Asploro Journal Of Biomedical And Clinical Case Reports .
Asploro Journal of Biomedical and Clinical Case ReportsOriginal ArticleIdentifying Barriers to Therapeutic Adherence in Type 2-Diabetes: AComplex and Multidimensional Clinical IssueMujtaba Hasan Siddiqui1, Iqbal Akhtar Khan2*, Fauzia Moyeen3, Khawar Abbas Chaudhary41Department of Medicine, Akhtar Saeed Medical & Dental College, Lahore, PakistanIndependent Scholar, Lahore, Pakistan3Consultant Diabetologoist, Diabetes Wellness Centre, Lahore, Pakistan4Department of Medicine, Continental Medical College, Lahore, Pakistan2Corresponding Author: Prof. Iqbal Akhtar Khan, MBBS, DTM, FACTM, PhDAddress: Independent Scholar, Lahore, Pakistan.Received date: 17 April 2019; Accepted date: 28 May 2019; Published date: 05 June 2019Citation: Siddiqui MH, Khan IA, Moyeen F, et al., “Identifying Barriers to Therapeutic Adherence in Type 2Diabetes: A Complex and Multidimensional Clinical Issue”. Asp Biomed Clin Case Rep, vol.2, no.1: 22-28, 2019.Copyright 2019 Siddiqui MH, Khan IA, Moyeen F, et al., This is an open access article distributed under theCreative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in anymedium, provided the original work is properly cited.AbstractThe problem of therapeutic non-adherence is a serious issue adversely affecting the adequate control andmanagement of Type2 Diabetes (T2D).This unwelcoming situation has been studied well on various spots on theglobe, with diverse results. The present study, aimed at identifying the barriers to therapeutic adherence, wasconducted on a set of proven cases of T2D, managed by primary healthcare providers. The adherence rate tomedication alone was 42% while to medication plus lifestyle recommendations 27%. Whereas sub-optimal healthliteracy, complexity of prescription and socioeconomic aspects were the main determinants, lapse on the part ofhealthcare system cannot be underscored. The present qualitative study was a preliminary investigation on asmall sample .The magnitude of the problem necessitates that a large scale multi-centre in-depth quantitativestudy in 5 dimensions (recommended by WHO): socio-economic factors, health care team and system relatedfactors, condition related factors , therapy related factors and patient related factors, be done on priority basis.This would pave the way for planning a well-designed intervention programme.KeywordsTherapeutic Adherence; Type2 Diabetes; Non-Adherence; Under-Adherence; Over-AdherenceQuoteIntroductiontype 2 diabetes (T2D), previously referred to as‘NIDDM’ or ‘Adult Onset’ or ‘Maturity Onset’ or‘Maturity Onset of Young (MODY)’ accounts for 90-95% of those with diabetes. It is a complex interactionbetween genetic, behavioural and environmentalfactors [3].Diabetes mellitus is a group of metabolic disorderscharacterized by hyperglycaemia resulting fromdefects in insulin secretion, action or both [2]. TheGlobally, an estimated 422 million adults wereliving with diabetes in 2014 compared to 108 million“Surprisingly often, evidence based treatments failto succeed because of the human factor known for afew decades as “patient’s non -adherence”. [1]Manuscript no: ASJBCCR-2-1-22-28Asp Biomed Clin Case RepVolume: 2Issue: 122
Citation: Siddiqui MH, Khan IA, Moyeen F, et al., “Identifying Barriers to Therapeutic Adherence in Type 2-Diabetes: AComplex and Multidimensional Clinical Issue”. Asp Biomed Clin Case Rep, vol.2, no.1: 22-28, 2019.Original Articlein 1980 rising from 4.7 % to 8.5 % in adult population.However, separate figures of prevalence for type 1 andtype2 do not exist. An estimated 1.6 million deaths aredirectly attributable to diabetes every year [4]. Theprevalence of T2D, in Pakistan, as estimated in 2016,was 11.77% (M:F - 11.20%:9.19%) [5].One of the major causes of uncontrolled T2D ispatient’s inadequate adherence to therapeutic regime.Adherence has been defined , by WHO, as “the extentto which a person’s behaviour taking medication,following a diet, and/or executing lifestyle changes,corresponds with agreed recommendations from ahealth care provider”[3]. It is preferable to phrase it“Therapeutic Adherence”, instead of ‘MedicationAdherence’, as the former covers both pharmacologicaland non-pharmacological