Internal Medicine

Irritable Bowel Syndrome (IBS) At a Glance

Rakesh Kumar Jha, Yanli Zou, Jin Li and Bing Xia

Cite this article as: BJMP 2010;3(4):a342
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Irritable bowel syndrome (IBS) is a common disorder characterized by abdominal pain and altered bowel habit. Hence, IBS is associated with a significantly impaired health-related quality of life (HRQOL) and reduced work productivity around the world. The incidence of IBS is rising dramatically worldwide. Currently, 7 – 10 % of people have IBS worldwide and it is 1.5 times more prevalent in younger women than in men.  Much research has been undertaken during the past several decades, which has lead to deep understanding about IBS, particularly the pathogenesis and management. This review summarizes the epidemiology, underlying pathophysiology, diagnosis and treatment about IBS that has been published in recent years. We hope this review can help to provide some reference in clinical practice for physicians in the management of  IBS.

Keywords:  IBS, Spastic Bowel syndrome, Nervous Bowel, Irritable colon, Splenic Flexure Syndrome, Functional Bowel Disease

Introduction :

Irritable bowel syndrome (IBS) is a common disorder characterized by abdominal pain and altered bowel habit for at least three months.(1)

IBS is further defined depending on the predominant bowel symptom: IBS with constipation (IBS-C) or IBS with diarrhoea (IBS-D). Those not classified as either IBS-C or IBS-D are considered as mixed IBS (IBS-M). Alternating IBS (IBS-A) defines patients whose bowel habits oscillate from diarrhoea to constipation and vice versa.

Synonyms: Spastic Bowel syndrome, Nervous Bowel, Irritable colon, mucous colitis, Splenic Flexure Syndrome, Functional Bowel Disease.(2)


IBS is a prevalent and expensive condition that is associated with a significantly impaired health-related quality of life (HRQOL) and reduced work productivity. IBS care consumes over $ 20 billion in both direct and indirect expenditures. Moreover, patients with IBS consume over 50% more health care resources than matched controls without IBS.(1)Based on strict criteria, 7 – 10 % of people have IBS worldwide. Community-based data indicate that diarrhoea-predominant IBS (IBS-D) and mixed IBS (IBS-M) subtypes are more prevalent than constipation-predominant IBS (IBS-C), and that switching among subtype groups may occur. IBS is 1.5 times more common in women than in men, is more common in lower socioeconomic groups, and is more commonly diagnosed

in patients younger than 50 years of age. Prevalence estimates of IBS range from 1 % to more than 20% in North America(7%).(1) In Asia the prevalence is about 5%.(3,4,5)Recently, a School-Based Study in china reported the prevalence of IBS in adolescents and children was 13.25%  and the ratio of boys to girls was 1:1.8.(6) Most patient with IBS in India are middle-aged men (mean age 39.4 years).(7)

Underlying pathophysiology:

Given the lack of definitive organic markers for IBS, the absence of a consolidated hypothesis regarding its underlying pathophysiology is not surprising. Nevertheless, important advances in research made during the past 50 years have brought us closer than ever to understanding the numerous existing aetiological factors involved in this multifaceted disorder, including environmental factors, genetic factors, previous infection, food intolerance, and abnormal serotonergic signaling in the GI tract.

Environmental factors :

The biopsychosocial model proposed by Engel(8) takes into account the interplay between biologic, psychological, and social factors. This model proposes that there is an underlying biologic predisposition for IBS that may be acted on by environmental factors and psychological stressors, which contribute to disease development, the patient's perception of illness, and impact on treatment outcomes. Different studies have shown that stress can result in release of stress-related hormones that affect colonic sensorimotor function (eg, corticotropin-releasing factor [CRF] and inflammatory mediators [eg, interleukin (IL)-1]), leading to inflammation and altering GI motility and sensation.

Genetics factors :

Twin studies have shown that IBS is twice as prevalent in monozygotic twins than in dizygotic twins.(9,10,11) IBS may be associated with selected gene polymorphisms, including those in IL-10, G-protein GNb3, alpha adrenoceptor, and serotonin reuptake transporter (SERT).

Post-infectious IBS (PI-IBS):

Culture positive gastroenteritis is a very strong risk factor for IBS. Different prospective studies show IBS symptoms developed in 7% to 32% of patients after they recovered from bacterial gastroenteritis.(12,13,14) Specific risk factors for the development of PI-IBS have been identified, including younger age, female sex, presence of severe infectious gastroenteritis for a prolonged period, use of antibiotics to treat this infection, and presence of concomitant psychological disorders (eg, anxiety).(12,13,15,16)

Small Intestinal bacterial overgrowth

Pimentel and colleagues(17,18) have shown that, when measured by the lactose hydrogen breath test (LHBT), small intestinal bacterial overgrowth (SIBO) has been detected in 78% to 84% of patients with IBS. Hence, a higher than usual population of bacteria in the small intestine has been proposed as a potential aetiological factor in IBS. While another study involving a review for the presence of gastrointestinal-related symptoms (including IBS) has shown that asensitivity of the LHBT for SIBO has been shown to be as low as 16.7%, and specificity approximately 70% and the test alone for small intestinal bacterial overgrowth were poor. Hence, combination with scintigraphy resulted in 100% specificity to assess the treatment responce, because double peaks in serial breath hydrogen concentrations may occur as a result of lactulose fermentation by cecal bacteria. (19,20)

Food intolerance :

Approximately 60% of IBS patients believe and different studies show that allergy to certain foods could trigger IBS symptoms. Recent research involving exclusion of foods patients had immunoglobulin (Ig) G antibodies, which are associated with a more delayed response after antigen exposure than IgE antibodies, resulted in significantly better symptom improvement than in patients in the non-exclusion group.(21)

Serotonin signaling in Gastrointestinal (GI) tract:

Normal gut physiology is predicated to be an interaction between the GI musculature and the autonomic nervous system (ANS), and central nervous system (CNS) by the neurotransmitter serotonin (5-hydroxytryptamine [5-HT]) . Impairment in this interaction affects GI motility, secretion, and visceral sensitivity leading to the symptoms associated with IBS .(22)

Preliminary steps toward making a positive diagnosis of IBS:

A careful history and physical examination are frequently helpful in establishing the diagnosis. A variety of criteria have been developed to identify a combination of symptoms to diagnose IBS. Different guidelines from different studies help in making a positive diagnosis of IBS based primarily on the pattern and nature of symptoms, without the need for excessive laboratory testing. In 1978, Manning and colleagues (23,24) proposed diagnostic criteria for IBS that were found to have a reasonable sensitivity of 78% and a specificity of 72%.(1) In 1984, Kruis and colleagues developed another diagnostic criteria with a high sensitivity of 77% and a specificity 89%. Likewise, in 1990 Rome I (25) criteria came with a sensitivity of 71% and specificity of 85%. RomeII(1999)(26) and Rome III(2006)(27) have not been evaluated yet. None of the symptom based diagnostic criteria have been evaluated and ideal reliability found.(1)

Summary of diagnostic criteria used to define IBS:(1)

In 1978, Manning defined IBS as a collection of symptoms, given below, but did not describe their duration. The number of symptoms that need to be present to diagnose IBS was also not reported in the paper, but a threshold of three positive is the most commonly used:

a)      Abdominal pain relieved by defecation

b)      More frequent stools with onset of pain

c)      Looser stools with onset of pain

d)      Mucus per rectum

e)      Feeling of incomplete emptying

f)       Patient-reported visible abdominal distension


Kruis in 1984, defined IBS by a logistic regression model that describes the probability of IBS. Symptoms need to be present for more than two years. Symptoms are as follows:

a)      Abdominal pain, flatulence, or bowel irregularity

b)      Description of character and severity of abdominal pain

c)      Alternating constipation and diarrhea


Signs that exclude IBS (each determined by the physician) :

a)      Abnormal physical findings and/or history pathognomonic for any diagnosis other than IBS

b)      Erythrocyte sedimentation rate >20 mm/2 h

c)      Leukocytosis >10,000/cc

d)      Anaemia (Hemoglobin < 12 for women or < 14 for men)

e)      Impression, the physician could perform a PR and see blood or the patient may report it.

Again in 1990, Rome I defined IBS as abdominal pain or discomfort relieved with defecation, or associated with a change in stool frequency or consistency, PLUS two or more of the following symptoms on at least 25% of occasions or days for three months:

a)      Altered stool frequency

b)      Altered stool form

c)      Altered stool passage

d)      Passage of mucus

e)      Bloating or distension


Rome II, in 1999, redefined the criteria as abdominal discomfort or pain that has two of three features for 12 weeks (need not be consecutive) in the last one year.

a)      Relieved with defecation

b)      Onset associated with a change in frequency of stool

c)      Onset associated with a change in form of stool


Recently , Rome III (2006) defined IBS as recurrent abdominal pain or discomfort three days per month in the last three months associated with two or more of:

a)      Improvement with defecation

b)      Onset associated with a change in frequency of stool

c)      Onset associated with a change in form of stool


The role of routine diagnostic investigation in patients with IBS:

Routine diagnostic investigation is based on the age of the patient, family history of selected organic diseases including colorectal cancer, inflammatory bowel disease(IBD), coeliac sprue and the presence of ‘alarm’ features(table1), such as rectal bleeding, weight loss, iron deficiency anaemia and nocturnal symptoms.(1)  In patient with typical IBS symptoms and no alarm features, routine diagnostic investigation (complete blood count, serum chemistry, thyroid function tests, stool for ova and parasites and abdominal imaging) is not recommended(1) because of a low likelihood of uncovering organic disease.


Table-1  Lists of alarm features:

Rectal bleeding

Weight loss

Iron deficiency anaemia

Nocturnal symptoms: abdominal pain

family history of of selected organic diseases: colorectalcancer, Inflammatory Bowel Disease(IBD), celiac sprue

 Summary of diagnostic investigation in patient with IBS : (1,2)



Diagnostic Investigations :

Routine serologic screening for coeliac sprue for patients with IBS-D and IBS-M.

Lactose Breath test done in lactose maldigestion despite dietary modification.

Colonoscopic Imaging done in IBS patient (>50 yrs age) with alarm feature to rule out organic diseases and screening of colorectal cancer.

Colonoscopy with random biopsies taken in IBS-D to rule out microscopic colitis.



Management of IBS:

The goal of IBS management is to provide relief of symptoms and improve overall well-being.(28) Most studies use a combination therapy including patient education and psychological therapies, diet and fibre therapy along with different types of new emerging pharmacological therapies.

Patient education and psychological therapies:

The majority of patients with IBS have anxiety, depression and features of somatization. Psychological therapies, including cognitive behavioral therapy, dynamic psychotherapy, hypnotherapy(1) shed new light on the management of patients with IBS. The outcome of psychological therapies is improved when delivered by a trained professional (physician, occupational therapist, nurse).(29)  A study by Guthrie(30) showed that psychological therapy is feasible and effective in two thirds of patients with IBS who do not respond to standard medical treatment.

Role of diet in IBS:

The concept of food intolerance and the consequent elimination of certain foods from the diet benefit symptoms of IBS. However, there is no sufficient evidence to support this.(1)

Therapeutic effect of dietary fibre, bulking agents and laxatives: The quality of evidence supporting the recommended use of dietary fibre or bulking agents to regularize bowel function is poor.(31) Ispaghula husk (Psyllium hydrophilic mucilloid ) and calcium polycarbophil are moderately effective and can be given a conditional recommendation because of the weakest type of evidence.(1)  Polyethylene glycol(PEG) laxative has a role in improving stool frequency but no effect on abdominal pain. Different clinical studies and expert opinion suggest that increased fibre intake may cause bloating, abdominal distension and flatulence.(32) So gradual adjustment of dose is advised for the use of these agents.

Therapeutic effect of antispasmodic agents including peppermint oil: 

Certain antispasmodics (hyoscine, cimetropium,and pinaverium and peppermint oil) may provide short-term relief of abdominal pain/discomfort in IBS.(33,34)Evidence for safety and tolerability


Mechanism of action

Targeted disorder

Clinical status




Phase2b complete


Guanylate cyclase-c agonist


Phase 3


Calcium channel blocker 


Phase 3


Kappa opioid agonist


Phase 2b complete


Motilin receptor agonist


Phase 2


5-HT 3 antagonist


Phase 3


5-HT 4 agonist 


Phase 2


5-HT 3 agonist


Phase 2


5-HT 3 antagonist and NE reuptake inhibition


Phase 2


Corticotropin-releasing hormone antagonist 


Phase 2


Corticotropin-releasing hormone antagonist


Phase 2


Glucagon-like peptide 

IBS pain

Phase 2


Alpha receptor agonist

IBS pain

Phase 2


Beta-3 receptor agonist


Phase 2

Espindolol (AGI-011)  

Beta receptor antagonist

IBS (all subtypes)

Phase 2


2,3 benzodiazepinereceptors 

IBS-D and IBS-M 

Phase 3

Table 1: Source: ACG Task Force on IBS(2009)

of these agents are very limited.The commonest adverse effects are dry mouth,dizziness and blurred vision.(34-36)

Therapeutic effect of anti-diarrhoeal medications:

The anti-diarrhoeal agent ‘Loperamide’ is effective at slowing down colonic transit and improving  stool consistency for the treatment of IBS-D with no severe adverse effects.(37) But safety and tolerability datas are still lacking in many studies.

Therapeutic effect of antibiotics: 

Many studies show well tolerance of a short term course of non-absorbable antibiotics (Rifaximin) is most effective for improvement of global symptoms in IBS-D and IBS patient with the predominant symptom of bloating and other associated symptoms, such as diarrhoea and abdominal pain.(38-40) While, the Unted States Food and Drug Administration (FDA or USFDA)  approved Rifaximin for treatment of traveler’s diarrhoea. Other antibiotics, Neomycin(41), Clarithromycin and Metronidazole(42) have been well evaluated for the management of IBS.

Therapeutic effect of Probiotics: 

Probiotics have a large number of properties that can benefit IBS. Bifidobacteria is the active agent in probiotic combination therapy.Whereas many studies show Lactobacilli to have no impact on symptoms.(43) But one Korean study concluded that the composite probiotics containing Bifidobacterium bifidum BGN4, Lactobacillus acidophilus AD031, and other species are safe and effective, especially in patients who excrete normal or loose stools.(44) Recently, P Moayyedi and colleague in their systematic review recommend that probiotics appear to be efficacious in IBS patients ,but the magnitude of benefit and the most effective species and strain are uncertain. (45) 

Therapeutic effect of the 5HT3 receptor antagonists: 

Alosetron (5-HT3 receptor antagonists), with dosage of 0.5 to 1 mg daily, is more effective and the commonest drug used for treatment of patients with IBS-D in spite of serious side effects including constipation and colon ischemia.The balance model of benefits and harms for ‘Alosetron’ is most encouraging in women who have not responded to conventional therapies.(46,47)

Therapeutic effect of 5-HT4 receptor agonists: 

Tegaserod (5-HT4 receptor agonist) is more effective for the treatment of IBS-C mostly in female and IBS-M. The side effects reported among the patient receiving Tegaserod are diarrhoea (commonest), cardiovascular events i.e. myocardial infarction, unstable angina, or stroke.(48,49) Currently Tegaserod is available from FDA through an emergency investigational new drug protocol. Other 5-HT4 agonists (Cisapride,Renzapride) have not demonstrated improvement compared with placebo.(50,51)

Therapeutic effect of the selective C-2 chloride channel activators: 

Lubiprostone (selective C-2 chloride channel activator) is effective for relieving symptoms of IBS-C, mostly in women, and has less frequent side-effects including nausea(8%), diarrhea(6%) and abdominal pain(5%).(52)

Therapeutic effect of antidepressants : 

Patients with prominent symptom of abdominal pain in IBS that fails to respond to peripherally acting agents often are considered for treatment with antidepressants (TCAs and SSRIs), however, limited data on safety and tolerability of these agents is shown.(53) Antidepressants have the combined effect of both central and peripheral mechanism in IBS.(54) SSRIs are better tolerated than TCAs and have a prokinetic effect hence work better in IBS-C.(53,55) whereas TCAs are of greater benefit for IBS-D.

Therapeutic effect of herbal therapies and acupuncture: 

Unique Chinese herbal mixtures show a benefit in IBS management.(56)  Traditional Chinese herbal remedies are routinely used in China to treat the condition, but so far have not been generally accepted by conventional Western medicine.(56,57) Bensoussan and colleague in one randomized, double-blind, placebo-controlled trial concluded that the Chinese herbal formulations appear to offer improvement in symptoms for some patients with IBS.(57)  A systematic review of different trials of acupuncture was inconclusive because of heterogenous outcomes.(58,59)  Hence further work is needed before any recommendations on acupuncture or herbal mixtures therapy.

Emerging therapies :

The improved understanding of underlying mechanisms in IBS is beneficial for the development of new pharmacological treatment options.

A brief overview of emerging agents in IBS therapy summarized in Table 1 (1)


IBS is a true medical disorder that has significant impact on those in agony with regard to symptom severity, disability, and impaired quality of life, which exceeds that of most GI disorders. Advances in research over the past several decades have paved the way for an ameliorable understanding of the underlying pathophysiology and standardized symptom-based approaches that can be implemented in making a positive diagnosis and development of innovative treatment options for multiple IBS symptoms. Although many unanswered questions remain, the progress is promising and it has equipped physicians better to efficiently diagnose IBS and choose from a growing armamentarium of treatment options.

Competing Interests
None declared
Author Details
RAKESH KUMAR JHA , MBBS, MD Department of Internal Medicine ( Gastroenterology ),Zhongnan Hospital, Wuhan University School of Medicine,Donghu Road 169,Wuhan 430071 Hubei Province, P.R. of China YANLI ZOU Yanli, MD Department of Internal Medicine ( Gastroenterology ),Zhongnan Hospital, Wuhan University School of Medicine,Donghu Road 169,Wuhan 430071 Hubei Province, P.R. of China JIN LI Jin, MD , Ph.D. Zhongnan Hospital, Wuhan University School of Medicine Donghu Road 169,Wuhan 430071 Hubei Province, P.R. of China BING XIA , MD, Ph.D Director of Department of Gastroenterology,Director of Department of Internal Medicine Chair of Clinical Center for Intestinal & Colorectal Diseases of Hubei Province, Zhongnan Hospital, Wuhan University School of Medicine,Wuhan 430071, Hubei, PR China
CORRESSPONDENCE: Prof. BING XIA , MD, PhD, Director of Department of Gastroenterology,Director of Department of Internal Medicine,Chair of Clinical Center for Intestinal & Colorectal Diseases of Hubei Province Zhongnan Hospital, Wuhan University School of Medicine Donghu Road 169,Wuhan 430071 Hubei Province, P.R. of China


