying free health facilities. There are anumber of associations like Officers WelfareAssociation, Employee’s Welfare association, Teacher’sassociation, Young diabetic welfare association, Non-diabetic patient welfare association. All are recognizedbodies of ministry of social welfare.

(Birdem Med J 2011; 1(1): 1-2 )

BIRDEM, the pioneer of non-government health carefacilities of the country, the unspoken monument to thegreat son of the soil Prof. Dr. Md. Ibrahim is servingthe nation for nearly seven decades keeping it’s motto“I am obliged for giving me the opportunity to serveyou” to the suffering humans.

Dengue: A seasonal fever (Moushumi jar)The first outbreak of dengue fever (Dhaka fever) wasdocumented in 1964 in Dhaka. The first outbreak ofdengue hemorrhagic fever (DHF) occurred in mid 2000.Aedis egypti mosquito was identified as the main vectorresponsible and in Chittagong aedes albopictus was alsoidentified as potential vector. The maximumtransmission period is from July to September. Thenumber of mosquito increases after rainfall, because theybreed in containers that hold clean water for more thanfive days. Higher temperature shortens the incubationtime for the virus and humid weather increases the bitingactivity of mosquito.

A National guideline for clinical management of denguehas been developed, based on the established WHOguidelines and distributed among medical officers ofthe country.

Countries that reported less than 1% of the total caseare Bhutan, Nepal and Timore Leste. Maldives andBangladesh reported about 1% of the cases. India,Myanmar and Srilanka reported 6% each. Thailand 23%and Indonesia 57% cases in South east Asia region(SEARO)of WHO.

Ensuring adequate fluid intake is the mainstay oftreatment. Whole thing is so far directed to preventionand personal protection from mosquito is important.Killing of mosquito and its larva is utmost necessity.

Development of birth control pill for female mosquitois an approach on the way. Malaysia is consideringreleasing genetically modified mosquitoes designedto combat aedes mosquito. Australian scientist aretrying to modify mosquitos by introducing bacteriain them so that female Aedis could not harbourdengue virus.

Dengue vaccine is on the way. In Thailand it has so farbeen tried on mice and monkeys. It will come intomarket in 2015.Antiviral drug using protease inhibitorsare being thought by researcher.

2

Birdem Medical Journal Vol. 1, No. 1, July 2011

ORIGINAL ARTICLES

circumference were both negatively correlated withtestosterone levels, with the association being stronger forwaist circumference. HbA1C level also reveal a negativeassociation with sexual dysfunction and hypogonadotropichypogonadism among type 2 diabetic men. Metabolicsyndrome is also associated with the low serum testosteronelevels in the study subjects. Conclusions: This study revealsthat serum total testosterone levels are lower in diabetic menwith signs/symptoms of hypogonadism .Hypogonadotropichypogonadism is frequent in diabetic hypogondal population.There is an association between poor glycaemic control andhypogonadism in male diabetic persons.

Key Words: Hypogonadism; Metabolic syndrome; DiabetesMellitus.

(Birdem Med J 2011; 1(1): 3-9)

Clinical and Biochemical Assessment of Hypogonadism inType 2 Diabetic Men

TALUKDER SKa, AFSANA Fb, LATIF ZAb, PATHAN Fb, ASHRAFUZZAMAN SMb, KHAN SJc, HABIBSHd, SAHA Sd

a. Talukder SK, Department of Endocrinology, Rangpur MedicalCollege, Bangladesh;

b. Afsana F, Latif ZA, Pathan F, Ashrafuzzaman SM, Departmentof Endocrinology, BIRDEM, Dhaka, Bangladesh,

c. Khan SJ, Department of Endocrinology, Enam Medical College,Savar, Bangladesh,

d. Habib SH, Saha S, Heaalth Economics Unit, BADAS, Dhaka,Bangladesh

Address of Correspondence: Dr. Samir Kumar Talukder,Diabetologist and Endocrinologist, Department of Endocrinology,Rangpur Medical College, Email: [email protected];[email protected], Cell: 01817564963Received: May 15, 2011 Accepted: June 28, 2011

AbstractAim: The aim of the study was to assess the prevalence ofclinical hypogonadism in type 2 diabetic men based on clinicalfeatures and available biochemical measures. Materials andMethods: In this study carried out in a tertiary level hospital,serum concentration of total testosterone was measured in170 type 2 diabetic (mean age 44.9±7.9 years) subjects whohave erectile dysfunction or other features of hypogonadism.Results: The mean total testosterone concentration in type 2diabetic men was 14.4±5.6 nmol/l. Fifty nine of 170 (34.7%)type 2 diabetic subjects had low serum testosterone levels(d”12 nmol/L). Luteinizing hormone (LH) and folliclestimulating hormone (FSH) concentrations in type 2 diabeticmen were inappropriately low with a very high prevalence ofhypogonadotropic hypogonadism. BMI and waist

IntroductionType 2 diabetes is the predominant form of diabetesworldwide, accounting for 90% of cases globally.1,2

Asian Indians have surprisingly higher prevalence oftype 2 diabetes compared to Caucasians. Excessiveinsulin resistance in Asian Indians compared toCaucasians may be one of the contributing factors. Thisdifference in the degree of insulin resistance may beexplained by either an environmental or a genetic factoror by combination of both.3-10.Diabetes mellitus is amedical condition which is often associated with malesexual dysfunction. Erectile dysfunction (ED) isestimated to occur in 28-75% of diabetic males and its

prevalence appears to increase with age & duration ofdiabetes. 11-14 The etiology of ED in type 2 diabetes isoften multifactorial and include poor metabolic control,diabetes-induced micro-and macrovascular alterations,autonomic neuropathy, hypogonadism, or a combinationof all these factors.15-17

Type 2 diabetes, which is not an autoimmune disorder isalso associated with other endocrine diseases, in particularhypogonadism in men. Androgen deficiency has recentlycome to the forefront of the medical literature after beingignored for decades. Important associations are beingdeveloped and confirmed in the literature betweenandrogen deficiency and metabolic disorders. Morespecifically, there is an important health impact relatedto metabolic syndrome (MetS), insulin resistance (IR),type 2 diabetes and ultimately vascular disease anderectile dysfunction (ED). Low concentrations oftestosterone are linked with IR and implicated inhyperglycaemia, hypertension, dyslipidaemia, and anincreased risk of vascular disease. 18-23

Insulin resistance is an important feature of type 2diabetes. It is being increasingly recognized that low

.

testosterone levels in men are associated with reducedinsulin sensitivity and type 2 diabetes.24 Serumtestosterone levels are lower in a large number ofJapanese patients with type 2 diabetes when comparedwith healthy men and suggested that testosteronesupplementation in hypogonadal men could decreaseIR and atherosclerosis.22 These observations suggestthat androgen deficiency plays a central role in thevarious pathologies encompassing the components ofMetS including type 2 diabetes, IR, obesity and ED.

Various guidelines for the diagnosis of hypogonadismare available. Joint guidelines for the diagnosis andtreatment of men with late onset hypogonadism-testosterone deficiency associated with aging have beenproduced by the International Society for the Study ofthe Aging male (ISSAM) and the European Associatinfor Urology (EAU).25 They recommend that, a totaltestosterome < 8 nmol /L in the presence of symptomsrequires substitution and >12 nmol/L does not. Insymptomatic men with a total testosterone between 8and 12 nmol /L trials of therapy can be considered. Boththe American Association of clinical Endocrinology andthe Endocrine Society recommend that the diagnosis ofhypogonadism should based on low serum testosteronelevels and signs / symptoms.26, 27

Signs and symptoms of low testosterone levels in adults,are decreased energy level, reduced or loss of libido,diminished spontaneous erectile function, depression,poor concentration and memory, hot flushes or sweats,and infertility.26 The clinical signs of hypogonadism areusually only manifest in the more overt cases and includefine wrinkling of facial skin, eunuchoid body habitus,loss of secondary sexual hair, decreased lean body mass,increased body fat, decrease testicular volume,gynaecomastia and osteoporosis .

Current evidence shows that there is a significantproportion of men with type 2 diabetes who havehypogonadism. Although, androgen status in diabeticmen is not routinely considered by the majority ofmedical practitioners, symptomatic patients should beconsidered to measure serum testosterone levels. Thepresent study was designed to assess hypogonadism intype 2 diabetic men, referred to Endocrine Department,BIRDEM. The general objective of the study was toidentify the clinical hypogonadism, based on signs /symptoms and biochemical measures available, in type

2 diabetic Bangladeshi men. The specific objectives ofthe study were to find out the type of hypogonadism intype 2 diabetic subjects and to find assosiation betweenlow testosterone level and glycaemic status in type 2diabetic subjects.

Materials and MethodsThe study was conducted in the Dept. of Endocrinology,Bangladesh Institute of Research and Rehabilitation inDiabetes, Endocrine and Metabolic Disorders(BIRDEM), Dhaka, Bangladesh during the period ofmay 2008- April 2009.It was a cross sectional study

Inclusion Criteria• Men with type 2 diabetes• Age 20-55 years• Presence of signs /symptoms that are suggestive of

hypogonadism

Exclusion Criteria:• Patients already receiving hormone replacement

therapy• Endocrine disorders other than DM• Patients receiving any medications that may alter

gonadal function• Surgical interventions likely to impair sexual

function• Patients with liver, renal and severe heart failure• Acute infections

Study Subjects:Study subjects were selected purposively about 450patients was interviewed at outdoor and indoordepartment of Endocrinology, BIRDEM. After takingbrief history, preliminary selection was done on the basisof signs/ symptoms of hypogonadism and exclusion ofother systemic illnesses. 350 patients were enlisted theirname after primary selection. History taken and clinicalexamination performed with a pre-structuredquestionnaire. Next morning following an overnight (10-12 hours) fast blood sample was collected. One hundredand seventy subjects were attended and investigatedproperly. A diagnosis of hypogonadism was made ifanybody had symptoms/ signs of hypogonadism andtotal testosterone d” 12 nmol/L. In a patient with lowtestosterone level LH. FSH, Prolactin and SHBG weremeasured for further assessment.

4


Anthropometric measurements and other physicalexaminations:

Standing height and weight was measured usingappropriate scales. Body mass index (BMI) of thesubjects were calculated using the formula: BMI =Weight (kg)/(Height in meter)2.Waist circumference wasmeasured to the nearest 0.5 cm with a soft nonelasticmeasuring tape. The tape was snug, but not so tight asto cause skin indentation or pinching. Horizontal armspan (between the out spread middle fingertips with thepatient standing against a flat backboard) was measuredto the nearest 0.5 cm .Lower segment was measuredfrom the top of the symphysis pubis vertically to thefloor with the subject standing straight. Then the uppersegment was determined by subtracting the lowersegment from the standing height measurement notedabove. Breast staging was done according to Marshaland Tanner stages of breast development. After properexposure of the subjects, pattern of pubic hair was seenand the stage of pubic hair was determined by marshaland Tanner staging. Testicular volume was estimatedwith the Prader Orchidometer.The fully stretched dorsalpenile length was measured in the flaccid state from thepubopenile skin junction to the tip of the glans .Subjectswere requested to fast at least 10 hours and fastingvenous blood sample (10 ml) was collected between8.00-9.00 A.M.

Statistical analysis:Statistical analysis was performed using SPSS softwarefor Windows Version 11.5.All data were expressed asmean with 95% confidence interval and percentage (%)as appropriate.

Results and ObservationsA total of 170 diabetic subjects were studied.

Clinical and biochemical characteristics of studysubjects.

Age (years) mean±SD was 44.9± 7.9. Weight (kg) mean±SD was 66.8±9.7 . BMI (kg/m2) mean ±SD was 24.6±2.9 . Mean±SD of waist circumference (cm) was91.6±7.6 Mean±SD of systolic blood pressure (mmHg)and diastolic blood pressure (mmHg) were 120.9±13.6and 79.4± 7.7. Right and left testicular volume (ml)mean±SD were 19.5± 4.4 and 20.0±4.2. Fasting bloodglucose (mmol/l), mean±SD was 7.7 ±2.3 Mean ±SDcholesterol (mg/dl), TG (mg/dl), LDL (mg/dl) were

185.3±34.9, 193.2±80.8, 114.0±32.6.. Mean ±SD ofHDL (mg/dl) was 32.6 ±5.4 .

Serum total testosterone (nmol/L) mean±SD was14.4±5.6. Mean±SD of serum SHBG (nmol/L), LH(mIU/l), FSH (mIU/ml), prolaction (mIU/ml) were36.0±16.5, 6.8±5.3, 8.0±6.9, 193.0±87.9

Maximum numbers (39.4%) of the subjects were foundin the age group of 40-49 years One hundred and thirtyone (77.0%) subjects had history of regular exercise (atleast 3 days a week). Alcohol consumption was verylimited. History of diminished nocturnal erection wasfound in 166 (97.6%) subjects. Decreased libido wasfound in 65(38.2%).Fourteen (8.2%) subjects gavehistory of sub-fertility.

Table I

Background characteristics of study subjects

n %Age in years20-29 5 2.930-39 38 22.440-49 67 39.4> 50 60 35.3Exercise

Yes 131 77.0No 39 23.0

SmokingSmoker 79 46.4Non smoker 91 53.5

Alcohol intakeYes 10 5.9No 160 94.1

Diminished nocturnal erectionYes 166 97.6No 4 2.4

LibidoNormal 105 61.8Decreased 65 38.2

Sub fertilityYes 14 8.2No 156 91.8

Testosterone< 8 nmol/l 29 17.08 –12 nmol/l 30 17.6>12 nmol/l 111 65.3

5

Clinical and Biochemical Assessment of Hypogonadism in Type 2 Diabetic Men Talukder SK et al

Frequency of hypogonadism according to low serumtotal testosterone (<12 nmol/L)

Subjects were divided into hypogonadal (serum totaltestosterone <12 nmol/L) and eugonadal (serum totaltestosterone >12nmol/L) according to serum totaltestosterone level. Out of which 59 (34.7%) hadhypogonadism. Hypogonadism was classified accordingto LH concentration (<50% of normal range wasclassified as lower level). In this way hypogonadotropichypogonadism was found in 34(57.6%). Normogo-nadotropic hypogonadism and hypergonadotropichypogonadism was found 17(28.8%) and 8(13.6%)respectively. In this observation hypogonadotropichypogonadism was found more in study subjects.Comparison of clinical and biochemicalcharacteristic of study subjects with normal or lowtotal testosterone.Age (years) as mean±SD of hypogonadal (low totaltestosterone) and eugonadal (normal total testosterone)study subjects were 43.9±7.4 and 45.5 ±8.1 respectivelyand did not different significantly (p=0.223). Durationof diabetes (years) in hypogonadal and eugonadal subjectswere 5.2±4.4 and 6.1± 5.1 respectively, not significantly(p=0.227) different. BMI (kg/m2) ,waist circumference(cm) were 24.8±2.9, 93.1±6.9 in hypogonadal subjectsand 24.5±2.8, 90.7±7.9 in eugonadal subjects

respectively. Right sided testicular volume (ml) wassignificantly (p=0.023) different in two groups; 19.0±4.7vs 20.6±3.8 in hypogonadal vs eugonadal subjectsrespectively. Left sided testicular volume (ml) was18.1±5.1 and 20.3±3.8 respectively, there was alsosignificant (p=0.002) difference in two groups. Inhypogonadal subjects HbA1C level was foundsignificantly (p= 0.001) higher than the eugonadalsubjects [8.9±1.6 and 7.8±1.3 respectively]. Among thefour components of lipid profile, serum TG (mg/dl) wassignificantly (p=0.031) different in two groups.[211.1±81.5 vs 183.5±79.0 in hypogonadal vs eugonadalsubjects]. Mean±SD of cholesterol, LDL, HDL were192.4±36.8, 117.8±31.9, 32.1±5.4 in hypogonadalsubjects and 181.6±33.5, 112.0±29.8, 32.8±5.4 ineugonadal subjects respectively. Serum total testosterone(nmol/l) as mean ±SD in hypogonadal subjects was9.5±1.8, whereas in eugonadal subjects was 18.6±4.1.Serum SHBG (nmol/l), and prolactin (mIU/ml) level werenot significantly different between the hypogonadal andeugonadal subjects . Serum LH and FSH (mIU/ml) wassignificantly (p=0.001, p=0.020) lower in hypogonadalsubjects than the eugonadal subjects .In this study, there was significant difference in testicularvolume, HbA1C level, serum TG, total testosterone, andLH , FSH level between the hypogoadal and eugonadalsubjects.

Table II

Comparison of clinical and biochemical characteristic of subjects with normal (eugonadal) or low(hypogonadal) total testosterone.

Hypogonadal (<12 nmol/l) Eugonadal (>12 nmol/l) P value(n=59) (n=111)

Mean ±SD Mean ±SDAge (years) 43.9 ±7.4 45.5 ±8.1 0.223NS

Duration of diabetes (years) 5.2 ±4.4 6.1 ±5.1 0.227 NS

BMI (kg/m2) 24.8 ±2.9 24.5 ±2.8 0.491 NS

Waist circumference (cm) 93.1 ±6.9 90.7 ±7.9 0.055 NS

Testicular vol Rt(ml) 19.0 ±4.7 20.6 ±3.8 0.023 S

Testicular vol LT(ml) 18.1 ±5.1 20.3 ±3.8 0.002 S

HbA1C (%) 8.9 ±1.6 7.8 ±1.3 0.001S

Cholesterol (mmol/l) 4.98 ±0.95 4.70 ±0.86 0.054 NS

TG(mmol/l) 2.38 ±0.92 2.07 ±0.90 0.031 S

LDL(mmol/l) 3.05 ±0.83 2.90 ±0.77 0.241 NS

HDL(mmol/l) 0.83 ±0.13 0.85 ±0.13 0.374 NS

Total testosterone (nmol/l) 9.5 ±1.8 18.6 ±4.1 0.001 S

SHBG (nmol/l) 35.8 ±14.8 36.2 ±17.7 0.894 NS

LH (mIU/ml) 4.6 ±4.4 8.6 ±6.6 0.001S

FSH (mIU/ml) 7.1 ±5.2 12.2 ±11.9 0.020 S

Prolactin (mIU/ml) 198.8 ±89.6 183.7 ±85.3 0.418 NS

6


Past medical history of study subjectsPast history of hypertension was found 33.9% and24.5% of hypogonadal and eugonadal subjectsrespectively. Previous history of coronary artery disease(CAD) was found 2.7% of eugonadal subjects. Bothhypertension and CAD were found 1.8% of eugonadalsubjects. But in majority of the subjects (66.1% ofhypogonadal and 70.9% eugonadal), no significant pastillness was found.

Distribution of hypogonadism among the study subjectsaccording to different age groups

Maximum subjects were found 40-49 years age group.Fifty or more than 50 age group were 17(28.8%) and20-29 years age group was 1(1.7%).

Association of low testosterone levels with clinicalvariables in study subjects (n=170)

BMI >25(kg/m2) was found in 32(54.2%) hypogonadalsubjects and 47(42.3%) eugonadal subjects. Waistcircumference WC e” 90 cm was found in 53(89.8%)hypogonadal subjects and 71(64.0%) eugonadalsubjects. Hypertension was found in 28(47.5%)hypogonadal subjects and 44(39.6%) eugonadalsubjects. History of smoking was found in 23(39.0%)hypogonadal subjects and 56(50.5%) eugonadalsubjects. History of regular exercise was found in47(79.7%) hypogonadal and 84(75.7%) eugonadalsubjects. History of alcohol ingestion was found in5(8.5%) hypogonadal and 5(4.5%) eugonadal subjects.Sensory neuropathy was found in 8(13.6%)hypogonadal and 23(20.7%) eugonadal subjects.

Table III

Association of low testosterone levels with clinicalvariables in study subjects (n=170)

Hypogonadal Eugonadal P(n =59) (n=111) valuen % n %

BMI >25 (kg/m2) 32 54.2 47 42.3 0.138 NS

WC e” 90 cm 53 89.8 71 64.0 0.001 S

Hypertension 28 47.5 44 39.6 0.326 NS

Smoking 23 39.0 56 50.5 0.153 NS

Exercise 47 79.7 84 75.7 0.556 NS

Alcohol intake 5 8.5 5 4.5 0.236 NS

Sensory neuropathy 8 13.6 23 20.7 0.249NS

Association of metabolic syndrome and hyogonadismamong the study subjects

Metabolic syndrome was present in 52 (88.1%) and67(60.4%) in hypogonadal and eugonadal subjects. Thedifference was statistically significant (p=0.001) inbetween the hypogonadal and eugonadal subjects.

Relationship of glycaemic status (HbA1C) to distributionof hypogonadism in study subjects

In diabetic hypogonadal subjects (n=59), 13(22.0%) hadgood glycaemic status (HbA1C <7%) and 46 (88.0%)had poor glycaemic status (HbA1C >7%). HbA1C 7.1-8% was found in 15(25.4%), 8.1-9% was found in12(20.3%), 9.1-10% was found in 9(15.3%) and >10%was found in 10(16.9%) of hypogonadal subjects. Thisstudy showed higher percentage of hypogonadalsubjects had poor glycaemic control.

Correlation of BMI , waist circumference and withHbA1C total testosterone

Total testosterone was correlated inversely with BMIand waist circumference in study subjects. Totaltestosterone was negatively correlated with HbA1C levelin study subjects.

Fig. 1: Correlation of BMI and total testosterone instudy subjects

Fig. 2: Correlation of waist circumference and totaltestosterone in study subjects

7


DiscussionPrevious studies19 showed that about one third of type2 diabetic men have low serum testosterone levels, butthese studies had not correlated this value withsymptoms. The present study clearly shows that thereis a high prevalence of symptomatic hypogonadism inmen with type 2 diabetes.

In the Baltimore longitudinal study on aging 8, 12, 19and 28% of men aged > 40, 50, 60 and 70 years,respectively, had serum total testosterone levels belowthe normal range 28. In the present study, the mean totaltestosterone levels in diabetic men were also progressivelylower in higher age groups. The frequencies ofhypogonadal symptoms were similar in all age-groupsof low testosterone in the present study and supportedthe similar results found in a previous study. 29

Gonadotropin Concentrations were not elevated in mostof the hypogonadal subjects of type 2 diabetes in presentstudy, and thus the primary defect in these patients wouldappear to be either in the pituitary gland orhypothalamus. In fact, the LH and FSH levels weresignificantly lower in the hypogonadal group than theeugonadal group. To rule out the possibility that thecause of hypogonadotropic hypogonadism was apituitary lesion, MRI of pituitary and perisellar regionwas done in 15 randomly selected hypogonadal subjects.None of the MRIs showed pituitary or hypothalamicabnormalities. Previously in a study, it was similarlyfound high prevalence of hypogonadotropichypogonadism in type 2 diabetes. 19

In this study, testosterone level is inversely correlatedwith waist circumference and BMI. A Possibleexplanation for this is the hypogonadal obesity cycle.30

Essentially, visceral adipocytes have a high activity ofthe enzyme aromatase which converts testosterone toestrogen. Testosterone inhibits the enzyme lipoproteinlipase ,which takes up free fatty acids into adipocytes.Lower levels of testosterone result in increasedtriglyceride levels in adipocytes, which promote furtheradipocyte proliferation and hence higher aromataseactivity. In this study, it was also shown that serum totaltestosterone negatively correlated with HbA1C level.This observation may suggest relation of hypogonadismto poor glycaemic control.