interventions.Adherence, Compliance and Concordance aresometimes used interchangeably. However, adherenceis an active choice of a patient to follow theinstructions of the prescriber while taking theresponsibility of his own wellbeing. Compliance, onthe other side, is a passive behaviour in which thepatient is following the list of instructions from thehealth care provider. Whereas, adherence andcompliance relate to medicine taking behaviour of thepatient, concordance refers to the interaction betweenthe clinician and the patient. To quantify the issue ofadherence, two more terms need to be clarified. Under-adherence has been defined as “having at least onemedication with 70% compliance and the Overadherence as having at least one medication with 120% compliance” [6].The patients’ reasons for deviating from the agreedprescription are diverse and may be intentional ornon-intentional [7].The intentional one refers to nonadherence that is deliberate and largely associatedwith patient’s motivation whereas unintentional one islargely driven by a lack of capacity or resources [8].The latter may be because of forgetfulness [9] or notknowing exactly how to use medicines [10]. It isimportant to note that the patients may become nonadherent during different stages of their treatment[11]. They may opt not to fill the prescription inpharmacy, overuse or underuse or even discontinueManuscript no: ASJBCCR-2-1-22-28Asp Biomed Clin Case RepVolume: 2prematurely. The gravity of the disease is also animportant factor for the patients because it motivatesthem to stick to the prescriber’s instructions [12]. Thenature of the ailment has its impact on the level ofadherence. Van Geffen et al, from Netherlands, havedemonstrated thatfrom those prescribedantidepressants, 4.2% did not start the medication atall while 23.7% filled only a single prescription [13].Conversely, adherence was found to be highest inthose with HIV infection [13].RationaleTherapeutic non-adherence in diabetics is aserious clinical problem worldwide. A meta- analysisof 569 studies of medication adherence revealed anaverage non-adherence rate of 25% [14]. Whereas,WHO’s definition of adherence focuses on patient’sbehaviour only, it does not indicate who is to be heldresponsible for this .The other notion, prevalent inour set up, is that incompetency of the prescriber isthe main determinant.The problem has been studied well on variousspots on the globe, with diverse results. This is apreliminary investigation aimed at identifying themagnitude of the problem in local population.Patients and MethodsObjective:To identify the barriers to therapeutic adherencein individuals with Type 2 DiabetesStudy Population:The present study was conducted on proven casesof uncomplicated T2D, on oral anti-hyperglycaemicpills, diagnosed and managed by primary careproviders. The common reason for referral (by thecare provider or by self) to the Diabetes Clinic wassub-optimal control of the disease. From amongst 108such individuals, during the study period of March2018 to February 2019, thirty three (M:F-18:15–55%:45%) were picked up. Their age ranged from 38to 65 years, were of middle socioeconomic status andsecondary level of education. They were evaluated byrelevant laboratory work-up and clinical assessment;and their prescriptions reviewed accordingly.Issue: 123
Citation: Siddiqui MH, Khan IA, Moyeen F, et al., “Identifying Barriers to Therapeutic Adherence in Type 2-Diabetes: AComplex and Multidimensional Clinical Issue”. Asp Biomed Clin Case Rep, vol.2, no.1: 22-28, 2019.Original ArticleInclusion Criteria: Those voluntarily willing to participate in thestudy Those on ambulatory careThe Prescriber:Exclusion Criteria: Those with co-morbidities Those with cognitive dysfunction Females ,pregnant or lactatingType of Study: Questionnaire based, descriptive, analyticalStudy Instruments: Interviews, reviews of laboratory reports,clinical evaluation and free discussions with theparticipants, on monthly basis, to identify theirdiabetes related issues and level of satisfactionwith the prescription medication and therecommendations for lifestyle modifications. The ‘claims’, at follow up visits by theparticipants’ of ‘all OK’ or ‘not OK’ werescrutinized in the light of