  1. Brandt LJ, Chey WD, Foxx-Orenstein AE et al. An Evidence-Based Systematic Review on the Management of Irritable Bowel Syndrome. Am J Gastroenterology2009;104:S1 – S35
  2. Avunduk C. Irritable bowel syndrome. Manual of gastroenterology:diagnosis and therapy 2002;3:223-227
  3. Lule GN, Amayo EO. Irritable bowel syndrome in Kenyans. East AfrMed J 2002;79:360–363
  4. Saito YA, Schoenfeld P, Locke GR. The epidemiology of irritable bowel syndrome in North America: a   systematic review. Am J Gastroenterol2002;97:1910–1915
  5. Ringel Y, Sperber AD, Drossman DA. Irritable bowel syndrome. Annu Rev Med2001;5:319–338
  6. Liu Dong, Li Dingguo, Xu Xiaoxing et al.An Epidemiologic Study of Irritable Bowel Syndrome   in Adolescents and Children in China: A School-Based Study.Pediatrics 2005;116;e393-e396.
  7. Ghoshal UC, Abraham P, Bhatt C, et al. Epidemiological and clinical profile of irritable bowel syndrome in India: report of the Indian Society of Gastroenterology Task Force. Indian J Gastroenterol 2008;27:22-28.
  8. Engel GL. The need for a new medical model: a challenge for biomedicine. Science 1977;196:129-136.
  9.  Falk P. Is IBS a genetic disorder? FBG Newsletter 2003:10-15.
  10.  Levy RL, Jones KR, Whitehead WE, et al. Irritable bowel syndrome in twins: heredity and social learning both contribute to etiology. Gastroenterology 2001;121:799-804.
  11. Morris-Yates A, Talley NJ, Boyce PM, et al. Evidence of a genetic contribution to functional bowel disorder. Am J Gastroenterol 1998;93:1311-1317.
  12. Barbara G, De Giorgio R, Stanghellini V, et al.  A role for inflammation in irritable bowel syndrome? Gut  2002;51(suppl 1):i41-i44.
  13. Mach T. The brain-gut axis in irritable bowel syndrome--clinical aspects. Med Sci Monit 2004;10:RA125-RA131
  14. Spiller RC, Jenkins D, Thornley JP, et al. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut  2000;47:804-811
  15. Barbara G, De Giorgio R, Stanghellini V, et al. New pathophysiological mechanisms in irritable bowel syndrome. Aliment Pharmacol Ther 2004;20:1-9.
  16. Dunlop SP, Jenkins D, Neal KR, et al. Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS. Gastroenterology 2003;125:1651-1659
  17. Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol 2000;95:3503-3506.
  18. Pimentel M, Chow EJ, Lin HC. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome. A double-blind, randomized, placebo-controlled study. Am J Gastroenterol 2003;98:412-419.
  19. Riordan S, McIver C, Walker B, et al.. The lactulose breath hydrogen test and small intestinal bacterial overgrowth. Am J Gastroenterol 1996;9:1795-1803.
  20. O'Leary C, Quigley EM. Small bowel bacterial overgrowth, celiac disease, and IBS: what are the real associations? Am J Gastroenterol 2003;98:720-722.
  21. Atkinson W, Sheldon TA, Shaath N, et al. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Gut 2004;53:1459-1464.
  22. Coates MD, Mahoney CR, Linden DR, et al. Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome. Gastroenterology  2004;126:1657-1664
  23. Manning AP, Thompson WG, Heaton KW, et al. Towards positive diagnosis of the irritable bowel. BMJ 1978;2:653-654
  24. Lembo TJ, Fink RN. Clinical assessment of irritable bowel syndrome. J Clin Gastroenterol 2002;35:S31-S36.
  25. Thompson WG, Creed FH, Drossman DA. Functional bowel disorders and functional abdominal pain. Gastroenterol Int. 1992;5:75-91.
  26. Thompson WG, Longstreth GF, Drossman DA, et al. Functional bowel disorders and functional abdominal pain. Gut 1999;45(suppl II):II43-II47.
  27. Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology  2006;130:1377-1390
  28. Brandt LJ, Bjorkman D, Fennerty MB, et al. Systematic review on the management of irritable bowel syndrome in North America. Am J Gastroenterol  2002;97:S7-S26.
  29. Tries J, Plummer MK, Wisconsin OTR. Biofeedback and bowel disorders: Teaching yourself to live without the problem. Available at: Accessed May 26, 2006.
  30. Guthrie E. Brief Psychotherapy with Patients with Refractory Irritable Bowel Syndrome. British Journal of Psychotherapy 1991; 8: 175–188. 
  31. Soltofit J, Gudmand-Hoyer E, Krag B et al. A double-blind trial of the effect of wheat bran on symptoms of irritable bowel syndrome. Lancet 1976;I:270-2.
  32. Snook J, Shepherd HA. Bran. supplementation in the treatment of irritable bowel syndrome. Aliment Pharmacology Ther 1994;8:511-4
  33. Nigam P , Kapoor KK , Rastog CK et al. Different therapeutic regimens in irritable bowel syndrome . J Assoc Physicians India 1984 ; 32 : 1041 – 4 .
  34.  Passaretti S , Guslandi M , Imbibo BP et al. Effects of cimetropium bromide on gastrointestinal transit time in patients with irritable bowel syndrome. Aliment Pharmacol Ther 1989 ; 3 : 276 .
  35. Schafer VE , Ewe K. The treatment of irritable colon. Efficacy and tolerance of buscopan plus, buscopan, paracetamol and placebo in ambulatory patients with irritable colon . Fortschr Med 1990 ; 108 : 488 – 92 .
  36. Glende M , Morselli-Labate AM , Battaglia G e t al. Extended analysis of a double blind, placebo-controlled, 15-week study with otilinium bromide in irritable bowel syndrome . Eur J Gastroenterol Hepatol 2002 ; 14 : 1331 – 8 .
  37. Hovdenak N . Loperamide treatment of the irritable bowel syndrome . Scand J Gastroenterol 1987 ; 130 : 81 – 4 .
  38. Ringel Y , Palsson OS , Zakko SF et al. Predictors of clinical response from a phase 2 multi-center efficacy trial using rifaximin, a gut-selective, nonabsorbed antibiotic for the treatment of diarrhea associated irritable bowel sydnrome . Gastroenterology 2008 ; 134 (suppl 1) : A550 (T1141) .
  39. Lembo A , Zakko SF , Ferreira NL et al. T1390 Rifaximin for the treatment of diarrhea associated irritable bowel syndrome: short term treatment leading to long term sustained response . Gastroenterology 2008 ; 134 (suppl 1) : A 545 (T1390) .
  40. Pimentel M , Park S , Kong S et al. A 10-day course of rifaximin, a nonabsorbable antibiotic, produces a durable improvement in all symptoms of irritable bowel syndrome: a double-blind randomized controlled study .Gastroenterology 2006 ; 130 : A134 .
  41. Pimentel M , Chow EJ , Lin HC . Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome. A double-blind, randomized, placebo-controlled study . Am J Gastroenterol 2003 ; 98 : 412 – 9 .
  42. Nayak AK , Karnad DR , Abraham P , et al. Metronidazole relieves symptoms in irritable bowel syndrome: the confusion with so-called ‘ chronic amebiasis ’ . Indian J Gastroenterol 1997 ; 16 : 137 – 9 .
  43. Guyonnet D , Chassany O , Ducrotte P et al. Effect of a fermented milk containing Bifidobacterium animalis DN-173 010 on the health-related quality of life and symptoms in irritable bowel syndrome in adults in primary care: a multicentre, randomized, double blind, controlled trial . Aliment Pharmacol Ther 2007;26:475 – 86 .
  44. Kyoung Sup Hong,Hyoun Woo Kang,Jong Pil Im et al. Effect of Probiotics on Symptoms in Korean Adults with Irritable Bowel Syndrome. Gut Liver 2009;3(2):101-107.
  45. P Moayyedi, A C Ford, N J Talley et al. The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review. Gut 2010;59:325-332.
  46. Chang L , Ameen VZ , Dukes GE e t al. A dose-ranging, phase II study of the efficacy and safety of alosetron in men with diarrhea-predominant IBS . Am J Gastroenterol 2005 ; 100 : 115 – 23 .
  47. Krause R , Ameen V , Gordon SH e t al. A randomized, double-blind, placebo-controlled study to assess efficacy and safety of 0.5 mg and 1 mg alosetron in women with severe diarrhea-predominant IBS . Am J Gastroenterol 2007 ; 102 : 1709 – 19 .
  48. Ford AC , Brandt L , Foxx-Orenstein A et al. Efficacy of 5HT4-agonists in non-diarrhea predominant irritable bowel syndrome: systematic review and meta-analysis . Am J Gastroenterol 2008 ; 103 (suppl 1) : S478 (1222)
  49. Chey WD , Pare P , Viegas A e t al. Tegaserod for female patients suffering from IBS with mixed bowel habits or constipation: a randomized controlled trial . Am J Gastroenterol 2008 ; 103 : 1217 – 25 .
  50.  Ziegenhagen DJ , Kruis W . Cisapride treatment of constipation-predominant irritable bowel syndrome is not superior to placebo . J Gastroenterol Hepatol 2004 ; 19 : 744 – 9 .
  51. George AM , Meyers NL , Hickling RI .Clinical trial: Renzapride therapy for constipation-predominant irritable bowel syndrome — multicentre, randomized, placebo-controlled, double-blind study in primary healthcare setting . Aliment Pharmacol Ther 2008;27:830–7 .
  52. Drossman DA , Chey WD , Panas R e t al. Lubiprostone significantly improves symptom relief rates in adults with irritable bowel syndrome and constipation (IBS-C): data from two twelve-week, randomized, placebocontrolled, double-blind trials . Gastroenterology 2007 ; 132 : 2586 – 7 .
  53. Talley NJ . SSRIs in IBS: sensing a dash of disappointment . Clin Gastroenterol Hepatol 2003 ;1:155- 9 .
  54. Clouse RE . Managing functional bowel disorders from the top down: lessons from a well-designed treatment trial . Gastroenterology 2003 ; 125 : 249 – 53 .
  55. Gorard DA , Libby GW , Farthing MJG. Influence of antidepressants on whole gut orocaecal transit times in health and irritable bowel syndrome . Aliment Pharmacol Ther 1994 ; 8 : 159 – 66 .
  56. Madisch A , Holtmann G ,Plein K et al.Treatment of irritable bowel syndrome with herbal preparations: results of a double-blind, randomized, placebocontrolled, multi-centre trial. Aliment Pharmcol Ther 2004; 19 : 271 – 9 .
  57. Alan Bensoussan, Nick J. Talley, Michael Hing , et al. Treatment of irritable bowel syndrome with Chinese herbal medicine. JAMA 1998;280:1585-1589.
  58. Fireman Z, Segal A, Kopelman Y, Sternberg A, Carasso R. Acupuncture Treatment for Irritable Bowel Syndrome. Digestion 2001;64:100-103 
  59. Julie A Reynolds, J Martin Bland, Hugh MacPherson. Acupuncture for irritable bowel syndrome – an exploratory randomised controlled trial. ACUPUNCTURE IN MEDICINE 2008;26(1):8-16.


Evidence based evaluation of syncope of uncertain origin

Vinoth Sankar, Steven Close and Stephen J Leslie

Cite this article as: BJMP 2010;3(4):a340
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Syncope is a common medical condition encountered in clinical practice. The pathophysiology can be complex and at times making a definitive diagnosis can be difficult. It can be associated with high rates of morbidity and mortality. Physicians’ approaches to this condition are varied and at times, due to lack of a methodical approach, potential life threatening conditions are missed. Some patients are under investigated while other patients are over investigated. This increases the already high health care costs associated with managing this condition. This article discusses an evidence based methodical approach to diagnosis and treatment of this often complex condition.
Keywords:  Syncope, Collapse, Guidelines


Syncope is a common condition encountered in acute medical practice. Many patients with syncope are initially labelled as having “collapse query cause”. It is defined as transient loss of consciousness (T-LOC) due to transient global cerebral hypoperfusion characterized by rapid onset, short duration, and spontaneous complete recovery1. Incidence of syncope is difficult to determine accurately as many cases remain unreported. Some studies quote an overall incidence rate of a first report of syncope to be 6.2 per 100 person-years. Clearly this is age related and the incidence increases dramatically in patients over the age of 70 years2. Syncope accounts for 1-6% of hospital admissions and 1% of emergency department (ED) visits per year3-5. Hospital episode statistics from NHS hospitals in England reported a total of 119,781 episodes of collapse/syncope for the financial year 2008-09 which is about twice the number of episodes reported in the year 1999-2000. About 80% of patients were admitted and they have an average length of stay of 3 days accounting for over 269,245 bed days during that financial year6.


Syncope is also associated with significant mortality and morbidity if left untreated. Literature reports a 6-month mortality of 10%, which can go up to 30% if cardiac syncope is untreated7. Non-cardiac syncope is associated with a survival rate comparable to people with no syncope2. Syncope is also a risk factor for fractures related to falls especially in elderly and can cause significant morbidity in this group8. In addition, there are significant health care related costs associated with management of syncope. Cost per diagnosis can vary from over £611 in the UK to €1700 in Italy. Hospitalisation alone accounted for 75% of cost in some studies9,10. Diagnosis of this condition can be difficult especially if there is a lack of structured approach. Over the last few years this topic has attracted enormous interest and several studies have been published, aiming at improving the approach to this condition. Standardised syncope pathways improve diagnostic yield and reduced hospital admissions, resource consumption and over all costs10. Recently the task force for the diagnosis and management of syncope of  the European Society of Cardiology published guidelines for the diagnosis and management of syncope1. However, in spite of the available evidence very few hospitals have standardised syncope pathways for the management of this complex condition. Only 18% of EDs have specific guidelines and access to a specialist syncope clinic11. This article focuses on evidence based structured evaluation of syncope. Current practice in the management of syncope Due to the difficulty in diagnosis and mortality associated with this condition, a cautious approach may be taken by physicians resulting in hospitalisation of majority of patients presenting with syncope. We recently audited the practice of syncope in our hospital, which is a tertiary centre in the north of Scotland. 58 patients admitted with this condition over a period of a month were included in the audit. It showed an average length of stay (LOS) of 4.76 days in these patients. Due to a lack of methodical approach and standardised pathway for management of this condition many patients were subjected to several inappropriate inpatient investigations significantly prolonging the LOS and increasing the cost. Only 7 (12%) cardiac events were observed in this group and in retrospect a good methodical approach would have predicted these events. It should be noted that even in the geriatric population, reflex syncope that carries a benign prognosis is more common than cardiac syncope2A systematic approach to the management of syncope (Figures 1 and 2).   The causes of syncope can be broadly divided in to cardiac causes and non-cardiac causes (Table 1). Initial evaluation leads to a diagnosis in less than 50% patients in most instances4,12-14. If there is uncertainty about diagnosis then the patient is risk stratified. High-risk patients are hospitalised, evaluated and treated whereas early discharge could be considered in low risk patients. Aetiology of Syncope41

Neurally-mediated (Reflex) Syncope Cerebro vascular
  • Vasovagal syncope
  • Carotid sinus syncope
  • Situational syncope

e.g., Micturition, post prandial, defecation, cough

  • Vascular steal syndromes
Cardiac Orthostatic
Structural cardio-pulmonary disease
  • Obstructive valvular heart disease/cardiomyopathies
  • Acute aortic dissection
  • atrial myxoma
  • pericardial tamponade
  • pulmonary embolus
  • pulmonary hypertension

Cardiac arrhythmias

  • Brady arrhythmias - Sinus node and AV node disease
  • Tachyarrhythmias - Paroxysmal supraventricular and ventricular tachycardia,
  • Inherited syndromes (prolonged QT, Brugada syndrome),
  • Pacemaker or Implantable Cardioverter Defibrillator malfunction

  • Autonomic failure
  • Primary autonomic failure syndromes e.g. Parkinson’s disease, multi system atrophy, pure autonomic failure
  • Secondary autonomic failure syndromes e.g. diabetic neuropathy, amyloid neuropathy
  • Drug and alcohol induced orthostatic syncope
  • Volume depletion

 Initial evaluation (Table 2)

  • History
  • Witness account
  • Physical examination
  • Vitals – heart rate, lying and standing blood pressure, oxygen saturation, blood glucose
  • Standard 12 lead ECG
  • Relevant blood tests (e.g. to rule out metabolic abnormality)
  • Pacemaker check if appropriate

 History Many patients with syncope are initially labelled as having “collapse query cause”. Loss of postural tone is termed “collapse”. Indeed, the term “collapse query cause” does not give any useful information regarding the underlying condition. A clear history from the patient and the bystander or witness (if available) is the key to the diagnosis. Firstly, determine if the collapse was associated with loss of consciousness (LOC). LOC can be transient (T-LOC) or prolonged. Categorising “collapse” is important at this stage as the aetiology and approach to each category is different (Figure 1). Secondly, establish if the collapse was syncopal. The LOC should be transient (e.g. did the patient regain consciousness in the ambulance, before or on arrival to hospital?), of rapid onset and associated with a spontaneous complete recovery. Also the mechanism should be due to transient global hypoperfusion. T-LOC secondary to other mechanisms such as trauma and brief seizures should be excluded. On occasions syncope could be associated with brief jerking movements mimicking seizures15. Also note that a transient ischemic attack (TIA), commonly listed as a differential diagnosis of syncope by physicians, is not a cause of syncope as this is not associated with global cerebral hypoperfusion. The absence of a coherent history because patient had no recollection of events and there was no witness account available can make this distinction difficult. This is also particularly difficult in the elderly with cognitive impairment. Other useful information includes whether the syncope was associated with postural change. Orthostatic hypotension occurs after standing. If present it will be useful to check drug history (new vasodepressive drugs). Features suggestive of Parkinson’s disease or amyloidosis may raise the possibility of autonomic neuropathy. A strong family history of sudden cardiac death may be of relevance. Table 3 summarises the features of neurally mediated and cardiac syncope. Table 3 Features suggesting neurally mediated and cardiac syncope42

Neurally mediated Cardiac
  • Preceded by prodrome
  • Related to particular activity - e.g., Micturition, postprandial, prolonged standing, unpleasant situations
  • Associated with nausea and vomiting
  • After exertion


  • Absence of prodrome, no warning
  • Associated with chest pain, breathlessness, palpitation
  • During exertion or supine
  • History of cardiac disease
  • Family history of sudden cardiac death

Physical examination The next step is a thorough physical examination. This should include an ABC approach if the patient is very ill and particular attention should be given to exclude immediate life threatening conditions such as pulmonary embolism, acute myocardial infarction, life threatening arrhythmias, acute aortic dissection, seizures etc… Recording the vital signs is important as it may give a clue to diagnosis (e.g., acute hypoxia may indicate massive pulmonary embolism). Recording postural blood pressure when lying and during active standing for 3 minutes is useful to exclude orthostatic hypotension1. Recording a deficit in blood pressure in both arms may be a useful clinical finding especially if acute aortic dissection is suspected. Thorough cardio respiratory examination may reveal an obvious condition such as cardiac failure or aortic stenosis. Patients should also be examined for potential injuries as a result of syncope. Standard ECG A 12 lead ECG should be performed in all patients admitted with syncope. The abnormalities in table 4 would suggest a cardiac aetiology. The QT interval should always be measured, as it is a commonly overlooked abnormality. Blood tests Blood tests are usually unhelpful in establishing a diagnosis but can detect metabolic abnormalities such as hypoglycaemia, electrolyte abnormalities and other causes to explain LOC especially when witness account is not available. An acute drop in haemoglobin suggests blood loss. One recent study claims the usefulness of brain natriuretic peptide (BNP) for predicting adverse outcomes in syncope but it is not externally validated yet and it is too early to recommend for routine clinical practice16Pacemaker check It is not uncommon to see a patient with a pacemaker implanted, admitted to hospital with syncope. In these circumstances, it is essential to rule out a device malfunction although this is not a common cause of syncope. A preliminary and easy test will be interrogating the pacemaker if available. This should pick up any problems with the pacemaker in most instances. With the above information establishing a diagnosis will be possible in a significant proportion of patients. Further investigations and management should be guided by the underlying diagnosis1. However in over half of patients the diagnosis may still be uncertain12,13,17. The following section explains the management of unexplained syncope. Risk stratification in patients with unexplained syncope (Tables 4 and 5) Table 4   ECG changes in ‘high-risk’ Syncope41

ECG changes favouring bradyarrhythmias
  • High degree AV blocks – Mobitz type 2 second degree AV block, complete heart block,   trifascicular block (first degree heart block with left bundle branch block (LBBB) or right   bundle branch block (RBBB) with axis deviation)
  • Bifascicular block (defined as either LBBB or RBBB combined with left anterior fascicular   block or left posterior fascicular block) especially if new
  • Other intraventricular conduction abnormalities (QRS duration >0.12 s)
  • Asymptomatic sinus bradycardia (<50 bpm), sinoatrial block or sinus pause >3 s in the   absence of negatively chronotropic medications

 ECG changes favouring tachyarrhythmias

  • Pre-excited QRS complexes (e.g. WPW syndrome)
  • Prolonged QT interval
  • Right bundle branch block pattern with ST-elevation in leads V1–V3(Brugada syndrome)
  • Negative T waves in right precordial leads, epsilon waves and ventricular late potentials   suggestive of arrhythmogenic RVD
  • Q waves suggesting myocardial infarction
  • Non sustained Ventricular Tachycardias


 Table 5 – Clinical features of high-risk syncope1,18-23

  • History of severe structural heart disease or heart failure, presence of ventricular arrhythmia
  • Syncope during exertion or supine
  • Absence of prodrome or predisposing or precipitating factors
  • Preceded by palpitation or accompanied by chest pain or shortness of breath
  • Family history of sudden cardiac death
  • Examination suggestive of obstructive valvular heart disease
  • Syncope associated with trauma
  • Systolic blood pressure less than 90mm Hg
  • Hematocrit less than 30% (acute drop in hemoglobin)

 When the cause of syncope is uncertain it is essential to risk stratify patients to enable appropriate treatment and further investigation. Risk stratification tools There are several scoring systems for risk stratification of syncope.  Syncope Evaluation in the Emergency Department Study (SEEDS), Osservatorio Epidemiologico sulla Sincope nel Lazio (OESIL score), Evaluation of Guidelines in SYncope Study (EGSYS score), San Francisco Syncope Rule (SFSR), The Risk stratification Of Syncope in the Emergency department (ROSE) and American College of Emergency Physicians clinical policy are the popular ones and each has its own advantages and disadvantages1,16,18-23. Discussing each scoring system is beyond the scope of this article and we shall restrict the discussion to the summary of these risk stratification tools (Table 5). It will be too early to include all the factors mentioned in the ROSE study, as it is not externally validated yet. It could be argued that taking all the risk factors described may increase admission rates but this approach may at least not miss the high-risk patient. This is a developing field and more evidence is likely to be published soon. High-risk vs. low-risk syncope: A high-risk syncope patient is the one where a cardiac cause is likely and where the short-term mortality is high due to major cardiovascular events and sudden cardiac death. High-risk syncope is said to be present if any of the features in the table 4 or 5 are present. Management of low-risk syncope Patients with a single or very infrequent syncope are usually reassured and discharged, as the short-term mortality is low1,2. Tilt table test is not usually required where a single or rare episode of neurally mediated syncope is diagnosed clinically. One exceptional circumstance where single rare episodes are investigated further with a tilt table test is when there could be an occupational implication (e.g. aircraft pilot) or if there is a potential risk of physical injury. Patients with recurrent unexplained syncope need to be further investigated (see below). Management of high-risk syncope / suspected cardiac syncope High-risk patients usually require hospitalisation and inpatient evaluation. Other high-risk patients who may be considered for admission are vulnerable patients susceptible to serious injuries, for example, elderly patient or a patient with multiple co-morbidities. Further investigations (Table 6)

Non invasive Invasive
  • Echocardiography
  • ECG monitoring
  • Telemetry
  • Holter monitoring
  • External loop recorder*
  • Carotid sinus massage
  • Cognitive testing (in elderly)
  • Ambulatory blood pressure monitoring
  • Tilt table test*
  • Exercise stress test
  • Implantable loop recorder*
  • Coronary angiography*
  • Electrophysiology*