Serum testosterone levels have been reported to be lowerin men with hypertension. 31 But the present study did

not show a significant association between testosteronelevels and history of hypertension. Similarly, this studyfound no significant association between testosteronelevels and smoking. The majority of cross- sectionalstudies have shown that low testosterone levels areassociated with a pro-atherogenic lipid profile high totaland LDL cholesterol and triglycerides (TG) and lowHDL cholesterol 32. In this study, high TG and low HDLwere found more in hypogonadal subjects than theeugonadal subjects, but the total cholesterol and LDLcholesterol did not vary between the two groups.

In this study, higher prevalence of metabolic syndrome(according to IDF criteria) was found among thehypogonadal subjects. Different components ofmetabolic syndrome were also significantly higheramong the hypogonadal subjects than the eugonadalsubjects. These observations suggest that androgendeficiency plays a central role in the various pathologiesencompassing the components of metS including centralobesity, insulin resistance, hyperglycaemia,dyslipidaemia and hypertension.

Conclusion:This study reveals that serum total testosterone levelsare lower in diabetic men with signs/symptoms ofhypogonadism .Hypogonadotropic hypogonadism isfrequent in diabetic hypogondal population. There isan association between poor glycaemic control andhypogonadism in male diabetic persons.

AcknowledgementWe are thankful to all the study participants andDepartment of Endocrinology for their kind supportthroughout the study period.

Disclosure:We did not get any type of financial support fromanywhere at home or abroad.

There is no conflict of interest.

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18. Simin D, Charles MA, Nahoul K Orssaud G, Kremski J, HillyV, Joubert E, Papoz L, Eschewed E (1997) : Associationbetween plasma total testosterone and cardiovascular riskfactor in healthy adult men: The Telecom Study . J ClinEndocrinol Metab. 82: 682-85.

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26. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM,Snyder PJ, Swerdloff RS, Montri vm (2006) : Testosteronetherapy in adult men with androgen deficiency syndromes :An Endocrine Society Clinical Practice Guideline. J clinEndocrinol metab 91 : 1995-2010.

27. Petak SM, Nankin HR, Spark RF et al. (2002) Americanassociation of Clinical Endocrinologists medical guidelinesfor clinical practice for the evaluation and treatment ofhypogonadism in adult male patients- 2002 update. EndocrinePract. 8 (6): 439-56

28. Harman SM, Metter EJ, Tobin JD et al (2001) : Longitudinaleffects of aging on serum total and tree testosterone levels inhealthy men. J Clin Endicrinol Metab 86: 724-31.

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9


done due to fetal distress in the study group and in controlgroup it was 20 percent. In study group, 22.5 percentCaesarean sections were done due to impending eclampsiaand eclampsia, 705 percent due to accidental haemorrhageand 5 percent due to IUGR. Maternal complication in studyand control subjects. In the case group, maximum numberof the women (16%) showed signs of impending eclampsia,while among control women, maximum number (10%)developed postpartum haemorrhage (PPH). 48 percentneonates were of low birth weight and in controls it was13.3 percent. Both hyperbilirubinaemia (40%) andhypoglycaemia (30%) were more in study group thancontrols (16.66% and 20%, respectively). Perinatal outcomeamong study group and controls. Neonatal survival was 82.0percent in study group and 86.7 percent in control group.Comparison of Perinatal outcome between the groups isnot statistically significant. Most of the perinatal mortalitywas due to prematurity (8%) and intrauterine death (6%).In control group, most of the perinatal deaths were due tocongenital anomalies (6.6%). Conclusion: The higherincidence among study group may be, in part, the result ofmore preterm birth or shortened gestational durationbecause early delivery is a consequence of preeclampsia.The higher rate in associated with preeclampsia was due toincreased incidence of IUD and prematurity.

Key Words: Incidence, Predisposing Factors, Complications,Preeclampsia, Diabetic Pregnancy

(Birdem Med J 2011; 1(1): 10-14)

The Incidence, Predisposing Factors, Complications andOutcome of Preeclampsia in Diabetic Pregnancy

JESMIN Sa, JAHAN Sa, KHAN M Ia, SULTANA Na, JERIN Ja, HABIB SHb, PAUL Dc

a. Jesmin S, Jahan S, Khan M I, Sultana N, Jerin J, Departmentof Gynaecology and Obstetrics, BIRDEM, Dhaka, Bangladesh;

b. Habib SH, Health Economics Unit, BADAS, Dhaka,Bangladesh

c. Paul D, Department of Biochemistry and Cell Biology,Biomedical Research Group, BIRDEM, Dhaka, Bangladesh.

Address of Correspondence: Dr. Suha Jesmin, Department ofGynaecology and Obstetrics, 122, Kazi Nazrul Islam Avenue,BIRDEM, Dhaka, Bangladesh, Phone no. 00 88 02 8616641-50 ex-2468; Cell no. 01817049292Received: May 16, 2011 Accepted: June 26, 2011

AbstractIntroduction: Preeclampsia is a serious complication ofpregnancy and common cause of fetal and maternalmorbidity as well as mortality worldwide. In diabetic women,the chance of preeclampsia is increased. The incidence ofpreeclampsia in diabetic pregnancy is approximately 10 to15 percent, which is associated with poor glycaemic control.Aim: This study was carried out to find the predisposingfactors related to preeclampsia and determine thecomplications of preeclampsia in diabetic pregnancy andalso the impact of preeclampsia in infants born to diabeticmothers. Methods: This prospective study was carried outat the Bangladesh Institute of Research and Rehabilitationin Diabetes, Endocrine and Metabolic Disorders(BIRDEM), Dhaka. The Patient population consisted of 80diabetic pregnant women who attended or admitted toBIRDEM hospital during the study period. The women weredivided into groups: 50 pregnant diabetic women withpreeclampsia were taken as case. 30 pregnant diabeticwomen without preeclampsia were taken as control.Diagnosis of preeclampsia was made on the basis of thecriteria of the Committee on Terminology of the AmericanCollege of Obstetrician and Gynecologist. Results: Pretermdelivery (<37 weeks gestation) was higher among studygroup (64%) compared to control (33.3%) women. Termdelivery was 36.0 vs 66.7 percent among case and controlwomen, respectively. The distribution is statisticallysignificant (P<0.01). 35 percent of Caesarean section was

Introduction:Pregnancy is a great stressful physiological conditionin women during their reproductive period. Diabetesmellitus is an important medical disorders in pregnancy,which is an important associated risk factors for mother

and the fetus during current pregnancy and also hasserious implications for their long-term well being.

Glycaemic control is critical during pregnancy, and thebenefits may result in a viable, healthy offspring.Pregnancy combined with diabetes is a period when apatient can readily see the result of benefits as aconsequence of glycaemic control and attention todiabetes care. Preeclampsia is a serious complicationof pregnancy and common cause of fetal and maternalmorbidity as well as mortality worldwide.

In our country, preeclampsia and eclampsia are leadingcauses of maternal mortality.1 In diabetic subjects, thereis a increased chance of preeclampsia, (which cause highblood pressure, swelling in body and appearance of

.

Birdem Medical JournalVol. 1, No. 1, July 2011

protein in urine) which leads to serious complicationsif not treated promptly. The incidence of preeclampsiain diabetic pregnancy is approximately 10 to 15 percent,which is associated with poor glycaemic control2. Properantenatal check-up and early diagnosis of preeclampsiain diabetic women, prompt treatment and strict controlof blood sugar may reduce the complications of diabeticpreeclampsia.

This study was carried out to find the predisposingfactors related to preeclampsia and determine thecomplications of preeclampsia in diabetic pregnancyand also the impact of preeclampsia in infants born todiabetic mothers.

Materials and Methods:This prospective study was carried out at the BangladeshInstitute of Research and Rehabilitation in Diabetes,Endocrine and Metabolic Disorders (BIRDEM), Dhaka.

The Patient population consisted of 80 diabetic pregnantwomen who attended or admitted to BIRDEM hospitalduring the study period. The women were divided intogroups:

a) 50 pregnant diabetic women with preeclampsia weretaken as case.

b) 30 pregnant diabetic women without preeclampsiawere taken as control.

The inclusion criteria for the case were as follows;Gestational protinuric hypertension, Patients withincreased systolic blood pressure of > 30 mmHg ordiastolic >15 mmHg over a baseline blood pressure after20 weeks of gestation, Blood Pressure of >140/90mmHg at least on two measurements taken 6 hours apartafter 20 weeks of pregnancy if prior blood pressure isnot known, Preconception diabetic women, Gestationaldiabetic women

The exclusion criteria for the case were as follows;History of Gestational hypertension without protinuria,Diabetes and Preeclampsia toxaemia (PET) with othersystemic disease like congestive cardiac failure, chronicliver disease, endocrinopathy and autoimmune disease.

Method:Diagnosis of preeclampsia was made on the basis ofthe criteria of the Committee on Terminology of theAmerican College of Obstetrician and Gynecologist. 3

Blood pressure measurement was taken with the patientin sitting position with right in a roughly horizontalposition at heart level. Blood pressure measurement wasdone every two weeks from 28 to 36 weeks and weeklyfrom 36 weeks gestation up to delivery.

Serial measurement of serum uric acid, creatinine andblood urea levels were done. Diagnosis of gestationaldiabetes was madder on the basis of WHO criteria.

The diabetic patients were managed with dietaryregulation and intensified by subcutaneous insulin therapywith goals to maintain fasting blood glucose level at <105mg/dl and postprandial glucose <140 mg/dl.

Statistical Analysis:Relevant data of each of the study subjects wererecorded on a predesigned data collection sheet. Datawere complied and appropriate statistical analyses weredone using computer based software, Statistical Packagefor Social Science (SPSS).

Results:Table I shows that 12.0 percent study group and 6.7percent control subjects had Oligohydramnios, 6.0percent case and 13.3 percent control subjects hadpolyhydramnios and 82.0 percent case and 80.0 percentcontrol subjects had adequate volume of liquor amnii.Liquor volume did not shoe any statistical differencebetween the two groups.

Table I

Volume of liquor amnii in study and control subjects:

Liquor amnii Case (n=50) Control (n=30) P valuea

No. (%) No. (%)Oligohydramnios 6 (12.0) 2 (6.7)Polyhydramnios 3 (6.0) 4 (13.3) 0.428 NS

Adequate 41 (82.0) 24 (80.0)aChi-square test, NSNot significant

11

The Incidence, Predisposing Factors, Complications and Outcome of Preeclampsia in Diabetic Pregnancy Jesmin S et al

In study group, 80percent and in control group, 66.7percent were delivered by LUCS which isstatistically significant (P<0.001) and 20.0 percentin study group and 33.3 percent in control grouphad normal vaginal delivery which is statisticallysignificant (P<0.01).

Table II

Mode of delivery in study and control subjects:

Mode of Delivery Case Control P

(n=50) (n=30) valuea

No. (%) No. (%)

LUCS (Lower Uterine 40 (80.0) 20 (66.7) 0.000***Caesarean Section)

NVD (Normal Vaginal 10 (20.0) 10 (33.3) 0.002**Delivery)

aZ-test, **Significant at P<0.01, ***Significant at P<0.001

Table III shows that preterm delivery (<37 weeksgestation) was higher among study group (64%)compared to control (33.3%) women. Term delivery was36.0 vs 66.7 percent among case and control women,respectively. The distribution is statistically significant(P<0.01).

Table III

Incidence of preterm delivery in study and controlsubjects:

Delivery Case Control P(n=50) (n=30) valuea

No. (%) No. (%)Preterm 32 (64.0) 10 (33.3) <0.01**Term 18 (36.0) 20 (66.7)

aChi-square test, **Moderately Significant

Table IV shows that 35 percent of Caesarean sectionwas done due to fetal distress in the study group and incontrol group it was 20 percent. In study group, 22.5percent Caesarean sections were done due to impendingeclampsia and eclampsia, 705 percent due to accidentalhaemorrhage and 5 percent due to IUGR.

Table IV

Indication of Caesarean section among study groupand control subjects

Indications Case Control(n=40) (n=20)No. (%) No. (%)

Impending eclampsia 8(20.0) 0Eclampsia 1 (2.5) 0Fetal distress 14 (35.0) 4 (20.0)History of previous 4 (10.0) 3 (15.0)Caesarean sectionFailed induction 4 (10.0) 5 (25.0)Malpresentation 2 (5.0) 2 (10.0)Accidental haemorrhage 3 (7.5) 0IUGR 2 (5.0) 0Bad obstetric history 2 (5.0) 2 (10.0)Macrosomia 0 4 (20.0)

Table V shows maternal complication in study and controlsubjects. In the case group, maximum number of thewomen (16%) showed signs of impending eclampsia,while among control women, maximum number (10%)developed postpartum haemorrhage (PPH).

Table-V

Maternal Complication in study group and controlsubjects

Complications Case Control(n=50) (n=30)No. (%) No. (%)

Impending eclampsia 8 (16.0) -Eclampsia 1 (2.0) -Accidental haemorrhage 3 (6.0) 1 (3.3)DIC 2 (4.0) -Cerebrovascular accident 0 -HELLP syndrome 6 (6.0) -PPH 2 (4.0) 3 (10.0)Wound infection 3 (6.0) 2(6.6)

Table VI shows 48 percent neonates were of low birthweight and in controls it was 13.3 percent. Bothhyperbilirubinaemia (40%) and hypoglycaemia (30%)were more in study group than controls (16.66% and20%, respectively).

12


Table VI

Perinatal morbidity in study group and controlsubjects

Morbidity Case Control (n=50) (n=30)No. (%) No. (%)

Low birth weight 24 (48.0) 4 (13.3)

Intrauterine growth retardation 8 (16.0) 1 (3.3)(IUGR)Birth asphyxia 6 (12.0) 2 (6.6)Respiratory distress syndrome 7 (14.0) 2 (6.6)(RDS)Hyperbilirubinaemia 20 (40.0) 5 (16.6)Hypoglycaemia 15 (30.0) 6 (20.0)Septicaemia 3 (6.0) 0Congenital anomaly 3 (6.0) 1 (6.6)

Table VII shows perinatal outcome among study groupand controls. Neonatal survival was 82.0 percent in studygroup and 86.7 percent in control group. Comparisonof Perinatal outcome between the groups is notstatistically significant.

Table VII

Neonatal outcome in study group and control subjects

Perinatal outcome Case Control P(n=50) (n=30) valuea

No. (%) No. (%)Survived 41 (82.0 ) 26 (86.7) 0.584 NS

Expired 9 (18.0 ) 4 (13.3)aChi-square test,NSNot significant

Here shows that in the study group, most of the perinatalmortality was due to prematurity (8%) and intrauterinedeath (6%). In control group, most of the perinatal deathswere due to congenital anomalies (6.6%).

Table VIII

Causes of Perinatal mortality

Causes Case (n=50) Control (n=30)No. (%) No. (%)

Congenital anomaly 2 (4.0) 2 (6.6)Intrauterine death 3 (6.0) 1 (3.3)Prematurity 4 (8.0) 1 (3.3)

Discussion:Preeclampsia is a serious complication of pregnancy.Diabetes and pregnancy may affect each other over arange of interaction from conception to delivery andpossibly even later. Pregnant women with diabetes haveas increased risk of developing preeclampsia. Theincidence of preeclampsia in diabetic patients in thisstudy was 10.82 %, which correlates with that Garneret al3 (9.9%) and Arias2 (10-15%). The vascularendothelial dysfunction associated with diabetes mellitusmay contribute to the increased incidence ofpreeclampsia among diabetic women5.

Thirty- four percent cases had family history ofhypertension, which is nearly similar to the findings ofHossain 4(39%). The rate of preeclampsia increasessignificantly with the increase in severity of diabetes.Several studies have reported an association betweenmaternal glycaemic control and adverse outcome, suchas preeclampsia, preterm delivery etc6. In this study, 64percent cases had poor glycaemic control, mostly in theirhalf of pregnancy, which may be due to late diagnosis.

Significantly more women delivered by Caeseareansection in the study group (80%) than in the controlgroup (66.6%) (P<0.001). The higher incidence ismostly due to early termination of pregnancy due tomaternal and fetal complications. The rate Caesareansection in control group was 66.6 percent, which issimilar to the findings of Khatun 7 (65%), but higherthan reported by Rokshana 8(57.45%).

The diabetic women with preeclampsia have asignificant higher rate of preterm deliveries. In this study,the rate of preterm (<37 week gestation) was 64 percent,which is slightly higher than Sibai et al 6 (57%). Indiabetic pregnancy without preeclampsia (control),preterm delivery was33.3 percent and according to Sibaiet al, it was 2704 percent. Other compliocations foundin study group were impending eclampsia (16%),eclampsia (2%), DIC (4%), HELLP syndrome (6%),accidental haemorrhage (6%) which was due toassociated preeclampsia. Wound infection occurredpossibly due to uncontrolled blood sugar.

The neonates of mother with preeclampsia (studygroup), in addition to having the threats associated withprematurely, are often compromised as a result ofuteroplacental insufficiency. Marker of such chronicintrauterine comprise include intrauterine growth

13

The Incidence, Predisposing Factors, Complications and Outcome of Preeclampsia in Diabetic Pregnancy Jesmin S et al

retardation (IUGR) and oligohydramnios. In this study,in the control group, the incidence of IUGR was 3.3percent which coincides with the findings of Sibai et al6 (5.4%). It may be due to poor control of hypertensionand associated in controlled blood sugar.

In the present study, oligohydramnios was percent in12 percent cases. It may be due to associated IUGR andplacental insufficiency. In control group,oilgohydramnios was present in 6.7% women andpolyhydramnios in 13.3 percent cases, which coincideswith the study of Rokshana 8 (12.77%).

Mother with preeclampsia usually has low-birth-weightbabies. In this study, among control subjects, 13.3percent had low-birth-weight babies, and in studysubjects, the rate was 48 percent.

In the study group, 30 percent neonates developedhypoglycaemia, percent hyperbilirubinaemia, 12 percentRDS, 14 percent birth asphyxia and 6 percentsepticaemia. In control group, 16.6 percent neonate’sdeveloped hyperbiliribinaemia, 20 percent developedhypoglycaemia and 6.6 percent each developed RDSand asphyxia. The higher incidence in study group maybe due to prematurity. Because of hepatic insufficiency,hyperbilirubinaemia may occur in preterm babies. RDSand birth asphyxia are common complications ofpreterm birth. Septicaemia may occur to less protectivepassive immunity 9.

Congenital anomalies occurred in study group in 4percent and in control group in 6.6 percent, which isalmost similar to the findings by Rokshana8 (4.6%).Incidence of IUD in study group is slightly higher (6%)than control group (3.3%). In present study, perinatalmortality rate was 18 percent in study group and 13.2

percent in control group, which is similar to the findingsof Khatun 7(14.29%).

Conclusion:The higher incidence among study group may be, inpart be, in part, the result of more preterm birth orshortened gestational duration because early deliveryis a consequence of preeclampsia. The higher rate inassociated with preeclampsia was due to increasedincidence of IUD and prematurity.

References:1. Begum MT, Begum A, Quadir E, Akhter S, Shamsuddin L,

Eclampsia: Still a Problem in Bangladesh Med Gen Med.2004; 6(4): 52.

2. Arias F. Practical guide to high-risk pregnancy and delivery.2nd ed. Harcourt Brace and Company, Asia Pte. Ltd., 1992:185-204, 280-86.

3. Barrett M. Schroeder Practice Guidelines. ACOG PracticeBulletin on Diagnosing and Managing Preeclampsia andEclampsia. Am Fam Physician. 2002 Jul 15;66(2):330-31.

4. Garner PR, D’Alton ME, Dudley DK. Pereclampsia in diabeticpregnancies. Am J Obstet Gynecol 1990; 163: 505-8.

5. Knock GA, McCarthy AL, Lowy C, Poston L. Association ofgestational diabetes with abnormal maternal vascularendothelial function. Br J Obstet Gynaecol 1997; 104: 229-34.

6. Sibai BM. Risk of preeclampsia and adverse neonatal outcomeamong women with pregestational diabetes mellitus. Am JObstet Gynecol 2000; 182: 366-68.

7. Khatun F. The study of pregnancy outcome in non-insulindependent and geatational diabetes mellitus (dissertation).Dhaka: Bangladesh College of Physicians and Surgeons, 1996.

8. Rokshana I. Management and outcome of pregnancy withdiabetes mellitus (dissertation). Dhaka: Bangladesh Collegeof Physicians and Surgeons, 1994.

9. Dutta DC. Textbook of obstetrics. 5th ed. New Central BookAgency, 2001: 490-501.

14


Clinical Spectrum and Management of DiabeticKetoacidosis: Experience in A Tertiary Care Hospital

RAHIM MAa, UDDIN KNb, ZAMAN Sc, MUSA AKMd, RAHMAN MRe, HOSSAIN MDf, AHMED AKMSf,AHMED JUa, SAMAD Tg, HAQUE HFg, DEWAN Pg, SARKER RSCg, DASTIDAR Sh

a. Rahim MA, Ahmed JU, Registrar, Internal Medicine, IbrahimMedical College and BIRDEM General Hospital, Shahbag,Dhaka-1000, Bangladesh.

b. Uddin KN, Professor and Head, Internal Medicine, IbrahimMedical College and BIRDEM General Hospital, Shahbag,Dhaka-1000, Bangladesh.

c. Zaman S, Assistant Registrar, Cardiology, NICVD, Sher-e-Bangla Nagar, Dhaka-1207, Bangladesh.

d. Musa AKM, Associate professor, Internal Medicine, IbrahimMedical College and BIRDEM General Hospital, Shahbag,Dhaka-1000, Bangladesh.

e. Rahman MR, Associate Professor and Resident Physician,Ibrahim Medical College and BIRDEM General Hospital,Shahbag, Dhaka-1000, Bangladesh.

f. Hossain MD, Ahmed AKMS, Assistant Professor, InternalMedicine, Ibrahim Medical College and BIRDEM GeneralHospital, Shahbag, Dhaka-1000, Bangladesh.

g. Samad T, Haque HF, Dewan P, Sarker RSC, Senior MedicalOfficer, Internal Medicine, BIRDEM General Hospital,Shahbag, Dhaka-1000, Bangladesh.

h. Dastidar S Medical Officer, Reproductive and Child HealthDepartment, NIPSOM, Mohakhali, Dhaka-1212, Bangladesh.

Address of Correspondence: Dr. Muhammad Abdur Rahim, FCPS(Medicine), Registrar, Department of Internal Medicine, IbrahimMedical College and BIRDEM General Hospital, Shahbag, Dhaka-1000, Bangladesh. E-mail: [email protected]: May 20, 2011 Accepted: June 29, 2011

AbstractBackground: Diabetic ketoacidosis (DKA) is an acutemetabolic complication of diabetes mellitus (DM). It maybe the presenting feature in type 1 DM, but more commonlyit complicates previously diagnosed diabetic patients, bothtype 1 and type 2. If not recognized early and treated in ajudicious way the outcome is often fatal.