clinical evaluation andreview of the lab work up.ResultsContrary to the old notion that all faults liewith non-cooperative patient or the incompetentprescriber, the barriers to optimal therapeuticadherence were identified at followingdimensions:The Patient: Inadequate knowledge of the nature of his/herown illness. Insufficient information of consequences of nonadherence/ under-adherence of the prescriptionmedication. Recourse to diverse care-providers (homeopaths,herbal medicine, natural healers, faith healersetc.) for additional/alternate advice, withresultant reduced trust in the efficacy ofprescription medication. Manipulating the prescription medication byaltering, substituting, pausing or even stoppingManuscript no: ASJBCCR-2-1-22-28Asp Biomed Clin Case Reppart thereof. Undermining (or even ignoring) the advice oflife style modification. Intentional non-adherence.Volume: 2 Lapse on his/her part to provide adequateinformation to the patient of nature and extentof illness, untoward effects of the drugs andadvice on lifestyle modification. Sub-optimal competency in communicationskills. Poor monitoring and follow up with resultantinability to modify or intensify the therapeuticregime. Inability to ratify individual patient’s selfmanagement.Socio-economic: Unaffordable prescriptions. Inadequacy of the concerns of patient’s beliefsand social set up.Therapy: Complexity of medication regime anddifficult schedule. Poly pharmacy.Health Care System: Non-existent /Non-functionalprimary carereferral system. Inability to organize well-structured trainingprogram in communication skills, for thephysicians. No check and balance system.Discussion“Drugs do not work in patients who do not takethem”Charles Everette Koop (1916-2013)-SurgeonGeneral of United StatesThe results of the study, although not unexpectedin setup like ours, were disappointing. The adherencerate to medication alone was 42% while tomedication plus lifestyle recommendations 27%. ThisIssue: 124
Citation: Siddiqui MH, Khan IA, Moyeen F, et al., “Identifying Barriers to Therapeutic Adherence in Type 2-Diabetes: AComplex and Multidimensional Clinical Issue”. Asp Biomed Clin Case Rep, vol.2, no.1: 22-28, 2019.Original Articleshows a lapse both on the parts of the patients and theprescribers.“Health Literacy” has been defined as “the degree towhich individuals have the capacity to obtain, processand understand basic health information and servicesneeded to make appropriate health decisions” [15].Sub-optimal health literacy is, undoubtedly, animportant bearing on the problem. However, the lapseon the part of the prescribers for not being considerateor being deficient in communication skills necessitatesprompt intervention. It is of interest to refer to anidentical study in Jordon [16] where the therapeuticadherence rates of the diabetics were analyzed asfollowing: 81.4% did not follow the diabetic meal plans 67.9% did not participate in physical exerciseprogramme 61.9% did not monitor their blood glucose levelat homeHowever, 91.9% were highly adherent to themedication advice.It is a melancholic reality that majority of our studypopulation was unclear about the true nature of theirdisease process and pros and cons of therapeuticadherence/non-adherence. Strom et al [17] andKvarnstrom et al [18], in Danish and Finnish studiesrespectively, gathered that the physicians frequentlydo not communicate to the patients about the basicinformation of the treatment plans. The patients maybe left with concerns about adverse effects with lack ofcomprehension of their own disease. Koch et al, on thebasis of a study in Netherlands, concluded thatcomplete and accurate information plays an importantrole in the behaviour of patients, especially in controland management of disease [19]. In a study by vanDelmen et al, the participating GPs agreed that thecommunication about adherence should be tailor madeby not thoughtlessly applying guidelines but by payingattention to patients’ needs [20]. Peschin et al, whilethspeaking at the “9 Power of Partnering (POP)Conference” advocated that improvement of healthliteracy and simplifying the terminology will helppatients to better comprehend the complexity of theirManuscript no: ASJBCCR-2-1-22-28Asp Biomed Clin