* Specialist Investigation Echocardiography Echocardiography is a relatively inexpensive and non-invasive investigation. It should be performed if there is a clinical suspicion of a significant structural abnormality of heart such as ventricular dysfunction, outflow tract obstruction, obstructive cardiac tumours or thrombus, pericardial effusion etc… The yield of this test is low in the absence of clinical suspicion of structural heart disease. However in the presence of a positive cardiac history or an abnormal ECG, one study detected LV dysfunction in 27% of patients and half of these patients had syncope secondary to an arrhythmia. In patients with suspected obstructive valvular disease 40% had significant aortic stenosis as a cause of syncope24ECG monitoring These tests have utility in identifying arrhythmogenic syncope. If a patient has syncope correlating with a significant rhythm abnormality during the monitoring period with the device, then the cause of syncope is due to the underlying rhythm abnormality. On the other hand, if no rhythm abnormality is recorded during a syncopal attack, then an underlying rhythm problem as a cause of syncope is excluded. Therefore, these tests are meaningful only if there is a symptom-rhythm correlation, which is the working principle of these devices. In the absence of syncope, during the monitoring period, these tests may pick up other abnormalities that may be relevant. For example, rapid prolonged supra-ventricular tachycardias, ventricular tachycardias, periods of high degree AV blocks (mobitz type 2 or complete heart block) or significant sinus pauses >3seconds (except during sleep, negatively chronotropic therapy and trained athletes), which will require further investigation or treatment. Telemetry  Telemetry can be used in inpatients. Although the diagnostic yield of this investigation is only 16%, given the high short-term mortality, this test is indicated in the high-risk group 1. Usually patients are monitored for 24 to 48 hours although there is no agreed standard period for monitoring25Holter monitoring This involves connecting the patient through cutaneous patch electrodes. It records the ECG activity conventionally over 24-48 hours or at times up to 7 days. It is particularly useful only in patients who have frequent regular symptoms (≥1 per week). For this reason, the yield of this test can be as low as 1-2% in unselected population1. Long inpatient waiting lists in some hospitals can significantly prolong the length of stay and cost. Selecting patients carefully for this test based on risk stratification will reduce costs and waiting lists. Carotid sinus massage This simple bedside test is indicated in patients over the age of 40 years with syncope of unexplained origin after initial evaluation. A ventricular pause lasting >3 s and/or a fall in systolic BP of >50mmHg defines carotid sinus hypersensitivity (CSH) syndrome. It is contraindicated in patients with recent cerebrovascular accidents (past 3 months) or with carotid bruit except when a Doppler study has excluded significant stenosis1Cognition test If an elderly patient had forgotten about the events, in the absence of an obvious cause, it may be useful to test cognition. If cognitive impairment is present, common problems associated with cognitive dysfunction should be considered e.g. falls, orthostatic hypotension. Other investigations In spite of the above tests if a cause is not determined, early specialist input is recommended for further investigation and treatment. The following non-invasive and invasive investigations may be appropriate in these circumstances. An external loop recorder This is a non-invasive form of electrocardiographic monitoring. The principle is same as that of Holter monitoring. External loop recorders have a loop memory that continuously records and deletes ECG. When activated by the patient, typically after a symptom has occurred, 5 – 15 min of pre-activation ECG is stored and can be retrieved for analysis. Studies have shown that they have increased diagnostic yield compared to Holter1. They should be considered in patients who have symptoms on a monthly basis. A Tilt table test This is indicated in cases of recurrent unexplained syncope after relevant cardiac causes of syncope are excluded and a negative Carotid sinus massage performed in the absence of contraindications. It is also indicated when it is of clinical value to demonstrate patients susceptibility to reflex syncope and thereby to initiate treatment. Other less common indications are recurrent unexplained falls, differentiate jerking movements secondary to syncope and epilepsy, diagnose psychogenic pseudo syncope and differentiate orthostatic and reflex syncope. Indication of this test in the context of a single unexplained syncope is discussed above. Ambulatory blood pressure monitoring This may be useful in patients with unexplained syncope particularly in old age to check if there is an element of autonomic failure and if a single set of orthostatic blood pressure recording is not helpful. In one study, it has been shown that 25% of the elderly patients admitted with falls or syncope had postprandial hypotension especially after breakfast26. It may be more readily available than a tilt table test in some centres. Exercise stress test This may be useful in a rare entity called exercise induced syncope. Outflow tract obstruction should be excluded by echocardiography before subjecting a patient to this test especially in the presence of relevant signs. However there is no evidence for supporting this test in investigating syncope in general population. Implantable loop recorders These are implanted subcutaneously. It needs to be activated either by the patient or a bystander after a syncopal attack. It is indicated in high-risk patients where a comprehensive evaluation did not establish an underlying diagnosis. In the absence of high risk factors, it is also indicated in patients with recurrent unexplained syncope especially if infrequent. Conventionally it is used as a last resort in patients with recurrent unexplained syncope as the initial costs are high. It has been shown in one study to be more cost effective than the conventional strategy and was more likely to provide a diagnosis in patients with recurrent unexplained syncope27. However patients with poor LV function and those at high risk of life-threatening arrhythmias were excluded from this study. Coronary angiography or CT coronary angiography This may be helpful in suspected myocardial ischemia or ischemia related arrhythmias. Electrophysiological study may be considered in certain circumstances by cardiologists. When a standardised pathway is used, diagnosis is ascertained in 21% patients on initial evaluation and further 61% patients with early investigations. Only in 18% patients the diagnosis was still uncertain12. Other studies have shown similar results28. Although these results are from a dedicated syncope unit following a standardised pathway, these could be extrapolated to any unit following these standardised pathways. Further management is dictated by the underlying diagnosis with early specialist input for appropriate treatment. Treatments Single or rare episodes of reflex syncope do not require treatment. However, recurrent troublesome reflex syncope may warrant treatment. Treatment modalities are primarily non-pharmacological such as tilt training, physical counter pressure manoeuvres (leg crossing, hand gripping) and ensuring adequate hydration29. If refractory to non-pharmacologic measures midodrine (alpha agonist) may be considered in patients with frequent hypotensive symptoms30,31. Fludrocortisone may be used in elderly but there is no trial evidence to support this. Betablockers have been presumed to lessen symptoms but are shown to be ineffective in several studies 32. They may potentially exacerbate bradycardia in carotid sinus syncope and are not recommended in treatment of reflex syncope. Treatment with cardiac pacing in reflex syncope is controversial and may be considered in patients with predominant cardio inhibitory response on carotid sinus massage (in CSH syndrome) or on tilt test (in reflex syncope). It should be noted that cardiac pacing has no effect on the often-dominant vasodepressor component of reflex syncope.  In patients with orthostatic hypotension, non-pharmacologic measures like increased salt and water intake, head up tilt sleeping, physical counter pressure manoeuvres, abdominal binders and compression stockings may help reducing symptoms. Midodrine is an efficient alternative in these circumstances and fludrocortisone also can be used.33,34Syncope secondary to cardiac arrhythmias needs treatment if a causal relationship is established. Potential reversible causes such as electrolyte abnormalities and drug induced causes should be excluded. Cardiac pacing is a modality of treatment in significant bradyarrhythmias secondary to sinus node or advanced AV nodal disease such as mobitz type 2 block, complete heart block or tri-fascicular block. Catheter ablation and anti-arrhythmic drug therapy are the main modalities of treatment for tachyarrhythmias. Implantable cardioverter defibrillator may be indicated in patients susceptible to malignant ventricular tachyarrhythmias. Treatment of syncope secondary to structural cardio pulmonary abnormality will need surgical intervention if possible. Driving and Syncope Doctors are poor at addressing and documenting this issue35. Table 7 gives some useful information from the DVLA website ( This information is country specific and subject to change. Table 7 – Driving and Syncope in the UK36

Type of Syncope Group 1 entitlement (car, motorcycle etc.,) Group 2 entitlement (Large goods vehicle, passenger carrying vehicle)
Simple faint No restrictions No restrictions
Unexplained syncope with low risk of recurrence* Allowed to drive 1 month after the event Allowed to drive 3 months after the event
Unexplained syncope with high risk of recurrence** and cause identified and treated Allowed to drive 1 month after the event Allowed to drive 3 months after the event
Unexplained syncope with high risk of recurrence** and cause not identified Licence is refused or revoked for 6 months Licence is refused or revoked for 12 months

*Absent clinical evidence of structural heart disease and normal ECG** Abnormal ECG, clinical evidence of structural heart disease, syncope causing injury, recurrent syncope Syncope unitsSyncope units aim to evaluate syncope (and related conditions) in dedicated units consisting of generalists and specialists with an interest in syncope. A sufficient number of patients are required to justify such a unit. They are well equipped with facilities for recording ECG, blood pressures, tilt table, autonomic function testing, ambulatory blood pressure monitoring, and invasive and non-invasive electrocardiographic monitoring. It has been shown to be cost effective and reduces health care delivery costs by reducing admission rates, readmission rates and event rates. Examples include the Newcastle model, Manchester model and the Italian model.12,18,37,38 Conclusions The incidence of syncope is increasing in the UK with an aging population. There is significant cost incurred in the delivery of health care for this condition. The approach to syncope varies widely amongst practising physicians due to lack of a methodical approach. A thorough initial evaluation yields a diagnosis in less than half of the patients. When the cause of syncope remains unexplained after initial evaluation, the patients should be risk stratified. While a patient with a single episode of low risk syncope can be reassured and discharged, those with high-risk features should be hospitalised for further management. Outpatient evaluation could be offered for low risk patients if recurrent. Early specialist input should be sought in high-risk syncope and recurrent unexplained syncope. This standardised approach or pathway will reduce cost by reducing hospitalisation, inappropriate investigations and length of stay. 

 Key Facts
  •  Collapse associated with transient loss of consciousness is called syncope if it is due to transient global cerebral hypoperfusion and characterized by rapid onset, short duration, and spontaneous complete recovery
  • Standardised syncope pathways improve diagnostic yield and reduce hospital admissions, resource consumption and over all costs
  • A thorough initial evaluation yields a diagnosis in less than half of patients. If the cause of syncope is undetermined after initial evaluation, patients should be risk stratified
  • Early discharge should be considered in low risk patients while high-risk patients need urgent evaluation.
  • Early specialist referral is recommended in patients with high risk syncope and recurrent unexplained syncope 

 Future Interests Syncope had been known for several decades and still remains a complex condition, as the exact mechanisms are poorly understood especially in non-cardiac syncope. Mechanism of syncope in the elderly patients may be different from those of young patients and studies should focus in understanding the mechanics. Further research is needed in risk stratifying syncope. It may enable us to develop more robust care pathways for management of syncope. The role of BNP in investigating and risk stratifying syncope need to be further clarified. In spite of sophisticated tests the cause of syncope in a proportion of patients remain uncertain. Studies should focus on the long-term outcome and management of syncope in this group. The role of implantable loop recorder in the investigation of syncope should be better defined and more studies should focus on when it should be offered in the pathway of management of syncope. Studies are also required to develop effective pharmacotherapies for this condition.  

Dr Robert Peel FRCP (Edin), Consultant Physician and Nephrologist, Raigmore Hospital, Inverness, UK
Competing Interests
None declared
Author Details
VINOTH SANKAR, MBBS, MRCP.Specialty Registrar, Acute Medicine,Ward 49, Aberdeen Royal Infirmary, Aberdeen, UK STEVEN CLOSE,MBChB, MRCP,Consultant and Clinical Lead Acute Medicine Aberdeen Royal Infirmary, Aberdeen, UK STEPHEN J LESLIE, BSc, MBChB, FRCP (Edin), PhD Consultant Cardiologist, Raigmore Hospital, Old Perth Road, Inverness,Highland Campus, University of Stirling, Centre for Health Science, Inverness, UK
CORRESSPONDENCE: Vinoth Sankar, MBBS, MRCP. Specialty Registrar, Acute Medicine, Ward 49, Aberdeen Royal Infirmary, Aberdeen, UK


(1) European Heart Rhythm Association (EHRA), Heart Failure Association (HFA), Heart Rhythm Society (HRS), European Society of Emergency Medicine (EuSEM), European Federation of Internal Medicine (EFIM), European Union Geriatric Medicine Society (EUGMS), et al. Guidelines for the diagnosis and management of syncope (version 2009): the Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology (ESC). Eur.Heart J. 2009 Nov;30(21):2631-2671.(2) Soteriades ES, Evans JC, Larson MG, et al. Incidence and prognosis of syncope. N.Engl.J.Med. 2002 Sep 19;347(12):878-885.(3) Martin GJ, Adams SL, Martin HG, et al. Prospective evaluation of syncope. Ann.Emerg.Med. 1984 Jul;13(7):499-504.(4) Kapoor WN. Evaluation and outcome of patients with syncope. Medicine (Baltimore) 1990 May;69(3):160-175.(5) Kapoor WN. Diagnostic evaluation of syncope. Am.J.Med. 1991 Jan;90(1):91-106.(6) hospital episode statistics. Available at: Kapoor WN, Karpf M, Wieand S, et al. A prospective evaluation and follow-up of patients with syncope. N.Engl.J.Med. 1983 Jul 28;309(4):197-204.(8) Campbell AJ, Reinken J, Allan BC, et al. Falls in old age: a study of frequency and related clinical factors. Age Ageing 1981 Nov;10(4):264-270.(9) Farwell DJ, Sulke AN. Does the use of a syncope diagnostic protocol improve the investigation and management of syncope? Heart 2004;90:52-58.(10) Brignole M, Ungar A, Bartoletti A, et al. Standardized-care pathway vs. usual management of syncope patients presenting as emergencies at general hospitals. Europace 2006 Aug;8(8):644-650.(11) Stockley CJ, Bonney ME, Gray AJ, et al. Syncope management in the UK and Republic of Ireland. Emerg.Med.J. 2009 May;26(5):331-333.(12) Brignole M, Ungar A, Casagranda I, et al. Prospective multicentre systematic guideline-based management of patients referred to the Syncope Units of general hospitals. Europace 2010 Jan;12(1):109-118.(13) Kapoor WN. Evaluation and management of the patient with syncope. JAMA 1992 Nov 11;268(18):2553-2560.(14) Crane SD. Risk stratification of patients with syncope in an accident and emergency department. Emerg.Med.J. 2002 Jan;19(1):23-27.(15) Song PS, Kim JS, Park J, Yim HR, et al. Seizure-like activities during head-up tilt test-induced syncope. Yonsei Med.J. 2010 Jan 31;51(1):77-81.(16) Reed MJ, Newby DE, Coull AJ, et al. The ROSE (risk stratification of syncope in the emergency department) study. J.Am.Coll.Cardiol. 2010 Feb 23;55(8):713-721.(17) Croci F, Brignole M, Alboni P, et al. The application of a standardized strategy of evaluation in patients with syncope referred to three syncope units. Europace 2002 Oct;4(4):351-355.(18) Shen WK, Decker WW, Smars PA, et al. Syncope Evaluation in the Emergency Department Study (SEEDS): a multidisciplinary approach to syncope management. Circulation 2004 Dec 14;110(24):3636-3645.(19) Colivicchi F, Ammirati F, Melina D, et al. Development and prospective validation of a risk stratification system for patients with syncope in the emergency department: the OESIL risk score. Eur.Heart J. 2003 May;24(9):811-819.(20) Del Rosso A, Ungar A, Maggi R, et al. Clinical predictors of cardiac syncope at initial evaluation in patients referred urgently to a general hospital: the EGSYS score. Heart 2008 Dec;94(12):1620-1626.(21) Quinn J, McDermott D, Stiell I, et al. Prospective validation of the San Francisco Syncope Rule to predict patients with serious outcomes. Ann.Emerg.Med. 2006 May;47(5):448-454.(22) Huff JS, Decker WW, Quinn JV, et al. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with syncope. Ann.Emerg.Med. 2007 Apr;49(4):431-444.(23) Suzuki M, Hori S, Aikawa N. Application of the recent American practice resources for risk stratification system for patients presenting to a Japanese emergency department because of syncope. Int.Heart J. 2007 Jul;48(4):513-522.(24) Sarasin FP, Junod AF, Carballo D, et al. Role of echocardiography in the evaluation of syncope: a prospective study. Heart 2002 Oct;88(4):363-367.(25) Bass EB, Curtiss EI, Arena VC, et al. The duration of Holter monitoring in patients with syncope. Is 24 hours enough? Arch.Intern.Med. 1990 May;150(5):1073-1078.(26) Puisieux F, Bulckaen H, Fauchais AL, et al. Ambulatory blood pressure monitoring and postprandial hypotension in elderly persons with falls or syncopes. J.Gerontol.A Biol.Sci.Med.Sci. 2000 Sep;55(9):M535-40.(27) Krahn AD, Klein GJ, Yee R, et al. Cost implications of testing strategy in patients with syncope: randomized assessment of syncope trial. J.Am.Coll.Cardiol. 2003 Aug 6;42(3):495-501.(28) Fedorowski A, Burri P, Juul-Moller S, et al. A dedicated investigation unit improves management of syncopal attacks (Syncope Study of Unselected Population in Malmo--SYSTEMA I). Europace 2010 May 27.(29) van Dijk N, Quartieri F, Blanc JJ, et al. Effectiveness of physical counterpressure maneuvers in preventing vasovagal syncope: the Physical Counterpressure Manoeuvres Trial (PC-Trial). J.Am.Coll.Cardiol. 2006 Oct 17;48(8):1652-1657.(30) Perez-Lugones A, Schweikert R, Pavia S, et al. Usefulness of midodrine in patients with severely symptomatic neurocardiogenic syncope: a randomized control study. J.Cardiovasc.Electrophysiol. 2001 Aug;12(8):935-938.(31) Samniah N, Sakaguchi S, Lurie KG, et al.. Efficacy and safety of midodrine hydrochloride in patients with refractory vasovagal syncope. Am.J.Cardiol. 2001 Jul 1;88(1):A7, 80-3.(32) Sheldon R, Connolly S, Rose S, et al. Prevention of Syncope Trial (POST): a randomized, placebo-controlled study of metoprolol in the prevention of vasovagal syncope. Circulation 2006 Mar 7;113(9):1164-1170.(33) Low PA, Gilden JL, Freeman R, et al. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. Midodrine Study Group. JAMA 1997 Apr 2;277(13):1046-1051.(34) van Lieshout JJ, ten Harkel AD, Wieling W. Fludrocortisone and sleeping in the head-up position limit the postural decrease in cardiac output in autonomic failure. Clin.Auton.Res. 2000 Feb;10(1):35-42.(35) Brooke BT, Southward RD. An audit of advice on fitness to drive during accident and emergency department attendance. Emerg.Med.J. 2006 Feb;23(2):103-104.(36) For Medical Practitioners - At a glance guide to the current medical standards of fitness to drive - issued by Drivers Medical Group, DVLA Swansea, Feb 2010; Available at: Parry SW, Frearson R, Steen N, Newton JL, et al. Evidence-based algorithms and the management of falls and syncope presenting to acute medical services. Clin.Med. 2008 Apr;8(2):157-162.(38) Petkar S, Cooper P, Fitzpatrick AP. How to avoid a misdiagnosis in patients presenting with transient loss of consciousness. Postgrad.Med.J. 2006 Oct;82(972):630-641.(39) Rubenstein LZ, Josephson KR. Falls and their prevention in elderly people: what does the evidence show? Med.Clin.North Am. 2006 Sep;90(5):807-824.(40) Parry SW, Tan MP. An approach to the evaluation and management of syncope in adults. BMJ 2010 Feb 19;340:c880.(41) Brignole M, Alboni P, Benditt DG, et al. Guidelines on management (diagnosis and treatment) of syncope-update 2004. Executive Summary. Eur.Heart J. 2004 Nov;25(22):2054-2072.(42) The European Society of Cardiology Guidelines for the diagnosis and management of syncope reviewed by Angel Moya, MD, FESC, Chair of the Guideline Taskforce with J. Taylor, MPhil. Eur.Heart J. 2009 Nov;30(21):2539-2540.

Cervicogenic headache: It is time to call for more attention

Yili Zhou

Cite this article as: BJMP 2010;3(3):a337
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Cervicogenic headache (CH) refers to head pain originating from the pathology in the neck.1 However, the diagnosis of CH is still controversial 2,3 and it is often misdiagnosed. The author was called to consult a patient in a university hospital not so long ago. The patient was a 28-year-old female with a history of headache for six months. Her headache was described as continuous, dull and achy. It was mainly in the right side occipital and parietal areas. Sometimes she felt a headache behind the eyes. Her headache got worse periodically, several times a month, with nausea, photophobia, and phonophobia. She had no previous history of headache until a whiplash injury six months before. She had been diagnosed as having ‘migraine’ and ‘post-traumatic headache.’ She had used all anti-migraine medications. ‘Nothing was working.’ The patient was admitted into hospital because of ‘intractable headache.’
On the day when the author saw the patient, she was lying on the bed, with the room light turned off and a bed sheet covering her head and eyes. She was given Dilaudid, 2mg/h continuous intravenous (IV) drip, for the headache. The patient had normal results from magnetic resonance imaging (MRI) of the brain and lumbar puncture. According to the patient, no doctors had touched the back of her head and upper neck since admission. The author examined the patient and found a jumping tenderness over the right greater occipital nerve. The patient was given 2ml of 2% lidocaine with 40mg of Kenalog for the right greater occipital nerve (GON) block. Her headache was gone within five minutes and the Dilaudid drip was immediately discontinued. At follow-up four weeks later, the patient was headache-free. This was a typical missed case of CH (occipital neuralgia).
The concept of CH was first introduced by Sjaastad and colleagues in 1983.4 The International Headache Society published its first diagnostic criteria in 1998 which was revised in 2004.5 Patients with CH may have histories of head and neck trauma. Pain is often unilateral. Headache is frequently localized in the occipital area. However, pain may also be referred to the frontal, temporal or orbital regions. Headaches may be triggered by neck movement or sustained neck postures.6 Headache is constant with episodic throbbing attacks, like a migraine. Patients may have other symptoms mimicking a migraine such as nausea, vomiting, photophobia, phonophobia, and blurred vision. Due to the fact that there is a significant overlap of symptoms between CH and migraine without aura, CH is often misdiagnosed as migraine. CH is commonly found in patients after whiplash injuries, especially in the chronic phase.7
Anatomical studies have provided a basis for the pathogenesis of CH. The suboccipital nerve (dorsal ramus of C1) innervates the atlanto-occipital (AO)joint and dura matter over in the posterior fossa. Therefore, a pathologic condition of AO joint is a potential source for occipital headache. It has been reported that pain from the C2-3 and C3-4 cervical facet joints can radiate to the occipital area, frontotemporal and even periorbital regions. Even pathology in C5 or C6 nerve roots have been reported to cause headache.8 The trigeminocervical nucleus is a region of the upper cervical spinal cord where sensory nerve fibres in the descending tract of the trigeminal nerve (trigeminal nucleus caudalis) are believed to interact with sensory fibres from the upper cervical roots. This functional convergence of upper cervical and trigeminal sensory pathway sallows the bidirectional referral of painful sensations between the neck and trigeminal sensory receptive fields of the face and head.
Clinicians should always put CH in the list of differential diagnoses when they work up a headache patient. A history of head/neck injury, and detailed examination of the occipital and upper cervical area, should be part of the evaluation. Patients with CH may have tenderness over the greater or lesser occipital nerve, cervical facet joints and muscles in the upper or middle cervical region. Diagnostic imaging such as X-ray, computerized tomography (CT) and MRI cannot confirm CH, but can lend support to its diagnosis.
Treatment of CH is empirical. This headache does not respond well to migraine medications. Treatment should be focused on the removal of the pain source from the occipital-cervical junction. Initial therapy should be directed to non-steroidal anti-inflammatory drugs (NSAIDs) and physical therapy modalities.9 GON block is easy and safe to perform in office.10 It is effective for the treatment for occipital neuralgia and CH.11 The author followed a group of patients after GON block. The pain relief effects of GON block lasted an average of 31 days (unpublished data). If patients do not respond to GON block, diagnostic medial branch block and radiofrequency (RF) denervation of the upper cervical facet joints can be considered. Early studies have reported positive results.12 A subsequent randomized study found no benefit of RF. However, there were only six cases in each group,13 which significantly limited the power and validity of the conclusion from that study. Surgical treatment of cervical degenerative disc disease may offer effective pain relief for CH. Jansen14 reported 60 cases of CH patients treated mainly with C4/5, C5/6 and C6/7 nerve root decompression. More than 63% patients reported long lasting pain freedom or improvement (> 50%).
CH is common, with a prevalence of 0.4% and 2.5% in the general population. However, compared with other common pain conditions, CH is less studied. A Medline search found 6818 abstracts for migraine in 2009, whereas only 86 abstracts on CH were found. CH has not been well studied and it is often misdiagnosed. It is time to call for more attention.