Objectives: The objectives of this study was to see thecommon presenting features of DKA, their precipitatingcauses, patterns of electrolyte imbalance, treatmentrequirement in early hours and to see the outcome.

Materials and methods: This cross sectional study was donein BIRDEM General Hospital on fifty adult patients whopresented with DKA over a period of nine months (January2007 to September 2007).

Results: Total number of patients were 50, male were 24and female were 26 (M:F =12:13). Mean age was 27.6 ±3.7 years. The incidence of DKA was more in known diabeticpatients (32, 64%), in comparison with new cases (18, 36%).

Frequency was more in poor village people (31, 62%).Vomiting (24, 48%) was the most frequent complaint,followed by fever (19, 38%), nausea (16, 32%), abdominalpain (14, 28%), weakness (13, 26%), polyuria (12, 24%)and polydypsia ( 8, 16%). Infection (18, 36%) was the mostcommon precipitating cause, closely followed byinadherence to insulin therapy (17, 34%). In 12 (24%) casesno cause could be identified. Glycaemic control was poor,HbA1c was >7% in 98% cases. Severe acidosis (pH < 7)was less common (4, 8%) and gross electrolyte imbalancewas uncommon but all patients required potassiumsupplementation in course of treatment. Neutrophilicleukocytosis was present in 44 (88%) cases, irrespective ofpresence of infection. Mortality was low (3, 6%).

Conclusion: Diagnosis and treatment of DKA is not difficultif recognized early. So, high index of suspicion is necessary,particularly in previously undiagnosed cases.

Key wards: Diabetic Ketoacidosis, Diabetes Mellitus.

(Birdem Med J 2011; 1(1): 15-20)

IntroductionDiabetic ketoacidosis is a medical emergency. It maybe the presenting feature of type 1 diabetes, but morefrequently it occurs in established diabetic patients- bothtype 1 and type 2. The cardinal biochemical features ofdiabetic ketoacidosis are hyperglycaemia,hyperketonaemia and metabolic acidosis1. Alberti’sdefinition2 describes ‘severe uncontrolled diabetesrequiring emergency treatment with insulin andintravenous fluids with a blood ketone body (acetoacetate and 3-hydroxybutyrate ) concentration ofgreater than 5 m.mol per litre’. For practical purpose,diagnostic criteria often includes a plasma bicarbonateconcentration of 15 m.mol per litre or less withsignificant ketosis (urine ketostix reaction at least ++or plasma ketostix reaction + or more) in a patient withhigh blood glucose. American Diabetic Association(ADA) has given a guideline3 of assessing severity ofdiabetic ketoacidosis and it’s differentiation fromhyperglycaemic hyperosmolar state (HHS).

.


The presence of no or near no insulin is the criticalunderlying defect in the pathogenesis of DKA coupledwith increased quantity of counter regulatory hormones.Insulin deficiency leads to hyperglycaemia, which inturn causes osmotic diuresis and dehydration.Withdrawal of insulin from insulin dependent patientslead to an early rise of plasma glucagon2 resulting inincreased fat metabolism and production of ketonebodies. As hyperglycaemia and ketoacidosis develop,dehydration and acidosis stimulate the release ofcatecholamines4 and cortisol5, leading to a vicious circlein which worsening metabolic decompensationstimulates further secretion of catabolic hormones. Inmoderate DKA, average 6 litres of fluid, 500 m.molNa, 400 m.mol Cl and 350 m. mol K are lost.1

Most patients present with polyuria, polydipsia, nausea,vomiting, generalized weakness and weight loss.Abdominal pain is a recognized feature, particularly inchildren. Patients are frequently dehydrated,hypotensive, tachycardic and dyspneic. Ultimately theybecome comatose. Features of infection may be present.

Precipitating causes of diabetic ketoacidosis includeinfection 30%, errors in management 15%, newlydiagnosed diabetes 10%, other identifiable medicaldisease 5% and in 40% cases no cause is found 6. Drugse.g. corticosteroids, thiazides and sympathomimetics areoften the culprits3.

The diagnosis of diabetic ketoacidosis is simple if it isconsidered in the differentials. A urine sample showingmarked glycosuria and ketonuria or an undiluted plasmasample giving a strongly positive result in nitroprussidetest for acetoacetate is sufficient for diagnosis. Thesecommon tests are often not done and there occurs delayin diagnosis. Differential diagnoses includeshyperglycaemic hyperosmolar state(HHS), lacticacidosis, other causes of metabolic acidosis like uraemia,salicylates, methanol, ethyline glycol poisoning etc.

Investigations include plasma glucose, blood urea,serum creatinine, serum electrolytes, serum osmolality,urinalysis, urine or plasma ketones and arterial bloodgas analysis. Bacterial cultures of urine, blood, throatswabs and chest X-ray are often required.

Successful treatment of DKA requires correction ofdehydration, hyperglycaemia, electrolyte imbalance,identification of precipitating cause and it’s treatmentand above all frequent monitoring1. Use of flow chart

documenting clinical status (blood pressure, intake-output chart and level of consciousness, if necessary),blood glucose, electrolytes and anion gap isrecommended 7.

The common complications of DKA and it’s treatmentare hypoglycaemia, hypokalaemia and hyperglycaemia.Cerebral oedema is a rare but fatal complication,occurring in 0.7-1.0% children with DKA with mortalityrate >70%, with only 7-14% patients recovering withoutpermanent morbidity3. Hypoxemia and rarelynoncardiogenic pulmonary oedema may complicatetreatment of DKA. Thromboembolic complications,DIC and rarely rhinocerebral mucormycosis can occurin diabetic patients with ketoacidosis 2.

The average mortality rate for ketoacidosis in developedcountries is currently estimated 5-10%, althoughreported rates vary greatly8. Mortality is greatly higherin less specialized centers and in elderly population9.

Many cases of DKA can be prevented by better accessto medical care, proper education and effectivecommunication with the health care provider during anintercurrent illness 3.

Materials and methodsThis cross sectional study was done in the Departmentof Medicine, BIRDEM General Hospital, Dhaka. Datawere collected from fifty hospitalized patients with adiagnosis of DKA who were admitted and managed ingeneral medical wards. The study period was ninemonths (January 2007 to September 2007). All adultpatients aged 18 years and above with a diagnosis ofDKA, whether previously known diabetic or newlydiagnosed case were included in the study. Patientshaving other causes of acidosis like chronic kidneydisease (CKD), those who required transfer to CriticalCare Units for treatment and those who were below theage of 18 years were excluded from the study.

ResultsTotal number of cases were 50, male were 24 and femalewere 26, M:F ratio was 12:13. Mean age was 27.6 ± 3.7years. Thirty one (62%) patients came from villagesand 19 (38%) patients were from urban and sub-urbanareas. Most (47, 94%) of the patients were from familyof low income group. Eighteen patients (36%) weredetected as diabetic first time at this admission (newcase) and 32(64%) patients were known diabetic (old

16


case). Among the 32 known diabetic patients, 24 (75%)patients were on insulin, 7 (21.88%) patients were onoral anti-diabetic agents (OAD), and 1 (3.13%) patientwas on medical nutrition therapy (MNT). (Figure 1)

The common presenting features were vomiting (26,52%), fever (19, 38%), nausea (16, 32%), abdominalpain (14, 28%) (including epigastric pain in 4 cases,suprapubic pain in 3 cases, right hypochondriac pain in2 cases and non-specific pain in 5 cases), polyuria (12,24%) and polydipsia (8, 16%). Other features wererelatively less common. Five (10%) patients had diabeticfoot (2 cases had gangrene of one or more toes, 2 caseshad abscess on dorsum of foot and 1 case had infectionof amputated stump of leg) and 1(2%) patient hadcellulitis and thrombophlebitis involving fore arm. Outof 50 cases, 4 (8%) cases had repeated history ofhospitalization with DKA.

All patients had hyperglycaemia (Figure 2), almost all49 (98%) had HbA1C > 7%.(Table I)

Thirty seven (74%) patients had +++ acetonuria and 13(26%) patients had ++ acetonuria at the time ofadmission. In a significant number of patients acetonuriapersisted for a longer time compared with clinical andbiochemical improvement of the patients evidenced bypH and bicarbonate levels. Thirty (60%) patients hadmoderate metabolic acidosis, 16 (32%) had mildmetabolic acidosis and 4(8%) patients had severemetabolic acidosis (ADA criteria)3. (Figure 3)

Infection was the commonest (18, 36%) precipitating cause,followed by inadherence to insulin therapy (17, 34%).Pancreatitis precipitated DKA in 3 (6%) cases, and in 12(24%) cases no cause was identified. (Figure 4)

Most of the patients had normal Na and K levels atpresentation and only three (6%) patients had severehyponatraemia and hypokalaemia (Table II). All patientsdeveloped hypokalaemia within twelve hours ofadmission during the process of correction of metabolicacidosis with treatment (with intravenous fluids andinsulin) and in all patients IV replacement of potassiumwas given.

Six (12%) patients had normal total white cell count(4000-11000/cmm of blood), in 17(34%) cases whitecell count was between 11000-15000/cmm of blood andin 27 (54%) cases total white cell count was > 15000/cmm of blood, though infection was present only in18(36%) cases.

Table I

Distribution of patients according to HbA1C level

HbA1C (%) Number of Patients Percent<7 1 27-8.5 9 188.6-10 24 48>10 16 32

During the first 24 hours of in-hospital treatment, eachpatient required, on an average of 4.12 litres ofintravenous fluids, 60 m.mol of potassium and 72 unitsof insulin.

Most patients (47, 94%) recovered from the acute crisisand only 3 (6%) patients expired within 48 hours ofadmission.

Fig.-1: Distribution of cases according to presenttreatment in known diabetic patients (Total 32)

Fig.-2: Distribution of patients according to randomblood glucose level (RBS m.mol/L) at presentation

17

Clinical Spectrum and Management of Diabetic Ketoacidosis: Experience in A Tertiary Care Hospital Rahim MA et al

Table-II

Distribution of patients according to serum sodiumand potassium levels at presentation

Serum sodium Number of Percent(m.mol/L) Patients<120 3 6121-125 2 4126-130 9 18131-135 6 12136-140 20 40141-145 6 12146-150 4 8>150 0 0Serum potassium (m.mol/L)<3 3 63-4.5 20 404.6-6 21 42>6 6 12

DiscussionThis study was done to see the common presentingfeatures of diabetic ketoacidosis, their precipitatingcauses, the glycaemic control of these patients,

electrolyte disturbances at presentation and theircorrection in first 24 hours and the outcome in BIRDEMGeneral Hospital, a tertiary care hospital. The study wascarried out on hospitalized adult patients aged 18 yearsand above. Total number of patients were 50. Amongthem, 32 (64%) patients were already diagnosed asdiabetic and 18 (36%) patients were diagnosed diabeticfirst time during this admission. There was slight femalepredominance, female : male ratio was 13:12. Mostpatients were from villages and many were of lowersocio-economic group. Female: male ratio in Denmark10

was 7.2 : 5.7. In a study in Taipei11 , it was found that67% DKA patients were female. In a small series ofpaediatric patients in India12 female: male ratio was 1:2.

Surprisingly, the typical features of polyuria, polydipsiaand weight loss which are the predominant features ofDKA, were relatively less common than nausea,vomiting and abdominal pain. Vomiting (24, 48%) wasthe most frequent symptom. Features of infection e.g.fever, cough, urinary symptoms and diabetic footinfection were also common.

Infection (18, 36%) was the commonest precipitatingcause in this study. In 17 (34%) cases DKA wasprecipitated by omission or error in insulin management.In 12 (24%) cases no cause was found and pancreatitisprecipitated DKA in 3 (6%) cases. In different studies,it was found that infection and drug non-compliancewere the most common precipitating causes and thesetwo collectively comprised 70-90% causes. In a studyin Nairobi13 34% cases were precipitated by omittinginsulin, 23.4% cases had infection. Non-compliance wasthe most common cause in Korea14, whereas in anotherstudy in Pakistan15, infection precipitated DKA in 63%cases of type 2 diabetes mellitus.

Of the 50 cases studied, 30 (60%) had moderatemetabolic acidosis, 16 (32%) had mild metabolicacidosis. The remaining 4 (8%) cases had severemetabolic acidosis. Most patients had grossly elevatedHbA1c, 24 (48%) cases had HbA1c > 8.5%, 16 (32%)cases had HbA1c > 10% . In a study in Nairobi13 >90%patients had HbA1c >8%.

In this study, most patients with mild to moderateacidosis did not have gross electrolyte imbalance. Mosthad normal or slightly low Na+ levels, high normal orslightly elevated K+ levels. Similar results were foundin a study in Pakistan15. Three patients had severe

Fig-3: Distribution of patients according to severity ofDKA (ADA criteria)

Fig.-4: Distribution of cases according to precipitatingcauses

18


hyponatraemia and hypokalaemia, but after initiationof treatment with intravenous fluid and insulin, allpatients developed hypokalaemia requiring intravenouscorrection. In a National Survey of Denmark16, similarobservation was found.

Most patients had grossly elevated blood sugar levelsand ++ or more ketonuria on urine ketostix test. Patientswere found to have ketonuria for longer period incomparison with their clinical and biochemicalimprovement evidenced by pH and HCO3- levels.Similar observation was reported in a small study inIndia12.

Forty four (88%) patients had neutrophilic leukocytosis.Among these 44 patients, only 18 patients had infection.In another study13 >65% patients had leucocytosis andin 55% patient there was no infection.

The outcome, in terms of in-hospital mortality (ingeneral medical wards), was quiet satisfactory. Only 3(6%) patients expired within 48 hours of admission andthese patients had severe acidosis with grosshyponatraemia and hypokalaemia at presentation.Among them, two patients were treated initially in lessspecialized hospitals, one had acute pancreatitis, onepatient was grossly neglected diabetes mellitus and hadhistory of repeated admissions with DKA. All otherpatients recovered. In the UK17, in-hospital mortalityrate was upto 14% because of variations in managementand various other factors, in Denmark16 it was 4% andin Korea14, in-hospital mortality was 11.8%. InNairobi13 29.8% patients expired in hospital within 48hours of admission.

Conclusion

In this cross-sectional observational study of fifty adultdiabetic ketoacidosis patients (treated in general medicalwards) in BIRDEM General Hospital, it was found thatDKA occurred more commonly in known diabeticpatients who were non-compliant to insulin treatmentor who had had infection. New cases were notuncommon. Polyuria, polydypsia, vomiting, abdominalpain and infection were common features. Theglycaemic control in these patients was poor. Severemetabolic acidosis was less common. In mild tomoderate acidosis, gross electrolyte disturbances wereinfrequent but hypokalaemia developed after initiationof treatment. Leukocytosis was common, even inabsence of infection and ketonuria persisted with

treatment in spite of clinical and biochemicalimprovement. The overall outcome was comparablewith developed countries. (The only limitation of thestudy was that, those patients who required treatment inCritical Care Units were not included in this study).

AcknowledgementI am indebated to Professor Mohammad Omar Faruq,Head of Critical Care Medicine of BIRDEM GeneralHospital for many valuable suggestions and commentsin the process of preparation of this manuscript.

References1. Frier BM, Fisher M. Diabetes Mellitus. In: Boon NA, Colledge

NR, Walker BR, Hunter JAA editors. Davidson’s Principles& Practice of Medicine. 20th ed. Edinburgh: ChurchilLivingstone.2006.p820-2.

2. Krentz AJ, Nattrass M. Acute Metabolic Complications ofDiabetes: Diabetic Ketoacidosis, Hyperosmolar non-ketoticHyperglycaemia and Lactic acidosis. In: Pickup JC, WilliamsG editors. Textbook of Diabetes. 3rd ed. vol 1 Massachussetts:Blackwell Science Ltd.2003.p32.2-15.

3. Diabetes Care. 2007 Jan; 30 (1 supl): s109-16.

4. Christensen NJ. Plasma norepinephrine and epinephrine inuntreated diabetics during fasting and after insulinadministration. Diabetes 1974;23:1-8.

5. Jacobs JS, Nabarro JDN. Plasma 11-hydroxycorticosteroidand growth hormone levels in acute medical illnesses. BMJ1969;2:595-8.

6. Nattrass M. Diabetic Ketoacidosis. Medicine International.Oxford: The Medicine Publishing Company Elsevier Ltd.2006 Nov; (1) :105.

7. Wyckoff J, Abrahamson MJ. Diabetic Ketoacidosis andHyperosmolar Hyperglycaemoc state. In: Kahn CR, Weir GC,King GL, Jacobson AM, Moses AC, Smith RJ editors. Joslin’sDiabetes Mellitus. 4th ed. Bosston: Joslin’s DiabetesCenter.2005.p896.

8. Schade DS, Eaton RP, Alberti KGMM, Johnston DG. DiabeticComa, Ketoacidotic and Hyperosmolar. Albuquerque:University of New Mexico Press,1981.

9. Gale EAM, Dornan TL, Tattersall RB. Severely uncontrolleddiabetes in the over-fifties. Diabetilogia 1981;21:25-8.

10. Henriksen OM, Roder ME, Prahl JB, Svendsen OL. Diabeticketoacidosis in Denmark: incidence and mortality from publichealth registries. Diabetes Res Clin Pract.2007 Apr; 76 (1):51-6.

11. Lin SF, Lin JD, Huang YY. Diabetic ketoacidosis: comparisonsof patient characteristics, clinical presentations and outcomestoday and 20 years ago. Chang Gunh Med J.2005 Jan; 28 (1): 24-30.

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Clinical Spectrum and Management of Diabetic Ketoacidosis: Experience in A Tertiary Care Hospital Rahim MA et al

12. Jahagirdar RR, Khadilkar VV, Khadilkar AV, Lalwani SK.Management of diabetic ketoacidosis in PICU. Indian JPediatr.2007 Jan; 74 (6):551-4.

13. Mbugua PK, Otieno CF, Kayima JK, Amayo AA, McLigeyoSO. Diabetic ketoacidosis: clinical presentation andprecipitating factors at Kenyatta National Hospital, Nairobi.East Afr Med J.2005 Dec; 82 (12 supl): s191-6.

14. Ko SH, Lee WY, Lee JH, Kwon HS, Lee JM, Kim SR, MoonSD, Song KH, Han JA, Ahn YB, Yoo SJ, Son HY. Clinacalcharacteristics of diabetic ketoacidosis in Korea over the pasttwo decades. Diabet Med. 2005 Apr; 22 (4): 466-9.

15. Jabbar A, Farooqui K, Habib A, Islam N, Haque N, Akhter J.Clinical characteristics and outcomes of diabetic ketoacidosisin Pakistani adults with type 2 diabetes mellitus. Diabet Med.2004 Aug; 21 (8) : 920-3.

16. Henriksen OM, Prahl JB, Roder ME, Svendsen OL. Treatmentof diabetic ketoacidosis in adults in Denmark: a nationalsurvey. Diabetes Res Clin Pract. 2007Jul; 77 (1) : 113-9.

17. Sharma V, Hadebe N. Diabetic ketoacidosis: principles ofmanagement. Br J Hosp Med (Lond). 2007 Apr; 68 (4): 184-9.

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Abstract:Objectives: The Prevalence and magnitude of childhoodobesity are increasing dramatically. The study wasundertaken to see the prevalence of metabolic syndromeamong children and adolescents with obesity, attending thePaediatric Endocrine OPD, BIRDEM.

Methods: A cross sectional study was conducted fromJanuary 2006 to December 2008 among obese children andadolescents (6-18 years) attending Paediatric endocrine outpatient department of BIRDEM. Children with any otherendocrine disorder, dysmorphism/syndrome were excluded.Obesity was defined as BMIe”95th percentile for age andsex using CDC growth chart. Children underwent two-houroral glucose tolerance test, anthropometric and bloodpressure measurement. Fasting serum insulin and lipidprofile were measured. Impaired glucose tolerance (IGT)was defined as fasting plasma glucose (FPG) <7 mmol/Land 2 hr post glucose load e”7.8 mmol/L to<11.1 mmol/L.Metabolic syndrome was identified if 3 or more of followingcriteria were met: BMI > 97th percentile for age and sex,

Prevalence of Metabolic Syndrome among Obese Childrenand Adolescents

MOHSIN Fa, BAKI Ab, NAHAR Jc, AKHTAR Sd, BEGUM Te, AZAD Kf, NAHAR Ng

a. Fauzia Mohsin, MBBS, FCPS, Associate professor, Departmentof Paediatrics, Bangladesh Institute of Research andRehabilitation in Diabetes, Endocrine and Metabolic Disorders(BIRDEM) and Ibrahim Medical College

b. Abdul Baki, MBBS, MD, Registrar, Department of Pardiatrics,BIRDEM and Ibrahim Medical College

c. Jebun Nahar, MBBS, DCH, MD, Associate Professor andResident Physician, Department of Paediatrics, BIRDEM andIbrahim Medical College

d. Shahida Akhter, MBBS, FCPS, Associate Professor, Departmentof Paediatrics, BIRDEM and Ibrahim Medical College

e. Tahmina Begum, FCPS, MD, M M Ed, Professor and Head,Department of Paediatrics, BIRDEM and Ibrahim MedicalCollege

f. Kishwar Azad, LRCP, MRCS, FCPS, MSc, Senior HonoraryConsultant, Department of Paediatrics, BIRDEM and IbrahimMedical College

g. Nazmun Nahar, MBBS, FCPS, FRCP, Professor, Departmentof Paediatrics, BIRDEM and Ibrahim Medical Colllege

Address of Correspondence: Dr. Fauzia Mohsin, Department ofPaediatrics, Bangladesh Institute of Research and Rehabilitation inDiabetes, Endocrine and Metabolic Disorders (BIRDEM) andIbrahim Medical College, 122, Kazi Nazrul Islam Avenue, Shahabag;Dhaka-1000; Bangladesh. Tel: 880-1713063141 (Mobile), Tel: 880-2-8855032 (H), Tel: 880-2-9661551-60/2371, Fax: 880-2-966781Email: [email protected]: May 30, 2011 Accepted: June 30, 2011

high triglyceride (TGe”150 mg/dl), low high-densitylipoprotein cholesterol (HDL cholesterol<40mg/dl), Systolicor diastolic blood pressure>95th percentile for age and sex,IGT.

Results: A total of 161 children presented with obesity. Maleto female ratio was 1.3:1. Mean age was 10.3±2.5 years.Metabolic syndrome was identified in 36.6% subjects (59out of 161, twentyfive male and 34 female). Higher BMIand hip circumference, systolic and diastolic hypertension,high TG, low HDL cholesterol and IGT were significantlyassociated with metabolic syndrome.

Conclusions: The prevalence of metabolic syndrome is highamong obese children and adolescents. Factors contributingtowards obesity needs to be identified and strategies shouldbe planned for prevention and management of this healthproblem.