Case RepVolume: 2disease [21]. It is evident that, in our study,comprehensive information about the medicationsand lifestyle modifications was either not given to thepatients or if given, not adequately picked by them.The studies conducted in Canada [22], UnitedStates [23], Spain[24], Finland[18], Singapore[25]and Ghana[26] have the common inference that pooradherence to medication regimes ,in diabetics, resultsin significantly worse clinical outcomes includinginadequate glycemic control, increased use ofhealthcare resources, increased out-patient care,hospitalization and re-hospitalization, higher medicalcosts and markedly huge mortality rates.The National Council on Patient Information andEducation United States (NCPIE), in 2007, publisheda report “Enhancing Prescription MedicationAdherence: A National Action Plan” to makerecommendations forimprovingmedicationadherence, the emphasis was given on “Educatebefore you Medicate” [27]. Needless to say that, forthe success of such a programme, the central positionof the patient must be recognized. Ibn Sina (980-1037CE), the author of “Kitab al-Qanun fi-al-Tibb”justifiably graded “The First Text Book of Medicine onEarth” [28] has discussed this aspect in detail. Whileenumerating “Seven Doctrines of Preservation ofHealth”, he highlighted key role of the individual inthe form of “Mudawa Salookia” (BehaviourModification) [29]. And this is what we mustprioritize in a joint team approach to resolve the issueof improving therapeutic adherence.The consequences of non-adherence are morepronounced in elderly, the fast-growing sector ofglobal population. Estimates range from 40% to 75%[30]. The more serious issue lies in taking more ofthe drug, in the mistaken belief that by doing so therecovery would be speeded up. Converselyforgetfulness leads to under-utilization or overutilization of the regimen. As a result they areexposed to both under-adherence and overadherence.Recourse to diverse care-providers (homeopaths,herbal medicine, natural healers, faith healers etc)because of low trust in the efficacy of prescriptionIssue: 125
Citation: Siddiqui MH, Khan IA, Moyeen F, et al., “Identifying Barriers to Therapeutic Adherence in Type 2-Diabetes: AComplex and Multidimensional Clinical Issue”. Asp Biomed Clin Case Rep, vol.2, no.1: 22-28, 2019.Original Articlemedication, for additional/alternate advice is ourcultural issue. The affordability is also an importantelement. Atinga et al., [26] while enumerating factorsinfluencing long term medication non-adherenceamong diabetics and hypertensives, in Ghana,identified that perception of inefficacy of theprescription medications turned to return to herbalmedicines and spiritual healing because of their easyaccessibility, perceived efficacy and affordability.Complexity of the regimen (number and frequency)has an important bearing on the adherence [31]. In asystematic review of the association between doseregimen and medication compliance, Claxton et alconcluded that the prescribed number of doses/perday is inversely related to compliance. Simpler lessfrequent dosing regime resulted in better complianceacross a variety of therapeutic classes [32].The “Federal Study of Adherence to Medications inthe Elderly (FAME)”, aimed to determine the effect ofa pharmacy intervention programme on medicationadherence and persistence identified the ways toimprove adherence [33].We need to highlight that a significant contributingfactor in therapeutic non-adherence, in our study, wasthe cost of medication. It has been found that even indeveloped countries like Australia ‘the out of pocketcosts of medications’ adversely affect the adherence inchronic diseases.[34].Needless to reiteratethateconomic problem is the main challenge in our set upwhere every expense on medical treatment is ‘out ofpocket’. Sir Frederick Grant Banting, in his NobelLecture on September 15, 1925, admitted “Insulin isnot a cure for diabetes, it is treatment”. The same istrue of the modern anti-hyperglycaemic oral pills.Diagnosis of a chronic bothersome and incommodiousdisease like diabetes comes to the family as a strongblow. How can we expect optimal therapeuticadherence in view of the high cost of medication, foran unlimited period, in a middle class family withalready over-stretched monthly budget?ConclusionWhereas, the problem of therapeutic non-adherenceis the “end result of complex set of interwoven factors”Manuscript no: ASJBCCR-2-1-22-28Asp Biomed Clin Case RepVolume: 2[35], it is still preventable. This needs onlycommitment.