Competing Interests
None Declared
Author Details
Dr YILI ZHOU MD PhD. Comprehensive Pain Management of North Florida,6830 NW 11th Place, Gainesville, Fl 32608 USA
CORRESSPONDENCE: Dr YILI ZHOU, Comprehensive Pain Management of North Florida 6830 NW 11th Place, Gainesville, Fl 32608 USA


1.  Bogduk N, Govind J. Cervicogenic headache: an assessment of the evidence on clinical diagnosis, invasive tests, and treatment. Lancet Neurol 2009; 8:959-68.
2.  Vincent MB. Cervicogenic headache: the neck is a generator: con. Headache 2010; 50:706-9.
3.  Becker WJ. Cervicogenic headache: evidence that the neck is a pain generator. Headache 2010; 50:699-705.
4.  Sjaastad O, Saunte C, Hovdahl H, Breivik H, Gronbaek E. 'Cervicogenic' headache: an hypothesis. Cephalalgia 1983; 3:249-56.
5.  The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004; 24 Suppl 1:9-160.
6.  Van SH, Van ZJ, Narouze S, Van Suijlekom H, Van Zundert J, Narouze S, Van Kleef M, Mekhail N. Cervicogenic headache. Pain Pract 2010; 10:124-30.
7.  Sjaastad O, Fredriksen T, Bakketeig L. Headache subsequent to whiplash. Curr Pain Headache Rep 2009; 13:52-8.
8.  Kawabori M, Hida K, Yano S, Iwasaki Y. [Cervicogenic headache caused by lower cervical spondylosis]. No Shinkei Geka 2009; 37:491-5.
9.  Ylinen J, Nikander R, Nykanen M, Kautiainen H, Häkkinen. Effect of neck exercises on cervicogenic headache: a randomized controlled trial. J Rehabil Med. 2010; 42:344-9.
10.  Weibelt S, Andress-Rothrock D, King W, Rothrock J. Suboccipital nerve blocks for suppression of chronic migraine: safety, efficacy, and predictors of outcome. Headache 2010; 50:1041-4.
11.  Tobin J, Flitman S. Occipital nerve blocks: when and what to inject? Headache 2009; 49:1521-33.
12.  Van Suijlekom HA, Van Kleef M, Barendse GA, Sluijter ME, Sjaastad O, Weber WE. Radiofrequency cervical zygapophyseal joint neurotomy for cervicogenic headache: a prospective study of 15 patients. Funct Neurol 1998; 13:297-303.
13.  Stovner LJ, Kolstad F, Helde G. Radiofrequency denervation of facet joints C2-C6 in cervicogenic headache: a randomized, double-blind, sham-controlled study. Cephalalgia 2004; 24:821-30.
14.  Jansen J. Surgical treatment of cervicogenic headache. Cephalalgia 2008; 28 Suppl 1:41-4.



Seroprevalence of Co-infection of Hepatitis B and Hepatitis C Genotypes among Adult Female Population of Karachi, Pakistan

Shazia Tabassum Hakim, Samina Noorali, Meaghen Ashby, Anisah Bagasra, Shahana U. Kazmi and Omar Bagasra

Cite this article as: BJMP 2010;3(3):a335
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Background: Both Hepatitis B virus (HBV) and Hepatitis C virus (HCV) are  aetiological agents of acute and chronic liver disease existing throughout the world. The high genetic variability of HBV and HCV genome is reflected by eight genotypes (A to H) and six genotypes (1 to 6), respectively. Each genotype has a characteristic geographical distribution, which is important epidemiologically. Previous studies from the province of Sindh, Pakistan have reported that genotypes D and A as well as D and B are prevalent HBV genotypes, and for HCV genotypes 3a and 3b to be dominant. The aim of this study was to investigate the prevalence of co-infection of both HBV and HCV genotypes in physically healthy females at two universities in Karachi, Sindh, Pakistan and HBV diagnosed patients41,42,56-59.

Methodology: Blood was collected from a total of 4000 healthy female volunteer students and 28 HBV diagnosed patients. Serum samples obtained were screened for Hepatitis B surface antigen (HBsAg), anti-HBs antibodies and anti-HCV antibodies by immunochromatography and ELISA. Genotyping was carried out for 6 HBV genotypes (A through F) and 6 HCV genotypes (1 through 6). Genotyping data of HBV and HCV positive individuals are described.

Results: Out of 4028 volunteers, 172 (4.3%) tested positive for HBsAg. All 172 serum samples were genotyped by PCR for both HBV and HCV. Out of 172 HBsAg positive samples, 89 (51.7%) showed a single HBV genotype D infection, followed by genotypes A (6.4%), F (4.6%), B (3.5%), E (1.7%), and C (1.7%). Out of 43 positive for HCV by PCR from the two universities and Anklesaria Hospital, 65.1% showed infection with 3a, followed by genotypes 5a (11.6%), 6a (11.6%), 3b (9.3%) and 2a (2.3%). Hence, the co-infection rate of both these viruses is 25% (43/172) among HBs Ag positive individuals.

Conclusion: Genotype D for HBV and genotype 3a for HCV appears to be the dominant genotype prevalent in Karachi’s population and co-infection of both these viruses does exist in HBsAg positive individuals.

Keywords:  Hepatitis B virus, Hepatitis C virus, type-specific primer-based genotyping


Both Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) are diseases characterized by a high global prevalence, complex clinical course, and limited effectiveness of currently available antiviral therapy. Approximately 2 billion people worldwide have been infected with the HBV and about 350 million live with chronic infection. An estimated 600,000 persons die each year due to the acute or chronic consequences of HBV 1, 2. WHO also estimates that about 200 million people, or 3% of the world's population, are infected with HCV and 3 to 4 million persons are newly infected each year. This results in 170 million chronic carriers globally at risk of developing liver cirrhosis and/or liver cancer 3, 4. Hence, HBV and HCV infections account for a substantial proportion of liver diseases worldwide.

These viruses have some differences, like HBV belongs to the Hepadnaviridae family and HCV belongs to the Flaviviridae family. HBV has a circular, partially double-stranded DNA genome of approximately 3.2 kb, whereas HCV has a single RNA strand genome of approximately 9.6 kb. HBV and HCV show some common biological features. Both HBV and HCV show a large heterogenicity of their viral genomes producing various genotypes. Based on genomic nucleotide sequence divergence of greater than 8%, HBV has been classified into eight genotypes labeled A through H 5,6,7,8. Different isolates of HCV show substantial nucleotide sequence variation distributed throughout the genome. Regions encoding the envelope proteins are the most variable, whereas the 5’ non-coding region (NCR) is the most conserved 9. Because it is the most conserved with minor heterogeneity, several researchers have considered the 5’ NCR the region of choice for virus detection by reverse transcription (RT)-PCR. Sequence analysis performed on isolates from different geographical areas around the world has revealed the presence of different genotypes, genotypes 1 to 6 10. A typing scheme using restriction fragment length polymorphism analysis of the 5’ NCR was able to differentiate the six major genotypes 11. Hence both HBV and HCV genotypes display significant differences in their global distribution and prevalence, making genotyping a useful method for determining the source of HBV and HCV transmission in an infected localized population 12 - 27.
Many studies have been conducted to study the prevalence of HBV and HCV co-infection among HIV-infected individuals and intravenous drug users globally 28 -3 4.There are only a few studies relevant to the epidemiology of these types of infection in the normal healthy population 35,36,37. The objective in this study was to determine the seroprevalence of HBV and HCV, co-infection of both these viruses and their genotypes, among an apparently healthy female population as well as from known HBV patients in Karachi, a major city in the province of Sindh, Pakistan. This study is also aimed at providing the baseline data on HBV/HCV co-infection, in order to gain a better understanding of the public health issues in Pakistan. We evaluated the antigen, antibody and genotypes of both HBV and HCV in 144 otherwise healthy female individuals and 28 diagnosed HBV patients.
Materials and Methods:
Study duration:From March 2002 to October 2006 & April 2009
Study participants: Total 4000blood serum samples were collected from healthy female student volunteers and 28 serum samples (April 2009) from already diagnosed Hepatitis B positive patients, aged 16 to 65 years from two Karachi universities and one Karachi hospital. University samples were obtained through the Department of Microbiology, University of Karachi and the Department of Microbiology, Jinnah University for Women. Hospital samples were obtained through the Pathological Laboratory of Burgor Anklesaria Nursing Home and Hospital.
Ethical Consent: Signed informed consent forms were collected from all volunteers following Institutional Review Board policies of the respective institutes.
Pre study screening:All 4028 volunteers had health checkups by a medical doctor before collection of specimens, they were asked about their history of jaundice, blood transfusion, sexual contacts, and exposure to needles, and if they had undergone any surgical and dental procedures.
Biochemical & Hematological screening:On completion of the medical checkups, volunteers were asked to give 5mL of blood for different haematological [(complete blood picture (CP), haemoglobin percentage (Hb%) and erythrocyte sedimentation rate (ESR)] and 10mL for different biochemical tests [(direct bilirubin, indirect bilirubin, total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP)]. Serological analysis:Samples were also subjected to serological analysis for hepatitis B surface Antigen (HBsAg), HBs antibodies and HCV antibodiesusing rapid immunochromatography kits (ICT, Australia and Abbott, USA). Confirmatory test for HBsAg was done by using ELISA (IMX, Abbott, USA).
All the above mentioned preliminary tests were conducted at the respective institutes in Karachi. Out of 4000 female volunteer from the two universities, 144 otherwise healthy females tested positive for HBsAg. 2 out of the 144 HBsAg positive females were also found to be positive for anti-HCV antibodies. The other 28 positive HBV patients from Anklesaria Hospital were only tested for HBsAg and all 28 were positive for HBsAg. Hence, a total of 172 HBV positive samples (144 + 28 = 172) including the 39 HCV positive serum samples obtained from Karachi were used for genotypic evaluation at Claflin University, South Carolina, USA. Specific ethnicity was not determined but we assume these study participants represent a collection of different ethnic groups in Pakistan.
DNA/RNA extraction and amplification of 172 HBV positive samples: DNA was extracted for HBV, and RNA was extracted for HCV analysis from 200μL of all 172 positive HBV serum samples using PureLink™ Viral RNA/DNA Mini Kit according to manufacturer’s instructions (Invitrogen, CA). Amplification was carried out using puReTaq Ready –To-Go PCR Beads (Amersham Biosciences, UK).
Determination of HBV and HCV genotypes by nested PCR: The primer sets for first-round PCR and second-round PCR, PCR amplification protocol, and primers for both HBV and HCV genomes and genotyping amplification for all 172 samples followed previously reported methods [45, 46]. First round amplification targeted 1063bp for the HBV genome and 470bp for the HCV genome. These respective PCR products for both HBV and HCV were used as a template for genotyping different HBV genotypes A to F and HCV genotypes from 1 to 6. HBV A through HBV F genotypes and HCV 1 through 6 genotypes for each sample were determined by separating the genotype-specific DNA bands on 2% agarose gels, stained with ethidium bromide. The sizes of PCR products were estimated according to the migration pattern of a 50bp DNA ladder (Promega, WI).
Before screening for HBV status, all 4000 healthy female volunteers from the Department of Microbiology, University of Karachi, and the Department of Microbiology, Jinnah University for Women were subjected to routine physical checkups for exclusion criteria i.e., either they were apparently unhealthy or malnourished (23 volunteers were excluded). All 4000 serum samples were screened by immunochromatography for the presence of HBsAg, anti HBs antibodies and anti-HCV antibodies. Positive results were confirmed by ELISA. Out of 4000 subjects 144 (3.6%) tested positive for HB surface antigen (HBsAg), 2 (0.05%) were positive for anti-HCV antibodies, and 3856 (96.4%) were negative for HBsAg and 3998 (99.95%) were negative for HCV antibodies by both immunochromatography and ELISA. Out of these 144 individuals who tested positive for HBsAg, 20 (13.8%) were positive for anti-HB surface antibodies and 2 (1.4%) tested positive for anti-HCV antibodies. The rest of the 28 serum samples obtained from already diagnosed HBV positive samples from Anklesaria Hospital were only tested for HBsAg and were all positive for HBsAg.
The haematological parameters: WBC count, RBC count, hematocrit and platelet count of the 172 HBsAg positive individuals were within the normal recommended range of values, while mean Hb% was 9.8±1.6 g/dL. Direct bilirubin (0 to 0.3 mg/dL), indirect bilirubin (0.1 - 1.0 mg/dL), total serum bilirubin (0.3 to 1.9 mg/dL), ALT (0 - 36 U/L), AST (0 - 31 U/L) and alkaline phosphatase (20 - 125 U/L) were also within the normal range for 129 HBsAg positive individuals, except for the raised ALT (>36 U/L) and AST (>31 U/L) levels in 38 participants with a previous history of jaundice who were also positive for HBsAg.
All 172 samples that were positive for HBsAg were confirmed for the presence of different HBV genotypes as well as for different HCV genotypes by PCR to see the co-infection of both these viruses. Genotyping was carried out at the South Carolina Center for Biotechology, Department of Biology, Claflin University, Orangeburg, SC, U.S.A. For HBV: Mix A primers were targeted to amplify genotypes A, B and C, and primers for Mix B were targeted to amplify genotypes D, E and F. For HCV: primers for Mix A were targeted to amplify genotypes 1a, 1b, 1c, 3a, 3c and 4. Primers of Mix B for HCV were targeted to amplify genotypes 2a, 2b, 2c, 3b, 5a, and 6a.
Table 1. Prevalence of both single and co-infection of HBV genotypes among the apparently healthy female student sample and known HBV positive patients from Anklesaria hospital in Karachi.
2 Universities Samples Percentage
Total HBV 144  
Genotype D 70 48.6%
Genotype A 8 5.5%
Genotype F 7 4.9%
Genotype B 5 3.5%
Genotype E 3 2.1%
Genotype C 2 1.4%
Co-infections of HBV Genotypes 49/144 34%
Genotype B/D 30/144 20.8%
Genotype A/D 11/144 7.6%
Genotype A/D 4/144 2.8%
Genotype B/C 4/144 2.8%
Anklesaria Hospital Samples Percentage
Total HBV 28  
Genotype D 19 67.9%
Genotype A 3 10.7%
Genotype B 1 3.6%
Genotype C 1 3.6%
Genotype F 1 3.6%
Co-infections of HBV Genotypes    
Genotype B/A 3/28 10.7%
Figure 1: Electrophoresis patterns of PCR products from different HBV genotypes as determined by PCR genotyping system. Genotype A: 68bp, genotype B: 281bp, genotype C: 122bp, genotype D: 119bp, genotype E: 167bp and genotype F: 97bp. 
Table 1 illustrates the prevalence of both single and co-infection of HBV genotypes from both the universities in Karachi and Anklesaria hospital. Representative 10 samples in Fig. 1 show single and co-infections for HBV.
Besides looking at the HBV genotypic status of these 172 patients by PCR, we also looked at the HCV genotypic status of the positive HBV patients by PCR so as to see if there was existence of co-infection of the two viruses i.e. HBV and HCV in the same individuals as only 2 samples tested positive for anti-HCV antibodies by rapid immunochromatography. Table 2 shows the prevalence of HCV genotypes among the apparently healthy female student population from the 2 universities in Karachi and known HBV individuals samples obtained from Anklesaria hospital. Fig. 2 shows different HCV genotype infection in the 10 representative samples shown in Fig. 1 showing HBV infection with different genotypes.
Table 2. Prevalence of HCV genotypes among the apparently healthy female student sample, and known HBV individuals from Anklesaria hospital in Karachi.
2 Universities Samples Percentage
Total HCV/Total HBV 39/144 27.1%
Genotype 3a 26/39 66.6%
Genotype 6a 5/39 12.8%
Genotype 3b 4/39 10.3%
Genotype 5a 4/39 10.3%
Anklesaria Hospital Samples Percentage
Total HCV/HBV 4/28 14.3%
Genotype 3a 2/28 7.14%
Genotype 2a 1/28 3.6%
Genotype 5a 1/28 3.6%
Figure 2: The sizes of the genotype-specific bands for HCV amplified by PCR genotyping method are as follows: genotype 2a, 190 bp; genotype 3a, 258 bp; genotype 3b, 232 bp; genotype 5a, 417 bp; and genotype 6a, 300 bp. 
To summarize the results it was found that out of 172 HBsAg positive samples from the two universities (144 HBV samples) and Anklesaria Hospital (28 HBV samples), 89 (51.7%) were genotype D, 11 were genotype A (6.4%), 8 were genotype F (4.6%), 6 were genotype B (3.5%), 3 were genotype E (1.7%), and 3 were genotype C (1.7%). Out of 43 positive for HCV by PCR from the two universities (39/144 HBV samples) and Anklesaria Hospital (4/28 HBV samples), 65.1% (28/43) showed infection with 3a, followed by genotypes 5a (5/43 = 11.6%), 6a (5/43 = 11.6%), 3b (4/43 = 9.3%) and 2a (1/43 = 2.3%).
Viral hepatitis due to HBV and HCV has significant morbidity and mortality worldwide. The global prevalence of HCV is 3% 38 and the carrier rate of HBsAg varies from 0.1% to 0.2% in Britain and the USA, to 3% in Greece and southern Italy and up to 15% in Africa and the Asia 39. Pakistan is highly endemic with HBV. Studies are too limited to give a clear picture of the prevalence of HBV at the national level, especially among apparently healthy individuals. Most previous studies targeted different small groups of individuals with some clinical indications, so they do not accurately reflect the overall prevalence in Pakistan40. Our previous study was conducted on a first group of 4000 healthy female students from the two universities i.e., Department of Microbiology, University of Karachi and Department of Microbiology, Jinnah University for Women for the prevalence of HBV. We have reported earlier that genotype D appears to be the dominant genotype prevalent in Karachi, Pakistan’s apparently healthy female population, and genotype B appears to be the next most prevalent genotype 41, 42. In this study we checked the prevalence of both HBV and HCV in a second group of 4000 healthy female students from the same two universities in Karachi mentioned above, as well as the already 28 diagnosed HBV patients from Anklesaria Hospital in Karachi, Pakistan.
Both HBV and HCV are present in the Pakistani population and there are varying reports of disease prevalence. HCV is one of the silent killer infections spreading undetected in Pakistan because there are often no clinical symptoms and, when HCV is diagnosed, considerable damage has already been done to the patient. In Pakistan alone, the prevalence of HBsAg has been reported to be from 0.99% to 10% in different groups of individuals 43 - 52 and 2.2% to 14% for HCV antibodies 53 - 56. A recent study conducted in Pakistan showed that out of 5707 young men tested, 95 (1.70%) were positive for anti-HCV and 167 (2.93%) for HBsAg 57. Our previous study showed the prevalence of HBsAg among young otherwise healthy women to be 4.5% 41,42. Our present study shows that the prevalence of HBsAg in otherwise young healthy women to be 3.6%, with 0.98% testing positive for anti-HCV antibodies. On the basis of other studies conducted in different provinces of Pakistan, we can say that there is a variation in the prevalence of HBsAg and HCV antibodies in the Pakistani population as the population sample selected is limited to a particular area or segment of the provinces. 
HBV and HCV genotyping is important to track the route and pathogenesis of the virus. In particular, the variants may differ in their patterns of serologic reactivity, pathogenecity, virulence, and response to therapy. Both HBV and HCV has genetic variations which correspond to the geographic distribution and has been classified into 8 genotypes (A to H) on the basis of whole genome sequence diversity of greater than 8% and 6 genotypes (1 to 6) using restriction fragment length polymorphism analysis of the 5’ non-coding region (NCR), respectively .
In this study genotyping was carried out for 6 HBV genotypes (A through F) and 6 HCV genotypes (1 through 6). This study suggests that the HBV D genotype is the most prevalent (114/144 = 79.2%) among otherwise healthy females alone or in co-infection with other HBV genotypes in Karachi, Sindh, Pakistan. In our previous study HBV D genotype was found to be ubiquitous (100%) among otherwise healthy females alone or in co-infection with other HBV genotypes in Karachi followed by genotype B 41,42. The earlier two studies conducted for prevalence of HBV genotypes in known hepatitis B positive patients in Pakistan report the prevalence of genotypes HBV A (68%) and HBV D (100%) in the province of Sindh 58,59. Interestingly, in this study we also found the HBV D genotype to be the prevalent genotype but it was followed by genotypes HBV A (5.5%) and HBV F (4.9%). The prevalence of genotype HBV B in this study was found to be 3.5% as our earlier study has shown the prevalence of genotype B in otherwise healthy females to be 16.1% 60. These findings respectively contradict and corroborate the previous studies for HBV genotype distributions reported here as the subjects in this study were also asymptomatic but comprised of second group of female volunteer students at the two universities. Out of 144 subjects positive for HBsAg, 10 reported a previous history of jaundice and the rest were not aware of their HBV status. In the nearby north Indian population, HBV D was reported as the predominant genotype (75%) in patients diagnosed with chronic liver disease (CLDB) 60. In this study we also found other HBV genotypes existed in the study population such as HBV genotype F (4.9%) followed by genotype E (2.1%), and genotype C (1.4%). We also saw mixed HBV infections of genotypes B and D, A and D, C and D as well as B and C (20.8%, 7.6%, 2.8% and 2.8%) among these otherwise healthy females. 
Among the 28 diagnosed HBV patients from Anklesaria Hospital, 67.9% showed HBV genotype D infection followed by genotype A infection (10.7%). In this group of 28 HBV positive patients we also saw infections with genotypes B (3.6%), C (3.6%) and F (3.6%). This group exhibited 10.7% co-infection with genotypes B and A.
As far as the HCV status of these 144 otherwise healthy females who were HBV positive is concerned only 2 (1.4%) tested positive for HCV antibodies by rapid immunochromatography. But the PCR results showed 39 (27.15%) of these 144 otherwise healthy females that were HBV positive for different genotypes were also positive for HCV including the 2 otherwise healthy females that tested positive for HCV antibodies by rapid immunochromatography. Of the 39 HCV positive otherwise healthy females, we found the predominant HCV genotype to be 3a (66.6%) followed by genotypes 6a (12.8%), 3b (10.3%), and 5a (10.3%) infections. The earlier study conducted with samples from women at the two universities in Pakistan had shown that among the HCV positive apparently healthy females 51.44% were genotype 3a, 24.03% exhibited a mix of genotype 3a and 3b, 15.86% were genotype 3b, and 4.80% were genotype 1b 42. Interestingly, among the group of 28 diagnosed HBV patients, the prevalence of HCV 3a genotype infection was dominant but was 7.1% much lower than that found in the otherwise healthy females, followed by infections with genotypes 2a (3.6%) and 5a (3.6%). Hence we see there is 25% co-infection of both these viruses i.e., HBV and HCV among the HBsAg positive individuals. The sample of 28 HBV positive patients was from a hospital located in the center of the metropolis that represents an area of Karachi where sanitation, malnourishment, illiteracy, and lack of awareness is very common. Prostitution can also be considered as one factor in some of the localities of Karachi in the spread of both HBV and HCV.
In conclusion, genotype D appears to be the dominant HBV genotype and genotype 3a for HCV appears to be prevalent in Sindh, Pakistan’s otherwise healthy young female population as well as in HBV diagnosed individuals. Co-infection of both the viruses i.e., HBV and HCV exists among HBsAg positive individuals. The young female participants were advised to seek appropriate medical care for both their own benefit and public health benefit.

