Internal Medicine

Diffuse Alveolar Haemorrhage with ANCA associated vaculitis-review of Literature

Fadi Hammoudeh, Muhammad K. Perwaiz, Setu Patolia, Frances M. Schmidt, Narayan Neupane,Neerja Gulati, Danilo Enriquez, Joseph Quist, Mehjabeen Zahir and Eneh Kennedy

Cite this article as: BJMP 2011;4(1):a402
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Patients with Wegner’s Granulomatosis often present with diffuse alveolar haemorrhage alongside the classical triad of haemoptysis, anaemia and progressive dyspnoea. The diagnosis is confirmed by bronchoalveolar lavage with serial aspirated aliquots of fluid revealing persistently bloody returns. Lung biopsy is very helpful if it shows granulomatous inflammation and vasculitis however it lacks sensitivity and specificity. Studies suggest that the detection of antineutrophilcytoplasmic antibodies (ANCA) along with Proteinase-3 can substitute for biopsy for the diagnosis of Wegner’s Granulomatosis in patients who present with diffuse alveolar haemorrhage.

Keywords:  Diffuse Alveolar Haemorrhage (DAH), Wegener’s Granulomatosis (WG), Anti-neutrophil cytoplasmic antibodies (ANCA), classical antineutrophil cytoplasmic antibodies (C-ANCA), anti proteinas-3 (PR3)