“It always seems impossible until it is done”—-Nelson Mandela (1918-2013 CE)Limitations of the studyThe study is qualitative with a small sample.There was no representation of the prescribers andthose of the pharmacists. All the participants werewithout diabetes associated co-morbidities. It is wellknown that multiple diseases and resultantpolypharmacy further challenge the goodcoordination of the health care.RecommendationsWhereas theWHO recommends that thedeterminants be considered in 5 dimensions: socioeconomic factors, health care team and systemrelated factors, condition related factors , therapyrelated factors and patient related factors [3], alarger multi-centre in-depth quantitative study(involving patients, prescribers and pharmacists )needs to be done on priority basis. This would pavethe way for planning a well-designed interventionprogramme.Ethical ConsiderationsThe procedures adopted in the present study werein accordance with the 1975 Declaration of Helsinki,as reviewed in October 2000.Source of FundingThis research did not receive any specific grantfrom funding agencies in the public, commercial, ornon-for-profit sectors.Conflict of InterestNoneAcknowledgementDr. Murad Ahmad Khan (Vancouver BC Canada)and Dr. Hamza Iltaf Malik (Coventry UnitedKingdom) deserve special thanks for their kind,motivating and stimulating discussions throughoutIssue: 126
Citation: Siddiqui MH, Khan IA, Moyeen F, et al., “Identifying Barriers to Therapeutic Adherence in Type 2-Diabetes: AComplex and Multidimensional Clinical Issue”. Asp Biomed Clin Case Rep, vol.2, no.1: 22-28, 2019.Original Articlethe conduct of this study.References[1] Kardas P, Lewek P, Matyjaszczyk M, “Determinantsof patient adherence: a review of systematic reviews”.Front Pharmacol, vol.4, no.91: 1-28, 2013.[2] ADA, “Diagnosis and Classification of Diabetesmellitus-American Diabetes Association”. DiabeticCare, vol.33, no.suppl 1: s62-s69, 2010.[3] WHO, “Adherence to long term therapies:Evidence for Action”. World Health Organization,Geneva: 2003.[4] WHO, “Global Report on Diabetes”. World HealthOrganization, Geneva: 2016.[5] Meo SA, Zia I, Bukhari IA, et al., “Type 2 Diabetesmellitus in Pakistan:Current prevalence and futureforecast”. J Pak Med Assoc, vol.66, no.12: 1637-42,2016.[6] Gellad W F, Grenard JL, Marcum ZA, “A systematicreview of barriers to medication adherence in theelderly: Looking beyond cost and regimen complexity”.Am J Geriatr Pharmacother, vol.9, no.1: 11-23, 2011.[7] Wroe AL, “Intentional and unintentionalnonadherence: a study of decision making”. J BehavMed, vol.25, no.4: 355–72, 2002.[8] Clifford S, Barber N, Horne R, “Understandingdifferent beliefs held by adherers, unintentionalnonadherers, and intentional nonadherers: applicationof the Necessity Concerns Framework”. J PsychosomRes, vol.64, no.1: 41–46, 2008.[9] Gupta S, Dhamija JP, Mohan I, et al., “Qualitativestudy of barriers to adherence to antihypertensivemedication among rural women in India”. Int JHyperten, vol.2019: 1-7, 2019.[10] Lehane E, McCarthy G, “Intentional sive framework for clinical research andpractice? A discussion paper”. Int J Nurs Stud, vol.44,no.8: 1468-77, 2007.[11] Vrijens B, De Geest S, Hughes DA, et al., “A newtaxonomy for describing and defining adherence tomedications”. Br J Clin Pharmacol, vol.73, no5: 691–705, 2012.[12] Nilsson JLG, Andersson K, Bergkvist A et al.,“Refill adherence to repeat prescriptions of cancerdrugs to ambulatory patients”. Eur J Cancer Care(Engl), vol.15, no.3: 235–37.Manuscript no: ASJBCCR-2-1-22-28Asp Biomed Clin Case RepVolume: 2[13] van Geffen EC, Gardarsdottir H, van Hulten R, etal., “Initiation of antidepressant therapy: do patientsfollow the GP’s prescription?”. Br J Gen Pract, vol.59,no.559: 81–87, 2009.[14] Hugtenburg JG, Timmers L, Elders PJ, et al.,“Definitions, variants, and causes of non-adherencewith medication: a challenge for tailoredinterventions”. Patient Preference Adherence, vol.7:675-82, 2013.