This work was partially supported from the grants: P2RR16461 (EXPORT): NIH, INBRE and EPS-044760: NSF EPSCoR.
Competing Interests
None declared
Author Details
SHAZIA TABASSUM HAKIM, SAMINA NOORALI, MEAGHEN ASHBY, OMAR BAGASRA: South Carolina Center for Biotechnology, Department of Biology, Claflin University, 400 Magnolia Street, Orangeburg, South Carolina 29115, U.S.A. ANISAH BAGASRA, Department of History and sociology, Claflin University, 400 Magnolia Street, Orangeburg, South Carolina 29115, U.S.A. SHAHANA U KAZMI, I.I.D.R.Lab., Department of Microbiology, University of Karachi, Karachi-75270, Pakistan
CORRESSPONDENCE: Dr. Shazia Tabassum Hakim, Associate Professor & Chairperson, Virology & Tissue Culture Laboratory, Department of Microbiology, Jinnah University for Women, Nazimabad, Karachi-74600, Pakistan


  1. de Franchis R, Hadengue A, Lau G, Lavanchy D, Lok A, McIntyre N, Mele A, Paumgartner G, Pietrangelo A, Rodés J, Rosenberg W, Valla D; EASL Jury. EASL International Consensus Conference on Hepatitis B. J Hepatol. 2003;39 Suppl 1:S3-25.
  2. WHO, Hepatitis B.
  3. WHO, Hepatitis C.
  4. Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med. 2001 Jul 5;345(1):41-52.
  5. Okamoto H, Tsuda F, Sakugawa H, Sastrosoewignjo RI, Imai M, Miyakawa Y, Mayumi M. Typing hepatitis B virus by homology in nucleotide sequence: comparison of surface antigen subtypes. J Gen Virol. 1988; 69: 2575-2583.
  6. Norder H, Courouce AM, Magnius LO. Complete genomes, phylogenetic relatedness, and structural proteins of six strains of the hepatitis B virus, four of which represent two new genotypes. Virology. 1994; 198: 489-503.
  7. Stuyver L, De Gendt S, Van Geyt C, Zoulim F, Fried M, Schinazi RF, Rossau, R. A new genotype of hepatitis B virus: complete genome and phylogenetic relatedness. J Gen Virol. 2000; 81: 67-74.
  8. Arauz-Ruiz P, Norder H, Robertson BH, Magnius LO. Genotype H: a new Amerindian genotype of hepatitis B virus revealed in Central America. J Gen Virol. 2002; 83: 2059-2073.
  9. Simmonds, P., E. C. Holmes, T. A. Cha, S. W. Chan, F. McOmish, B. Irvine, E. Beall, P. L. Yap, J. Kolberg, and M. S. Urdea. Classification of hepatitis C-virus into six major genotypes and a series of subtypes by phylogenetic analysis of the NS5 region. J. Gen. Virol. 1993;74:2391–2399.
  10. Cha, T. A., E. Beall, B. Irvine, J. Kolberg, D. Chein, G. Ruo, and M. S. Urdea.  At least five related but distinct hepatitis C viral genotypes exist. Proc. Natl. Acad. Sci. USA. 1992; 89:7144–7148.
  11. Murphy, D., B. Willens, and G. Delage. Use of the non-coding region for the genotyping of hepatitis C-virus. J. Infect. Dis. 169:473–474. Miyakawa Y, Mizokami M (2003) Classifying hepatitis B virus genotypes. Intervirology. 1994; 46: 329-338.
  12. Liu CJ, Kao JH, Chen PJ, Lai MY, Chen DS. Molecular epidemiology of hepatitis B viral serotypes and genotypes in Taiwan. J Biomed Sci. 2002; 9: 166-170.
  13. Kao JH, Chen PJ, Lai MY, Chen DS. Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B. Gastroenterology. 2000; 118: 554-559.
  14. Kao JH, Chen PJ, Lai MY, Chen DS. Clinical and virological aspects of blood donors infected with hepatitis B virus genotypes B and C. J Clin Microbiol. 2002; 40: 22-25.
  15. Bae SH, Yoon SK, Jang JW, Kim CW, Nam SW, Choi JY, Kim BS, Park YM, Suzuki S, Sugauchi F,Mizokami M. Hepatitis B virus genotype C prevails among chronic carriers of the virus in Korea. J Korean Med Sci . 2005;20: 816-820.
  16. Ferreira RC, Teles SA, Dias MA, Tavares VR, Silva SA, Gomes SA, Yoshida CF, Martins RM. Hepatitis B virus infection profile in hemodialysis patients in Central Brazil: prevalence, risk factors, and genotypes. Mem Inst Oswaldo Cruz. 2006; 101: 689-692.
  17. Kar P, Polipalli SK, Chattopadhyay S, Hussain Z, Malik A, Husain SA, Medhi S, Begum N.  Prevalence of hepatitis B virus genotype D in Precore Mutanrs among chronic liver disease patients from New Delhi, India. Dig Dis Sci. 2007; 52: 565-569.
  18. Alavian SM, Keyvani H, Rezai M, Ashayeri N, Sadeghi HM.  Preliminary report of hepatitis B virus genotype prevalence in Iran. World J Gastroenterol. 2006; 12: 5211-5213.
  19. Abbas Z, Muzaffar R, Siddiqui A, Naqvi SA, Rizvi SA. Genetic variability in the precore and core promoter regions of hepatitis B virus strains in Karachi. BMC Gastroenterol . 2006;6: 20.
  20. Amini-Bavil-Olyaee S, Alavian SM, Adeli A, Sarrami-Forooshani R, Sabahi F, Sabouri E, Tavanga, HR, Azizi M, Mahboudi F. Hepatitis B virus genotyping, core promoter, and precore/core mutations among Afghan patients with hepatitis B: a preliminary report. J Med Virol. 2006; 78: 358-364.
  21. Huy TT, Ishikawa K, Ampofo W, Izumi T, Nakajima A, Ansah J, Tetteh JO, Nii-Trebi N, Aidoo S, Ofori-Adjei D, Sata T, Ushijima H, Abe K. Characteristics of hepatitis B virus in Ghana: full length genome sequences indicate the endemicity of genotype E in West Africa. J Med Virol. 2006; 78: 178-184.
  22. Olinger CM, Venard V, Njayou M, Oyefolu AO, Maiga I, Kemp AJ, Omilabu S.A., le Faou A, Muller CP. Phylogenetic analysis of the precore/core gene of hepatitis B virus genotypes E and A in West Africa: new subtypes, mixed infections and recombinations. J Gen Virol. 2006; 87: 1163-1173.
  23. 23.Campos RH, Mbayed VA, Pineiro Y, Leone FG. Molecular epidemiology of hepatitis B virus in Latin America. J Clin Virol. 2005; 34: S8-S13.
  24. Parana R, Almeida D. HBV epidemiology in Latin America. J Clin Virol . 2005;34:   S130-S133.
  25. 25.Stuyver L, De Gendt S, Van Geyt C, Zoulim F, Fried M, Schinazi RF, Rossau, R. A new genotype of hepatitis B virus: complete genome and phylogenetic relatedness. J Gen Virol. 2000; 81: 67-74.
  26. 26.Sanchez LV, Tanaka Y, Maldonado M, Mizokami M, Panduro A. Difference of hepatitis B genotype distribution in two groups of Mexican patients with different risk factors. High prevalence of genotype H and G. Intervirology. 2007; 50: 9-15.
  27. 27.Arauz-Ruiz P, Norder H, Robertson BH, Magnius LO. Genotype H: a new Amerindian genotype of hepatitis B virus revealed in Central America. J Gen Virol . 2002;83: 2059-2073.
  28. Larke, B., Y. W. Hu, M. Krajden, V. Scalia, S. K. Byrne, L. R. Boychuk, and J. Klein. Acute nosocomial HCV infection detected by NAT of a regular blood donor. Transfusion. 2002; 42:759–765.
  29. Larsen C, Pialoux G, Salmon D, Antona D, Le Strat Y, Piroth L, Pol S, Rosenthal E, Neau D, Semaille C, Delarocque Astagneau E. Prevalence of hepatitis C and hepatitis B infection in the HIV-infected population of France, 2004. Euro Surveill. 2008;13(22). pii: 18888.
  30. Lee HC, Ko NY, Lee NY, Chang CM, Ko WC. Seroprevalence of viral hepatitis and sexually transmitted disease among adults with recently diagnosed HIV infection in Southern Taiwan, 2000-2005: upsurge in hepatitis C virus infections among injection drug users. J Formos Med Assoc. 2008;107(5):404-11.
  31. Jain M, Chakravarti A, Verma V, Bhalla P. Seroprevalence of hepatitis viruses in patients infected with the human immunodeficiency virus. Indian J Pathol Microbiol. 2009;52(1):17-9.
  32. Nagu TJ, Bakari M, Matee M. Hepatitis A, B and C viral co-infections among HIV-infected adults presenting for care and treatment at Muhimbili National Hospital in Dar es Salaam, Tanzania. BMC Public Health. 2008;8:416.
  33. Kim JH, Psevdos G, Suh J, Sharp VL. Co-infection of hepatitis B and hepatitis C virus in human immunodeficiency virus-infected patients in New York City, United States. World J Gastroenterol. 2008;14(43):6689-93.
  34. Anna Gyarmathy V, Neaigus A, Ujhelyi E. Vulnerability to drug-related infections and co-infections among injecting drug users in Budapest, Hungary. Eur J Public Health. 2009.
  35. Yun H, Kim D, Kim S, Kang S, Jeong S, Cheon Y, Joe K, Gwon DH, Cho SN, Jee Y. High prevalence of HBV and HCV infection among intravenous drug users in Korea. J Med Virol. 2008;80(9):1570-5.
  36. Yildirim B, Barut S, Bulut Y, Yenışehırlı G, Ozdemır M, Cetın I, Etıkan I, Akbaş A, Atiş O, Ozyurt H, Sahın S. Seroprevalence of hepatitis B and C viruses in the province of Tokat in the Black Sea region of Turkey: A population-based study. Turk J Gastroenterol. 2009 ;20(1):27-30.
  37. Demirtürk N, Demirdal T, Toprak D, Altindiş M, Aktepe OC. Hepatitis B and C virus in West-Central Turkey: seroprevalence in healthy individuals admitted to a university hospital for routine health checks. Turk J Gastroenterol. 2006;17(4):267-72.
  38. Bonkovsky HL, Mehta S. Hepatitis C: a review and update. Journal of the American Academy of Dermatology, 2001; 44:159–79.
  39. Sherlock S, Dooley J, eds. Diseases of the liver and biliary system. London, Blackwell Science, 2002:290–316.
  40. Malik IA, Legters LJ, Luqman M, Ahmed A, Qamar MA, Akhtar KA, Quraishi MS, Duncan F, Redfield RR. The serological markers of hepatitis A and B in healthy population in Northern Pakistan. J Pak Med Assos. 1988; 38: 69–72.
  41. Noorali S, Hakim ST, McLean D, Kazmi SU, Bagasra O. Prevalence of Hepatitis B virus genotype D in females in Karachi, Pakistan. J Infect Developing Countries. 2008;  2:373-378.
  42. Hakim ST, Kazmi SU, Bagasra O. Seroprevalence of Hepatitis B and C Genotypes Among Young Apparently Healthy Females of Karachi-Pakistan. Libyan J Med. 2008; 3: 66-70.
  43. Ahmed M, Tariq WUZ. Extent of past hepatitis B virus exposure in asymptomatic Pakistani young recruits. Pak J Gasteroenterol. 1991; 5: 7–9.
  44. Rehman K, Khan AA, Haider Z, Shahzad A, Iqbal J, Khan RU, Ahmad S, Siddiqui A, Syed SH. Prevalence of seromarkers of HBV and HCV in health care personnel and apparently healthy blood donors. J Pak Med Assoc.1996; 46: 152–154.
  45. Zuberi SJ, Samad F, Lodi TZ, Ibrahim K, Maqsood R. Hepatitis and hepatitis B surface antigen in health-care personnel. J Pak Med Assoc. 1997; 27: 373-375.
  46. Yousuf M, Hasan SMA, Kazmi SH. Prevalence of HbsAg among volunteer blood donors in Bahawalpur division. The Professional. 1998; 5: 267-271.
  47. Qasmi SA, Aqeel S, Ahmed M, Alam SI, Ahmad. A. Detection of Hepatitis B virus in normal individuals of Karachi. J Coll Physicians Surg Pak. 2000; 10: 467–469.
  48. Zakaria M, Ali S, Tariq GR, Nadeem M.Prevalence of anti-hepatitis C antibodies and hepatitis B surface antigen in healthy male naval recruits. Pak Armed Forces Med J. 2003; 53: 3–5.
  49. Farooq MA, Iqbal MA, Tariq WUZ, Hussain AB, Ghani I. Prevalence of hepatitis B and C in healthy cohort. Pak J Pathol. 2005; 16: 42–46.
  50. Abbas Z, Shazi L, Jafri W. Prevalence of hepatitis B in individuals screened during a countrywide campaign in Pakistan. J Coll Physicians Surg Pak. 2006; 16: 497-498.
  51. Masood Z, Jawaid M, Khan RA, Rehman SU. Screening for hepatitis B and C: a routine preoperative investigation? Pak J Med Sci. 2005; 21: 455–459.
  52. Bhopal FG, Yousaf A, Taj MN. Frequency of hepatitis B and C: surgical patients in Rawalpindi general hospital. Prof Med J. 1999; 6: 502-509.
  53. Zuberi SJ. An overview of HBV/HCV in Pakistan. Journal of the Pakistan Medical Association. 1998; 37:S12–8.
  54. Mujeeb SA, Aamir K, Mehmood K. Seroprevalence of HBV, HCV and HIV infections among college going first time voluntary blood donors. Journal of the Pakistan Medical Association. 2000; 50:269–70.
  55. Asif N, Khokar N, Ilahi F. Seroprevalence of HBV, HCV and HIV infection among voluntary non-remunerated and replace-ment donors in Northern Pakistan. Paki-stan journal of medical sciences. 2004; 20:24–8.
  56. Khokar N, Gill ML, Malik GJ. General seroprevalence of hepatitis C and hepatitis B virus infections in population. Journal of the College of Physicians and Surgeons Pakistan. 2004; 14(9):534–36.
  57. T. Butt and M.S. Ami. Seroprevalence of hepatitis B and C infections among young adult males in Pakistan. Eastern Mediterranean Health Journal. 2008; 14(4): 791-797.
  58. Idrees M, Khan S, Riazuddin S. Common genotypes of hepatitis B virus. J Coll Physicians Surg Pak. 2004; 14: 344-347.
  59. Abbas Z, Muzaffar R, Siddiqui A, Naqvi SA, Rizvi SA. Genetic variability in the precore and core promoter regions of hepatitis B virus strains in Karachi. BMC Gastroenterol . 2006; 6: 20.
  60. Chattopadhyay S, das BC, Kar P. Hepatitis B virus genotypes in chronic liver disease patients from New Delhi, India. World J Gastroenterol. 2006; 12: 6702-6706.

Elevated pancreatic enzymes within the content of liver abscess in a patient with a history of chronic pancreatitis.

Muhammad Z Bawany and Thomas Sodeman

Cite this article as: BJMP 2010;3(3):a331
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Liver abscess accounts for 48% of visceral abscesses 1 and presents with significant morbidity and mortality. The overall incidence of pyogenic liver abscess is 3.6 per 100,000 populations, 2 however; elevated pancreatic enzymes within the content of a liver abscess have never been reported in the literature.

A 36-year-old African American male with a history of chronic pancreatitis presented to the emergency department for abdominal pain in the epigastric area along with nausea, vomiting, diarrhoea, fever. His symptoms began 3-4 days before presentation. The abdominal pain was dull in nature and 6/10 in intensity, non-radiating. His past medical history was significant for HTN, diabetes mellitus and chronic diarrhoea secondary to chronic pancreatitis.
On admission the patient was alert and oriented, blood pressure was 97/44 mm Hg, heart rate 16 beats per minute, respiration 16 per minute, oxygen saturation 94% on room air and temperature 102*F. Abdominal examination revealed hyperactive bowel sounds and tenderness in the epigastrium & RUQ. Liver span was 14 cm. The rest of the examination was unremarkable.
Laboratory work revealed: Haemoglobin 9.8 g/dl, WBC 22.1 Thou/mm3 with segmented neutrophils of 81% and 9% bands, BUN 54 mg/dl, Cr 4.7 mg/dl, total protein 10.4 g/dl, albumin 1.8 g/dl, total bilirubin 1.1 mg/dl, direct bilirubin 0.3 mg/dl, AST 98 IU/L, ALT 38 IU/L, alkaline phosphatase 250 IU/L, amylase 81 units/L, lipase 10 units/L, lactate 2.3 mmol/L and INR 1.39.
The patient was started on fluids and meropenem for broad spectrum coverage. However his condition worsened and he developed acute respiratory distress syndrome secondary to sepsis necessitating intubation. Due to his abdominal pain he underwent a computer tomography (CT) scan of the abdomen, which revealed pancreatic calcifications and multiple liver abscesses; the largest measuring 7.5cm in the right lobe of the liver (Figure 1). 
Figure 1
As the patient’s condition did not improve, he underwent liver abscess drainage. Fluid analysis showed ph 4.0, LDH 39 units/L, glucose 81 mg/dl, protein 1.6 g/dl, lipase of 16 units/L and amylase 68 units/L. The presence of amylase and lipase in the liver abscess without any evidence of a fistula between liver and pancreas on CT scan was unexpected, therefore it was decided to leave the catheter in situ for continuous drainage. 3 Even though his blood and fluid cultures remained negative during the hospital stay he was continued on antibiotics, which may have meant that the initial antibiotic therapy rendered the blood cultures negative. The success of management was assessed with a hepatic CT 10 days post drainage and was demonstrated by the observation of improvement in the patient’s general condition, as indicated by normal temperature, decreased draining catheter output and the resolution of deranged laboratory values. The catheter was then removed and the patient was discharged.
Liver abscesses develop via seeding through portal circulation, directly via spread from biliary infections or from surgical or penetrating wounds and also from systemic organs via haematogenous spread. In our case the most reasonable explanation was through the involvement of portal circulation due to recurrent pancreatitis.
The morbidity and mortality rate for liver abscesses ranges from 2 – 12 % depending on the severity of underlying co-morbidities. 2 The clinical manifestations, as in our case, are characterized by abdominal pain (50-75%), 4, 5 fever (90%), nausea and vomiting. Other symptoms may include weight loss, malaise and diarrhoea. On physical exam RUQ tenderness, guarding, rebound tenderness, hepatomegaly and occasional jaundice can be appreciated. The diagnosis of a liver abscess can be made by radiographic imaging followed by aspiration and culture of the abscess material. Liver abscesses can be either polymicrobial or monomicrobial, unlike in the case with our patient, whose abscess was sterile. Depending on the microbial results additional sources of infection should be evaluated. Drainage of abscesses can be percutaneous 6 or open surgical. Percutaneous drainage with coverage of antibiotics was successful in our patient. 
In summary, we present a case of pancreato-liver abscess in a patient with a history of chronic calcified pancreatitis. It was treated with antibiotics and percutaneous drainage, with satisfactory resolution. To our knowledge this has never been reported in the literature and more work needs to be done to understand the pathophysiology of elevated pancreatic enzymes in the context of a liver abscess in a patient with a history of chronic pancreatitis.

Competing Interests
None declared
Author Details
MUHAMMAD Z BAWANY M.D. Department of Internal Medicine University of Toledo Medical Center Ohio USA THOMAS SODEMAN M.D. FACP, Department of Internal Medicine University of Toledo Medical Center Ohio USA
CORRESSPONDENCE: Muhammad Z Bawany M.D. 3000 Arlington Ave, Mail Stop 1150, Toledo OH USA 43614


1. Altemeier WA, Culbertson WR, Fullen WD, et al Intra-abdominal abscesses. Am J Surg 1973;125:70-79. 
2. Meddings L, Myers RP, Hubbard J, et al. A population-based study of pyogenic liver abscesses in the United States: incidence, mortality, and temporal trends. Am J Gastroenterol;105:117-124.
3. Rajak CL, Gupta S, Jain S, et al. Percutaneous treatment of liver abscesses: needle aspiration versus catheter drainage. AJR Am J Roentgenol 1998;170:1035-1039
4. Rahimian J, Wilson T, Oram V, et al. Pyogenic liver abscess: recent trends in etiology and mortality. Clin Infect Dis 2004;39:1654-1659.
5. Mohsen AH, Green ST, Read RC, et al. Liver abscess in adults: ten years experience in a UK centre. QJM 2002;95:797-02.
6. Zerem E, Hadzic A. Sonographically guided percutaneous catheter drainage versus needle aspiration in the management of pyogenic liver abscess. AJR Am J Roentgenol 2007;189:W138-142.


Coronary vasospasm in a patient with respiratory failure: A case report and a brief review.

Mujeeb Sheikh, Satjit Adlakha, Steven Bruhl and Shaffi Kanjwal

Cite this article as: BJMP 2010;3(3):a330
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Coronary vasospasm is an episodic, augmented, contractile response of coronary smooth muscles to variety of stimuli in the setting of established endothelial dysfunction. Various physiological including cold, stress and pathological factors like smoking, and ethanol have been well known to precipitate vasospasm. Despite these omnipresent factors, coronary vasospasm has become infrequent, in particular due to judicious use of medication including calcium channel blockers, statins and aspirin. We present a case of severe coronary vasospasm resulting in haemodynamic instability, in a patient with hypoxic respiratory failure. Recurrent symptomatic episodes required coronary angiography for the diagnosis and patient was successfully treated with calcium channel blockers.