Diffuse Alveolar Haemorrhage (DAH) is a rare but serious and frequently life-threatening complication of a variety of conditions. DAH refers to a clinical syndrome resulting from injury to the alveolar capillaries, arterioles, and venules leading to red blood cell accumulation in the distal air spaces because of leakage of alveolar capillaries. Most cases of DAH are caused by capillaritis associated with systemic autoimmune diseases such as ANCA-associated vasculitis, anti-GBM disease, and systemic lupus erythematosus.1 Treatment is with immunosuppressants for patients with autoimmune causes and respiratory support if needed.
Diffuse alveolar haemorrhage syndrome is not a specific entity but is a syndrome that suggests a differential diagnosis and a specific sequence of testing.
Many disorders can cause alveolar haemorrhage; they include
  1. Autoimmune disorders (e.g., systemic vasculitides, Goodpasture's syndrome, antiphospholipid antibody syndrome)
  2. Pulmonary infections (e.g., invasive aspergillosis, hantavirus infection)
  3. Toxic exposures (e.g., trimellitic anhydride, isocyanates, crack cocaine, certain pesticides)
  4. Drug reactions (e.g., propylthiouracil, diphenylhydantoin, amiodarone, methotrexate, , nitrofurantoin, bleomycin, montelukast, infliximab
  5. Cardiac disorders (e.g., mitral stenosis)
  6. Coagulation disorders caused by diseases or anticoagulant drugs
  7. Isolated pauci-immune pulmonary capillaritis
  8. Idiopathic pulmonary haemosiderosis
  9. Bone marrow or solid organ transplantation.
Clinical Presentation
The clinical presentation of diffuse alveolar haemorrhage may reflect either alveolar bleeding alone or features of the underlying cause (e.g., haematuria in Wegener granulomatosis, arthritis in systemic lupus erythematosus). Hence, its recognition requires a high degree of suspicion. Some patients present with severe acute respiratory distress requiring mechanical ventilation. However, dyspnoea, cough, and fever are the common initial symptoms and are most often acute or subacute (i.e., present for less than a week). The fever is usually due to the underlying cause, such as lupus. Haemoptysis may be absent at the time of presentation in up to a third of patients because the total alveolar volume is large and can absorb large amounts of blood, without extending more proximally into the airways. Apparent haemoptysis, if present, must be differentiated from haematemesis or pseudohaemoptysis (alveolar flooding with fluid that resembles blood, as in Serratia marcescens pneumonia, in which the reddish hue of the infecting organism can create the impression of alveolar bleeding).
Chest X-ray and Chest CT scan typically shows bilateral infiltrates (figure 1 &2)
Figure 1
Figure 2
DAH & ANCA associated vasculitides
Wegener's Granulomatosis (WG) is an uncommon disease that affects about 1 in 20,000 to 1 in 30,000 people.  WG is defined by the triad of granulomatous inflammation of the respiratory tract, vasculitis of small to medium-size vessels and necrotizing glomerulonephritis. The onset of WG may be indolent with few symptoms, or it may have a rapid and severe onset. About 90% of patients have symptoms of a cold or runny nose or sinusitis that fail to respond to the usual therapeutic measures and last considerably longer than the usual upper respiratory tract infection. Other symptoms include nasal membrane ulcerations and crusting, saddle-nose deformity, inflammation of the ear with hearing problems, inflammation of the eye with sight problems, cough (with or without the presence of blood), pleuritis, (inflammation of the lining of the lung), rash and/or skin sores, fever, lethargy weakness, loss of appetite, weight loss, arthritic joint pain, night sweats, and haematuria which may or may not be indicated by a change in urine colour.Thediagnosis of WG depends on the combination of clinical presentation, serological markers, and histopathological findings. ANCA is a sensitive and specific marker for ANCA-associated systemic vasculitis. In a study done by U. Schönermarck et al,9 624 ANCA- positive patients were included, (C-ANCA: 333, P-ANCA: 291). C-ANCA were highly sensitive (81%) and specific (99.5%) for WG, resulting in high positive predictive value (PPV) (94%). Many studies showed that combining proteinase 3 (PR3) and C-ANCA results(C-ANCA/PR3) increases specificity and Positive Predictive Value close to 100%, but reduces sensitivity close to 70%.10,11,13,14 In summary, the presence of C-ANCA & PR3 antibody is highly suggestive of WG. This led to reevaluation of the role of biopsy for diagnosis of WG in multiple studies.4, 14, 15
The site of biopsy is dependent upon the clinical status. A nasal or sinus biopsy may be the least invasive way to diagnose WG. Renal biopsy is helpful if there is evidence of renal insufficiency or glomerulonephritis. A lung biopsy should only be considered if potentially diagnostic tissue cannot be obtained from any other site.1 Hoffman et al performed a total of 82 open lung biopsies in patients with small vessel vasculitis of which 89% showed evidence of combined vasculitis and necrosis, granulomas and necrosis were found in 90%.16 59 transbronchial biopsies were performed in 48 patients and only four specimens had evidence of vasculitis and granulomas were identified in an additional three. Thus, the role of transbronchial biopsies in these patients is limited and open lung biopsies are more informative but carry a higher morbidity and mortality.
The incidence of DAH has beenreported as between 7-45% in Wegner’s Granulomatosis (WG), and 10-30% in Microscopic Polyangitis (MPA).3, 5, 6 The lungs are the most commonly affected organ in WG with evidence of involvement in over 90% of patients during the course of their disease; in 9% it is the only organ affected. 5,7 In MPA lung involvement is less common than inWG, and occurs in up to 50% of cases during the course of the disease.8 Pulmonary involvement ranges from subclinical changes on high resolution computed tomography to devastating haemoptysis. Approximately 5% of patients will have a fulminant presentation requiring assisted ventilation.
Patients with DAH with or without glomerulonephritis, who are found to have ANCA positive can be generally assumed to have WG or MPA. The type of ANCA (PR3-ANCA or MPO-ANCA) found is irrelevant with respect to the initial management of this patients.1 The backbone of therapy is the early identification of disease followed by the rapid induction of disease control with immunosuppression. Early recognition is crucial, because the prompt institution of supportive measures and immunosuppressive therapy is required for survival. The intensity of the initial treatment depends on the severity of the disease. Based on the European Vasculitis Study Group (EUVAS), which categorized the patients in groups according to the severity of their disease, the presence of DAH put the patient in the severe disease group.17 The management of these patients is a combination of corticosteroid and cyclophospamide. S.L Hogan showed that cyclophosphamide reduces mortality and increase the likelihood of inducing remission in patients with ANCA-associated vasculitis. 18
DAH is animportant cause of morbidity and mortality in ANCA- associated vasculitis, the mortality rate may reach 66%, which is six times greater than vasculitis without alveolar hemorrhage.3,19,20,21 Based on the high mortality rate with DAH in ANCA-associated vasculitis, and reduction in mortality shown with cyclophosphamide, treatment with cyclophosphamide should be started as early as possible, based on the clinical presentation and the presence of ANCA, without waiting histological confirmation.
DAH leading to acute respiratory distress syndrome is a rare and life threatening condition in adults with ANCA positive vasculitis. Patients with DAH with or without glomerulonephritis, who are found to have ANCA positive can be generally assumed to have WG or MPA, and diagnostic lung biopsy may be deferred. Early institution of treatment with prednisone and cyclophosphamide can significantly reduce morbidity and mortality.
Key points
1.      Patients with Wegner’s Granulomatosis often present with diffuse alveolar haemorrhage. These patients must be treated promptly as delay in treatment results in high morbidity and mortality.
2.      Lung biopsy is very helpful if it shows granulomatous inflammation and vasculitis however it lacks sensitivity and specificity.
3.      Detection of C-ANCA with Proteinase-3 can substitute for biopsy in the diagnosis of WG in patients who present with diffuse alveolar haemorrhage.