[15] US Department of Health and Human Services.Healthy People, Washington DC: 2000.[16] Khattab M, Khader YS, Al-Khawaldeh A et al.,“Factors associated with poor glycemic control amongpatients with Type 2 Diabetes”. J DiabetesComplications, vol.24, no.2: 84-89, 2010.[17] Storm A, Benfeldt E, Andersen SE, et al., “Basicdrug information given by physicians is deficient, andpatients’ knowledge low”. J Dermatolog Treat, vol.20,no.4: 190–93, 2009.[18] Kvarnström K, Airaksinen M, Liira H, “Barriersand facilitators to medication adherence: a qualitativestudy with general practitioners”. BMJ Open, vol.8,no.1: e015332, 2018.[19] Koch T, Kralik D, Sonnack D, “Women livingwith type 2 diabetes: The intrusion of illness”. JClinNurs, vol.8, no.6: 712-22, 1999.[20] van Dulmen S, van Bijnen E, “What makes them(not) talk about proper medication use with theirpatients? An analysis of the determinants of GPcommunication using reflective practice”. Int J PersCen Med, vol.1, no.1: 27–34, 2011.[21] Peschin S, Doane CM, Roberts ME, et al., “PatientAdherence:Identifying Barriers and DefiningSolutions”. Am J Pharm befits: 2010.[22] Brundisini F, Vanstone M, Hulan D, et al., “Type2 diabetes patients’ and providers’ differingperspectives on medication nonadherence: aqualitative meta-synthesis”. BMC Health Serv Res,vol.15, no.516: 1-82, 2015.[23] Polonsky WH, Henry RR, “Poor medicationadherence in type 2 diabetes: recognizing the scope ofthe problem and its key contributors”. Patient PreferAdherence, vol.10: 1299-307, 2016.[24] Barba EL, de Miguel MR, Hernandez-Mijares A,et al, “Medication adherence and persistence in type 2diabetes mellitus: perspectives of patients, physiciansand pharmacists on the Spanish health Care system”.Issue: 127
Citation: Siddiqui MH, Khan IA, Moyeen F, et al., “Identifying Barriers to Therapeutic Adherence in Type 2-Diabetes: AComplex and Multidimensional Clinical Issue”. Asp Biomed Clin Case Rep, vol.2, no.1: 22-28, 2019.Original ArticlePatient Preference Adherence, vol.11: 707-18, 2017.[25] Lin LK, Sun Y, Heng BH, et al., “Medicationadherence and glycemic control among newlydiagnosed diabetes patients”. BMJ Open DiabRes Care,vol.5, no.1: e000429, 2017.[26] Atinga RA, Yarney L, Gavu NM, “Factorsinfluencing long-term medicationnon-adherenceamong diabetes and hypertensive patients in Ghana: Aqualitative investigation”. PLoS One, vol.13, no.3:e0193995, 2018.[27] NCIPE, “Enhancing Prescription MedicineAdherence: A National Action Plan”. Rockville M.D.: 138, 2007.[28] Ronan CA, “The Cambridge Illustrated History ofWorld’s Science”. Cambridge University Press: 1984.[29] Khan MA,Raza F, Khan IA, “IBN Sina and theroots of the seven doctrines of preservation of health”.Acta Med Hist Adriat, vol.13, suppl.2: 87-102, 2015.[30] Salzman C, “Medication compliance in theelderly”. J Clin Psychiatry, vol.56, suppl-1: 18-22, 1995.[31] Zekovic M, Krajnovic D, Marinkovic V, et al.,“The Complexity of Adherence Issue: A Review of itsscope and determinants”. Acta Medica Medianae,vol.55, no.1: 51-57, 2016.[32] Claxton AJ, Cramer J, Pierce C, “A systematicreview of the association between dose regimens andmedication compliance”. Clin Ther, vol.23, no.8:1296-310, 2001.[33] Walter Reed Army Medical Center, “FederalStudy of Adherence to Medications in the Elderly(FAME)”. Clinical Trials.gov: 2006.[34] Heidari P, Cross W, Crawford K, “Do out ofpocket costs affect medication adherence in adultswith rheumatoid arthritis? A systematic review”.Semin Arthritis Rheum, vol.48, no.1: 12-21, 2018.[35] Forsyth P, Richardson J, Lowrie R, “Patientreported barriers to medication adherence in heartfailure in Scotland”. Int J Pharm Pract: 2019.Keywords: Therapeutic Adherence; Type2 Diabetes; Non-Adherence; Under-Adherence; Over-AdherenceManuscript no: ASJBCCR-2-1-22-28Asp Biomed Clin Case RepVolume: 2Issue: 128
Mujtaba Hasan Siddiqui1, Iqbal Akhtar Khan2*, Fauzia Moyeen3, Khawar Abbas Chaudhary4 1Department of Medicine, Akhtar Saeed Medical & Dental College, Lahore, Pakistan 2Independent Scholar, Lahore, Pakistan 3Consultant Diabetologoist, Diabetes Wellness Centre, Lahore, Pakistan 4Department of Medicine, Continental Medical College, Lahore, Pakistan
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