Keywords:  Myocardial infarction; respiratory failure; coronary vasospasm; Diltiazem


Myocardial ischemia from coronary artery vasospasm can lead to variety of presentation including stable angina, unstable angina, myocardial infarction and sudden death 1. Although, pathognomic clinical scenario includes symptom of chest pain, transient ST-segment elevation on the electrocardiogram(ECG), and vasospasm on a coronary angiography, atypical presentations have also been reported 2. Various known physiological factors including stress, cold, hyperventilation and pharmacological agents including cocaine, ethanol, 5-Fluouracil, and triptans can precipitate a vasospastic attack. 3-7.We report a case of ST-segment elevation due to right coronary artery vasospasm, in patient with hypoxic respiratory failure, and successful treatment with calcium channel blockers.

Case description
A 56 year old man was admitted for the repair of a large ventral incisional hernia. The patient had a prior history of morbid obesity, chronic obstructive pulmonary disease (COPD), hypertension and cigarette smoking. The postoperative course was complicated by bilateral pneumonia leading to respiratory failure requiring mechanical ventilation. An electrocardiogram at the time of intubation was essentially normal. Aside from bilateral rhonchi and crackles on lung auscultation, the rest of the physical examination findings were unremarkable. Arterial blood gases at the time of intubation demonstrated PH 7.33, PO2 58 mmHg, PCO2 65 mmHg, HCO3ˉ 20 mmol/L, suggestive of hypoxia and concomitant respiratory acidosis. Baseline laboratory studies including cardiac enzymes were within normal limits. The patient was treated with intravenous vancomycin for methicillin-resistant staphylococcus pneumonia. On postoperative day 4, the patient had recurrent episodes of transient ST-elevation on a bedside monitor (Fig.1).
Figure 1
These episodes lasted for 3-5 minutes and were associated with significant bradycardia and hypotension. In view of recurrent episodes, haemodynamic instability, and underlying risk factors of coronary artery disease, cardiac catheterization was performed. Coronary angiography revealed a 90% stenosis with haziness of the mid-right coronary artery without any other significant epicardial disease. An intravascular ultrasound (IVUS) was performed and was followed by administration of 100 mcg of intracoronary nitroglycerin; the lesion was reduced to almost 20%. (Fig.2).
Figure 2
The diagnosis of prinzmetals angina was made, based on clinical course and angiographic results and prompt therapy with diltiazem (120 mg per day) was initiated. The patient had no further recurrences of similar episodes during the hospitalization and on follow up at 3 months.
The prevalence of vasospasm has been reported to be higher in Japanese and Korean population as compared to the western population. A recent multi-institute survey in Japan documented spasm in 921 (40.9%) of the 2251 consecutive patients who underwent angiography for angina pectoris 8. In contrast to the traditional risk factors for atherosclerotic coronary artery disease, the incidence of smoking, age and dyslipdaemia has been reported higher in patients with coronary vasospasm 9. Endothelial dysfunction is now considered to the major inciting factor in the pathogenesis of the vasospasm 10. Vasospastic angina (VA) with normal coronary arteries on the angiography, impaired endothelial-dependent and endothelial-independent vasodilatation has been frequently observed in these patients. Vascular tone is normally regulated by production of vasodilator factors like nitrous oxide (NO), prostacyclin and vasoconstricting agents like endthelin-1. In the presence of dysfunctional endothelium the agents that normally cause vasodilatation lead to paradoxical vasoconstriction, due to direct muscle stimulation, like acetylcholine.
Stress, whether physical or mental stress has been shown to induce coronary vasospasm and myocardial ischemia. In a study by Kim et al, coronary spastic angina was diagnosed in 292 patients out of 672 coronary spasm provocation tests. Among 292 patients, 21 (7.2%) had myocardial infarction and 14 out of these 21 had experienced severe emotional stress before the event 11. Recently, animal studies have also shown that high circulatory level of stress hormones (cortisol) exaggerate coronary vasoconstriction through Rho-Kinase activation 12. Hypoxia has been seen in animal models to predispose to vasospasm through superoxide formation, which leads to loss of vasodilator function of NO.(13)
The ECG changes that occur during attack include ST-segment elevation, and or peaking of T wave from total or subtotal coronary occlusion 1. In some cases spasm can involve more than one artery leading to ST-segment elevation in multiple leads, which may predispose to ventricular tachycardia or fibrillation 14. Coronary spasm is diagnosed by angiography, and spasm can occur at the site of atherosclerotic plaque or in normal segment of the coronary artery. In patients with equivocal diagnosis, provocative tests including administration of acetylcholine, hyperventilation to induce spasm may be required for the diagnosis.
Current first line therapy involves used of calcium channel blockers (CCB) alone or in combination with long acting nitrates. In a study comparing the effect of long acting nitrates (Isosorbide dinitrate 40mg/day) versus calcium channel blockers (amlodipine 5mg/day or long acting nifedipine 20mg/day) on coronary endothelium and vasoconstriction between patients with normal or minimally diseased coronary artery, treatment with long acting nitrates was associated with less favourable effects on coronary endothelial functions 15. Sudden withdrawal of CCB in patients with known vasospasm can lead to rebound of symptoms and may prove dangerous. In patients with refractory symptoms alpha-blockers, nicorandil have been used. Although beta blockers are believed to enhance vasospasm, Betaxalol, a selective beta-1 blocker, has been found to be effective in the treatment of variant angina due to its vasorelaxing effects 16. In addition, elimination of or control of all other risk factors or precipitants is very important for successful treatment. In drug refractory cases the percutaneous coronary intervention or coronary artery bypass graft has been performed for the ischemia relief 17.
Our patient had multiple precipitating factors for vasospasm. Endothelial dysfunction from severe physical illness and sepsis could have precipitated the VA. Furthermore, hypoxia from respiratory failure could have also been an inciting agent and cannot be ruled out. It is worth mentioning that intensive care unit patients frequently have coexistence of both the underlying risk factors and the precipitating factors for vasospasm, yet VA as a clinical syndrome is uncommonly seen or reported.
The clinician needs to be aware of coronary artery vasospasm as it can pose a serious medical threat. Early diagnosis and treatment may result in improved outcomes from vasospastic angina.

Competing Interests
None Declared
Author Details
MUJEEB SHEIKH MD Assistant Professor, Department of Internal Medicine, 3000, Arlington Avenue, University of Toledo Medical Center, Toledo, Ohio SATJIT ADLAKHA, D.O Cardiology fellow 3000, Arlington Avenue, University of Toledo Medical Center, Ohio, USA STEVEN BRUHL M.D Cardiology fellow 3000, Arlington Avenue, University of Toledo Medical Center, Ohio, USA SHAFFI KANJWAL M.D, 3000, Arlington Avenue Department of Pulmonary and Critical Care, University of Toledo Medical Center, Toledo, Ohio, USA
CORRESSPONDENCE: Mujeeb Sheikh, Assistant Professor, Department of Internal Medicine 3000, Arlington Avenue, University of Toledo Medical Center, Toledo, Ohio.


1. Nakamura M, Takeshita A, Nose Y. Clinical characteristics associated with myocardial infarction, arrhythmias, and sudden death in patients with vasospastic angina. Circulation. 1987 Jun;75(6):1110-6.

2. Xiang DC, He JX, Hong CJ, Qiu J, Ma J, Gong ZH, et al. [Clinical features of patients with atypical coronary artery spasm]. Zhonghua Xin Xue Guan Bing Za Zhi. 2006 Mar;34(3):227-30.

3. Keller KB, Lemberg L. The cocaine-abused heart. Am J Crit Care. 2003 Nov;12(6):562-6.
4. Ando H, Abe H, Hisanou R. Ethanol-induced myocardial ischemia: close relation between blood acetaldehyde level and myocardial ischemia. Clin Cardiol. 1993 May;16(5):443-6.
5. Bathina JD, Yusuf SW. 5-Fluorouracil-induced coronary vasospasm. J Cardiovasc Med (Hagerstown). 2009 Jun 25.
6. Shimizu M, Hata K, Takaoka H, Kanazawa K, Shinke T, Matsumoto H, et al. Sumatriptan provokes coronary artery spasm in patients with variant angina: possible involvement of serotonin 1B receptor. Int J Cardiol. 2007 Jan 8;114(2):188-94.
7. Teragawa H, Kato M, Yamagata T, Matsuura H, Kajiyama G. The preventive effect of magnesium on coronary spasm in patients with vasospastic angina. Chest. 2000 Dec;118(6):1690-5.
8. Yasue H, Sasayama S, kikuchi K, Okumura K, Matsubara T, Miwa K. The study on the role of coronary spasm in ischemic heart disease. Osaka:National Cardiovascular Center; 2000; Osaka:National Cardiovascular Center. Osaka: Annual report of the research on cardiovascular diseases; 2000. p. 96-7.
9. Sugiishi M, Takatsu F. Cigarette smoking is a major risk factor for coronary spasm. Circulation. 1993 Jan;87(1):76-9.
10. Yasue H, Nakagawa H, Itoh T, Harada E, Mizuno Y. Coronary artery spasm--clinical features, diagnosis, pathogenesis, and treatment. J Cardiol. 2008 Feb;51(1):2-17.
11. Kim PJ, Seung KB, Kim DB, Her SH, Shin DI, Jang SW, et al. Clinical and angiographic characteristics of acute myocardial infarction caused by vasospastic angina without organic coronary heart disease. Circ J. 2007 Sep;71(9):1383-6.
12. Hizume T, Morikawa K, Takaki A, Abe K, Sunagawa K, Amano M, et al. Sustained elevation of serum cortisol level causes sensitization of coronary vasoconstricting responses in pigs in vivo: a possible link between stress and coronary vasospasm. Circ Res. 2006 Sep 29;99(7):767-75.
13. Zou MH, Bachschmid M. Hypoxia-reoxygenation triggers coronary vasospasm in isolated bovine coronary arteries via tyrosine nitration of prostacyclin synthase. J Exp Med. 1999 Jul 5;190(1):135-9.
14. Nishizaki M, Arita M, Sakurada H, Suzuki M, Ashikaga T, Yamawake N, et al. Polymorphic ventricular tachycardia in patients with vasospastic angina--clinical and electrocardiographic characteristics and long-term outcome. Jpn Circ J. 2001 Jun;65(6):519-25.
15. Ninomiya Y, Hamasaki S, Saihara K, Ishida S, Kataoka T, Ogawa M, et al. Comparison of effect between nitrates and calcium channel antagonist on vascular function in patients with normal or mildly diseased coronary arteries. Heart Vessels. 2008 Mar;23(2):83-90.
16. Suzuki J, Watanabe K, Tsuruoka T, Sueda S, Funada J, Kitakaze M, et al. Beneficial effects of betaxolol, a selective antagonist of beta-1 adrenoceptors, on exercise-induced myocardial ischemia in patients with coronary vasospasm. Int J Cardiol. 2003 Oct;91(2-3):227-32.
17. Sugimoto A, Morino Y, Ikari Y. Stent implantation for diffuse and multiple coronary spasm in a patient with variant angina refractory to optimal medical therapy. J Invasive Cardiol. 2007 Nov;19(11):E320-3.

Coronary Artery Disease in Africa: Community based study of Risk Factors

R.K.Pal and Ali Grera

Cite this article as: BJMP 2010;3(2):326
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According to estimates of the World Health Organization (WHO), in 2005, out of 58 million total deaths in the world due to different causes 30 percent (17.4 million) were due to cardio vascular diseases, mainly heart disease and stroke. 53 percent of global deaths due to coronary heart disease occurred in males and 47 percent in women. The common modifiable risk factors identified were unhealthy diet, physical inactivity and tobacco use, leading to raised blood pressure and blood glucose, abnormal blood lipids and becoming overweight.1 The WHO MONICA Project - an international collaboration of researchers from 21 countries, studied more than 30 populations, mainly from Europe, over a period of ten years, from the mid-1980s to the mid 1990s. More than seven million men and women aged between 35 and 64 years of age were monitored to examine if and how certain coronary risk factors and new treatments for heart disease contribute to the decline or increase of heart disease rates in these communities. 2

Hence it has been observed that there have been number of studies on risk factors in patients of Coronary Artery Disease (CAD) but comparatively few studies are available on risk factors in healthy community members in Africa and still fewer on comparison of risk factors for CAD in the patients and community members from the same population. The present study was conducted on 528 community members in Tripoli the capital of Libya including 70 individuals having a history of suffering from Myocardial infarction (MI). The comparison of both the groups of same community revealed that hypertension followed by smoking, diabetes and increased body mass index were more prevalent in the community members with history of MI. It was alarming to note that these risk factors earlier thought to be more frequent after the age of 50 years are now present in higher numbers in the younger age groups of 35 to 54 and 15 to 34 years as well. As most of the risk factors stated above are modifiable there seems to be urgent need of initiating a National Health Programme on prevention and control of these risk factors. The priorities and strategy of such a National Programme has also been suggested in brief for consideration of the national decision makers. 

Keywords:  Coronary Artery Disease, Coronary Heart Disease, Risk factors


As highlighted in the World Health Report 2002, just a few Non Communicable Disease (NCD) risk factors, account for the majority of non communicable disease burden. These risk factors; tobacco use, alcohol consumption, raised blood pressure, raised lipid levels, increased BMI, low fruit/vegetable intake, physical inactivity, and diabetes, are the focus of the STEPs approach to NCD risk factor surveillance. 3

 A tool for surveillance of risk factors, WHO STEPS, has been developed to help low and middle income countries get started. It is based on collection ofstandardised data from representative populations of specified sample size to ensure comparability over time and across locations. Step one gathers information on risk factors that can be obtained from the general population by questionnaire. This includes information on socio-demographic features, tobacco use, alcohol consumption, physical inactivity, and fruit/vegetable intake. Step two includes objective data by simple physical measurements needed to examine risk factors that are physiologic attributes of the human body. These are height, weight, and waist circumference (for obesity) and blood pressure. Step three carries the objective measurements of physiologic attributes one step further with the inclusion of blood samples for measuring lipid and glucose levels.4 The risk factors studied by MONICA project of the World Health Organization (WHO), included cigarette smoking, blood pressure, blood cholesterol and body weight.5In many resource-poor settings, laboratory access can be difficultand expensive.  A screening algorithm that includesgender, age, cardiovascular disease history, blood pressure,weight and height, and a urine dipstick test for glucose andprotein is likely to be more practical and may well providemuch of the predictive value of more complex blood-based assessments.6In addition, such algorithms should, wherever possible, useregional data on morbidity and mortality, because backgroundrates vary considerably between regions.WHO/ISH (World Health Organization/International Society of hypertension) risk prediction charts provide approximate estimates of cardiovascular disease (CVD) risk in people who do not have established coronary heart disease, stroke or other atherosclerotic disease. They are useful as tools to help identify those at high cardio vascular risk, and to motivate patients, particularly to change behavior and, when appropriate, to take antihypertensive, lipid-lowering drugs and aspirin.8  After reviewing the above information about standardised methods available for identifying the risk factors for CAD, the present study was undertaken to assess the prevalence of risk factors in the community in Tripoli, the capital of Libya. The aim of this paper also includes suggesting priorities and strategy to deal with the risk factors that were found most important. Appropriate statistical tests were applied using the software SPSS 17 for determining the relative importance of different risk factors. The specific statistical tests have been stated below. Material and Methods
528 individuals were selected from general community for the study by random sampling from different geographical areas of Tripoli. They were interviewed about risk factors for CAD and where possible, facts stated by them were validated from medical records available with them. Their body weight, height and blood pressure were also recorded. The intern doctors posted with community medicine department were briefed and trained by faculty members for the above observations and recording the body measurement and blood pressure using the uniform technique. The WHO/ISH risk prediction colourcharts for Eastern Mediterranean Region B (which includes Libya) were used as questionnaire for the study. The option of charts available for settings where blood cholesterol can’t be measured was selected as it was found difficult to convince the individuals not suffering from disease to provide blood samples.  The following criteria were used for defining Blood Pressure, BMI, Diabetes & MI : According to the WHO definition, individuals with systolic blood pressure ≥ 140 mmHg or those with diastolic blood pressure ≥ 90 mmHg were considered hypertensive. 21.  Known cases of diabetes were termed as individuals for whom the diagnosis of diabetes had been established by a physician in the past, or those who were under treatment with anti diabetic drugs. 22  Body mass index (BMI) is calculated as weight divided by height squared (kg/m2). Overweight is defined as BMI 25–29.9 kg/m2, and obesity as BMI ≥ 30 kg/m2 for all subjects.19 Known cases of Myocardial Infarction (MI) were termed as individuals for whom the diagnosis of MI had been established by a physician in the past. Observations The comparison of population characteristics of people with and without having a MI stated in the table below reveals that: distribution of males and females was similar in both the groups. 88% of individuals with a MI were from age group 35 and above. Whereas 11.43%  of people with MI were from age group 15 to 34 years which shows the need of starting screening as well as control of risk factors from teenage.  Using SPSS software, independent sample t test was applied on age distribution of individuals with and without history of MI. The result revealed that the mean age of individuals with a positive history of MI was 54. It was 43.74 for subjects with negative history of MI. The difference of age between the above 2 groups was found highly significant (P>0.001). In the same manner using SPSS software, Chi square test was applied on sex distribution of individuals with and without history of MI. The result revealed that the difference in sex distribution in the two groups was not significant (P = 0.522)  Table 1 : Age & Sex wise distribution of persons with and without MI: 

Characteristics Individuals with MI in percentage, (N= 70) Individuals without MI in percentage, (N = 458)
Sex;     Male 68.57 (48) 68.78 (315)
            Female 31.43 (22) 31.22 (143)
Age 15-34 years 11.43(8) 34.93 (160)
35-54 years 30.00 (21) 37.55 (172)
55 & above 58.57 (41) 27.51 (126)

  Independent risk factors As presented in Fig.1, in males with MI in terms of percentage the most prevalent risk factor was found to be hypertension (11.05% higher than non MI group), followed by diabetes (higher by 10.78%), smoking (higher by 8.12%) and BMI 25 & above (higher by 5.13%). As presented in Fig.2, in females with MI in terms of percentage the most prevalent risk factor was found to be hypertension (20.55% higher than non MI group), followed by BMI 25 & above (higher by 8.77%) and diabetes (higher by 6.85%). There were no smokers in the female group with MI and only one smoker was found in the females without MI.  Using SPSS software, under general linear model, multivariate analysis was performed after splitting the cases under male and female. History of MI was kept as fixed factor and age, history of hypertension, diabetes and stroke, smoking, systolic blood pressure and BMI were kept as dependent variables. The results reveal that in the males with positive history of MI, value of P was less than 0.001(highly significant) for age, History of hypertension & diabetes and systolic BP of140 and greater, followed by history of stroke (P>0.002) suggesting that prevalence of these variables were significantly higher in males with history of MI. The prevalence of BMI 25 & above (P>0.616) and smoking (P>0.882) in males with history of MI was found insignificant. In case of females with positive history of MI, the only variable having significant prevalence was f history of hypertension (P>0.008). An important reason for inability to assess significance for other variables in females may be the smaller number of females of only 22 with history of MI.  Among the community members with MI, 94.38% males and 78.57% females had one or the other risk factor which have been stated above. Hence with focused attention to health education and screening for risk factors, identifying most of the individuals at risk of MI, should be possible.  
(Fig.1) Distribution of Risk Factors in Males with and without MI  (The total number of responses are more than number of respondents because of more than one risk factor being present in many respondents)   (Fig.2) Distribution of Risk Factors in Females with and without MI  (The total number of responses are more than number of respondents because of more than one risk factor being present in many respondents)  Combination of risk factors Out of 48 males with MI, 22 (45.83%) had both diabetes and hypertension and half of them (22.92%) were also smokers. The next group among males having multiple risk factors were that of smokers 14 (29.17%), out of which half (14.58%) also had hypertension. Out of 22 females with MI, 13 (59.09%) had hypertension and 27.27 % out of them were also diabetic. The next group was that of diabetics 3 (13.64%). Hence looking at the combination of risk factors in both males and females with MI the most common risk factor in terms of prevalence was found to be hypertension followed by smoking in men and diabetes in women. As Hypertension and BMI in age group of 35 to 54 years were found to be significant and commonly present risk factors, the data was further explored.  Systolic BP 140 and above: The percentage of persons with MI having a systolic BP of 140 and above in the age group 35 to 54 years was more than double in comparison to the percentage expected by number of persons present in this age group that is 66.67% as stated in Fig.3, against 30% as stated above in Table1. Hence in this age group there appears to be considerable opportunity of detecting and treating cases of hypertension in the general community before they reach to the advanced stage  of coronary artery disease and MI.  (Fig.3) Age wise distribution of blood pressure (both sexes) Body Mass Index: As presented below in Fig.4, the percentage of overweight and obese individuals were found to be 5 to 9 percent higher in those with MI than those without MI. The percentage of obese people increased by 2 times in both the groups that is with and without MI as age advanced to 35-54 years from 15-34 years. The percentage of overweight individuals was 1.48 times in those without MI and 1.77 times in those with MI in age group 35-54 years in comparison to the age group of 15-34 years.  (Fig. 4) Age wise distribution of weight (both sexes) 
Discussion:  Comparison with other relevant studies: In our study the most common risk factors observed in community members without  MI were hypertension (total 24.35%, males 23.78 & females 25.88), followed by diabetes (total 21.13%, males 19.56 & females 25.29) and smoking (Total 27.26%, males 37.33 & females 0.59) as stated above in Fig.1 & 2. In similar studies performed in countries of Mediterranean region14-18 26% of study population were found to be suffering from hypertension, 40% males and 13% females were smokers and 14.5% were suffering from diabetes. 13   The percentage of diabetics was 10.6 in study population aged 30 years and above in Iran11.  The percentage of diabetics were 11% in males and 7% in females in United Arab Emirates (UAE)10 and the figures were the similar in Saudi Arabia in subjects aged 30 years and above were 17.3% and 12.18% respectively.9. All the above studies were performed in the period from year 2000 to 2004 except the study in UAE which was performed in 1995. It can be seen from our study in Libya that in comparison to mean percentage for the same risk factors in other countries of Mediterranean Region, the percentage of hypertension was lower by about 2%.  In Libya the percentage of total diabetics in the general community was greater by 6.6%,  while the percentage of smokers were less by about 13% in males and 12.5% in females.  The percentage of total overweight and obese individuals in all age groups and both sexes were 66.6 % in the general community without MI in our present study (Fig,4). The percentage for those overweight and obese in individuals above 19 years of age was 26.2%  in study from Iran12 and 27 % in UAE10 in the age group of 30 to 64 years. The study of 12 countries of the Eastern Mediterranean Region(EMR) by  the WHO conducted in  2004, reveals that regional adjusted mean for these countries was 43 % for overweight and obese individuals in all age groups and both sexes20. Hence in comparison to developing countries of the region having similar religious, social and dietary situation among the risk factors for CAD, diabetes and obesity can be seen as emerging major risk factors in Libya followed by hypertension and smoking. Smokers among females were found to be uncommon in Libya.        Conclusion  The findings of this study reveal that in comparison to those without MI the prevalence of following risk factors was higher in individuals with MI. In males aged 35 to 54, the percentage of those with a systolic BP of 140 and greater was more than double and in females 1.6 times greater.  Those with diabetes were greater by 10.78% in males and 6.85% in females, while smokers were higher by 8.12% in males.  The percentage of diabetes in individuals without MI was 21.13%.  The prevalence of smokers was found to be 37.33% in males without MI which suggests urgent need for prevention and control measures. Considering multiple risk factors out of 48 males with MI, 22 (45.83%) had both diabetes and hypertension and half of them (22.92%) were also smokers. Out of 22 females with MI, 13 (59.09%) had hypertension and 27.27 % out of them were also diabetic. In view of large number of individuals having risk factors of CAD in Tripoli, we would like to recommend that health education for preventing overweight and obesity, hypertension, smoking and diabetes may be started with school children and their parents as early as primary school. The screening for above risk factors needs to be implemented in the age group of 34 years and above for detecting individuals at risk as close to 34 years as possible. This step needs to be followed by relevant health education and treatment as soon as possible. More studies on a larger population sample are required from different geographical areas of Libya to refine our focus on the target population identified. At the same time waiting for action, till these additional studies are completed, is not recommended. To make the comparison of risk factors more fruitful among different countries and in the same country over time, we need to agree on uniform criteria such as using WHO/ISH risk prediction charts.  Limitations of present study It is a cross sectional study based on the questions stated in WHO/ISH prediction charts for situations where collecting blood samples is not feasible. Due to the small sample size we can only say that the prevalence of MI is indicative of the pattern observed. These figures may get refined as we cover a larger number of the population over time. Due care has been taken in selecting sample size to represent different geographical divisions of Tripoli and to ensure that this is a random sample, but it is a systematic random sample and not the stratified random sample. Hence within each geographical division all the socio economic strata of community may not have been proportionately represented.   AppendixThe questionnaire used for the study is stated below. It is based on the questionnaire recommended on page 21 of WHO/ ISH risk prediction charts for Eastern Mediterranean Region B of W.H.O. in which Libya is included.QuestionnairePrecautions: Do not interview persons below the age of 14 years. You should take height, weight and Blood Pressure of the person yourself, before recording it in the form below 