Key Words: Obesity, Children, Adolescent, Metabolicsyndrome

(Birdem Med J 2011; 1(1): 21-25)

Introduction:The prevalence of childhood obesity has risen severaltimes in past few decades in developed as well asdeveloping countries.1,2Urbanization, unhealthy dietsand increased sedentary lifestyles have contributed tothe increased prevalence of childhood obesity,particularly in developing countries.3 The prevalenceof obesity was found to be17.9% and that of overweightwas 23.6% among affluent school children andadolescents in Dhaka.4 Childhood obesity is associatedwith several metabolic and endocrine derangementsincluding hyperinsulinaemia, glucose intolerance,hypertension and dislipidaemia that predisposeindividuals to early development of cardiovasculardisease and type 2 diabetes mellitus (T2DM).Theclustering of these cardiovascular and metabolic riskfactors have been identified as metabolic syndrome. 5,6

The prevalence of metabolic syndrome varied from28.7% to 50% in various studies among obese childrenand adolescents.7-9 We have found a high rate ofImpaired glucose tolerance (IGT) and dislipidaemia inobese children and adolescents.10 Limited data is

.


available from our country on metabolic syndrome inchildren and adolescents and hence the present studywas conducted to see the prevalence of metabolicsyndrome among obese children and adolescents.

Methods:A cross sectional study was conducted from January2006 to December 2008 among children and adolescentsattending Paediatric endocrine outpatient Department(OPD) of BIRDEM with the complaints of excessiveweight gain.

Obese children and adolescents aged 6-18 years wereincluded in the study. Children with any other endocrinedisorder, dysmorphism/syndrome were excluded.History was obtained from all subjects and physicalexamination was performed. Blood pressure wasmeasured using appropriate sized cuff encircling at least2/3rd of upper arm. Anthropometric measurement ofweight, standing height, waist and hip circumferencewere taken. Weight was measured using a bathroomscale to the nearest 100 gram. Standing height wasmeasured with stadiometer and measurement was doneto nearest 0.1 cm. The waist circumference wasmeasured at the level midway between the lower ribmargin and iliac crest, at the level of umbilicus with thechild breathing out gently. The hip circumference wasmeasured at the maximum width over the buttocks atthe level of the greater trochenter with a plasticmeasuring tape. The body mass index (BMI) wascalculated as weight in kilogram (Kg) divided by squareof the height in meter. Obesity was defined as BMIe”95th

centile for age and sex using CDC growth chart.11

Children underwent two-hour oral glucose tolerance test(OGTT). Patients were kept on unrestrictedcarbohydrate diet for at least three consecutive daysprior to the test and kept fasting for 8-14 hours on thenight before doing the test. Blood was collected at “0minute” for estimation of glucose, serum insulin, lipidprofile and other relevant investigations. Thenanhydrous glucose was given in the amount of 1.75mg/kg body weight (maximum 75 gram) dissolved in waterfor OGTT. The second sample of blood glucose wascollected at “120 minute”. Estimation of blood glucoseand lipid profile was done by enzymatic colorimetricmethod using multichannel autoanalyzer. Impairedglucose tolerance (IGT) was defined as fasting plasmaglucose (FPG) <7 mmol/L and 2 hr post glucose load

>7.8 mmol/L to<11.1 mmol/L.12 Diabetes Mellitus(DM) was defined as FPGe”7mmol/L or 2 hr postglucose loade”11.1mmol/L.12 Insulin resistance index(Ins-resistance index)was determined by homeostaticmodel and calculated as the product of the fasting plasmainsulin level (µUnit/ml) and the fasting plasma glucoselevel (mmol/l),divided by 22.5.13 Total cholesterole”200mg/dl,Triglyceride (TG) e”150 mg/dl, low-densitylipoprotein cholesterol(LDL cholesterol) e” 130mg/dl,high-density lipoprotein cholesterol (HDLcholesterol)<40mg/dl were designated abnormal..14.15

Hypertension was defined as BPe”95th percentile forage and sex16.

Metabolic syndrome(MT) was identified if 3 or moreof following criteria were met: BMI > 97th percentile,high TG, low HDL cholesterol , Systolic or diastolicblood pressure>95th percentile, IGT. 9

Data were analysed using SPSS software ( version12).Student T test and Chi-Square test was performedwhen applicable. P value of < 0.05 was consideredsignificant. Descriptive statistics were reported as mean(±SD).

Results:A total of 161 children presented with obesity. Male tofemale ratio was 1.3:1. Mean age was 10.3±2.5 years.Metabolic syndrome was identified in 36.6% ofsubjects(59 out of 161).There was a femalepredominance with 34 female and 25 male (female tomale ratio 1.36:1).Clinical and biochemical data of children with metabolicsyndrome (Group 1) and without metabolic syndrome(group 2) are shown in table 1. While comparing theclinical phenotype and biochemichal data of obesechildren and adolescents with metabolic syndrome(group 1) and without metabolic syndrome (group 2)BMI, hip circumference, systolic blood pressure,diastolic blood pressure, Blood glucose at 2 hour ofOGTT and triglyceride was found significantly higheramong the former group. HDL cholesterol was lower ingroup 1 compared to that of group 2. Fasting seruminsulin was measured in 34 subjects. Mean serum insulinlevel was not significantly different among the twogroups. Mean insulin-resistance index (Ins-resistanceindex) was higher in the former group, although it wasnot statistically significant. The clinical and metabolicprofile of children and adolescents of both groups areshown in TableI.

22


Among the 59 children and adolescents with metabolicsyndrome BMI >97th percentile was found in51(86.4%), low HDL-Cholesterol in 44 (74.5%), highTG in 41(69.4%), IGT in 19 (32.2%), diastolichypertension in 18 (30.5%) and systolic hypertensionin 16 (27.1%) of subjects. Fig I shows the frequency ofvarious components of metabolic syndrome.On Chi-square analysis BMI>97th percentile (p=0.01),high TG (p=0.000), low HDL cholesterol(p=0.000),IGT(p=0.000), Systolic hypertension(p=0.008) anddiastolic hypertension(p=0.02) were significantlyassociated with metabolic syndrome. No association wasfound with family history of diabetes, presence of highcholesterol and high LDL cholesterol (Table II)

Table IShowing clinical and biochemical data of children with metabolic syndrome (group1) and without metabolic

syndrome (group 2)

Group 1 Group 2 p-valueAge(Yrs) 10.56(±1.95) 10.40(±2.63) 0.73Weight (Kg) 60.15(±14.77) 56.07(±16.17) 0.14Height (cm) 143.48(±12.27) 142.68(±14.84) 0.74BMI kg/m2 29.02(±3.76) 27.46(±3.74) 0.02Waist (cm) 87.80(±9.81) 85.41(±10.33) 0.25Hip (cm) 96.66(±10.63) 91.36(±11.12) 0.02Waist/hip 0.90(±0.05) 0.93(±0.09) 0.06Systolic BP(mm of Hg) 114.79(±13.02) 107.58(±14.58) 0.005Diastolic BP(mm of Hg) 74.93(±10.11) 68.98(±9.53) 0.001Fasting Plasma glucose(mmol/l) 4.85(±0.59) 4.76(±0.63) 0.41Plasma glucose at 2 hr of OGTT(mmol/l) 7.26(±1.27) 6.73(±1.26) 0.02Insulin (µU/ml) 22.05(±8.68) 21.91(±15.35) 0.97Ins-resistance index 4.72(±1.94) 3.84(±2.24) 0.27TG(mg/dl) 200.89(±83.96) 131.03(±55.08) 0.00 Cholesterol (mg/dl) 182.14(± 36.05) 181.91(±41.88) 0.97LDL cholesterol(mg/dl) 106.31(± 32.89) 112.06(±39.40) 0.39HDL cholesterol(mg/dl) 35.75(±7.43) 42.34(±9.86) 0.00

Fig.-I: Showing frequency of various components ofmetabolic syndrome

Table II

Showing association of various factors in obese subjects with and without metabolic syndrome (MetS)

Characteristics With Met S, n=59 n (%) Without Met S, n=102 n (%) P valueBMI>97th percentile 51(86.44) 71(69.64) 0.01High triglyceride level 41(69.49) 23(22.54%) 0.000High total cholesterol 17 (28.81) 26(25.49%) 0.64Low HDL cholesterol 44 (74.57) 35(34.31) 0.000High LDL cholesterol 13(22.03) 24(23.52) 0.82Family H/O diabetes present 32(54.23) 46 (45.09) 0.48IGT present 19(32.20) 8(7.84) 0.000Systolic hypertension present 16(27.11) 11(10.78) 0.008Diastolic hypertension present 18(30.50) 16(15.68) 0.02

23

Prevalence of Metabolic Syndrome among Obese Children and Adolescents Mohsin F et al

Discussion:In our study the prevalence of metabolic syndrome inobese children and adolescence is 36.6%.This iscomparable with the figures of 28.7% to 37.5% reportedin other studies carried out among obese children andadolescents.7,17,18 In one study in USA the prevalenceof metabolic syndrome increased with the severity ofobesity, it was 38.7% in moderately obese subjects (aBMI z-score of 2 to 2.5) and reached 49.7% in severelyobese subjects(a BMI z-score above 2.5).9

The metabolic syndrome in adults is defined as a Clusterof cardiovascular and diabetes risk factors includingabdominal obesity (expressed by waist circumference),dyslipidaemia, glucose intolerance and hypertension.3There are a range of published metabolic syndromedefinition in paediatrics 7-9,17,19 and the result of studyon metabolic syndrome in children and adolescent canvary with the criteria used to define metabolic syndrome.We have adopted the criteria from Weiss et al 9 whereobesity was defined on the basis of BMI instead of waistcircumference. Waist circumference and waist hip ratioare difficult to interpret in children as body proportionchanges during childhood and adolescents. We haveslightly modified the criteria for abnormal TG and HDLcholesterol level. A TG level of more than 95th percentileand HDL cholesterol level of less than 5th percentilefor their population was designated as abnormal byWeiss. In our study a TGe”150mg/dl and HDLcholesterol<40mg/dl was taken as abnormal as used byothers in case of children and adolescents.14

In our study BMI was significantly higher in childrenwith metabolic syndrome as found in other studies7,9,20

Metabolic syndrome was more frequent in female thanmales, which does not agree with the data reported inother studies of similar age.7-9 A study carried out amongadult population in Bangladesh has found higherprevalence of metabolic syndrome in females usingInternational Diabetes Foundation (IDF) criteria.21 Wedid not find age, family history of diabetes to beassociated with metabolic syndrome in agreement withCook et al.7 In the present study the waist-hip ratio inobese children in all age group was more than 0.9indicating abdominal adiposity. Waist -hip ratio is anexcellent predictor of abnormalities of lipids and glucosemetabolism in the adult population and similarcorrelation have been made for paediatric obesity22. Aratio greater than 0.8 in women and 0.9 in men is

associated with an increased risk of insulin resistanceand associated disease23. Several studies have shownthat waist circumference more than 90th percentile aremore likely to have multiple risk factors7,18,24-26In ourstudy we have not found any association of waistcircumference and waist hip ratio with metabolicsyndrome. Surprisingly hip conference was higher inchildren with metabolic syndrome. We have foundsimilar association of hip circumference with IGT inour previous study.10 This can be due to racial differencein fat distribution but needs further studies to comment.Moreover body proportion normally changes with ageand may vary among different races and ethnic groups.

We found IGT, high triglyceride, systolic and diastolichypertension and low HDL cholesterol to be associatedwith risk of metabolic syndrome as found in otherstudies.9,18 This is expected as these are components ofmetabolic syndrome. Insulin resistance index werehigher in subjects with metabolic syndrome comparedto those without metabolic syndrome but did not reachstatistical significance. This may be due to the fact thatserum level of insulin could be measured in a smallnumber of subjects. Various studies among obesechildren and adolescents have found higher insulinresistance index to be important risk factor for metabolicsyndrome.9,18

The present study has certain limitations. It was a cross-sectional, clinic based study. Only obese children wereincluded and it was not a case-control study. Risk factorsfor obesity were not identified. The prevalence ofmetabolic syndrome as found in our study can varydepending on various criteria used while definingpaediatric metabolic syndorome.

We have found a high rate of metabolic syndrome inour obese subjects. Lifestyle modification can lead toreduction in the incidence of metabolicsyndromere.27,28,29 Obesity is of critical importance inthe development of metabolic syndrome and needs tobe prevented in childhood.

References:1. Wang Y, Lobstein T. Worldwide trends in childhood

overweight and obesity. Int J Pediatr Obes 2006;1:11-25.

2. Suwan L, Junjan AC, Puetpaiboon A. Increasing obesity inschool children in a transitional society and the effect of weightcontrol program. South East J Trop Med Pub Hlth1993; 24:590-94.

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3. Alberti KG,Kimmet P,Shaw P.Metabolic Syndrome-a newworldwide definition.A consensus statement from theInternational Diabetic Federation.Diabet Med 2006;23:469-80.

4. Mohsin F, Tayyeb S, Baki A, Sarker S, Zabeen B, Begum Tet al Prevalence of obesity among affluent school children inDhaka. Mymensingh med J 2010 ;19:549-54.

5. Sinha R, Fisch G, Teague B,William V,TamborlaneWV,Banyas B et al.Prevalence of Impaird Glucose Toleranceamong children and adolescents with marked obesity.N EnglJ Med 2002;346:802-10.

6. Aggoun Y.Obesity,metabolic syndrome and cardiovasculardisease. Pediatr Res 2007;61:653-59.

7. Cook S, Weitzman M, Auinger P,Nguyen M,William HD.Prevalence of a metabolic syndrome phenotype in adolescents.findings from the third National Health and NutritionExamination Syrvey.1988-1994.Arch PediatrAdolesc Med2003;157;821-27.

8. Cruz ML, Weigensberg MJ, Huang TT,Ball G,Shbi GQ,,GoranMI .The metabolic syndrome in overweight Hispanic youthand the role of insulin sensitivity. J Clin EndocrinolMetab2004;89:108-13.

9. Weiss R, Dziura J, Burgert TS,TamborlaneWV,TaksaliSE,YeckelCW et al.Obesity and the MetabolicSyndrome in Children and Adolescents.N Engl JMed2004;350:2362-74.

10. Metabolic profile of obese children and adolescents inBangladesh (Abstract). Mohsin F, Tayyeb S, Baki A, ZabeenB,Begum T, Azad K, Nahar N. Poster presentation at the5the APPES scientific meeting (October 29-November1,2008), Seoul, Republic of Korea

11. Kuczmarski RJ, Oglen CL, Grummer Strawn LM. 2000 CDCgrowth charts; United States. Washington DC:Center forDisease Control and Prevention/National Center for HealthStatistics. Advance data 314:1-28.

12. The expert committee on the diagnosis and classification ofdiabetes Mellitus. Report of the expert committee on thediagnosis and classification of diabetes mellitus. DiabetesCare 1999;22:1:S5-9.

13. Mathews DR, Hosker JP,Rudenski AS,Naylor BA,TreacherDF,Turner RC. Homeostasis Model Assesment:Insulinresistance and beta cell function from fasting plasma glucoseand insulin concentrations in man. Diabetologia 1985;28:412-19.

14. Gillian S,Boyd BS, Joanna Koenigsberg BS,FalknerB,Gidding S,Hassink S. Effect of obesity and high bloodpressure on plasma lipid levels in children andadolescents.Pediatrics 2005;116:442-46.

15. Third Report of the National Cholesterol Education programExpert Panel on Detection, Evaluation and Treatment of High

Blood Cholesterol in Adults (Adult treatment PanelIII).Bethesda MD :National Heart, Lung and BloodInstitute;2001.

16. Report of the second task force on Blood Pressure Control inChildren-1987. National Heart, Lung and Blood Institute,Bethesda, MD. Pediatrics1987; 79:1-25.

17. DeFerranti SD,,Kimberlee G,Ludvig DS,Neufeld EJ,Newburger JW,Rifai N. Prevalence of the Metablic Syndromein American Adolescents:Finding from the Third NationalHealth and Nutrotion Examination Survey.Circulation2004;110:2494-97.

18. Bustos P, Saez K,Gleisner A,Ulloa N,Calvo C,Asenjo S.Metabolic syndrome in obese adolescents.Pediatric Diabetes2010;11:55-60.

19. Ford ES,Ajani UA,Mokdad AH . The metabolic syndromeand concentrations of C-reactive protein among U.S. youth.Diabetes Care 2005;28:878-81.

20. Saland JM, Update on the metabolic syndrome inchildren.Curr Opin Pediatr 2007;19:183-91.

21. Sayeed S,Banu A, Khanam PA,Alauddin S,Makbul S,BegumT et al. Prevalence of metabolic syndrome in three urbancommunities of Dhaka City. Ibrahim Med Coll J 2008;2: 44-8.

22. Shinomiya M, Ishikawa Y, Shiraj K. The significance of waist-hip ratio in obese children. Int J Obes1990; 14:135

23. Caro J. Insulin resistance in obese and nonobese man. J ClinEndocrinol and Metab. 1991;73:692.

24. Bloch CA, Clemons P, Sperling MA. Puberty decreases insulinsensitivity. J Pediatr. 1987;110:481-87.

25. Ng VW, Kong AP, Choi KC,Ozaki R,Wong GW,So WY et al.BMI and waist circumference in predicting cardiovascularrisk factor clustering in Chinese adolescents. Obesity.2007;15:494-503.

26. Hirschler V,Calcagno ML,Aranda C,Maccallini G,JadzinskyM.Can the metabolic syndrome identify children with insulinresistance? Pediatric Diabetes 2007;8:272-77.

27. Kang HS,Gutin B,Barbeau P,Owens S,Lemmon CR,AllisonJ et al.Physical training improves insulin resistance syndromemarkers in obese adolescents.Med Sci Sports Exerc2002 ;34 :1920-27.

28. Ritenbaugh C,Teufel-Shone NI,Aickin MG,Jennie RJ,PoirietS.Dillingham DC et al.A lifestyle intervention improvesplasma insulin level among native American high schoolyouth. Prev Med 2003;36:309-19.

29. Chen AK, Roberts CK, Barnard RJ. Effect of a short termdiet and exercise intervention on metabolic syndrome inoverweight children. Metabolism 2006;55:871-78.

25

Prevalence of Metabolic Syndrome among Obese Children and Adolescents Mohsin F et al

AbstractObesity is a global health problem including bangladeshresulting in major morbidity and premature death. Thecauses of this epidemic are complex and multifactorial, butfundamentally lead to an excess calorie intake over energyexpenditure. Modern lifestyles, incorporating altered eatingpatterns, access to cheap, highly palatable, energy-denseyet nutritionally poor foods, sedentary habits and labor-saving devices, have hugely accelerated the problem duringlast few years. Till date safe and efficacious drug therapiesremains unmet. The two drugs for the long-term treatmentof obesity, Orlistat and Sibutramine, provide only modestweight-loss benefits and are associated with high attritionrates owing to side effects. Currently neuroendocrine controlof energy homeostasis and major pharmacologicaltreatments for obesity in the pipeline. The discovery of leptin

REVIEW ARTICLES

Overview on Obesity - A ReviewASHRAFUZZAMAN SM

Dr. S.M. Ashrafuzzaman, M.D. (Endocrinology & Metabolism),Associate Professor of Endocrinology, BIRDEMAddress of Correspondence: Dr. S.M. Ashrafuzzaman, Departmentof Endocrinology BIRDEM, Room No 1216 Phone 8616641-50 Ext2355, Mobile +88 01819814071Received: May 21, 2011 Accepted: June 30, 2011

and other gut hormones as major neuroendocrineregulators of bodyweight is leading the way to thedevelopment of attractive therapeutic approaches to thelong-term manipulation of energy homeostasis in favor ofappetite reduction and weight loss. It is hoped that this maybe associated with a relative paucity of central or unexpectedside effects. The rest of this article will concentrate on thesetherapeutic strategies. Still shortcomings of medicaltreatment encouraged the Barriatric surgery specially formorbid obese subjects. Though many advantages areascribed including remission and improvement of Type 2diabetes mellitus, long term metabolic and nutritional effectsstill remains questionable. Comparative data amongdifferent procedures of Barriatric surgery are alsoinsufficient.

(Birdem Med J 2011; 1(1): 26-29 )

Introduction:Obesity has become one of the most importantpubl ic heal th problems in the worldwide1.Bangladesh is not an exception. In all ages obesityis increasing. Due increase in prevalence of obesity,the complications and co morbidities of obesityalso increasing. Obesity means excess of body fat,overweight means weight more than Normal. Thebody mass index (BMI) is the accepted standardmeasure of overweight and obesity for children twoyears of age and older 2. Body mass index providesa guideline for weight in relation to height and isequal to the body weight divided by the heightsquared (Weight in Kg/Ht in M2). For Children andadolescent other measures of obesity, includingweight-for-height and measures of regional fat

distribution (eg, waist circumference and waist-to-hip ratio) may be considered. As children approachadulthood, the 85th and 95th percentile BMI forage and sex are approximately 25 and 30, thethresholds for overweight and obesity in adultsrespectively 3.

A growing consensus supports the following definitionsfor children between 2 and 20 years of age :

• Underweight — BMI <5th percentile for age andsex.

• Normal weight — BMI between the 5th and 85thpercentile for age and sex.

• Overweight — BMI between the 85th and 95thpercentile for age and sex.

• Obese — BMI >95th percentile for age and sex.

• Severe obesity — BMI >120 percent of the 95thpercentile values, OR a BMI >35. This correspondsto approximately the 99th percentile, or BMI z-score >2.334.

.

Prevalence and trends — The prevalence of obesityamong school-aged children (6 to 11 years) andadolescents (12 to 19 years) in the United Statesdramatically increased between 1976-1980 and 2007-2008 (from 6.5 to 19.6 percent in children, and from5.0 to 18.1 percent in adolescents)1,6. The prevalenceof obesity also doubled for preschool-aged children (2to 5 years) from 5 percent in 1976-1980 to 10.4 percentin 2007-2008. Among infants and toddlers, theprevalence of high weight for recumbent length was 9.5percent in 2007-2008. In an study in 2006 Bangladeshhas prevalence of School Children 27.7 % (6-9 years)7.

Etiology: It is very complex and multifactorial, stillnot well understood. The possible factors that maycontribute to the obesity are given bellow:

Environmental(increasing trends in glycemic index offoods, sugar-containing beverages, larger portion sizesfor prepared foods, fast food service, diminishing familypresence at meals, decreasing structured physicalactivity, shortened sleep duration, and changes inelements of the built environment (eg, availability ofsidewalks and playgrounds)

TelevisionVideo gamesSleepMedication

Virus: Preliminary evidence suggests the possibility thatobesity can be triggered or exacerbated by exposure toa virus. Adenovirus 36 increases body fat in severalanimal models 8.

Genetic: Genetic factors play a permissive role andinteract with environmental factors to produce obesity.Studies suggest that heritable factors are responsible for30 to 50 percent of the variation in adiposity, but mostof the genetic polymorphisms responsible have not yetbeen isolated. A few specific syndromes and single-genedefects which are linked to obesity in childhood havebeen identified

Metabolic programming: There is increasing evidenceto support a role for “metabolic programming” in thedevelopment of obesity. Metabolic programming refersto the concept that environmental and nutritionalinfluences during critical periods in development,particularly during gestation, can have permanent effectson an individual’s predisposition to obesity andmetabolic disease.