Competing Interests
None declared
Author Details
<p> Fadi Hammoudeh MD,&nbsp;Muhammad K. Perwaiz MD, Setu Patolia MD,&nbsp;Frances M. Schmidt MD,&nbsp;Narayan Neupane, MD,&nbsp;Neerja Gulati MD,&nbsp;Danilo Enriquez MD,&nbsp;Joseph Quist,MD&nbsp;Mehjabeen Zahir MD, Eneh Kennedy MD, - Interfaith Medical Center at 1545 Atlantic Avenue Brooklyn, NY</p>
CORRESSPONDENCE: Muhammad K. Perwaiz MD, Fellow pulmonary department, Interfaith medical center at 1545 Atlantic Avenue Brooklyn, NY


1.  Specks U. Diffuse alveolar haemorrhage syndromes. Curr Opin Rheumatol 2001; 13:12-17.2.  Travis W. Colby T. Lombard C, et al: A clinicopathologic study of 34 cases of diffuse pulmonary haemorrhage with lung biopsy confirmation. Am J Surg Pathol 1990 ;14:11123.  D. R. Thickett, A. G. Richter, N. Nathani, G. D. Perkins and L. HarperPulmonary manifestations of anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis.  Rheumatology 2006;45:261–2684.  Travis WD, Hoffman GS, Leavitt RY et al. Surgical pathology of the lung in Wegener's granulomatosis. Review of 87 open lung biopsies from 67 patients. Am J Surg Pathol. 1991;15(4):315-335.  J F Cordier, D Valeyre, L Guillevin, R Loire and J M Brechot Pulmonary Wegener's granulomatosis. A clinical and imaging study of 77 cases. Chest 1990; 97: 906-9126.  S J HAWORTH, C 0 S SAVAGE, D CARR, J M B HUGHES, A J REES Pulmonary haemorrhage complicating Wegener's granulomatosis and microscopic polyarteritis British Medical Journal.  1985;290(15);1775-17787.  Aine Burns Pulmonary Vasculitis Thorax 1998; 53:220–2278.  Octavian C. Ioachimescu. Diffuse alveolar haemorrhage: Diagnosing it and finding the cause. Cleveland Clinic Journal of Medicine .2008;75(4): 258-2809.  U. Schönermarck, P. Lamprecht, E. Csernok, W. L. Gross. Prevalence and spectrum of rheumatic diseases associated with proteinase 3-antineutrophil cytoplasmic antibodies (ANCA) and myeloperoxidase-ANCA. Rheumatology 2001;40:178-18410.  Langford CA. Wegener granulomatosis. Am J Med Sci 2001;321:76-82.11.  Falk RJ, Jennette JC. ANCA small-vessel vasculitis. J Am Soc Nephrol 1997; 8:314-22.12.  Hagen EC, Daha MR, Hermans J et al. Diagnostic value of standardized assays for anti neutrophil cytoplasmic antibodies in idiopathic systemic vasculitis. EC/BCR Project for ANCA Assay Standardization Kidney Int. 1998;53(3):743–53.13.  Moosig F, Lamprecht P, Gross WL. Wegener's Granulomatosis: the current view. Clin Rev Allergy Immunol.  2008;35(1-2):19-2114.  Bosch X, Guilabert A, Espinosa G, et al. Treatment of antineutrophil cytoplasmic antibody associated vasculitis: a systematic review. JAMA. 2007; 298(6):655–6915.  Mar EJ, Matsubara O, Nelia S. Tan-Liu et al. The pulmonary biopsy in the early diagnosis of Wegener's (pathergic) granulomatosis: A study based on 35 open lung biopsies. Hum Pathol. 1988;19(9):1065-7116.  Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener’s granulomatosis: an analysis of 158 patients. Ann InternMed 1992;116:488–9817.  Stephen K. Frankel, Gregory P. Cosgrove, Aryeh Fischer, Richard T. Meehan and Kevin K. Brown Update in the Diagnosis and Management of Pulmonary Vasculitis Chest 2006;129;452-46518.  SL Hogan, PH Nachman, AS Wilkman, JC Jennette and RJ Falk Prognostic markers in patients with antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis Journal of the American Society of Nephrology.1996;7:23-3219.  Gisele Zandman-Goddard MD Diffuse Alveolar Haemorrhage in Autoimmune Diseases. IMAJ 2002;4:461-46220.  Lin Y, Zheng W, Tian X, Zhang X, Zhang F, Dong Y. Antineutrophil cytoplasmic antibody-associated vasculitis complicated with diffuse alveolar haemorrhage: a study of 12 cases. J Clin Rheumatol. 2009;15(7):341-4.21.  Chen GX, Dong Y, Ju ZB . A clinical analysis of 32 patients with diffuse alveolar haemorrhage in diffuse connective tissue diseases. Zhonghua Nei Ke Za Zhi. 2008;47(5):362-5