S.N. Question Subject
    1 2 3 4 5
1 Name of Person:          
2 Address in Libya          
4 Age          
5 Sex: M / F          
6 Do you smoke: Yes / No          
8 Do you have History of suffering from Diabetes:   Yes / No          
9 Hist. of suffering from: Mayo cardial Infarction: Yes/ No          
10 History of suffering from Stroke: Yes /   No          
12 History of suffering from Hypertension: Yes /   No          
13 Height in Cms:          
14 Weight in Kg:          
15 Systolic Blood Pressure ( in mm of Hg):          


Competing Interests
None Declared
Author Details
R.K.PAL, Department of Community Medicine, Al Fateh University of Medical Sciences, Tripoli, Libya. ALI GRERA, Department of Community Medicine, Al Fateh University of Medical Sciences, Tripoli, Libya.
CORRESSPONDENCE: R.K.PAL, Department of Community Medicine, Al Fateh University of Medical Sciences, Tripoli, Libya.


1. Preventing chronic diseases – a vital investment, World Health Organization,
2. WHO Study on Heart Disease, Press Release WHO/10, 28 February 2000. (
3. The World Health Report 2002: reducing risks, promoting healthy life. Geneva, World Health Organization, 2002:57– 61, 162.
4. Summary, Surveillance of risk factors for non communicable diseases, The WHO STEP wise approach, WHO/NMH/CCS/01.01 Rev.1, 2003.
5. Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998; 97: 1837–1847.
6. Mendis S, Lindholm LH, Mancia G, Whitworth J, Alderman M, Lim S, Heagerty T. World Health Organization (WHO) and International Society of Hypertension (ISH) risk prediction charts: assessment of cardiovascular risk for prevention and control of cardiovascular disease in low and middle-income countries. J Hypertens. 2007; 25: 1578–1582.
7. Barzi F, Patel A, Gu D, Sritara P, Lam TH, Rodgers A, Woodward M. Cardiovascular risk prediction tools for populations in Asia. J Epidemiol Community Health. 2007; 61: 115–121.
8. CVD Risk reduction guide, questions and answers, page 9, W.H.O.,September 2007.
9. Risk factors of coronary artery disease in different regions of Saudi Arabia, A.K. Osman and M.M. Al-Nozha, Vol. 6, Issue 2/3, 2000, page 465-474.
10. El-Mugamer IT et al. Diabetes, obesity and hypertension in urban and rural people of Bedouin origin in United Arab Emirates. Journal of tropical medicine and hygiene, 1995, 98(6):407-15.
11. Azizi F., Modifying life style for the prevention of non-communicable disease, Iranian journal of endocrinology and metabolism, 2002, 4(2):81–4.
12. Clustering of coronary artery disease risk factors in patients with type 2 diabetes and impaired glucose tolerance, F. Sajjadi, N. Mohammadifard, R. Kelishadi, N. Ghaderian, H. Alikhasi and M. Maghrun, 1088 La Revue de Santé de la Méditerranée orientale, Vol. 14, No 5, 2008.
13. Al-Nozha MM et al. Coronary artery disease, in Saudi Arabia, Saudi medical journal, 2004, 25(9):1165–71.
14. National survey on the major non communicable diseases, Lebanon. Final Report,2003. Cairo, WHO Regional Office for the Eastern Mediterranean.
15. Diabetes atlas, 2nd ed. Brussels, International Diabetes Federation, 2003.
16. Mokhtar N et al. Diet, culture and obesity in northern Africa. Journal of nutrition, 2001, 131(3):887–92s.
17. Mokdad AH et al. Prevalence of obesity, diabetes, and obesity-related health factors.Journal of the American MedicalAssociation, 2003, 289(1):76–9.
18. National Health Survey of Pakistan1990–1994. Islamabad, Pakistan Medical Research Council, 1998.
19. North American Association for the Study of Obesity,The practical guide. Identification,evaluation and treatment of overweight and obesity in adults. Bethesda, Maryland, National Institutes of Health, 2000 (NIH Publication No. 00–4084).
20. O. Khatib, Noncommunicable diseases, risk factors and regional strategies for prevention and care, Eastern Mediterranean Health Journal, Vol. 10, No. 6, 2004.
21. Azizi F et al. Determinates of serum HDLC level in a Tehran urban population: the Tehran Lipid and Glucose study. Nutrition, metabolism and cardiovascular diseases, 2002, 12:80–9.
22. The Expert Committee of the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes, 2000, 25:S5–20.

Obesity Hypoventilation Syndrome. Where do we stand 50 years later?

Roop Kaw

Cite this article as: BJMP 2010;3(2):323
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Initial reports of Obesity Hypoventilation Syndrome (OHS) date back as early as 18891, but it was not until 1955 that Auchincloss2 and colleagues described a case of obesity and hypersomnolence paired with alveolar hypoventilation.  Burwell3 coined the term Pickwickian syndrome describing the constellation of morbid obesity, plethora, oedema and hypersomnolence.  Hypercapnia, hypoxaemia and polycythemia were described on laboratory testing. Obstructive Sleep Apnea (OSA) had not been described at that time and came to be recognized for the first time in the mid 1970s. With attention shifting to upper airway obstruction, hypercapnia began to get lesser emphasis and confusion began to emerge in describing OSA and OHS.  The term ‘Pickwickian’ began to be used for OSA-related hypersomnolence in the obese patient regardless of the presence of hypercapnia.  This confusion was finally settled by the American Academy of Sleep Medicine (AASM) in its published guidelines in 1999.4  The AASM statement identified that awake hypercapnia may be due to a predominant upper airway obstruction (OSA) or predominant hypoventilation (Sleep Hypoventilation Syndrome) easily distinguished by nocturnal polysomnography (PSG) and response to treatment.  Both disorders are invariably associated with obesity and share a common clinical presentation profile.

Salient features of OHS consist of obesity as defined by a BMI > 30kg/m2, sleep disordered breathing, and chronic daytime alveolar hypoventilation (PaCO2 ≥ 45 mmHg and PaO2 < 70 mmHg). 4  Sleep disordered breathing, as characterized by polysomnography in OHS, reveals OSA (Apnea-hypopnea index [AHI]>5) in up to 90% of patients and sleep hypoventilation (AHI<5) in up to 10%.5  Daytime hypercapnia and hypoxaemia are the hallmark signs of OHS and distinguish obesity hypoventilation from OSA.  Severe obstructive or restrictive lung disease, chest wall deformities and hypoventilation from severe hypothyroidism, and neuromuscular disease need to be excluded before a diagnosis of OHS is established.  As obesity is becoming more prevalent in western society, this disorder has gained more recognition in recent years.  However, patients with this syndrome may still go undetected and untreated.  No population-based prevalence studies of OHS exist till date but, at present, can be estimated from the relatively well known prevalence of OHS among patients with OSA.  Recent meta-analysis with the largest cohort of patients (n=4250) reported a 19% prevalence of OHS among the OSA population, confirming an overall prevalence of about 3 per 1000.6
Whilst transient rectifiable nocturnal hypercapnia is common in patients with OSA, awake hypercapnia in OHS appears to be a final expression of multiple factors.  There has been a debate about BMI and AHI not being the most important independent predictors of hypercapnia in obese patients with OSA.  More definitive evidence for the role of OSA, however, is suggested by resolution of hypercapnia in the majority of patients with hypercapnic OSA or OHS with treatment, with either PAP or tracheostomy, without any significant changes in body weight or respiratory system mechanics. Yet some recent studies have shown that nocturnal hypoxaemia and diurnal hypercapnia, persist in about 50% of such individuals even after complete resolution of OSA with CPAP or tracheostomy.  This raises questions such as how good is AHI as a measure of severity of OSA?
It is intuitive to argue that obesity may exert its effect through mass loading of CO2 due to (increased production via) higher basal metabolic rate or reduced functional residual capacity on lung function.  But why do only some severely obese patients with OSA go onto develop OHS?  Is the pathophysiology driven by the severity of BMI?  Whilst weight loss, particularly surgically-induced, clearly shows resolution of both OSA and hypercapnia7, the role of BMI as an independent factor for hypercapnia has been challenged by the fact that only a small fraction of severely obese patients do in fact develop chronic diurnal hypercapnia.  More importantly, not only can PaCO2 be normalized in a majority of patients without weight loss and with positive airway pressure therapy (PAP), but awake hypercapnia can develop even at lower BMIs among the Asian population.  Some investigators have tried to explain the incremental role of BMI as follows.  In situations where AHI is not a presumed independent predictor of nocturnal hypercapnia, potential pathophysiologic contributors can include pre-event (apnea or hypopnea) amplitude in relation to the post-event amplitude.8  Such inciting events for nocturnal hypercapnia may then be perpetuated in the daytime by factors such as AHI, functional vital capacity (FVC), FVC/FEV1, or BMI as shown in the largest pooled data to date.6  It has been shown that, for a given apnea/interapnea duration ratio, a greater degree of obesity is associated with higher values of PaCO2.9 However the same group of investigators, in another study, did not find any of these factors to be related to the post-event ventilatory response.8
Looking further at the breath by breath cycle, the post-event ventilatory response in chronic hypercapnia may relate to eventual adaptation of chemoreceptors perhaps in consequence to elevated serum bicarbonate known to blunt the ventilatory drive.10 Or it may relate to whole body CO2 storage capacity which is known to exceed the capacity for storing O2.11 With definite evolution in our understanding of hypercapnia among obese patients, these questions continue to dominate. Some of the more pressing ones include: are the predictors of daytime hypercapnia different from those of nocturnal hypercapnia in obese patients with OSA?  An understanding of these facts can help us with the more important understanding of the associated morbidity and mortality from OHS and its correct management.  In addition, what is the true effect of untreated OHS on mortality independent of the co-morbidities related to obesity and OSA?  Can morbidities like cor pulmonale and pulmonary hypertension be reversed with treatment of OHS?  How do we treat patients with OHS who fail CPAP/ BiPAP short of tracheostomy?

Competing Interests
None Declared
Author Details
ROOP KAW, MD, Assistant Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University | Staff, Departments of Hospital Medicine and Outcomes Research (Anesthesiology Institute).
CORRESSPONDENCE: A-13, Medicine Institute I Cleveland Clinic, 9500 Euclid Ave | Cleveland, OH 44195


1. Lavie P. Who was the first to use the term Pickwickian in connection with sleepy patients? History of sleep apnoea syndrome. Sleep Med Rev 2008;12(1):5-17.
2. Auchincloss JH Jr, Cook E, Renzetti AD. Clinical and physiological aspects of obesity, polycythemia and alveolar hypoventilation. J Clin Invest 1955; 34: 1537-45.
3. Burwell CS, Robin ED, Whaley RD, Bicklemann AG. Extreme obesity associated with alveolar hypoventilation; a Pickwickian syndrome. Am J Med 1956; 21: 811-818.
4. The Report of an American Academy of Sleep Task Force. Sleep-related breathing disorders in adults: Recommendations for syndrome definition and measurement techniques in clinical research. Sleep, 1999; 22: 667-689.  
5. Mokhlesi B, Tulaimat A, Faibussowitsch I, Wang Y, Evans AT. Obesity hypoventilation syndrome: prevalence and predictors in patients with obstructive sleep apnea. Sleep Breath 2007; 11:117-124.
6. Kaw R, Hernandez AV, Walker E et al. Determinants of hypercapnia in Obese patients with hypercapnia: A systematic review and Meta-analysis of Cohort studies. Chest 2009; 136(3): 787-96.
7. Sugerman HJ, Fairman RP, Sood RK, et al. Long-term effects of gastric surgery for treating respiratory insufficiency of obesity. Am J Clin Nutr 1992; 55: 597S-601S.  
8. Berger KI, Ayappa I, Sorkin IB, Norman RG, Rapoport DM, Goldring RM. Post event ventilation as a function of CO2 loading during respiratory events in obstructive sleep apnea. J Appl Physiol 2002; 93:917-924. 
9.  Ayappa I, Berger KI, Norman RG  et al. Hypercapnia and Ventilatory periodicity in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2002; 116: 1112-1115. 
10.  Goldring RM, Turino GM, Heinemann HO. Respiratory –renal adjustments in chronic hypercapnia in man. Extracellular bicarbonate concentration and regulation of ventilation. Am J Med 1971;51: 772-784.
11.  Nunn JF. Oxygen in: Applied Respiratory Physiology. 3rd ed. Butterworths, London 1987,p. 235



“Influenza-2009” - An Escape from Disaster.

Shailpreet Kaur Sidhu, Nidhi Singla and Jagdish Chander

Cite this article as: BJMP 2010;3(2):320
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In April 2009, World Health Organization declared the first ever public health emergency affecting overseas countries, territories and communities of the world with a new strain of the influenza A virus causing a global pandemic. This novel strain (H1N1) of the virus appears to be of swine origin and contains a unique combination of gene segments that have not been previously identified in swine or human influenza viruses. The symptoms of the 2009 H1N1 flu virus are clinically similar to those of seasonal influenza and have ranged from mild to severe. The neuraminidase inhibitors provide valuable defences against the virus, but their massive use has lead to the development of resistance to these antiviral agents. Vaccination is the only effective way to protect people from contracting illness during epidemics and pandemics of influenza.
Keywords:  Pandemic, Influenza, H1N1, Flu, Influenza A virus