Endocrine diseases: Endocrine causes of obesity areidentified in less than 1 percent of children andadolescents with obesity.Nutrition during gestation and Early in life:Individuals born small for gestational age (SGA) or largefor gestational age (LGA) have higher rates of insulinresistance during childhood, even after controlling forobesity status 9. Similarly, many population-basedstudies confirm an association between birth-weight(reflecting fetal nutrition) and later diabetes, heartdisease, insulin resistance, and obesity 10.

Maternal endocrine factors: Younger age of the motherat menarche was an independent predictor of the child’sobesity status, after adjustment for the maternal obesitystatus as well as socioeconomic factors 11

Weight categories for adults and youth5

Category Adults (21+yrs) Youth (2-20 yrs) CDC, AAP, IOM, ES, IOTFUnderweight BMI <18.5 BMI <5th percentile for ageNormal weight BMI 18.5-24.9 BMI 5th to <85th percentileOverweight BMI 25-29.9 BMI 85th to <95th percentileObesity BMI > 30 BMI > 95th percentileClass III obesity (super obesity) BMI > 40 Not used*

AAP: American Academy of Pediatrics; IOM: Institute of Medicine; ES: Endocrine society; CDC: Centers for Disease Control;IOTF: International obesity task force.

* In children, a proposed definition of severe obesity is BMI >120 percent of the 95th percentile.

N.B. For Asians the cut-off values are considered -2.5 points in each category (Recommended by IDF):

BMI: > 25(23) , 30(27.5) and 40(37.5) : Within bracket Cut-Off value for Asians from Overweight to Morbid Obesity

27

Overview on Obesity - A Review Ashrafuzzaman SM

Complications and Co morbidities:Endocrine co morbidities of obesity include impairedglucose tolerance, diabetes mellitus, hyperandrogenism,and abnormalities in growth and puberty. Obesity inchildren and adolescents may be accompanied byaccelerated linear growth and bone age. Overweight hasbeen associated with early onset of sexual maturationin girls. However, this relationship is inconsistent 12. Incontrast, obesity in boys may be associated with delayedonset of sexual maturation 13. HTN Dyslipidemia OtherCV risk like MI ,ACS may be associated with Obesity.Obesity is also associated with spectrum of NAFLD14,15. Increased prevalence is noted with obesity of someGI or breast cancer .Pulmonary (Obstructive SleepApnea), Orthopedic(Osteoarthritis) and psychological(Depression) co morbidity also increases with obesity.Benign intracranial Hypertension may also occur.Dermatological problems (intertrigo, furunculosis, cystlipoma ) also may increase with increased weight.

Treatment: As many of our obese patients are Type 2diabetic I shall focus more in the management of Obesitywith type 2 diabetes. The challenges of weight loss indiabetes are some OAD gain weight (Sulfonylurea,TZD), some of them cannot do adequate exercise, somemay use antidepressants, some time Calorie restrictionmay cause Hypoglycemia. The role of Endocrinologistis from front line as a member of the team, starting withto find any secondary cause of Obesity. Weight loss formanagement as well as prevention of type 2 diabetes.Endocrinologists’ are the leader of medically directedweight loss programme. They will also take care of Preand Post operative Barriatric surgery patient . Startingfrom self directed weight loss patient will requirecommercial community based behavioral programmefor weight loss . Then comes medically managedstructured programme with low calorie diet andPharmacotherapy. Finally comes the question ofBarriatric Surgery and Long term medial management.Many recommendations are there more acceptable is tostart with 1200-1500 Kcal if < 250 Pounds and 1500-1800 Kcal if >250 Pounds. < 30 % Calorie should comefrom fat. Gradually building > 175 Mins /week physicalactivity should be done.

For pharmacotherapy available drugs are Orlistat ,Phentermine Diethylpropion . Sibutramine isWithdrawal from the market due to CV toxicity. Threenewer agents are before FDA but none is approved.

Orcaserin, Contrave (Buprepion+Naltrexon), Qnexa(Topiramate+ Phentermine) etc may have side-effect likecardiac, Congenital Malformation(Cleft plate etc). Othermolecules yet to be approved are Phendimetrazine,Benzephetamine, Mazindol etc.Tips for managingpatients with Orlistat is to discuss about mechanism ofaction and Bowel leak. Start 120 mg before each mealand reduce fat intake. Metamucil may reduce bowelsymptoms. Longer time gives more benefit but mayshows vitamin deficiency. So it’s better to useMultivitamin concomitantly. Patient can achieve 5-8 %weight loss in 4-6 months. It lowers waist circumference,LDL & Triglyceride and increases HDL. Phentermineis FDA approved for short term. It should be used withlow calorie diet and acts by appetite reduction. It maycause restlessness, tachycardia, insomnia increased BPetc. Weight loss may be 4-5 % in six months. But longterm weight maintenance is challenging. Some may needBarriatric surgery with BMI> 40 or >35 with Comorbidities. Type 2 Diabetes usually improved byMetabolic parameters and some may cures.

References:1. Ogden CL, Flegal KM, Carroll MD, Johnson CL. Prevalence

and trends in overweight among US children and adolescents,1999-2000. JAMA 2002; 288:1728.

2. Deurenberg P, Weststrate JA, Seidell JC. Body mass index asa measure of body fatness: age- and sex-specific predictionformulas. Br J Nutr 1991; 65:105.

3. Jolliffe D. Extent of overweight among US children andadolescents from 1971 to 2000. Int J Obes Relat Metab Disord2004; 28:4.

4. Flegal KM, Wei R, Ogden CL, et al. Characterizing extremevalues of body mass index-for-age by using the 2000 Centersfor Disease Control and Prevention growth charts. Am J ClinNutr 2009; 90:1314.

5. William J Klish. Definition; epidemiology; and etiology ofobesity in children and adolescents Up To Date. Vol 19.1

6. Ogden CL, Carroll MD, Curtin LR, et al. Prevalence of highbody mass index in US children and adolescents, 2007-2008.JAMA 2010; 303:242.

7. Mohsin FS,Tayya B,Baker A,Sarker S,Zabeen B,Begum T ,etal.Prevalence of obesity among affluent school children inDhaka. Mymensingh Med J. 2010 Oct;19(4):549-54.

8. Pasarica M, Shin AC, Yu M, et al. Human adenovirus 36induces adiposity, increases insulin sensitivity, and altershypothalamic monoamines in rats. Obesity (Silver Spring)2006; 14:1905.

9. Huxley R, Owen CG, Whincup PH, et al. Is birth weight arisk factor for ischemic heart disease in later life? Am J ClinNutr 2007; 85:1244.

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10. Barker DJ, Winter PD, Osmond C, et al. Weight in infancyand death from ischaemic heart disease. Lancet 1989; 2:577.

11. Ong KK, Northstone K, Wells JC, et al. Earlier mother’s ageat menarche predicts rapid infancy growth and childhoodobesity. PLoS Med 2007; 4:e132.

12. Laron Z. Is obesity associated with early sexual maturation?Pediatrics 2004; 113:171.

13. Wang Y. Is obesity associated with early sexual maturation?A comparison of the association in American boys versus girls.Pediatrics 2002; 110:903.

14. Speiser PW, Rudolf MC, Anhalt H, et al. Childhood obesity.J Clin Endocrinol Metab 2005; 90:1871.

15. Matteoni CA, Younossi ZM, Gramlich T, et al. Nonalcoholicfatty liver disease: a spectrum of clinical and pathologicalseverity. Gastroenterology 1999; 116:1413.

29

Overview on Obesity - A Review Ashrafuzzaman SM

Abstract:Extensively drug-resistant (XDR) tuberculosis is defined asdisease caused by Mycobacterium tuberculosis withresistance to at least isoniazid and rifampicin, anyfluoroquinolone, and at least one of three injectable second-line drugs (amikacin, capreomycin, or kanamycin). Thisdefinition in immensely valuable for more uniformsurveillance in varied international settings. The prevalenceof tuberculosis drug resistance has risen to the highest rateever recorded. Although the gold standard for drug-susceptibility testing has been the agar proportion method;due to it’s time consumption, more sensitive, specific andrapid diagnostic tests are required. It is difficult todifferentiate XDR tuberculosis from non-XDR tuberculosis

a. Ahmed JU, Rahim MA, Registrar, Department of InternalMedicine & Pulmonology, BIRDEM

b. Hossain D, Shaheen AKM, Assistant Professor, Department ofInternal Medicine & Pulmonology, BIRDEM

c. Musa AKM, Associate Professor, Department of InternalMedicine & Pulmonology, BIRDEM

d. Uddin KN, Professor, Department of Internal Medicine &Pulmonology, BIRDEM

Address of Correspondence: Dr. Jamal Uddin Ahmed, MBBS,FCPS (Medicine), Registrar, Department of Internal Medicine &Pulmonology, BIRDEM, Room No. 1537, 14th Floor, BIREDMHospital, Phone: 01671064214, Email: jmldollar@ gmail.comReceived: May 30, 2011 Accepted: June 30, 2011

Extensively Drug-Resistant (XDR) Tuberculosis: A ReviewAHMED JUa, MUSA AKMc, HOSSAIN Db, RAHIM MAa, SHAHEEN AKMb, UDDIN KNd

clinically, although the former is associated with greatermorbidity and mortality. The treatment of XDR tuberculosisshould include agents to which the organism is susceptible,and should continue for a minimum of 18—24 months.However, treatment continues to be limited in tuberculosis-endemic countries largely because of weaknesses in nationaltuberculosis health-care models. The ultimate strategy tocontrol drug-resistant tuberculosis is one that implementsa comprehensive approach incorporating innovation fromthe political, social, economic, and scientific realms.

Key words: Extensively drug-resistant (XDR) tuberculosis,Mycobacterium tuberculosis

(Birdem Med J 2011; 1(1): 30-36)

Introduction:Extensively drug-resistant (XDR) tuberculosis hasreceived substantial attention since the initial report ofan association of XDR-TB with extremely high mortalityin patients co-infected with M. tuberculosis and HIV ina rural area of South Africa in the year 2006.1 XDRstrains of M. tuberculosis have now been identified inat least 49 countries around the globe.2

From the advent of tuberculosis chemotherapy in the1940s, hints of resistance were evident. When SelmanWaksman accepted the Nobel Prize in 1952 for hislaboratory’s discovery of streptomycin, he claimed thedrug would lead the path to the elimination of “The GreatWhite Plague”.3, 4 Such statements were premature -strains of streptomycin-resistant Mycobacteriumtuberculosis were found within months of the drug’swidespread use.5 The classic 1948 British Medical

Research Council (BMRC) trial that investigated theefficacy of streptomycin monotherapy showed that mostpatients who were treated with the drug developedresistant strains.6

As the tuberculosis chemotherapy era evolved,increasing cases of drug resistance continued to occurmainly as a result of inadequate regimens and non-adherence to therapy. Researchers initially suspectedthat these resistant organisms had reduced fitness andthus could be classified as being less virulent.7, 8 Thisassumption was reversed in the 1990s with the rise inmultidrug-resistant (MDR) tuberculosis—ie, Mtuberculosis resistant to at least rifampicin plusisoniazid.9 Substantial attention was focused upon NewYork City (NY, USA) where a virulent and transmissiblestrain had spread among immunocompromisedpopulations.10, 11 Awareness of tuberculosis drugresistance was refocused with a study presented inAugust, 2006, at the XVI International AIDSConference in Toronto, Canada, which described anepidemic of XDR tuberculosis in a rural hospital inKwaZulu-Natal Province, South Africa.12

Definition of XDR tuberculosis:The term XDR tuberculosis was first developed by theUS Centers for Disease Control and Prevention (CDC)in March, 2005.13 It came to public focus in October,2005, at the 36th Union World Conference on LungHealth in Paris, France.14, 15 The original definition

.


was proposed in March, 2006, in CDC’s Morbidity andMortality Weekly Report, defining it as M tuberculosiswith resistance to at least isoniazid and rifampicin amongthe first-line tuberculosis drugs and resistance to at leastthree of the six main classes of second-line drugs(aminoglycosides, polypeptides, fluoroquinolones,thioamides, cycloserine, and aminosalicylic acid).16 Thisdefinition was subsequently revised in October, 2006,during the first meeting of the WHO Global XDR-TBTask Force. The classification, which continues to beaccepted, requires resistance of M tuberculosis to at leastisoniazid and rifampicin, any fluoroquinolone, and atleast one of three injectable second-line drugs(capreomycin, kanamycin or amikacin).17 The revisionwas made to facilitate reproducibility of drug-susceptibility testing and to focus attention on drugsaccessible in resource-limited settings. Moreover, theclassification has also been shown to have value in itsability to predict poorer outcomes.18

Epidemiology:In the face of rising cases of MDR tuberculosis, WHOand the International Union Against Tuberculosis andLung Diseases (IUATLD) established the Global Projecton Anti-tuberculosis Drug Resistance Surveillance inthe early 1990s.19 One of the most important outcomesof the project was the formation of an internationalquality assurance programme supervised bysupranational reference laboratories (SRLs).20 There arecurrently 26 SRLs that assist over 100 nationallaboratories in six continents by standardizing cultureand drug-susceptibility techniques. To determine the rateof XDR tuberculosis, CDC and WHO assessed 17,690M tuberculosis isolates collected by 25 SRLs from2000—2004.16 The study found that 20% of the isolatesmet MDR-tuberculosis criteria and 2% were classifiableas XDR tuberculosis. Population-based assessmentshowed that 4%, 15%, and 19% of XDR-tuberculosiscases were obtained from the USA, South Korea, andLatvia, respectively.16

In a rural hospital in Tugela Ferry, KwaZulu-NatalProvince, South Africa, 1539 individuals were testedfor tuberculosis from January, 2005, to March, 2006,542 had at least one culture that was positive for Mtuberculosis. Of these 542 patients with confirmedtuberculosis, 53 had XDR tuberculosis. 21 Factors thathave fuelled this South African epidemic includeineffective tuberculosis treatment in the context of a high

prevalence of HIV, lack of proper diagnostic testing,and poor infection control practices. 22, 23

The occurrence of MDR tuberculosis has reached itshighest level, with cases reported in a record 49countries. In South Africa, Tomsk Oblast (RussianFederation), and Estonia—all countries with a highburden of tuberculosis—5·7%, 6·6%, and 23·7% of allMDR-tuberculosis cases were XDR, respectively.

Figure: Countries with XDR-tuberculosis cases inDecember, 2006, and June, 2008

The USA, a country with a low tuberculosis prevalence,recently reclassified 1·9% of MDR-tuberculosis casesas XDR tuberculosis. 3

31

Extensively Drug-Resistant (XDR) Tuberculosis: A Review Ahmed JU et al

According to ICDDRB report, MDR surveillance iscontinuing at Shyamoli TB clinic, Dhaka, Bangladeshin collaboration with National TB control programme(NTP). In their observation, out of 657 isolates, multi-drug resistance was observed in 5.5% isolates. It wassignificantly higher among persons who receivedtuberculosis treatment for e” one month. (15.4% vs3.0%)

Mechanisms of resistance and fitness in XDRtuberculosis:The basis of tuberculosis drug resistance is the selectionof bacterial mutants with innate resistance tochemotherapy.24, 25 Epidemics of drug-resistant diseasecan be generated by three interrelated mechanisms: (1)conversion of wildtype pan-susceptible strains to drug-resistant strains during treatment (acquired resistance);(2) increasing development of resistance in drug-resistant strains because of inappropriate chemotherapy(amplified resistance); and (3) transmission of drug-resistant cases (transmitted resistance).26

Acquired and amplified drug resistances are the primarymeans by which tuberculosis drug-resistant strains havebeen generated. However, the key determinant that hasled to the exponential rise in XDR-tuberculosis cases islikely to have been transmitted resistance. The role oftransmitted resistance can be elucidated by noting theclonal strains evident in tuberculosis outbreaks. TheMDR-tuberculosis outbreak in the early 1990s in NewYork City, fuelled by the HIV epidemic and urbansettings, was primarily associated with a clinicallyvirulent strain of Beijing/W genotype. 27 Moreover, 39(85%) of 46 isolated XDR-tuberculosis strains in theTugela Ferry outbreak in South Africa belonged to theKwaZulu-Natal (KZN) genotypic family of strains.21

The transmission of drug-resistant tuberculosis largelydepends on the virulence of the mutated organism.28-30

Diagnostic tests for XDR tuberculosis:The gold standard for drug-susceptibility testing hasbeen the agar proportion method on Lowenstein-Jensenmedium and Middlebrook 7H11 agar.31 But, there areseveral disadvantages. The reproducibility and accuracyof drug-susceptibility testing for second-lineantituberculosis drugs remains questionable. Thetechnique can take up to 4—8 weeks for finalized results.Thus, the inability to detect drug resistance rapidly couldincrease the likelihood of an isolate developing

resistance through ineffective chemotherapy,32

likelihood of transmission of resistant strains and thepotential to produce clusters of secondary infections.33

Line-probe hybridization assays in conjunction withnucleic-acid amplification offer a promising route torapid identification of isoniazid and rifampicinresistance and are currently being studied by the WHOSRLs.35

Other molecular methods that could be used in thedetection of drug-resistant tuberculosis strains 34 includethe molecular beacon assay, luciferasemycobacteriophage strategy, dideoxy fingerprinting,direct sequencing of PCR products, and heteroduplexanalysis. These methods are generally described asproviding results rapidly and being highly sensitive.However, they are also labour intensive and costlycompared with the agar proportion method.

One particular form of testing that has received muchattention because of its potential application in resource-limited settings is the microscopic-observation drug-susceptibility (MODS) assay. A median time of only 7days (IQR 6—8 days) is needed for both diseaseidentification and drug-susceptibility testing.36

Clinical course of XDR tuberculosis:MDR tuberculosis is associated with a high mortalityin individuals with HIV or other immunosuppressiveconditions.37 The even poorer clinical outcomesassociated with XDR tuberculosis was initiallydocumented in the first CDC report of the disease in2006.13 During 1993—2002, patients with XDRtuberculosis were 64% more likely to die duringtreatment than patients with MDR tuberculosis.10, 13

An appreciation for the substantial morbidity andmortality associated with co-infection with XDRtuberculosis and HIV was heightened by the findings inKwaZulu-Natal.21 Fifty two (98%) of 53 patients withXDR tuberculosis died during the study period. Fortyfour (83%) of the 53 XDR-tuberculosis patients agreedto HIV testing and all tested positive for co-infection.The first published case reports of XDR tuberculosis inIndia noted that among 54 HIV-positive patients, 4(33%) of 12 diagnosed MDR tuberculosis cases werereclassified as XDR tuberculosis after drug-susceptibility testing.37 All the patients with XDRtuberculosis died within 2-6 months of diagnosis. Arecent study from South Korea described the clinical

32


outcomes of 43 HIV-uninfected patients with XDRtuberculosis.38 Treatment failure, defined as a lack ofculture conversion, was noted in 19 (44%) patients withXDR tuberculosis compared with 46 (27%) non-XDR-tuberculosis patients. Moreover, the mortality was 14%in those with XDR tuberculosis and 8% in those withMDR tuberculosis. A five-fold increase in the risk ofdeath in patients with XDR tuberculosis was seen in astudy done in Germany and Italy.39 XDR-tuberculosispatients required longer hospital stays and longertreatment durations, mainly because of clinicalcomplications (ie, sputum conversion).

Treatment of XDR tuberculosis:The principles of treatment for MDR-TB and for XDR-TB are the same. Treatment requires extensivechemotherapy for up to two years. Second-line drugs aremore toxic than the standard anti-TB regimen and cancause a range of serious side-effects including hepatitis,depression and hallucinations. Patients are oftenhospitalised for longer periods, in isolation. In addition,second-line drugs are extremely expensive compared withthe cost of drugs for standard TB treatment.

Strategies to treat drug-resistant tuberculosis can becategorized as either standardized or individualised.40

Standardized regimens are determined on representativedrug-resistance surveillance data of specific regions.Individualized regimens are more specific in that theytake into account previous antituberculosis treatments

and drug-susceptibility testing of the particular isolate.XDR tuberculosis requires individualized treatmentgiven the inability of standardized regimens toaccurately address both first-line and second-linetreatment resistance.41, 42 Individualized regimens arealso the only reliable means by which the amplificationof drug resistance may be avoided.43 Unfortunately, thedifficulty in performing drug-susceptibility testing inmany resource-limited countries has led to long-termuse of inadequate empiric regimens that could lead tofurther acquired resistance.44

The length of treatment for XDR tuberculosis has notbeen firmly established and is often based on individualclinical presentations.45 Key factors determiningtreatment duration include cost, drug availability,toxicity, bactericidal capacity, clinical improvement, andpatient adherence. 41 Typical MDR-tuberculosisregimens can consist of up to five drugs, and WHOrecommends their use for a minimum of 18 months oftreatment after culture conversion to negative 46, 47

Treatment of XDR tuberculosis should include agentsthat the strain of M tuberculosis has proven to besusceptible to. Any first-line agent to which the isolatehas shown to be susceptible, and any appropriatesecond-line drugs should be used to achieve a regimenwith a minimum of four to five effective medications.48

Treatment with this regimen should be continued for aminimum of 18—24 months.

Grouping of anti-tubercular drugs:

Grouping Drugs (Abbreviation)Group 1- First-line oral Isoniazid (H); Rifampicin (R); Ethambutol (E);antituberculosis agents Pyrazinamide (Z)Group 2 - Injectable Streptomycin (S); Kanamycin (Km); Amikacinantituberculosis agents (Am); Capreomycin (Cm); Viomycin (Vi)Group 3 Ciprofloxacin (Cfx); Ofloxacin (Ofx); LevofloxacinFluoroquinolones (Lfx); Moxifloxacin (Mfx);e Gatifloxacin (Gfx)°Group 4 -Oral bacteriostatic Ethionamide (Eto); Protionamide (Pto);second-line antituberculosis Cycloserine (Cs); Terizidone (Trd)°; Raminosalicylicagents acid (PAS); Thioacetazone (Th)hGroup 5 -Antituberculosis agents Clofazimine (Cfz); Amoxicillin/Clavulanate (Amx/ with unclearefficacy (not recom-mended by Clv); Clarithromycin (Clr); Linezolid (Lzd)WHO for routine usein MDR TI3 patients)

33


A possible treatment regimen is as follows- Thetreatment is divided into 2 phages: An initial phase of 6months, which is extended to 9 months if the sputumculture is positive at 4th month; to be followed by acontinuation phase of minimum 18 months. Sputumsmear examination should be conducted monthly duringinitial phase and quarterly during continuation phase.Sputum culture should be done at least at 4, 6, 12, 18,24th month.

A study in the Tomsk oblast of Russia, reported that 14out of 29 (48.3%) patients with XDR-TB successfullycompleted treatment.49 In Hong Kong the overalltreatment success rate of XDR tuberculosis comparedto MDR tuberculosis is 38% vs 63%.