Painless aortic dissection presenting with congestive heart failure

Usman Ali, Wai Hang Cheung and Ashis Banerjee

Cite this article as: BJMP 2011;4(1):a401
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A 44 year old man, previously in good health, presented with congestive heart failure, the onset of which was probably four weeks previously. A diagnostic label of community acquired pneumonia led to delay in the diagnosis of type A aortic dissection.

This required surgical management which resulted in a good outcome. The absence of chest pain may have contributed to the delay in diagnosis. Aortic dissection should form part of the differential diagnosis of unexplained acute congestive heart failure. 

Case History

A 44 year old male presented to the emergency department complaining of shortness of breath. The symptoms had commenced suddenly four weeks ago. He had been breathless at rest, and subsequently developed a productive cough with white sputum. He denied chest pain. He was known to have the sickle cell trait but was otherwise in good health. He was a non-smoker.
Since the onset of symptoms, and prior to this admission, the patient presented to two different emergency departments. The working diagnosis was, and remained, community acquired pneumonia. On initial presentation empirical treatment for a community acquired pneumonia was commenced. Failure to improve resulted in additional cover for atypical organisms and the prescription of a short course of steroids on the subsequent admissions.
Initial observations revealed the patient was tachypnoeic and tachycardic, with a respiratory rate of 25 breaths per minute, heart rate of 114 beats per minute. He was apyrexial (temperature of 36.5°C ). Pulse oximetry showed an oxygen saturation of 94% on room air. His blood pressure was recorded as 183/99 millimetres of mercury.
On examination large volume peripheral pulses, raised jugular venous pressure (5 cm), bi-basal crepitations, and bilateral ankle oedema were elicited/identified. Auscultation of the heart revealed a loud diastolic murmur audible throughout the praecordium.
A 12 lead ECG showed normal sinus rhythm, normal axis and left ventricular hypertrophy. Arterial blood gas analysis on room air showed a pH of 7.46, pa02 9.6 kPa, pCO2 4.3 kPa, HCO3 23.8 mmol/L, BE + 0.8 and lactate of 0.7 mmol/L. Routine venous blood tests did not identify any elevated markers of infection or inflammation. A chest radiograph (Figure 1) showed cardiomegaly and pulmonary oedema.
Figure 1
The patient was administered oxygen and given a diuretic to improve his ventilation.
The working diagnosis was congestive cardiac failure in the presence of what was presumed to be a new murmur. Urgent echocardiography revealed an aortic root of 6.2cm diameter at sinus level, with an evident dissection flap. There was no obvious haematoma. Severe free flowing aortic regurgitation, a dilated hyperdynamic left ventricle and a 0.7 cm diameter pericardial effusion anteriorly were also noted. It was concluded that the patient had a sealed 7cm type A aortic dissection. This was confirmed by a CT scan (Figure 2).
Figure 2
Large bore venous access was obtained and an intravenous beta blocker (Labetalol) administered. Urgent transfer to a tertiary cardio-thoracic surgical centre was made. He underwent aortic root and valve replacement, along with coronary artery bypass grafting to the right coronary artery using a reversed long saphenous vein graft. Postoperatively, he was anticoagulated on Warfarin, and was also placed on beta blockade therapy (Bisoprolol), a diuretic (Frusemide), an ACE inhibitor (Ramipril), and a statin (Simvastatin).
Aortic dissection is a medical emergency. If left unrecognised or untreated mortality can be as high as 80% in two weeks, or 90% within three months1,2. 96 % of patients with aortic dissection present primarily with chest pain. The remaining 10% present with symptoms secondary to impairment of blood supply to other organ systems3. Dissections involving the ascending aorta present with retrosternal chest pain, while interscapular pain suggests involvement of the descending aorta. Pleuritic pain may indicate haemorrhage in the pericardial sac, with the potential for acute cardiac tamponade.
Only 6% of aortic dissections present with acute congestive cardiac failure. Patients presenting with aortic dissection and congestive cardiac failure are more likely to present without chest pain and have a valvular abnormality. When chest pain is present, the pain is more often mild and less likely to be abrupt in onset. Patients are less likely to be hypertensive on presentation and more likely to present in shock. These patients are more likely to have Stanford type A dissection . Congestive cardiac failure does lead to a delay in surgical intervention4.
Congestive cardiac failure is usually due to aortic regurgitation from aortic valve disease, incomplete aortic leaflet closure, or aortic valve disruption. In the setting of unexplained cardiac failure aortic dissection should be considered, especially when an aortic regurgitant murmur has been detected clinically. Heart failure has been associated with supravalvular aortic stenosis in the presence of a painless type A dissection, in a patient presenting with persistent cough5. Rupture of aortic dissection into the right atrium, right ventricle, or main pulmonary artery may lead to a left to right shunt and congestive heart failure6.
Painless aortic dissection has been recorded in other contexts, particularly with chronic dissection and in patients with Marfan’s syndrome.The absence of chest pain should not exclude aortic dissection.