Forty one years after the last influenza pandemic, while everyone was worrying about the avian influenza A (H5N1) virus causing a pandemic, an apparent new chapter is opened with the emergence of new strain of influenza A virus. On 24th April, the World Health Organization (WHO) declared the first ever public health emergency of international concern indicating the occurrence of confirmed human cases of swine influenza in Mexico and United States.1 Subsequently the Centre for Disease Control and Prevention (CDC) confirmed that these human influenza cases were caused by a novel strain of influenza A virus to which there is little or no population immunity.2 On June 2009, the WHO rated the pandemic alert from phase 5 to 6, signalling that the first pandemic of the 21st century was underway. It was however stressed that the rise in the pandemic alert level was mainly attributed to the global spread of the virus rather than its severity. The pandemic potential of influenza A viruses has been ascribed to their genetic and antigenic instability and there ability to transform by constant genetic re-assortment or mutations, which can result in the emergence of novel progeny subtypes capable of both infecting and leading to sustained person to person transmission.3 The newly emerged strain contains a combination of gene segments that have not been previously identified in swine or human influenza viruses.4
Historical Perspectives
Influenza has been recognised for hundreds of years, but the cause was unknown for most of this time. Hippocrates had defined this disease about 2400 years ago, but lacked laboratory confirmation.5 The year 1580, marks the first instance of influenza recorded as an epidemic even though there is possibility that there were many prior influenza epidemics.6 The word influenza (meaning influence), first used in 1743 originated from the Latin word “Influenza”, named so because the disease was considered to be caused by unfavourable astrological conditions. Since 1700, there have been approximately a dozen influenza A virus pandemics and the lethal outbreak of 1918-1919 is dubbed as the greatest medical holocaust in recorded history, killing up to 50 million people worldwide.7
The earliest evidence of influenza A virus causing acute respiratory illness in pigs was traced to the 1930s. Swine influenza A viruses are antigenically very similar to the 1918 human influenza A virus and they may all have originated from common ancestor.8 From 1930 to 1990, classic swine influenza A was the commonest swine influenza virus circulating amongst the swine population during which the virus did not undergo much genetic change. Antigenic variants of these classical influenza viruses emerged in 1991 and the real antigenic shift occurred at the ends of last century when the classical swine influenza virus re-assorted with human influenza A virus and a North American lineage avian influenza virus. This resulted in the emergence of multiple subtypes including H1N2 and H3N2. In the past few years, sporadic cases of human infections caused by swine influenza A virus have occurred, mainly due to subtypes. Occupational exposure to swine was the most important risk factor for infection and fortunately all patients recovered without resulting in efficient, sustained human to human transmission.9
Origin of 2009 Strain
The pandemic that began in March 2009, was originally referred to as “swine flu” because laboratory testing showed that many of the genes in this new virus were very similar to influenza viruses that normally occur in pigs (swine) in North America. But further study has shown that this new strain of virus represents a quadruple re-assortment of two swine strains, one human strain and one avian strain of influenza. The largest proportion of genes come from swine influenza viruses (30.6% from North American swine influenza strains, and 17.5% from Eurasian swine influenza strains), followed by North American avian influenza strains (34.4%) and human influenza strains (17.5%).10 Analysis of the antigenic and genetic characteristics of the pandemic influenza A virus demonstrated that it’s gene segments have been circulating for many years, suggesting that lack of surveillance in swine is the reason that this strain had not been recognized previously.11 This novel strain is antigenically distinct from seasonal influenza A and possesses previously unrecognised molecular determinants that could be responsible for the rapid human to human transmission. Moreover, antigenic drift has occurred amongst different lineages of viruses, therefore, cross protection antibodies against avian, swine and human viruses are not expected to exist. Emerging scientific data support the hypothesis of a natural genesis, with domestic pigs a central role in the generation and maintenance of the virus. Protein homology analysis of more than 400 protein sequences from the new influenza virus as well as other homologous proteins from influenza viruses of the past few seasons also confirmed that this virus has a swine lineage.1 Phylogenetic analysis has suggested that initial transmission to humans occurred several months before the recognition of the outbreak and multiple genetic ancestry of this influenza A is not indicative of artificial origin.11
Situation Update
In March 2009, an outbreak of respiratory illness was first noted in Mexico, which was eventually identified as being related to influenza A.12 The outbreak spread rapidly to the United States, Canada and throughout the world as a result of airline travel.13 On 11th June 2009, the WHO raised its pandemic alert to the highest level i.e. phase 6, indicating widespread community transmission on at least two continents.14
Pandemic influenza was the predominant influenza virus circulating in the US, Europe, northern and eastern Africa and in Australia. Activity of the virus has initially peaked and then declined in North America and in parts of western, northern and Eastern Europe, but activity continued to increase in parts of central and southeastern Europe, as well as in central and south Asia. As of 28th  February 2010, worldwide more than 213 countries and overseas territories or communities have reported laboratory confirmed cases of pandemic influenza 2009, including at least 16455 deaths; a number the WHO acknowledges significantly underreported the actual number.15 Most of the deaths have been related to respiratory failure resulting from severe pneumonia and acute respiratory distress syndrome.16
In India, the number of confirmed cases till March 2010 was 29,953 and a total of 1410 deaths were reported. The rate of infection has been highest among children and young individuals of <24 years of age. To date, pandemic influenza A infections are uncommon in persons older than 65 years, possibly as a result of pre-existing immunity against antigenically similar influenza viruses that circulated prior to 1957.17 High rates of morbidity and mortality has been noted among children and young adults with underlying health problems including chronic lung disease, immunosuppressive conditions, cardiac disease, pregnancy, diabetes mellitus and obesity.18
Transmission and Shedding
Novel virus is contagious and can transmit from human to human in ways similar to other influenza viruses. The main route of transmission between humans is via inhalation of infected respiratory droplets (range in size from 0.08 µm to 0.12 µm) produced after coughing and sneezing.19 Transmission via contact with surfaces that have been contaminated with respiratory droplets or by aerosolised small-particle droplets may also occur. In addition to respiratory secretions, all other body fluids (including diarrhoeal stool) should also be considered potentially infectious.
The estimated incubation period is unknown and could range from 1 to 7 days, although the median incubation period in most cases appears to be approximately 2 days.20 Shedding of the virus begins the day prior to the onset of symptoms and can persist for 5-7 days in immunocompetent individuals. The amount of virus shed is greatest during the first 2-3 days of illness. Persons who continue to be ill, for a period of longer than 7 days after illness onset, should be considered potentially contagious until symptoms have resolved. Longer periods of shedding may occur in children (especially young infants), elderly adults, and patients with chronic illnesses and immunocompromised hosts who might be contagious for longer periods.
Clinical Manifestations
According to the CDC, in humans the symptoms of the 2009 “flu” virus are similar to those of influenza and of influenza-like illness in general. The illness with the virus has ranged from mild to severe and symptoms include fever, cough, sore throat, body aches, headache, chills and fatigue, which are usual features of influenza virus. The 2009 outbreak has shown an increase percentage of patients reporting diarrhoea and vomiting.16 As these symptoms are not specific to swine flu hence a differential diagnosis of probable swine flu requires not only symptoms but also a high likelihood of swine flu due to person’s recent history. The CDC advised physicians to consider swine influenza infection in the differential diagnosis of patients with acute febrile respiratory illness who have either been in contact with persons with confirmed swine flu or who were in states that have reported swine flu cases during the 7 days preceding their illness onset.
The overall severity with this 2009 virus has been less than what was observed during the influenza pandemic of 1918-1919. Most patients appear to have uncomplicated, typical influenza-like illness and recovered without requiring any medical treatment. About 70% of people who have been hospitalised have had one or more medical conditions, which include pregnancy, diabetes, heart disease, asthma and kidney disease.21 The most common cause of death is acute respiratory distress syndrome. The other causes of death are severe pneumonia with multifocal infiltrates (leading to sepsis), high fever (leading to neurological problems), dehydration (from excessive vomiting and diarrhoea) and electrolyte imbalance. Fatalities are more likely in young children (<5 years), elderly (>65 years) and in people with underlying conditions, which include pregnancy, asthma, lung diseases, diabetes, morbid obesity, autoimmune disorders, immunosuppressive therapies, neurological disorders and cardiovascular disease.22
Laboratory Diagnosis
All diagnostic laboratory work on clinical samples from suspected cases of virus infection should be done in a Biosafety Level 2 (BSL-2) Laboratory. Suspected cases of novel infection should have respiratory specimens (nasopharyngeal, nasal or oropharyngeal swab, bronchoalveolar lavage and endotracheal aspirate) collected to test for the 2009 flu virus. Specimens should be placed into sterile viral transport media (VTM) and to be kept at 4°C. Real time reverse transcriptase polymerase chain reaction (RT-PCR) is the recommended sensitive method for the detection of virus, as well as to differentiate between pandemic 2009 and regular seasonal flu.23 The other rapid influenza diagnostic tests (RIDTs), although provide results within 30 minutes or even less, none of these tests can distinguish between influenza A virus subtypes. Moreover, RIDTs do not provide any information about antiviral drug susceptibility. Isolation of the virus in cell cultures or embryonated eggs is another method for diagnosis of infection, but may not yield timely results for clinical management and negative viral culture does not exclude the influenza A infection.
However, most people with flu symptoms do not need a test for pandemic 2009 flu, specifically because the test results usually do not affect the recommended course of treatment. The CDC recommends testing only for people who are hospitalised with suspected flu and persons having underlying medical conditions and those with weak immune systems.24 It is also expressed that treatment should not be delayed by waiting for laboratory confirmation of test results, but rather make diagnosis based on clinical and epidemiological backgrounds and start treatment early.
The virus isolates in the 2009 outbreak are found to be resistant to amantidine and rimantidine. The CDC recommends the use of neuraminidase inhibitors as the drugs of choice for treatment and prevention of 2009 influenza in both children and adults.25 Tamiflu (oseltamivir phosphate) and Relenza (zanamivir) are the two FDA-approved influenza antiviral drugs and a third neuraminidase inhibitor peramivir is an experimental drug approved for hospitalised patients in cases where the other available methods of treatment are ineffective or unavailable. Antiviral drugs not only make the illness milder but also prevent serious flu complications. However, the majority of people infected with the virus make a full recovery without requiring medical attention or antiviral drugs. Treatment is recommended for patients with confirmed or suspected 2009 influenza who have severe, complicated or progressive illness or who are hospitalised. People who are not from the at-risk group and have persistent or rapidly worsening symptoms should also be treated with antivirals. Therapy should be started as soon as possible, since evidence of benefit is strongest when treatment is started within 48 hours of illness onset.26 Treatment should not be delayed while awaiting the results of diagnostic testing nor should it be withheld in patients with indications for therapy who present >48 hours after the onset of symptoms. Beside antivirals, supportive care at home or in hospital, focuses on controlling fevers, relieving pain and maintaining fluid balance as well as identifying and treating any secondary infections or other medical problems.
Major Concern
The neuraminidase inhibitors oseltamivir and zanamivir provide valuable defences and have been used widely for treatment and chemoprophylaxis of 2009 pandemic influenza A.But the recent emergence of resistance to these antiviral drugs is a matter of immediate concern. Influenza A strain resistant to oseltamivir has been reported from a variety of geographical locales and poses a challenge for the management of severely compromised patients.27 The CDC warned that the indiscriminate use of antiviral medications to prevent and treat influenza could ease the way for drug resistant strains to emerge, which would make the fight against the pandemic much harder. Most of the patients recover spontaneously without any medical attention and use of antiviral medications should be reserved primarily for people hospitalised with pandemic flu and persons, with pre-existing or underlying medical conditions who are at higher risk for influenza-related complications. It has also been emphasised that early treatment once a patient has developed symptoms, rather than chemoprophylaxis, should reduce opportunities for the development of oseltamivir resistance.26 The degree to which these drugs will remain effective for the treatment of the novel strain of influenza in the coming months is still a question.
What’s next?
The only possible way to combat the situation is large scale immunization. Antiviral drugs are not a substitute for vaccinination and are used only as an adjunct to vaccines in the control of influenza. Vaccines are one of the most effective ways to protect people from contracting illness during epidemics and pandemics of influenza. The seasonal vaccines do not confer any protection against 2009 H1N1; new vaccines have been licensed and are available.28 The vaccines are available in both live-attenuated and inactivated formulations. Two types of vaccines are approved by the FDA for use in the prevention of 2009 pandemic influenza virus. These are TIV (“flu shot” of trivalent inactivated vaccine) and LAIV (nasal spray of live attenuated vaccine). The inactivated vaccine is contraindicated in patients with severe allergic reaction to eggs or any other component of the vaccine. The live attenuated vaccine is licensed for persons aged 2 through 49 years who are not pregnant, are not immunocompromised and have no underlying medical conditions. Children less than 5 years who have asthma and are taking long term aspirin therapy should also not receive live vaccines. Otherwise, both vaccines are safe and highly immunogenic and a single administration leads to robust immune response in 80% to 90% of adults aged 18-64 years and in 56% to 80% of adults aged 65 years and older with in about 10 days.29 Children younger than 10 years will require two administrations of the vaccine separated by at least 21 days. Adverse effects following vaccination are minor, just like those of seasonal influenza vaccine and are self limiting. Concerns regarding the risk of Guillain-Barre syndrome (GBS) after vaccination have been raised. Various studies have suggested that the risk of GBS is higher from influenza itself rather than from the vaccine and the other adverse effects.30 The CDC is now encouraging everyone including people of 65 years and above to get vaccinated against the 2009 strain of influenza.
The Government of India has recently approved a split virus, inactivated, non-adjuvant monovalent vaccine (Panenza by Sanofi Pasteur) to inoculate frontline health workers and those who have a high risk of getting infected.31 Groups of health care workers has also been singled out by the European council for attention and immunization.32 Infection control practices in the health care settings should be followed along with as per the guidelines.33 Patients should also be educated regarding the other preventive measures, including using tissues to cover their mouth and nose when coughing and sneezing, developing good hand washing techniques, use of alcohol based hand-rubs, avoiding contact with ill persons if possible and staying home when ill unless medical attention has been given.
The flu season seems to be dying down in 2010 but the war is yet not over. Lessons must be learnt from the previous influenza pandemics and it is still important to get vaccinated against the flu and be prepared, as activity as well as virulence might increase again in the coming season. The words of Margaret Chan (Director General, WHO) to be remembered that “the virus writes the rule and this one like all influenza viruses can change the rules, without rhyme or reason, at any time”.


Competing Interests
None declared
Author Details
Shailpreet Kaur Sidhu, MD, Demonstrator Nidhi Singla, MD, Assistant Professor Jagdish Chander, MD, MAMS, Professor & Head Department of Microbiology, Government Medical College Hospital, Sector 32, Chandigarh.
CORRESSPONDENCE: Dr Nidhi Singla Assistant Professor H.No. 1205, Sector 32-B, Chandigarh 160030 (India)


1. Mathew BC, Daniel RS, Cambell IW. Swine – origin influenza A (H1N1) pandemic revisited. Libyan j Med 2009; 4: 176-9.
2. Centre for Disease Control and Prevention (CDC).Update: Swine influenza A (HINI) infections-California and Texas, April 2009. MMWR Morb Mortal Wkly Rep 2009; 58: 435-7.
3. Taubenberger JK, Morens DM. The pathology of influenza virus infections. Annu ssRev Pathol 2008; 3: 499-22.
4. Luan YC, Shin RS, Pei-Len S, et al. Novel Swine-origin influenza virus A (H1N1): The first pandemic of the 21st Century. J Formos Med Assoc 2009; 108: 526-32.
5. Martin PM, Martin-Granel E .Twenty five hundred years evolution of the term epidemic. Emerg Infect Dis 2006; 12: 976-80.
6. Sagar G, Angela C. Swine influenza A (H1N1) strikes a potential for global disaster. Journal of Emergencies Trauma and Shock 2009; 2: 99-05.
7. Johnson NP, Mueller J. Updating the accounts: Global mortality of the 1918-1920 Spanish influenza pandemic bull. Hist Med 2002; 76: 105-15.
8. Reid AH, Taubenberger JK .The origin of the 1918 pandemic influenza virus: A continuing enigma. J Gen Virol 2003; 84: 2285-92.
9. Patrick CY Woo. Swine influenza: Then and now: Hong Kong Med J 2009; 15: 166-7.
11. Cohen J. Swine flu outbreak: Out of Mexico? Scientists ponder swine flu's origins. Science 2009; 324: 700.
13. Khan K, Arino J, Hu W, et al. Spread of a novel influenza A (H1N1) virus via global airline transportation. N Engl J Med 2009; 361: 212.
14. World Health Organization. World now at the start of 2009 influenza pandemic. Available at: http:/ pandemic phase6_20090611/en/index.html (Accessed June 11, 2009).
15. World Health Organization. Pandemic (H1N1) 2009 - update 90. Available at: (Accessed March 5, 2010).
16. Louie JK, Acosta M, Winter K, et al. Factors associated with death or hospitalization due to pandemic 2009 influenza A (H1N1) infection in California. JAMA 2009; 302: 1896.
17. Belshe RB. Implications of the emergence of a novel influenza virus. N Engl J Med 2009; 360: 2667.
19 Clem A, Galwankar S. Avian influenza: Preparing for a pandemic. J Assoc Physicians India 2006; 54: 563-70.
20. Cao B, Li XW, Mao Y, et al. Clinical features of the initial cases of 2009 pandemic influenza A () virus infection in China. N Engl J Med 2009; 361: 2507.
21. World Health Organization. Human infection with new influenza A (H1N1) virus: Clinical observations from Mexico and other affected countries. Available at: http:/ (Accessed May 28, 2009).
22. Hospitalized patients with novel influenza A infection: California, April- May, 2009. Morb Mortal Wkly Rep 2009; 58: 536.
23. Centers for Disease Control and Prevention Interim Guidance on Specimen Collection, Processing, and Testing for Patients with Suspected Novel Influenza A (H1N1) Virus Infection. Available at collection.htm (Accessed November 23, 2009).
24. Centers for Disease Control and Prevention. Influenza Diagnostic Testing during the
2009-2010 Flu Season. Available at: public_qa.htm (Accessed November 23, 2009).
25. Centers for Disease Control and Prevention. Antiviral Drugs and Swine Influenza. Available at: (Accessed April 27, 2009).
26.Centers for Disease Control and Prevention. Interim recommendations for the use of antiviral medications in the treatment and prevention of influenza for the 2009-2010 season. Available at: (Accessed December 15, 2009).
27. Pandemic (H1N1) 2009 briefing note 1: Viruses resistant to oseltamivir (Tamiflu) identified. Wkly Epidemiol Rec 2009; 84: 299-399.
28. Centers for Disease Control and Prevention. Update in influenza A (H1N1) 2009 monovalent vaccines. MMWR Morb Mortal Wkly Rep 2009; 58:1100-1101. 
29. Fauci AS. Statement by Dr. Anthony Fauci, Director, National Institute of allergy and Infectious Diseases, NIH, regarding early results from clinical trials of 2009 H1N1 influenza vaccines in healthy adults. Available at: (Accessed November 12, 2009).
30. Stowe J, Andrews N, Wise L, Miller E. Investigation of the temporal association of Guillain – Barre syndrome with influenza vaccine and influenza like illness using the United Kingdom General Practice Research Database. Am J Epidemiol 2009; 169:382- 88.
31. Sanofi’s H1N1 vaccine approved for use. Available at: http// (Accessed March 16, 2010).
32. Nicoll A. A new decade, a new seasonal influenza: the council of the European union recommendation on seasonal influenza vaccination. Euro Surveill 2010, 15(1): 1-2.
33. Centers for Disease Control and Prevention. Interim Guidance for infection control for care of patients with confirmed or suspected novel influenza A (H1N1) virus infection in healthcare settings. Available at infection control.htm (Accessed September 18, 2009).


Aorto-enteric fistulas: a cause of gastrointestinal bleeding not to be missed

Louise MacDougall, John Painter, Terry Featherstone, Claus Overbeck, Shyju Paremal and Suvadip Chatterjee

Cite this article as: BJMP 2010;3(2):317
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Aorto-enteric fistulas are a rare cause of gastrointestinal (GI) bleeding. The high mortality associated with this condition and relatively low incidence make this a diagnostic and management challenge. This case report describes a classic presentation of such a case along with a discussion on the diagnosis and treatment of this condition. We hope that this will be a clinical reminder to all physicians particularly those involved in managing GI hemorrhage in an acute medical take.

Clinical Presentation

A 87-year old man was referred to hospital with a five day history of lethargy and increased urinary frequency. He denied symptoms of gastrointestinal bleeding or abdominal pain. His past medical history included diabetes mellitus, chronic kidney disease, peripheral vascular disease and surgery for repair of ruptured aortic aneurysm 6 weeks ago. Systemic examination, including per rectal examination, was normal. Haemoglobin was 83g/L and C-reactive protein was 148 (Normal <5). Twelve hours after admission he developed pyrexia (37.8 degree) accompanied with tachycardia (103 beats per minute) and hypotension (BP 87/43). Soon afterwards, he had a small amount (<50 mls) of fresh haemetemesis. He also complained of lower back pain and clinical examination revealed tenderness in the left iliac fossa. He was cross-matched for blood and initiated on intra-venous fluids. As his Rockall score was six an urgent oesophago-gastro-duodenoscopy (OGD) was planned. Over the next few hours he complained of increasing central abdominal pain and had several episodes of melaena. In view of the history of recent aortic surgery and current GI bleed the possibility of aorto-enteric fistula (AEF) was considered. An urgent contrast CT scan of the abdomen (Figure 1) was therefore arranged prior to OGD.
Figure 1: Contrast CT scan demonstrating the aorta (A) with extravasation of contrast (B) and a large collection (C) around it with trapped air suggestive of infection.
Contrast computed tomogram (CT) scan of the abdomen revealed an inflammatory soft tissue mass anterior to the infra-renal aortic graft with pockets of gas and leakage of contrast into it. These findings were suggestive of an AEF. The patient was informed of the diagnosis of AEF and the need for emergency surgical repair to which he consented. During the operation the vascular surgeons found that the duodenum was adherent to the aortic graft with evidence of fistulisation and infection, thus confirming the diagnosis. Although operative repair appeared to be successful, the patient continued to bleed on the table due to disseminated intravascular coagulation and died twenty fours after admission.
AEF is defined as a communication between the aorta and the GI tract.1 The diagnosis of AEF should be considered in every patient with a GI bleed and a past history of aortic surgery.2 Our case patient had had emergency repair of a ruptured aortic aneurysm with a prosthetic graft 6 weeks prior to his current admission.
AEFs are a rare cause of gastro-intestinal (GI) hemorrhage. AEFs can be primary or secondary. Primary AEF (PAEF) is a communication between the native aorta and the GI tract.1 The incidence of PAEF ranges from 0.04 to 0.07%.3 PAEFs commonly arise from an abdominal aortic aneurysm of which 85% are atherosclerotic.1
Secondary AEFs (SAEF) are an uncommon complication of abdominal aortic reconstruction.4  The incidence of SAEF ranges from 0.6% - 4%.Generally two types of SAEFs have been described. Type 1, termed as true AEF develops between the proximal aortic suture and the bowel wall. These usually present with massive upper GI hemorrhage.4 Type 2, or the paraprosthetic–enteric fistula does not develop a communication between the bowel and the graft and accounts for 15% to 20% of SAEFs.4 In this type of fistula, bleeding occurs from the edges of the eroded bowel by mechanical pulsations of the aortic graft. Sepsis is more frequently associated with this type of AEF (75% of cases).4 The mean time interval between surgery and presentation with SAEF is about 32 months6 but the time interval can vary from 2 days to 23 years.7 AEFs can involve any segment of the GI tract but, 75% involve the third part of the duodenum and the affected part is generally proximal to the aortic graft.8
The pathogenesis of AEF is not fully understood but two theories exist. One theory suggests repeated mechanical trauma between the pulsating aorta and duodenum causes fistula formation and the other suggests low-grade infection as the primary event with abscess formation and subsequent erosion through the bowel wall.9 The latter theory is felt to be most likely. The majority of grafts show signs of infection at the time of bleeding and up to 85% of cases have blood cultures positive for enteric organisms.10
The main symptom of AEF is GI bleeding. Secondary AEFs have been traditionally said to present with a symptom triad (as in our patient) of abdominal pain, GI bleeding and sepsis; however, only 30% of patients present in this manner.11 Patients often have a “herald bleed” which is defined as a brisk bleed associated with hypotension and hematemesis that stops spontaneously followed by massive gastro-intestinal haemorrhage in 20% – 100% of patients.8 Sometimes the GI bleeding can be intermittent.
The commonest investigations for diagnosis of AEFs are OGD, conventional contrast CT scan and angiography.12 OGD is often the initial investigation, as in any upper GI bleed mainly because of lack of clinical suspicion of the diagnosis. The endoscopic findings vary from those of a graft protruding through the bowel wall to fresh bleeding in distal duodenum to that of an adherent clot or extrinsic compression by a pulsating mass with a suture line protruding into the duodenum.13   Less than 40% of patients have signs of active bleeding at OGD.8 Conventional CT with contrast is widely available and most commonly performed to diagnose AEFs. Perigraft extravasation of contrast is a pathognomic  sign of AEF and this may be associated with signs of graft infection i.e perigraft fluid and soft tissue thickening along with gas.12 Multi-detector CT and MRI are more sensitive diagnostic imaging tools with MRI now being used mainly in patients with renal failure to avoid the use of contrast.12
PAEFs can be treated with endovascular stent placement in selected cases especially in those who cannot tolerate emergency surgery.12 The treatment of choice in SAEFs is graft resection and establishment of an extra-anastomotic circulation with repair of the duodenal wall although overall survival rates vary from 30% to 70%.13
SAEFs are a catastrophic complication of aortic surgery. AEFs are relatively rare and need a high index of suspicion in the appropriate clinical situation in order to diagnose this condition. Left untreated they are universally fatal. Surgical repair carries a very high mortality.

Competing Interests
None declared
Author Details
Louise MacDougall, John Painter, Suvadip Chatterjee, Department of Gastroenterology, Sunderland Royal Hospital. United Kingdom. Terry Featherstone, Department of Radiology, Sunderland Royal Hospital. United Kingdom. Claus Overbeck, Department of Vascular Surgery, Sunderland Royal Hospital. United Kingdom. Shyju Paremal, Department of Medicine, Sunderland Royal Hospital. United Kingdom.
CORRESSPONDENCE: Dr Suvadip Chatterjee, MRCP(UK), MRCP(Ireland), MD, Specialist Registrar in Gastroenterology. Sunderland Royal Hospital. Kayll Road. Sunderland, SR4 7TP


1.Ihama Y, Miyazaki T, Fuke C, Ihama Y, Matayoshi R, Kohatsu H, Kinjo F. An autopsy case of a primary aortoenteric fistula: a pitfall of the endoscopic diagnosis. World Journal of Gastroenterology 2008 August 7; 14(29):4701-4704.
2.Asfoor A M A, Nair G R. Secondary Aorto-duodenal fistulas. Bahrain Medical Bulletin Vol29, No 2,June 2007 : 1- 6.
3. Saers SJ, Scheltinga MR. Primary aortoenteric fistula.Br J Surg 2005;92:143 – 152.
4.Mohammadzade M A, Akbar H M. Secondary Aortoenteric fistula. Medscape General Medicine.2007; 9(3):25: 1-4.
5.Elliot JP, Smith RF, Sizlagyi DE. Aorto-enteric and paraprosthetic enteric fistula. Problems of diagnosis and management. Arch of Surg.1974;108:479.
6. Bastounis E, Papalambros E, MermingasV, Maltezos C, Diamantis T, Balsa P. Secondary aortoduodenal fistulae. J Cardiovasc Surg. 1997; 38: 457 – 464.
7.Shindo S, Tada Y, Sato O, et al. A case of aortoenteric fistula occurring 27 years after aorto-femoral bypass surgery, treated successfully by surgical management. Surg Today.1993;23: 993-997.
8.Busuttil SJ, Goldstone J. Diagnosis and management of aortoenteric fistulas. Semin Vasc Surg. 2001;14: 302 – 311.
9.Bussetil RW,Reese W,Baker JD,et al.Pathogenesis of aortoduodenal fistula, experimental and clinical correlates. Surgery. 1979;85:1-12.
10. Rosenthal D, Deterling Jr RA, O’Donnel Jr TF, et al. Positive blood culture as an aid in the diagnosis of secondary aortoenteric fistula. Arch Surg. 1979;114: 1041 -4.
11. Lau H, Chew DK, Gembarowicz RM, Makrauer FL, Conte M. Secondary aortoduodenal fistula. Surgery. 2001;130: 526-527.
12. Odemis B, Basar O, Ertugul I, Ibis M, Yuksel I, Ulcar E ,Arda K. Detection of an aorto-enteric fistula in a patient with intermittent bleeding. Nature Clinical Practice Gastroenterology and Hepatology.2008 (5):226 – 230.
13. Champion MC, Sullivan SN, Coles JC, Goldbach M, Watson WC. Aortoenteric fistula. Incidence, presentation, recognition and management. Ann Surg 1982(3): Vol 195; 314-317.

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