Surgical treatment should also be considered if clinicallysignificant parenchymal lung disease is localized andhigh-grade resistance is present.50 Bilateral disease canalso be approached surgically but requires multiple,staged resections. Cure rates of MDR tuberculosis canbe greater than 90% with post-surgical chemotherapy.51

In view of the multiple drug cross-resistance patterns,new antituberculosis drugs with novel mechanisms ofaction are necessary if XDR tuberculosis is to besuccessfully treated. Future treatment also requiresdevelopment of drugs with minimal adverse events.Ideally, such agents would not have pharmacologicalinteractions with antiretroviral drugs commonly usedto treat HIV. Promising new compounds with highpotency against M tuberculosis include a diarylquinolinecompound (R207910, also called TMC207) and twonitroimidazole compounds (PA-824 and OPC-67683).52-54 Moreover, tuberculosis vaccines arecurrently being tested which might serve asimmunotherapeutic agents to accompany tuberculosisdrug regimens.55

Prevention:A multifaceted approach is advocated to address theXDR-tuberculosis epidemic. The WHO Global XDR-TB Task Force initially established comprehensiverecommendations in 2006 after recognizing the impactof the disease.56

Recommendations of the WHO Global Task Force onXDR-TB, Oct 9, 2006.

• Improve global tuberculosis control by enhancingthe testing and care of HIV-infected populations

• Develop programme management and treatmentguidelines of XDR tuberculosis in high and lowHIV prevalence settings

• Strengthen laboratory diagnostic services to ensurerapid and accurate drug-susceptibility testing

• Reducing transmission in health-care settings andother high-risk areas to improve infection control

• Increase disease surveillance efforts to accuratelyassess epidemiological trends

• Enhance educational advocacy and researchfunding to encourage development of new drugsand diagnostics

• Improve global tuberculosis control by enhancingthe testing and care of HIV-infected populations

Conclusion:The rising prevalence of XDR tuberculosis has broughta resurgence of interest in drug-resistant tuberculosis.Because of a confluence of several epidemiologicalfactors—such as the HIV pandemic and inadequate casedetection and treatment completion—virulent XDR-tuberculosis strains have been increasingly reportedworldwide. The development of highly sensitive andrapid laboratory tests for tuberculosis diagnosis alsoremains an area worthy of further investigative efforts.Immediate action can be implemented through the useof currently available strategies such as enhanced HIVdetection and treatment, improved tuberculosisdiagnostics (ie, MODS and line-probe hybridisationassays), effective infection control policies (ie, isolation,natural ventilation, and respiratory masks), andincreasing local advocacy/research efforts

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10. Frieden TR, Sterling T, Pablos-Mendez A, Kilburn JO,Cauthen GM, Dooley SW. The emergence of drug-resistanttuberculosis in New York City. N Engl J Med 1993; 328:521-26.

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13. Holtz TH. XDR-TB in South Africa: revised definition. PLoSMed 2007; 4: 161-64.

14. Shah NS, Wright A, Drobniewski F. Extreme drug resistancein tuberculosis (XDR-TB): global survey of supranationalreference laboratories for Mycobacterium tuberculosis withresistance to second-line drugs. Int J Tuberc Lung Dis 2005;9 (suppl 1): 77-83.

15. Holtz TH, Riektsina V, Zarovska E, Laserson KF, Wells CD,Leimane V. Extreme drug-resistance and treatment outcomeunder DOTS-Plus, Latvia, 2000—2002. Int J Tuberc LungDis 2005; 9 (suppl 1): 258-62.

16. CDC. Emergence of Mycobacterium tuberculosis withextensive resistance to second-line drugs-worldwide, 2000—2004. MMWR Morb Mortal Wkly Rep 2006; 55: 301-05.

17. CDC. Extensively drug-resistant tuberculosis—United States,1993—2006. MMWR Morb Mortal Wkly Rep 2007; 56: 250-53.

18. Raviglione MC, Smith IM. XDR tuberculosis—implicationsfor global health. N Engl J Med 2007; 356: 656-59.

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20. Laszlo A, Rahman M, Espinal M, Raviglione M. Qualityassurance program for drug susceptibility testing ofMycobacterium tuberculosis in the WHO/IUATLDSupranational Reference Laboratory Network: five rounds ofproficiency testing, 1994—1998. Int J Tuberc Lung Dis 2002;6: 748-56.

21. Gandhi NR, Moll A, Sturm AW. Extensively drug-resistanttuberculosis as a cause of death in patients co-infected withtuberculosis and HIV in a rural area of South Africa. Lancet2006; 368: 1575-80.

22. Raviglione MC, Uplekar MW. WHO’s new Stop TB Strategy.Lancet 2006; 367: 952-55.

23. Dowdy DW, Chaisson RE, Moulton LH, Dorman SE. Thepotential impact of enhanced diagnostic techniques fortuberculosis driven by HIV: a mathematic model. AIDS 2006;20: 751-62.

24. Gillespie SH. Evolution of drug resistance in Mycobacteriumtuberculosis: clinical and molecular perspective. AntimicrobAgents Chemother 2002; 46: 267-74.

25. Dorman SE, Chaisson RE. From magic bullets back to theMagic Mountain: the rise of extensively drug-resistanttuberculosis. Nat Med 2007; 13: 295-98.

26. Blower SM, Chou T. Modeling the emergence of the “hotzones”: tuberculosis and the amplification dynamics of drugresistance. Nat Med 2004; 10: 1111-16.

27. Frieden TR, Woodley CL, Crawford JT, Lew D, Dooley SM.The molecular epidemiology of tuberculosis in New York City:the importance of nosocomial transmission and laboratoryerror. Tuber Lung Dis 1996; 5: 407-13.

28. Blower SM, Gerberding JL. Understanding, predicting andcontrolling the emergence of drug-resistant tuberculosis: atheoretical framework. J Mol Med 1998; 76: 624-36.

29. Dye C, Williams BG. Criteria for the control of drug-resistanttuberculosis. Proc Natl Acad Sci USA 2000; 97: 8180-85.

30. Dye C, Espinal MA. Will tuberculosis become resistant to allantibiotics? Proc Biol Sci 2001; 268: 45-52.

31. Brodie D, Schuluger NW. The diagnosis of tuberculosis. ClinChest Med 2005; 26: 247-71.

32. Farmer P, Bayona J, Becerra M. The dilemma of MDR-TB inthe global era. Int J Tuberc Lung Dis 1998; 2: 869-76.

33. Espinal MA. Time to abandon the standard treatment regimenwith first-line drugs for failures of standard treatment. Int JTuberc Lung Dis 2003; 7: 607-08.

34. Lemus D, Martin A, Montoro E, Portaels F, Palomino JC.Rapid alternative methods for detection of rifampicinresistance in Mycobacterium tuberculosis. J AntimicrobChemother 2004; 51: 130-33.

35. WHO. Molecular line probe assays for rapid screening ofpatients at risk of multidrug-resistant tuberculosis (MDR-TB).Policy statement. Geneva: World Health Organization, 2008.

36. Moore DA, Evans CA, Gilman RH. Microscopic-observationdrug-susceptibility assay for the diagnosis of TB. N Eng JMed 2006; 355: 1539-50.

37. Singh S, Sankar MM, Gopinath K. High rate of extensivelydrug-resistant tuberculosis in Indian AIDS patients. AIDS2007; 21: 2345-47.

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38. Kim H, Hwang SS, Kim HJ. Impact of extensive drugresistance on treatment outcomes in non-HIV-infected patientswith multidrug-resistant tuberculosis. Clin Infect Dis 2007;45: 1290-95.

39. Migliori GB, Ortmann J, Girardi E. Extensively drug-resistanttuberculosis, Italy and Germany. Emerg Infect Dis 2007; 13:780-81.

40. Yew WW, Leung CC. Management of multidrug-resistanttuberculosis: Update 2007. Respirology 2008; 13: 21-46.

41. Dhingra VK, Rajpal S, Mittal A, Hanif M. Outcome of multi-drug resistant tuberculosis cases treated by individualizedregimens at a tertiary level clinic. Indian J Tuberc 2008; 55:15-21.

42. Mukherjee JS, Rich ML, Socci AR. Programmes andprinciples in treatment of multidrug-resistant tuberculosis.Lancet 2004; 363: 474-81.

43. Rich ML, Socci AR, Mitnick CD, Nardell EA. Representativedrug susceptibility patterns for guiding design of retreatmentregimens for MDR-TB. Int J Tuberc Lung Dis 2006; 10: 290-96.

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45. Iseman M. A clinician’s guide to tuberculosis. Philadelphia:Williams, and Wilkins, Lippincott, 2000.

46. Mitnick C, Bayona J, Palacios E. Community-based therapyfor multidrug-resistant tuberculosis in Lima, Peru. N Engl JMed 2003; 348: 119-28.

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48. Iseman MD, Madsen L, Goble M, Pomerantz M. Surgicalintervention in the treatment of pulmonary disease caused bydrug-resistant Mycobacterium tuberculosis. Am Rev RespirDis 1990; 141: 623-25.

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50. Pomerantz BJ, Cleveland JC, Olson HK, Pomerantz M.Pulmonary resection for multidrug-resistant tuberculosis. JThorac Cardiovasc Surg 2001; 121: 448-53.

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CASE REPORTS

A Case Report On Peripartum CardiomyopathySAFDER AMBa, MIR SAb, MIAH BMc, TAMANNA RJd, MOHIBULLAH AKMe

a. Dr. A.M.B. Safdar, MBBS, FCPS (Medicine), JuniorConsultant, Cardiology Department, BIRDEM

b. Dr. Ahmed Salam Mir, MBBS, Assistant Registrar, CardiologyDepartment, BIRDEM

c. Dr. Md. Babul Miah, MBBS, Senior Medical Officer,Cardiology department, BIRDEM

d. Dr. Rownak Jahan Tamanna, MBBS, MD (Cardiology),Assistant Professor, Cardiology Department, BIRDEM

e. Dr. A. K. M. Mohibullah, MBBS, MD (Cardiology), Professor& Head, Cardiology Department, BIRDEM

Address of Correspondence: Dr. A. M. B. Safdar, MBBS, FCPS(Medicine), Junior Consultant, Cardiology Department, BIRDEM

Received: May 25, 2011 Accepted: June 30, 2011

Abstract:A 32 year-old primigravida with gestational diabetes &subclinical hypothyroidism on replacement therapy and noprevious cardiac problem, developed features of shock fewhours after elective caesarian section at term, in the absenceof any chest pain or palpitation. Following resuscitationshe developed features of acute left ventricular failure. ECGshowed nonspecific T changes, chest x-ray revealed enlargedcardiac shadow with pulmonary congestion, arterial bloodgas analysis was normal with supplemental oxygen. Serialcardiac markers were normal & serum d-Dimer wasnegative. Echocardiogram revealed dilatation of all cardiac

chambers with global hypokinesia & severe left ventricular(LV) systolic dysfunction. She was diagnosed as a case ofperipartum cardiomyopathy and treated conservatively withmedications. Her condition improved dramatically & shebecame symptom-free by the 5th post-operative day (POD)and subsequently discharged on 9th POD. Follow-upechocardiogram after 6 weeks revealed regional wall motionabnormality, normal chamber dimensions and fair LVsystolic function.

Key words: cardiomyopathy,Pericardium

(Birdem Med J 2011; 1(1): 37-42)

Introduction:Peripartum cardiomyopathy(PPCM) is a rare butpotentially fatal disease which presents with symptomsof heart failure primarily due to left ventricular (LV)systolic dysfunction presenting in the last part (mean32-38 weeks) of pregnancy and up to 5-6 months postdelivery1-5. It is clinically very similar to other forms ofnon-ischemic dilated cardiomyopathy except for itsunique relationship with pregnancy1-2 and the higherlikelihood for full recovery in almost half of the cases3.However it can still result in chronic disability andultimately death in relatively young women in theirreproductive years. This emphasizes the need for athorough understanding of PPCM, so that the earlydiagnosis & institution of effective multi-disciplinarymanagement can influence patient’s long term prognosis.

Case ReportMrs. X, a 32 year-old primigravida from old town,Dhaka, with history of amenorrhoea for 37+2 weeks,got admitted in BIRDEM Hospital for elective lowersegment caesarian section (LSCS). Her pregnancyperiod was uneventful. She had regular antenatal check-up & was properly immunized as per schedule. She wasdiagnosed of having gestational diabetes mellitus(GDM) & subclinical hypothyroidism in the early partof pregnancy on the basis of OGTT & thyroid functiontests. There was no past history of any major illness.She was getting levothyroxine, iron, folic acid andcalcium supplements. Her blood sugar was wellcontrolled with dietary & nutritional measures alone.She was a homemaker with sedentary life style & camefrom an upper middle-class family. Both her parentswere alive & suffering from diabetes. Prior to conceptionher menstrual history was normal.

At the time of admission, she was mildly anemic withnormal vital parameters. There was no edema orcyanosis. Bed side urine test was normal. Abdomen wasdistended due to gravid uterus with fundal heightcorresponding 35 weeks of gestation; fetal movementwas present. Fetal heart sounds were audible. Othersystemic examinations were unremarkable.Investigations done prior to operation revealed

.


She was resuscitated with oxygen, IV saline,noradrenaline, blood transfusion & shifted to ICU. InICU, although blood pressure gradually became normal,she later on developed breathlessness along withtachypnea, diminished breath sounds in lower chest andbi-basal crepitations. She was diagnosed provisionallyas a case of cardiogenic shock, acute left ventricularfailure, status post (S/P) LSCS, GDM & subclinicalhypothyroidism. A differential diagnosis of amnioticfluid embolism was kept in the mind.Investigations in ICU revealed nonspecific T changesin follow-up ECG, normal arterial blood gas with oxygensaturation >90% with supplemental O2 @ 4l/min viafacemask. Serum D-dimer was negative. Serial serumtroponins I levels and other cardiac markers werenormal. Initial portable chest x-ray revealed pulmonary

hemoglobin 8.9 gm% with normal total and differentialcount of WBC. Both fasting & post-prandial bloodglucose levels were normal as well as total protein,serum albumin levels and renal function tests. SerumTSH was within normal range & USG revealed singlelive fetus with gestational age corresponding to 34weeks.

She underwent LSCS two days following admissionunder spinal anesthesia. Bleeding during LSCS wasaverage. Three hours later, in the post-operative ward,she suddenly developed shock with cold clammyextremities, feeble pulse & non-recordable BP. Therewas no associated chest pain or palpitation. ECGrevealed sinus tachycardia with nonspecific T changes.Abdomen was soft with contracted uterus, dressing wasdry. Per vaginal bleeding was average.

Fig.-1:

congestion with probable enlarged cardiac shadow.Follow-up x-ray chest in upright posture revealedenlarged cardiac shadow with bilateral pulmonarycongestion, more marked on the left.

Initial bed side 2-D, m-mode echocardiogram revealedglobal hypokinesia with dilatation of all 4 chambers &severe LV systolic dysfunction (EF-30%). Pulmonarytrunk including the main branches was normal indimension. Follow-up echocardiogram with colordoppler study on the next day revealed globalhypokinesia, dilated left ventricle, severe LV systolicdysfunction (EF-30%), grade ¼ PR, with trivial MR.

38

A Case Report On Peripartum Cardiomyopathy Safder AMB et al

Fig.-2:

Fig.-3:

Her general conditions improved on conservativemanagement with oxygen supplementation, frusemide(initially parenteral), digoxin, spironolactone,trimetazidine, fluid and salt restriction. The patientgradually improved and in the fifth post-operative daybecame symptom-free. She was finally diagnosed as acase of – Cardiogenic shock & acute left ventricularfailure due to peripartum cardiomyopathy (PPCM),Status post LSCS, GDM & subclinical Hypothyroidism.

She was discharged on the 9th post-operative day withoral frusemide, spironolactone, losartan potassium,digoxin, calcium, iron, folic acid & vitamin supplements.She was properly counseled about contraception, timefor future pregnancy & risk of recurrence of PPCM &was asked to come for follow-up after 6 weeks. Follow-up echocardiogram at that time revealed mild antero-septal wall hypokinesia with fair LV systolic function(EF-50%) and normal dimension of cardiac chambers.

DiscussionPeripartum cardiomyopathy (PPCM) is an infrequentbut critical disorder in which a destabilized heart isdiagnosed within the last months of pregnancy or earlypuerperium and often complicating obstetrics as wellas anesthetic management. Usually, it occurs early in

the postpartum period, with about 45% in the first weekand 75% within the first month1. It is largely a diagnosisof exclusion. Other causes of heart disease must be ruledout first before making a diagnosis of PPCM. It is thendiagnosed in previously healthy women presenting withsymptoms of heart failure and evidence of decreasedLV systolic function from late pregnancy to earlypuerperium.

A relationship between pregnancy and dilatedcardiomyopathy was first noted in 1870 when Virchowand Porak first reported autopsy evidence of myocardialdegeneration in patients who died in the puerperium6.In 1937 Gouley et al7 described the clinical andpathologic features of seven pregnant patients who hadsevere and often fatal heart failure. The incidence ofPPCM was one case per 1374 live births in an Indianstudy8. PPCM occurs in 1 in 3,000 to 1 in 4,000pregnancies in the United States9. In South Africa, thereported incidence is higher (1: 1,000 live births) 10. Amuch higher incidence of 1:300 live births has beenreported from Haiti11 and an extremely high rate of 1%has been described in Nigeria12. Higher rates indeveloping countries may be due to variations in localcultural as well as puerperal practices, ecological factors,environmental influence, diagnostic criteria andreporting pattern used13.

Risk factors favoring development and recurrence ofPPCM include the following: 1) advanced maternal age(>30 years), 2) multiparity, 3) Afro-American race, 4)twin pregnancy, 5) pre-eclampsia, 6) gestationalhypertension, 7) chronic hypertension, 8) obesity, 9)prolonged use of tocolytics (â2 stimulants e.g.terbutaline). PPCM is still regarded as a disease ofunknown etiology. However there are several hypotheseslike selenium deficiency, inflammatory pathologyleading to myocarditis (viral infection or auto-immuneresponse to released fetal antigen). Recent evidence inan animal (mice) model suggests a role for a 16 kDaprolactin derivative produced by proteolytic cleavageof prolactin secondary to unbalanced oxidative stresspresent during late pregnancy and early puerperium14-

15. In certain cultures where the incidence of PPCM ishigh, certain cultural practices performed during thepuerperium such as consuming lake salt or rock salt(known as ‘kanwa’ which has a particularly high sodiumcontent) to promote the flow of breast milk and theheating of the body by sitting on a clay bed with a fire

Fig.-4:

39


beneath to keep warm (a belief felt to ward off infection)have both been suggested as contributory factors in itsdevelopment as well16-17.

Presentation of PPCM is similar to that of patientspresenting with Left ventricular failure due to othercauses. The clinical presentation is most often dyspnea(90%), tachycardia (62%), and edema (60%)18. Somecase studies also cite unusual presentations, includingmultiple thromboembolic events19 and acute hypoxia20.The classical symptoms of heart failure can be masked- especially in obese women. Onset occurs one monthprior to delivery and up to five months after delivery.However, the majority of women present postpartum.Possible complications include thromboembolism,arrhythmias, organ failure, obstetric & perinatalcomplications (premature delivery, small for date andlow birth weight babies, intrauterine growth retardationand fetal deaths). PPCM is largely a diagnosis ofexclusion. Other causes of heart disease such ascongenital heart disease or acquired conditions that is,myocardial infarction causing LV dysfunction,pulmonary hypertension or valvular heart disease mustbe ruled out first before making a diagnosis of PPCM.The diagnosis of PPCM poses many challenges, as manywomen in the last month of normal pregnancyexperience similar symptoms to that of early heartfailure, such as shortness of breath on exertion, nocturnaldyspnea and cough, fatigue, palpitations and pedaledema, making differentiation difficult.

Original diagnostic criteria for PPCM were developedby Demakis et al in 19715. They did not includeechocardiographic findings because echocardiographywas not readily available at that time. In 1999,echocardiographic criteria21 were incorporated in a newdefinition. Diagnostic criteria for PPCM include:

• Onset of heart failure in last month of pregnancy to5-6 months post partum.

• Without any other demonstrable cause of heartfailure.

• Absence of any heart disease before pregnancy.• Echocardiography criteria to include

o An ejection fraction <45%, fractional shortening<30% or both, and

o End-diastolic dimension (LVIDd) >2.7 cm/m2body surface area.

The most common and confusing differential diagnosisof PPCM is Idiopathic Dilated Cardiomyopathy(IDCM). Though PPCM is identical to IDCM in severalways, most researchers now accept PPCM as a distinctentity for the following reasons 22-23:

• PPCM occurs at a younger age and is generallyassociated with better prognosis.

• The incidence of PPCM is higher than IDCM.

• PPCM occurs mostly postpartum (78 - 93%),whereas IDCM usually manifests by the secondtrimester.

• PPCM exclusively affects pregnant women andrecurrent PPCM is seen to manifest again in theperipartum period.

• Varying types of hemodynamic patterns are seenin PPCM compared to IDCM.

• Unique sets of antigen and antibodies againstmyocardium are seen in PPCM compared to IDCMpatients.

• The incidence of myocarditis is higher in PPCMthan in IDCM.

• Heart size returns to normal after delivery in agreater percentage of PPCM patients compared toIDCM.

• Contrary to IDCM, PPCM may lead to rapidworsening of clinical condition.

All patients should have routine blood tests to excludeanemia, electrolyte disturbance, and kidney, liver andthyroid dysfunction, inflammatory markers, a septicscreen and viral serology. Cardiac markers such astroponins and CK-MB are not helpful alone in reachinga diagnosis. . Radiological signs of heart failure such ascardiomegaly, pulmonary congestion and pleuraleffusion may be found on chest x-ray. ECG may showsinus tachycardia or other arrhythmias such as atrialfibrillation, atrial flutter, ventricular tachycardia,intraventricular block pattern, nonspecific ST-T changesand LV hypertrophy pattern. Moreover, the ECG maydemonstrate no significant changes24.Echocardiography confirms ventricular failure withincreased left ventricular end-diastolic dimensions anddecreased ejection fraction (LVEF) and differentiatesPPCM from other causes of heart failure, such as valvedisease, etc. Invasive evaluation, such as cardiac

40


catheterization or endomyocardial biopsy, is oftenunnecessary for diagnosis or treatment. Coronaryangiography is not routinely indicated, as coronaryarteries are usually normal in PPCM. The role ofendomyocardial biopsy in the diagnosis of PPCM iscontroversial. It is not routinely recommended, becauseof its limited availability, higher complication rate &low specificity. The pathology identified onendomyocardial biopsy is often nonspecific.

The treatment for peripartum cardiomyopathy is similarto that for other nonischemic dilated cardiomyopathies;however, consideration must also be given for the fetus.Non-pharmacological therapy Includes low sodium diet(<4 gm/day), fluid restriction (<2 L/day) and modestdaily exercise (i.e., walking).

The cornerstone of optimal oral pharmacologic therapyfor cardiomyopathy begins with afterload reduction withuse of angiotensin converting enzyme inhibitors (ACEI)or angiotensin II receptor blockers (ARB).Unfortunately, pregnancy is a contraindication to theuse of ACEI and likely the ARB as well. In thiscircumstance, the combination of hydralazine andnitroglycerin or amlodipine can be safely used inpregnancy to provide needed afterload reduction.Preload reduction can be accomplished with diureticsand low-dose oral nitrates. In pregnancy diuretics mustbe used with caution as to avoid dehydration. Oralinotropic therapy is provided by digoxin. Furthermore,the deleterious effects of excessive sympathetic nervoussystem activation may be blocked and reversed withlow-dose â-blockers. In the treatment of acutely ill orhighly symptomatic patients, intravenous preload andafterload reducing agents (nitroprusside, nitroglycerin)or inotropic agents (dobutamine, dopamine, milrinone)should be considered. Intravenous nitroglycerin,dobutamine, dopamine, and milrinone can be used inpregnant patients if medically necessary. Invasivehemodynamic monitoring is often used to guide the acutephase of this therapy. As there is a high incidence inthromboembolism in this population, anticoagulationwith either heparin or warfarin should be stronglyconsidered. However warfarin should be avoided duringpregnancy as it can cause birth defects.

Cardiac transplantation offers a final yet very viablealternative for patients with peripartum cardiomyopathywho do not improve or who continue to deteriorate with

medical management. Due to limited availability ofdonor hearts, it may become necessary to support thepatient with an intra aortic balloon pump (IABP) orventricular assist device (VAD) as a bridge to transplant.

No specific treatment has been identified to significantlyalter the morbidity of PPCM. Small trials have reportedbenefits of pentoxifylline, intravenous immunoglobulin,and bromocriptine. Pentoxifylline decreased TNFálevels and increased EF in patients with PPCM25.Intravenous immunoglobulin (IVIG) improved EFcompared to standard treatment in one smallretrospective study of 6 cases compared to 11 controls26.Case reports of recovery from PPCM withbromocriptine treatment have been described27-29.

There are several possible outcomes in PPCM. Somewomen remain stable for long periods, while others getworse slowly. Others get worse very quickly and maybe candidates for a heart transplant. The death rate maybe as high as 25-50%. The prognosis is poor in patientswith persistent cardiomyopathy. Subsequent pregnanciesare often associated with recurrence of left ventricularsystolic dysfunction. The risk of recurrence in womenwho have completely recovered LV function after theirprevious pregnancy is lower than previously believed.Ideally, every woman planning a future pregnancyshould have echocardiography performed, and, even ifit is normal, they ought to have dobutamine stressechocardiography as well. Women with a full recoveryof LV function on both echocardiography anddobutamine stress test can be advised that the risks ofmajor complications are relatively low. Women withpersistent LV dysfunction are advised not to pursuefurther pregnancies.

ConclusionPPCM is an uncommon but potentially life threateningcardiac failure of undetermined etiology taking placein late pregnancy or early on in puerperium.Thromboembolism and cardiac arrhythmia are commoncomplications. Diagnosis of PPCM should essentiallyinclude echocardiographic substantiation of leftventricular dysfunction. Treatment is generally the sameas for heart failure with left ventricular systolicdysfunction with some possible exceptions because ofthe risks of certain drugs to the unborn child. In resistantcases, management with immunosuppressive drugs,immunoglobulin and pentoxifylline can be thought of.

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For those who do not improve with conventional medicaltherapy, have persistent cardiomegaly, or have moderateto severe mitral regurgitation, referral to a cardiactransplant center should be considered. In the presenceof persistent heart failure, further pregnancy is notrecommended. If inevitable, subsequent pregnancy inpatients with enhanced cardiac function should bemanaged in a multidisciplinary unit. Prognosis is linkedto recovery of ventricular dysfunction.

References1. Elkayam U, Akhter MW, Singh H. Pregnancy-associated

cardiomyopathy: clinical characteristics and a comparisonbetween early and late presentation. Circulation2005;111:2050-55.

2. Cunningham FG, Pritchard JA, Hankins GD. Peripartum heartfailure: idiopathic cardiomyopathy or compoundingcardiovascular events? Obstet Gynecol 1986;67:157-68.

3. Demakis JG, Rahimtoola SH, Sutton GC. Natural course ofperipartum cardiomyopathy. Circulation. 1971;44:1053-61.

4. Demakis JG, Rahimtoola SH. Peripartum cardiomyopathy.Circulation 1971;44:964-8.

5. Homans DC. Peripartum cardiomyopathy. N Engl J Med1985;312:1432-37.

6. Sakakibara S, Sekiguchi M, Konno S. Idiopathic postpartumcardiomyopathy, report of a case with special references toits ultra-structural changes in the myocardium as studied byendomyocardial biopsy. Heart 1970;80:385-95.

7. Gouley B, McMillan T, Bellet S. Idiopathic myocardialdegeneration associated with pregnancy and especially thepuerperium. Am J Med Sci 1937;19:185-99.

8. Pandit V, Shetty S, Kumar A. Incidence and outcome ofperipartum cardiomyopathy from a tertiary hospital in SouthIndia. Trop Doct 2009;39(3):168-69.

9. May HV. Peripartum cardiomyopathy: clinical and therapeuticcharacteristics. J La State Med Soc 1991;143(5):45-48.

10. Desai D, Moodley J, Naidoo D. Peripartum cardiomyopathy:experiences at King Edward VIII Hospital, Durban, SouthAfrica and a review of the literature. Trop Doct 1995;25:118-23.

11. Fett JD, Christie LG, Carraway RD, et al. Five-year prospectivestudy of the incidence and prognosis of peripartumcardiomyopathy at a single institution. Mayo Clin Proc2005;80:1602-06.

12. Sanderson JE, Adesanya CO, Anjorin F. Postpartum cardiacfailure- heart failure due to volume overload? Am Heart J1979;97:613-21.

13. Veille JC, Zaccaro D. Peripartum cardiomyopathy: summaryof an international survey on peripartum cardiomyopathy. AmJ Obstet Gynecol 1999;181(2):315-19.

14. Reuwer AQ, Reuwer PJ, van der Post JA. Prolactinfragmentation by trophoblastic matrix metalloproteinase as apossible contributor to peripartum cardiomyopathy and pre-eclampsia. Med Hypotheses 2009 Sep 10. [Epub ahead of print].

15. Hilfiker-Kleiner D, Silva K, Drexeler H. Peripartumcardiomyopathy: Recent insight into its pathophysiology.Trends Cardiovasc Med 2008;18:173-79.

16. Trevitt L. Attitudes and customs in child birth among Hausawomen in Zaria City. Savanna 1973;2:223-26.

17. Davidson NM, Trevitt L, Parry EH. Peripartum cardiac failurean explanation for the observed geographic distribution inNigeria. Bull World Health Organ 1974;51:203-08.

18. Chapa JB, Heiberger HB, Weinert L. Prognostic value ofechocardiography in peripartum cardiomyopathy. ObstetGynecol 2005;105(6):1303-08.

19. Carlson KM, Browning JE, Eggleston MK. eripartumcardiomyopathy presenting as lower extremity arterialthromboembolism. A case report. J Rep Med Obstet Gynecol2000;45(4):351-53.

20. Cole WC, Mehta JB, Roy TM. “Peripartum cardiomyopathy:echocardiogram to predict prognosis,” Ten Med2001;94(4):135-38.

21. Hibbard JU, Lindheimer M, Lang RM. A modified definitionfor peripartum cardiomyopathy and prognosis based onechocardiography. Obstet Gynecol 1999;94:311–16.

22. Pearson GD, Veille JC, Rahimtoola S. Peripartumcardiomyopathy: National Heart, Lung and Blood Instituteand Office of rare Diseases. (National Institute of Heart).Workshop recommendations and review. JAMA2000;283:1183-88.

23. Avila WS, de Carvalho MEC, Tschaen CK. Pregnancy andperipartum cardiomyopathy. A comparative and prospectivestudy. Arq Bras Cardiol 2002;79:484-93.

24. Witlin AG, Mable WC, Sibai BM. Peripartumcardiomyopathy: an ominous diagnosis. Am J Obstet Gynaecol1997;176:182-88.

25. Sliwa K, Woodiwiss A, Candy G. Effects of pentoxifylline oncytokine profiles and left ventricular performance in patientswith decompensated congestive heart failure secondary toidiopathic dilated cardiomyopathy. Am J Cardiol2002;90(10):1118-22.

26. Bozkurt B, Villaneuva FS, Holubkov R. Intravenous immuneglobulin in the therapy of peripartum cardiomyopathy. J AmColl Cardiol 1999;34(1):177-80.

27. De Jong JS, Rietveld K, Van Lochem LT. Rapid left ventricularrecovery after carbergoline treatment in a patient withperipartum cardiomyopathy. Eur J Heart Fail 2009;11:220-22.

28. Habedank D, Kuhenle Y, Elgeti T. Recovery from peripartumcardiomyopathy after treatment with bromocriptine. Eur JHeart Fail 2008;10:1149-51.

29. Hilfiker-Kleiner D, Meyer GP, Schieffer E. Recovery frompostpartum cardiomyopathy in 2 patients by blockingprolactin release with bromcriptine. J Am Coll Cardiol 2007;50:2354.

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AbstractA three month old exclusively breast fed, immunized, malebaby having presented with high continued fever for 5 days.There was no clue to any infection. It was treated as viralfever. As soon as Kawasaki Disease was suspected, on about12th day of fever, appropriate treatment was started. Thebaby developed multiple coronary artery aneurysms, largepericardial effusion and a rare complication, right brachialartery thrombosis resulting in pulselessness andsubsequently dry gangrene of right hand and forearm.

Effusion was tapped .The baby died following amputationof the limb - probably of a major adverse cardiac event.

Early diagnosis and appropriate treatment according toguidelines on time are essential for saving life of childrenwith Kawasaki disease. Lack of awareness about the diseaseis a problem in our country.

Key word: Kawasaki Disease; coronary aneurysm;peripheral artery thrombosis, dry gangrene

(Birdem Med J 2011; 1(1): 43-45)

Kawasaki Disease - A Rare Presentation in a BangladeshiInfant- A Case Report

AKHTER Sa, ISLAM SMSb, ISLAM Na, BAKI Aa, AHMED Aa, NAHAR Ja, ZABEEN Ba, MOHSEN Fa,NAHAR Na

a. Akhter S, Islam N, Baki A, Ahmed A, Nahar J, Zabeen B, Mohsen F, Nahar N , Department of Pediatrics, BIRDEMGeneral Hospital and Ibrahim Medical College.

b. Islam SMS, Ibrahim Cardiac Hospital and Research Institute(ICHRI).

Address of Correspondence: Akhter S, Department of Pediatrics,BIRDEM General Hospital and Ibrahim Medical College.Received: May 26, 2011 Accepted: June 30, 2011

IntroductionKawasaki disease (KD) is an acute, self limitingvasculitis of unknown origin. The incidence is increasingworldwide 1,2. It commonly affects children less than 5years, but it is rarely seen in infants of less than 3 monthsage2. KD is characterized by high continued fever of 5days or longer duration, bilateral non-exudativeconjunctivitis, erythema of lips and mouth, changes inextremities, polymorphous exanthema and cervicallymph-adenopathy. Coronary arterial ectasia oraneurisms occur in about 20% of untreated patients andmay cause ischemic heart disease or sudden death in2%3, 4, 5. Although it can occur among all age groups,the under five children have the highest incidence ofKawasaki disease; little is known about its incidence orprevalence in Bangladeshi children. Diagnosis ofKawasaki disease is challenging in young infantsbecause of its rarity, as well as for its frequentlyincomplete presentations6. Coronary complication is acommon association of KD, and it also complicatesincomplete KD7,8. As in many other developingcountries, Kawasaki disease is not very commonly

reported in Bangladesh6. Because of under reporting ofthis disease, KD often does not come as a differentialdiagnosis in our physician’s mind. Milder cases arereadily missed.

The aim of this case report is to create awareness thatKawasaki disease is not absent in this country, and maybe, its incidence is rising as most investigators believeit is related to, if not caused by an infectious disease. This disease should be kept in mind as a differentialdiagnosis in otherwise unexplained high continued feverin infants and young children, especially those aged less than 5 years, as early diagnosis and treatment ofsuch cases may be life saving.

Case ReportA three month, appropriately immunized exclusivelybreastfed male baby with dark complexion presentedwith history of 5 days fever, which was high grade andcontinued, maximum recorded temperature was >1050F.His palms, soles, lips and tongue were red withblanching rash over trunk and limbs; conjunctivae wereinjected without any discharge. There was no historyof contact with any febrile patient. He had been takingbreast milk well and bowels and bladder movednormally. Complete blood count (CBC) and blood forculture & sensitivity were sent. Blood reports excludedbacterial cause of fever. Though no focus of infectionwas found, a third generation oral cephalosporin wasstarted for a benefit of doubt. About the 5th day of fever,the baby developed loose stools, which was doubted to

.


On examination, his right fore-arm was cool, radial andbrachial pulses were absent, and there was an induratedarea, about 3 cms x 2 cms in size, over distal third offore-arm (Figure 1). The baby was admitted in PediatricGeneral Ward of BIRDEM. CBC was sent; it showedthrombocytosis (4, 54,000/cu mm). Aspirin andintravenous immunoglobulin (IVIG) infusion wasstarted within first 24 hours of admission.

Bluish discoloration rapidly spread to involve otherfingers, and extended proximally towards elbow. All hisfour limbs on and off became cold, with simultaneouslysweating of fore-head; pulses were rapid and of lowvolume, and heart sounds were muffled. IV Heparin wasstarted; streptokinase was added. In the mean timeechocardiography was done which showed multiplelarge and medium sized aneurysms involving both rightand left coronary arteries and major branches, includinga giant one in the right coronary (Figure 2).

This baby had pancarditis -there was dilatation of LV,stretching of mitral valve-annulus & moderate mitralregurgitation, and huge pericardial effusion in whichthe heart was swinging (Figure 2). Heparin wastemporarily stopped with a plan for pericar-diocentesis.

The baby was immediately transferred to a Cardiac ICUof the city where about 300ml of pericardial fluid wasdrained by a senior pediatric cardiologist. Close monitoringand treatment were continued. Platelet count progressivelywent up to 8,00,000/ mm3 in third week. PT & APTT werenormal all along. IV Urokinase, Warfarin, MethylPrednisolone were administered at different times to containand prevent further thromboembolic complication.Ischemic changes initially progressed proximally in rightforearm and then stopped leaving a well circumscribedmargine distal to elbow. In several days the right hand andfore-arm became dry and gangrenous With(Figure 3).His consultant vascular surgeon removed the ischemiclimb. Following amputation of the limb, the baby diedsuddenly on first post operative day- most probably ofa major adverse cardiac event.

be side effect of the oral antibiotic. The fever subsidedafter 12 days. In the mean time, he developed a coolright forearm, increased sweating of forehead andbecame restless. That was confused with effect of toohot weather. In a few days it was followed by blue-discoloration of the tip of the thumb (Figure 1).

Fig.-1: Bluish discoloration of tip of fingers and rightfore-arm

Fig.- 2: Coronary arterial huge aneurism andpericardial effusion

Fig.-3: Dry gangrene in right forearm and hand

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DiscussionThe baby had his fever started before he completed 3months of age. Onset of KD before this age is rare9.Incomplete presentation often occurs in young infants1,5. Our case, rather, had a typical presentation. The likelyreason for delayed diagnosis was that most of thephysicians in Bangladesh are more concerned withinfectious diseases, and non-contagious illnesses strikeour mind rather late. As a result an antibiotic was readilyprescribed. Though not frequently reported, KD is notabsent in our country6. Blue discoloration of fingertipsmade the physician alert, which is a rare complicationof the disease. Our case had thrombocytosis, 454,000/cu mm in the second week, and it went up to 800,000/cu mm in the third week. This progressivethrombocytosis is also supported by previous study10.Fever of 5-day or longer duration without any foci andan elevated platelet counts along with relevant clinicalfeatures should be treated as a KD. Echo-cardiogramshowed multiple aneurysmal dilatations of the coronaryarteries, including a giant lesion in the right one. This isthe hall mark in diagnosis of KD6. Also there werefeatures of cardiac dilatation and regurgitation of mitralvalves, and large pericardial effusion- all suggestedpancarditis. The baby had developed extensive drygangrene of right fore-arm. This is a very rarecomplication; rather a high predictor of mortality3, 5.He was given IVIG within 2 weeks of onset of disease,along with aspirin and methyl prednisolon. But hisplatelet count did not come down. The baby was a poorresponder to IVIG. Both these conditions are associatedwith worse prognostic signs. He also had a largeperipheral artery thrombosis. He was administered withthrombolytics too. The poor response to thrombolyticsand not performing a thrombectomy resulted in graveishchemic damage to the right forelimb, the drygangrene. The sympathetic block to prevent arterialspasm in right upper limb could not be undertaken. Allthese measures needed a skill that we clearly lacked.The cause of death of this baby was not identifiedbecause autopsy of dead bodies is not a routine practicein our country. The baby died on the 1st post operativeday. Sudden cardiac death is not un-common in KD11,

12. But in this case exposure to an extra trauma – theamputation, on the background of rather generalizedvasculitis and multiple coronary aneurysms likely hadcaused myocardial infarction due to acute thrombosisand /or rupture of aneurysms.

ConclusionClinical diagnosis of KD in infancy requires high indexof suspicion. Early diagnosis and treatment are importantto prevent coronary artery aneurysms which aresignificantly more frequent in patients with delayeddiagnosis.Physicians should keep Kawasaki disease as adifferential diagnosis in presence of un-explained highcontinued fever of 5 days or longer duration, and watchfor other ‘major clinical features’.

References1. Karyian SM, dindar A, Gurakan B. An Evaluation of Children

with Kawasaki Disease in Istanbul : a Retrospective Follow-up Study. Clinics ( Sao Paulo ). 2010: 65(12): 1261-65

2. Nakamura Y, Yashiro M, Uehara R, Sadakane A, Chihara I,Aoyama Y, Kotani K, Yanagawa H. Epidemiologic Featuresof Kawasaki Disease in Japan : Results of the 2007-2008Nationwide Survey. J Epidemiol.2010;20(4):302-7. Epub2010 Jun 5).

3. Zsadanyi J, Lakatos L, Herszeg L. Fatal Outcome of KawasakiSyndrome in a 4 week Old Infant. Orv Hetil;1991;132:2102-03

4. Vanlieferinghen PH, Brunet F, Beufrfre AM, Borderon C,Dechelotte P. Sudden Unexpected Death in an Infant due to aRuptured Coronary Aneurism revealing Kawasaki Disease.Arch pediatr 2002; 9:1248-51.

5. Tomta S, Chung K, Mas M, Gidding S, Shulman ST.Peripheral Gangrene Associated with Kawasaki Diease. ClincInfect Dis 1992; 14:121-26.

6. Singh S, Kawasaki T. Kawasaki Disease – an IndianPerspective. Indian Pediatr. 2009 Jul;46(7): 563-71.

7. HsiehYC,Wu MH, Wang JK, Lee PI et al Clinical Features ofatypical Kawasaki Disease: Journal of Microbiological andImmunological Infections 2002; 35(1): 57-60

8. Rowley AH. Incomplete (atypical) Kawasaki Disease.Paediatric Infectious Disease Journal 2002; 21(6): 563-65.

9. Gainzi J, Miron D, Spiegel R, Fink D, Horowitz Y. KawasakiDisease in Very Young Infants: High Prevalence of atypicalPresentations and Coronary Arteritis. Clin Pediatr (Phila)2003;42:263-67.

10. NewburgerJW, Takahashi M, Gerber MA, GewitzMH, TaniLY, Burns JC, et al.committee on Rheumatic fever,Endocarditis and Kawasaki Disease, Council on theCardiovascular Diseases in the Young, American HeartAssociation. Diagnosis, Treatment and Long TermManagement of Kawasaki Disease: a Statement from theCommittee on Rheumatic Fever, Endocarditis and KawasakiDisease. Pediatrics 2004;114:1708-33.

11. Kato H, Sugimura T, Sato N, Hashino K, Maeno Y, et al.Long term Consequences of Kawasaki Disease. A 10 -21-year Follow-up Study of 594 Patients. Circulation 1996;94:1379-85.

12. Dajani AS, Taubert KA, Gerber MA, Shulman ST, Ferrieri P,Freed M, et al. Diagnosis and Therapy of Kawasaki Diseasein Children. Circulation 1993;87:1776-80.

45

Kawasaki Disease - A Rare Presentation in a Bangladeshi Infant- A Case Report Akhter S et al

Abstract:A case is reported which states calcific metamorphosis ofpulp in a mandibular left lateral incisor and concomitantpulp necrosis of both central incisors for a single trauma.There was a large periapical lesion associated with the teeth.Conventional endodontic treatment was performed on teethwith pulp necrosis, but the canal with calcificmetamorphosis could not be negotiated with endodonticfiles. The periapical lesion was surgically removed anddiagnosed as acute periapical abscess on histopathology.During the surgical procedure root apices of calcified tooth

Surgical Management of Calcific Metamorphosis of Pulp:A Case Report

KULSUM Ua, FARZANA Fb

a. Dr. Umme Kulsum, BDS, DDS, MS (Cons. Dentistry),Associate Professor, Department of Conservative Dentistry,Dhaka Dental College, Dhaka, Bangladesh.

b. Dr. Farhad Farzana, FCPS (Part II) trainee, Department ofConservative Dentistry & Endodontics, Dhaka Dental College& Hospital, Dhaka, Bangladesh

Address of Correspondence: Dr. Umme Kulsum, AssociateProfessor, Department of Conservative Dentistry, Dhaka DentalCollege, Dhaka, BangladeshReceived: May 30, 2011 Accepted: June 30, 2011

as well as other teeth were removed and retrograde cavitywas prepared and filled with glass ionomer cement i.eapicectomy was done.The bony defect was filled withcalcium hydroxyappatite crystal. Six months later the teethwere asymptomatic and radiological follow-up showedgradual healing of the bony cavity.

Keywords: Retrograde filling, apicectomy, calcificmetamorphosis of pulp, calcium hydroxyappatite crystal.

(Birdem Med J 2011; 1(1): 46-50)

Introduction:Calcific metamorphosis is defined as a pulpal responseto trauma that is characterized by deposition of hard tissuewithin the root canal space.1 Initially, calcification is aprocess involving the reduction in size of the intradentalcavities as a result of hard-tissue formation by the cellsof the vital pulp; it tends in complete calcification as aresult of dentin deposition inside the tooth. 2

The mechanism of hard tissue formation during calcificmetamorphosis is characterized by an osteoid tissue thatis produced by the odontoblasts at the periphery of thepulp space or can be produced by undifferentiated pulpalcells that undergo differentiation as a result of thetraumatic injury. This results in a simultaneousdeposition of a dentin-like tissue along the periphery ofthe pulp space and within the pulp space proper. Thesetissues can eventually fuse with one another, producingthe radiographic appearance of a root canal space thathas become rapidly and completely calcified. 1

Calcifications of varying extent develop in teeth thathave been subjected to luxation

trauma. Pulpal necrosis occurs with some major delayin 20% of teeth with radiologically detectablecalcifications. Calcifications have been observed in2.3% of patients following

Le Fort I operations; according to other studies, theincidence may be as high as 30%. 2 Further causes thathave been described include surgery-related changes inperfusion and in combined surgical and orthodontictreatment. Calcifications in the pulp chamber have alsobeen observed following orthodontic treatment.2

The clinical picture of calcific metamorphosis has beendescribed by Patterson and Mitchell as a tooth that isdarker in hue than the adjacent teeth and exhibits a darkyellow color because of a decrease in translucency froma greater thickness of dentin under the enamel. 1 Pulptesting ceases to have any diagnostic value once thecalcification has reached an advanced stage. Radiographalone can never be used as a basis for determiningwhether complete calcification has taken place; theseteeth always require clinical verification.2

The radiographic appearance of calcific metamorphosisis partial or total obliteration of the pulp canal space witha normal periodontal ligament space and intact laminadura. Complete radiographic obliteration of the root canalspace, however, does not necessarily mean the absenceof the pulp or canal space; in the majority of the casesthere is a root canal space with pulpal tissue.1

Periapical lesions of endodontic origin are alwaysmanifestations of a disease that develops from the

.


presence of microorganisms in the root canal system (or,in rare cases, in the periapical region). Healing can takeplace only if these bacteria are removed as completely aspossible. Therefore, root canal treatment is stronglyindicated in a tooth with a partially (apparently) calcifiedroot canal system and apical periodontitis. 2

Calcifications completely or partially block and obscurethe access into the root canal systems and can hamperpreparation, disinfection and obturation. Searching forcalcified root canal systems carries an increased risk ofperforation. However, if all attempts still fail to resultin complete exposure and instrumentation of the rootcanal system, the clinician should consider root endresection or apicectomy, hemisection or extraction. 2

The purpose of this article is to describe a clinical caseof calcific metamorphosis of pulp associated with acuteperiapical abscess treated by apicectomy and retrograde-filling with glass ionomer cement and filling of bonycavity with hydroxyappatite crystal.

Case ReportA 23 year-old male, named Md. Monirul Islam wasreferred to the Department of Conservative Dentistry& Endodontics, Dhaka Dental College & Hospital, withpain and swelling in his mandibular left lateral incisor.The patient described recent severe pain over 3 days,but no previous history or any signs or symptoms. Hegave a history of trauma about 15 years back. The patientcould not recollect about the treatment he received atthat time. The medical history was noncontributory.Yellow discoloration on mandibular left central incisorwas noticed (Fig-1). Both central incisors and leftlateral incisors were sensitive to percussion, but failedto respond to pulp sensitivity testing. The labial gingivawas tender on palpation. A periapical radiographrevealed a large radiolucent area of (13 x 8) mm2

involving apices of the mandibular central incisors andleft lateral incisor. Left central incisor showed openapex (not divergent) and the left lateral incisor wascalcified (Fig-2). A clinical diagnosis of calcificmetamorphosis of pulp in mandibular left lateral incisor,pulp necrosis of mandibular central incisors with chronicperiapical abscess was established. Taking into accountthe canal with calcific metamorphosis and open apices(not divergent) and the periapical radioluscency, the firststep of treatment was root canal treatment and the needfor apicectomy followed by retrograde filling was inconsideration.

Following isolation of the teeth pus was drained throughaccess cavity of both mandibular central incisors. Aradiograph was obtained with files inserted in the rootcanals to establish working length. Both canals weredebrided thoroughly and prepared by standardizedtechnique to a size 35 file. Copious irrigation with 1%sodium hypochlorite solution was carried out throughoutthe procedure. After drying the root canals with paperpoints, calcium hydroxide was applied and cavity wastemporarily sealed with zinc oxide eugenol cement.

An access opening was made on the left lateral incisortooth at the same visit but the root canal could not benegotiated with an endodontic file and EDTA as thecanal was calcified. Then decision was made forcombined nonsurgical and surgical endodontictreatment.

One week later, the right central incisor tooth was sealedwith gutta-percha point and zinc-oxide eugenol cement

Fig.-1: Periapical abscess in mandibular incisors

Fig.-2: Preoperative radiograph showing calcificationof mandibular left lateral incisor

47

Surgical Management of Calcific Metamorphosis of Pulp: A Case Report Kulsum U & Farzana F

After 7 days, the patient returned and apical surgerywas performed to remove a portion of the withundebrided space and to retroseal the canal. The surgicalintervention consisted of apical curettage, apicectomy,root-end preparation and retrofilling.

An intrasulcular incision along with two verticalincisions at each end was made under local anaesthesia,a full thickness flap was retracted, and bone removedto gain access to the lesion and to the apical third of theroot. The granulation tissue was removed with the helpof surgical curette (Fig-4) and sent for histopathologicalexamination (Fig-5). The lower left central incisor toothwhich was with open apices was sealed through and

through with gutta-percha point and zinc oxide eugenolsealer followed by coronal sealing. The resectioninvolved the apical 3 mm of the root on both teeth i.e.on calcified canal and open apex, with a bevel of 0degree angle to the long axis of the tooth, using a highspeed diamond fissure bur, followed by finishing witha diamond finishing bur and irrigation with sterile saline.

The root-end was prepared with a round diamond bur 3mm into root dentine to receive the glass ionomer fillingmaterial. The cavity was dried and glass ionomer fillingwas prepared and placed on to the root-end cavity. Thebony cavity was cleaned with normal saline and filledwith calcium hydroxyappatite crystal (Fig-6). Sutureswere used to close and healing and healing period wasuneventful.

Histopathological examination showed fibro edematousinfiltration with inflammatory cells suggestive of wallof an abscess.

using lateral condensation technique, followed bycoronal sealing. A postoperative radiograph wasobtained (Fig-3). The left central incisor was decidedfor through and through obturation during surgicalprocedure because of presence of pus as well as openapex.

Fig.-3: Obturation of mandibular right Central incisor.

Fig.-4 : Removal of abscess wall with curette

Fig.-5: Tissue for Histopathological examination.

Fig.-6: Hydroxyappatic crystal in the bony cavity.

48


At 3-month and 6 months follow-up examinations, thepatient was asymptomatic and radiographic evidenceof gradual healing was confirmed by a decrease in thesize of the periapical radiolucency.

DiscussionDepending on its severity, injury to the oral cavity caninvolve all dental tissues3. Biological consequences oftraumatic luxation injury include pulp necrosis,calcification and root resorption either internal and/ orexternal along with bone resorption 4. The cause of pulppathology is infectious products from an infected pulpspace or from the periapical area. Microorganism thatcolonize these areas release their product into theperiapical tissue and causes a lesion in the bone. Theseverity of destruction is dependent on the amount ofproducts as well as the resistance of the host. Theinflammatory development might be acute, and leadingto a periapical abscess or chronic with sign of aperiapical granuloma or cyst 5. The reported caseshowed almost all biological consequences of traumaticinjury.

Most of the recent literature indicates that endodontictreatment is unnecessary unless the tooth is symptomaticor there is radiographic evidence of pulp necrosis andinfection i.e., periapical radiolucency 2. Signs of pulpnecrosis and infection may be seen in a small percentageof calcified canals particularly in which the pulp appearsalmost totally calcified and in teeth with complete rootformation. 6

Assessment of the status of the pulp was difficult sincethese teeth do not usually respond to thermal sensibilitytesting. Most, however, do respond to electrical stimulusand therefore the electrical pulp sensibility testing isthe desirable method for assessing the status of the pulpin calcified canals. The reported case was non-responsive to thermal sensibility test; electricalsensibility could not be performed because ofeconomical consideration 6 . In the present case,radiographic complete calcific metamorphosis of pulpin a mandibular lateral incisor was associated with alarge periapical lesion with concomitant pulp necrosisof both central incisors and thus endodontic treatmentwas inevitable.

Pulp chamber was flooded with 1% sodiumhypochlorite. Canal with calcific metamorphosis wasinstrumented with fine file, though radiographicinterpretation suggested for complete blockage.Ethylenediamine tetraacetic acid (EDTA) solution wasused to assist in canal penetration. Surgical OperatingMicroscope (SOM) for visualization and magnification,

Fig.-7: Radiograph immediately after Apicectomyshowing retrofilling.

Fig.-8: Three month follow-up radiograph afterapicectomy

Fig.-9: Six month follow-up radiograph afterapicectomy radiograph showing gradual healing.

49

Surgical Management of Calcific Metamorphosis of Pulp: A Case Report Kulsum U & Farzana F

Ultrasonic (US) tip 7 or Laser light 8 for locating andnegotiating calcified canal was not chosen because offinancial consideration.

Symptomatic teeth that exhibit complete calcificmetamorphosis radiographically or in which the canalscannot be negotiated must be treated with periradicularsurgery.1

In the present case, all attempts with available facilitiesfailed in negotiation and instrumentation of the calcifiedcanal and decided for apicectomy followed byretrograde filling. Apicectomy and retro-preparationwas performed with conventional method.

Laser-powered apicectomy and ultrasonic retro-preparation was not chosen because of non-availabilityand financial consideration.

Periapical surgery is successful in 25.0-99.0% of cases,and success is influenced by many factors including thetooth involved, surgical procedure, complex anatomyof the root canal, quality of root canal filling, apicalrepair and the length of follow-up.9,10,11 In this case, 3mm apical resection was performed with 0 bevel.According to Cohen et al. the length of root for resectiondepends upon the frequency of lateral canals and apicalramifications at the root-end. They found that when 3mm of apex is resected, the lateral canals are reducedby 93 percent and apical ramifications decreased by 98per cent. Whereas a root resection of 3 mm at a 0 degreebevel angle eliminates most of the anatomic featuresthat are possible cause of failure. 1

In the present case, retrograde filling was undertakenwith glass-ionomer cement, which has been shown tohave good apical sealing properties, availability and isless expensive. Though this cement is more sensitive tocontamination with saliva and blood unlike expensiveMTA, it exhibits satisfactory periapical healing afterapical surgery 12.

The bony cavity was filled with calcium hydroxyappatitecrystal, a non-resorbable alloplastic material as studiesshowed reduction of the osseous defects greater inhydroxyappatite than curettage only 13.

Conclusion:Because of the calcific metamorphosis of pulp and anacute periapical abscess with concomitant pulp necrosis,

combined nonsurgical and surgical endodontic therapywas indicated in this case. Follow-up radiograph over 6months showed marked reduction of size of theradiolucency and thereby healing.(Fig:8-9)

Referrences:1. Garg N, Garg A.Pulp and Periradicular tissue.In:Garg N, Garg

A. editors.Textbook of Endodontics 1st edition .NewDelhi:Jitendar P Vij,..2007:7-21

2. Michael Hulsmann, Claudia Barthel. Problem in gainingaccess to the root canal system. In:Problems in Endodontics.4th

edition.Germany:Quintessence International,1997;8:145-272.

3. Trope M, Chivian N. Traumatic injuries. In:Cohen S.burmsRC eds.Pathways of the pulp, 6th ed, . Mosby, St Louis.1994;16; 436-85.

4. Trope M, Lucia Blanco, Noah Chivian, and Asgeir Sigurdsson.The Role of Endodontics after Dental Traumatic Injuries.In:Cohen S,Kenneth M eds.Pathways of the Pulp. 9th edition.Mosby, St Louis.1994; 17; 436-85.

5. Prodeep M,Prosant MNikhil B,Nitika B.Principles ofmanagement of calcified canals.Indian J Dent Sc 2010;2(5):3-5

6. Moule AJ, Moule CA, The endodontic management oftraumatized permanent anterior teeth: a review. AustralianDental J (Suppl.1); 2007; 52: (1 Supple): S 122-73.

7. Richard Mounce. Locating and Managing Calcified Canals:Optimal Strategies. Dental News 2007; 14: 4.-7

8. Selden S.The role of dental operating microscope in improvednonsurgical treatment of calcified canals.Oral Surg Oral MedOral Pathol 1989;68:93-8.

9. Molven O, Halse A, Grung B, Surgical management ofendodontic failures: indications and treatment results. Int DentJ 2007; 41:33-42.

10. Grung B, Molven O, Halse A, Periapical surgery in aNorwegian country hospital: follow-up findings of 477 teeth.J Endod 1990; 16: 411-17.

11. Testori T, Capelli M, Milani S, Weinstein RL, Success andfailure of radicular surgery: a longitudinal retrosprectiveanalysis. Oral Surg Oral Med Oral Radiol Endod 1999; 87:493-98.

12. Jesslen P, Zetterqvist L, Heimdahl A, Longterm result ofamalgam versus glass ionomer cement as apical sealer afterapicectomy. Oral Pathol Oral Radiol Endod 1995; 79: 101-103.

13. Thorkild Karring, Jan Lindhe, Pierpaolo Cortellini.Regenerative periodontal therapy.InLindhe J,Karring T,eds.Clinical Periodontology and Implant Dentistry. 3rd edition ,.Lange .London. 1997; 20: 597-46.

50


AbstractHepatic granulomas are found in about 3 to 10% of liverbiopsies. In the liver, granulomas often merely serve as themorphologic clue to some underlying systemic process whileliver function is well preserved. In approximately 15% of casesno aetiology can be established despite extensiveinvestigations. Here we report a case of 43 years old ladywith history of right upper quadrant pain with occasionalfever and vomiting which was attributed to her gall bladder

Granulomatous Hepatitis: A Rare Case ReportAMIN AAa, MONDAL SKb, ULLAH MEc

1. Prof. Md. Abdullah -Al –Amin, Head of the Department,Surgery & MISC, BIRDEM & Ibrahim Medical College,Dhaka, Bangladesh.

2. Dr. Samiron Kumar Mondal, Assisstant Professor, Dept ofSurgery & MISC BIRDEM & Ibrahim Medical College, Dhaka,Bangladesh.

3. Dr. Mahmud Ekram Ullah, Registrar, Dept of Surgery & MISC,BIRDEM & Ibrahim Medical College, Dhaka, Bangladesh.

Address of Correspondence: Prof. Md. Abdullah- Al –Amin,Email: [email protected]: May 30, 2011 Accepted: June 30, 2011

stones. Her liver function tests(LFT), hematological,biochemical test results were normal and all the viral markerswere negative. During laparoscopic cholecystectomy, the liverwas found to be studded with numerous grayish white smallnodules. Liver biopsy was done which revealed non-caseatinggranulomatous hepatitis.

Key words: Granulomatous hepatitis, liver biopsy

(Birdem Med J 2011; 1(1): 51-53)

IntroductionGranulomatous hepatitis is a multifactorial infiltrativeliver disorder with or without additional hepaticinflammation and fibrosis. The term “granulomatoushepatitis” is often used, but the condition is not a truehepatitis. Epithelioid granulomas have been reportedin about 3–10% of unselected liver biopsies1, withnumerous underlying aetiologies described. There maybe insignificant incidental findings, but more often theyreflect clinically relevant disease —usually a systemicdisorder rather than primary liver disease. A specificaetiological agent cannot be identified in approximately15% of cases despite serological, immunological,microbiological, and radiological investigations leadingto a diagnosis of ‘idiopathic granulomatous hepatitis’.A few such patients have a syndrome of recurrent fevers,myalgias, fatigue and other systemic symptoms.

Case reportA 43-year-old diabetic woman was admitted in ourhospital with right upper abdominal pain and vomitingwith low grade fever and sonographic evidence of gallbladder stone. She had the history of dyspepsia andpersistent dull ache in upper abdomen for 3 months.

During this period, she also had occasional fever andvomiting. But there were no history of jaundice or anyrespiratory symptoms and her bowel and bladder habitwere also normal. Her past medical history includespulmonary tuberculosis 1½ years back for which shehad received full 6 months course of anti TBchemotherapy.

On examination, her right hypochondrium was slightlytender and liver was palpable about 2 cm from costalmargin without any clinical stigmata of chronic liverdisease. Murphy’s sign was positive. Her chest was clear,vital signs were normal and there were no other abnormalclinical findings. She was diagnosed as a case of acuteon chronic cholecystitis.

Her LFT results were normal. Findings of a full bloodexamination and urea, electrolytes, sugar and creatininelevels were all within normal limits. Results ofserological tests for hepatitis A, B and C were negative.USG of abdomen revealed mild hepatomegaly withcholelithiasis.

We planned for laparoscopic cholecystectomy. Duringlaparoscopy, the liver was found to be enlarged and it’ssurface was studded with numerous grayish white smallnodules (Fig 1). Gall bladder wall thickness was normaland there was no pericystic adhesion. GB lumencontained multiple small, soft, black stones. Rest of theabdominal organs and the peritoneum looked normaland there was no ascites either. Liver tissue was takenfor biopsy.

Histopathology revealed non-caseating granulomatousreaction with aggregates of epithelioid histiocytes andLanghans giant cells. Some of the granulomas are

.


DiscussionGranulomatous hepatitis is an uncommon condition witha lengthy list of possible causes2. Infectious disordersare the most important (TB, Viral, Parasitic, fungal) andsarcoidosis is common among noninfectious causes. Avariety of drugs can be responsible (eg, quinidine,sulfonamides, allopurinol). It may also be found inprimary liver disease like primary biliary cirrhosis and

auto immune hepatitis. Other rare causes include non-Hodgkin’s lymphoma, polymyalgia rheumatica, juvenilechronic arthritis, graft versus host disease etc. In somecases no etiology can be established and thus labelled“idiopathic”. These patients are typically middle agedwomen who have an excellent prognosis3.

In the liver, granulomas often incite little or nohepatocullular reaction and merely serve as themorphologic clue to some underlying systemic process;and liver function is well preserved like that in ourpatient.

In most situations, liver function test results are onlymildly deranged, usually with a disproportionateelevation of alkaline phosphatase. Bilirubin levels aretypically normal or only mildly elevated, unlessconcomitant hepatocellular injury coexists2.

Histological examination of liver tissue provides crucialinformation in the differential diagnosis of hepaticgranulomas4. However, the morphologic pattern is oftennonspecific and the diagnosis should be pursued withappropriate studies (eg, cultures, skin tests, laboratoryand x-ray studies, and other tissue specimens) whichhad been done in our patient.

Hepatic granulomas of infective or drug etiology regresscompletely after appropriate therapy. Without anetiologic diagnosis, it is generally best to follow thepatient rather than blindly treat with antibiotics or othertherapies. Corticosteroids may be helpful in idiopathicgroup but should be given only if TB and other infectivedisorders can confidently be excluded2 particularly inthe endemic area.

In our patient, the biopsy did not show bile ductdestruction characteristic of primary biliary cirrhosis,or any evidence of malignancy. The patient was nottaking any offending drugs. Histological appearance anddistribution of granulomas was not consistent either withthe diagnosis of hepatic sarcoidosis or with TB. Ziehl-Neelsen stain for AFB were negative. Moreover, shedid not have any constitutional features of TB and herchest was normal along with negative MT test andnormal ESR. In most cases, TB involvement of the liveroccurs in disseminated TB. However, Negative cultureresult / PCR on liver biopsy specimen could haveconfirmed it5,6. Perhaps thereby, our patient fell intothe idiopathic category.

coalescing and some are discrete amidst infiltration bychronic inflammatory cells. The bile ducts were all intactand no evidence of malignancy was seen (Fig 2). GBwall showed chronic cholecystitis.

Postoperative recovery was uneventful and she wasdischarged on 2nd POD.

Fig.-1: Liver surface studded with numerous grayishwhite small nodules (laparoscopic view)

Fig -2: Non-caseating hepatic granuloma (microscopicview)

52


ConclusionA wide variety of underlying conditions can causegranulomatous hepatitis with resulting prognostic andtherapeutic implications. The idiopathic subgroup doesvery well though the exact cause remains undetermined.Steroid therapy is beneficial in some cases but shouldbe given only after excluding potential infective causes.

References1. Sartin JS, Walker RC. Granulomatous hepatitis: a retrospective

review of 88 cases at the Mayo Clinic. Mayo Clin Proc 1991;66:914–18.

2. Zakim D, Boyer TD, editors. In: Hepatology:. 3rd ed. Vol 3.Philadelphia: WB Saunders;1996: 1472.

3. Gaya DR, Thorburn D, Oien KA, Morris AJ, and Stanley AJ.Hepatic granulomas: a 10 year single centre experience. JClin Pathol. 2003 November; 56(11): 850–53.

4. Eu JL, Paul DRJ, Peter C, Paul JG. Granulomatous hepatitis:tuberculosis or not? MJA 2008; 188 (3): 166-67

5. Wiener RS, Della-Latta P, Schluger NW. Effect of nucleicacid amplification for Mycobacterium tuberculosis on clinicaldecision making in suspected extrapulmonary tuberculosis.Chest 2005; 128: 102.

6. Alcantara-Payawal DE, Matsumura M, Shiratori Y, et al.Direct detection of

7. Mycobacterium tuberculosis using polymerase chain reactionassay among patients with hepatic granuloma. J Hepatol1997; 27: 620-27.

53

Granulomatous Hepatitis: A Rare Case Report Amin AA et al

IMAGES IN MEDICAL PRACTICE

Quiz: Images in Medical PracticeCourtesy: Safder AMB

A 43 years old male presented with recurrent convulsion. He had some paular lesion on the face & hand and patchon the forearm; the images of which are given below. A skull x-ray and CT scan of brain was done.

Q. What is the likely diagnosis?

Papular lesion on face Patch on forearm

X-ray skull (Lateral view) CT scan of Brain

.

(Birdem Med J 2011; 1(1): 54)

LETTER TO THE EDITOR

.

(Birdem Med J 2011; 1(1): 55)

BIRDEM NEWS

BIRDEM NEWS

• 2nd unit of BIRDEM (BIRDEM-2) has been inaugurated by HonorablePrime Minister on 29.07.2011. It is a 100 bed hospital. It was financedby Ministry of Women & Child Welfare. It would be run by BangladeshDiabetic Samity (BADAS).

• 2nd Successful liver transplant was done on 06.08.2011.

• 1st Successful liver transplant in Bangladesh was done at BIRDEM on03.06.2010.

(Birdem Med J 2011; 1(1): 56)

.

FROM THE DESK OF EXECUTIVE EDITOR

1st issue of BIRDEM Medical Journal

To have a journal of BIRDEM was long cherished desire. 1st meeting withformation editorial board was held on May 11, 2011 with Professor NazmunNahar, Academic Director as Chair. An editorial board was formed.

A final shape was proposed and finalized in two subsequent meeting. It wasdecided to publish 2 issues (January & July) in each year. Principles of journalswas decided. It will primarily entertain the works of BIRDEM staffs but willremain open for all.

This peer reviewed journal will be a valuable collection of different articles ofall disciplines. It will publish CME articles, article of researchers of differentdisciplines. We have already registered web sites (www.birdem.med.j.org).We are trying to disseminate the journal to different web site and databases(HINARI, Free Medical Journal, Bangladesh Publishing Group, Bangla JOL,Google, etc).

Eagerly waiting for your valuable advise and new article.

Prof. Khwaja Nazim UddinExecutive EditorBIRDEM Medical Journal

(Birdem Med J 2011; 1(1): 57)

.

NAME OF THE REVIEWER OF ARTICLES IN THIS ISSUE

Professor Mohammad Omar Faruq

Professor Jalaluddin Ashraful haque

Professor Tahmina Begum

Professor Reza bin Zaid

Dr.Zahurul Alam

Dr.Rwnak jahan Tamanna

Dr.Delwar hossian

Dr.Feroj Amin

Dr. Muhammad Abdur Rahim

Dr.Jamaluddin Ahmed

Bipin Bihari Karmaker

(Birdem Med J 2011; 1(1): 58)

Documents

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