Competing Interests
<p> None declared</p>
Author Details
<p> Usman Ali, MB,BS FY2 doctor, Wai Hang Cheung, MB,BS ST3 in Medicine, Ashis Banerjee, MS, FRCS, FCEM Consultant, Emergency Department Chase Farm Hospital, Enfield</p>
CORRESSPONDENCE: <p> Ashis Banerjee, Consultant/ lead clinician in emergency medicine Chase Farm Hospital, The Ridgeway, Enfield EN2 8JL, Middlesex</p>


1. Hirst AE, Johns VJ, Kime SW, Dissecting aneurysm of the aorta. A review of 505 cases. Medicine 1958; 37:217-279

2. Harris PD, Malm JR,  The management of acute dissection of the thoracic aorta. Am Heart J 1969; 78: 419-422

3. Link MS, Pletrzak MP, Aortic dissection presenting as superior vena cava syndrome. Am J Emerg Med 1994; 12:326-328

4. Januzzi, JL, Eagle KA, Cooper JV, Fang J, Sechtem U, Mymel T, Evangelista A, Oh JK, Llovet A, O’Gara PT, Nienaber CA, Isselbacher EM: Acute aortic dissection presenting with congestive heart failure: results from the International Registry of Acute Aortic Dissection. J AM Coll Cardiol. 2005,46:733-735

5. Sakamoto, H, Watanabe, Y, Sugimori, H, Heart failure due to severe supravalvular aortic stenosis in painless type A aortic dissection. Ann Thorac Surg, 2008, 85: 1441-1443

6. Spier, LN, Hall, MH, Nelson, RL, et al. Aortic dissection: rupture into right ventricle and right pulmonary artery. Ann Thorac Surg,1995, 59: 1017-1019

To ‘D’ or not to ‘D’ in the older person, that is the question.

John Agens

Cite this article as: BJMP 2010;3(4):a352
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In anticipation of new recommendations from the Institute of Medicine and others, it behooves physicians and healthcare providers to review their knowledge base concerning adequate vitamin D intake for fall and fracture prevention in the elderly. There is enough new data for the Institute of Medicine to consider a new Dietary Reference Intake, or DRI, for vitamin D.1 A recent review by Bischoff-Ferrari et al, of numerous randomized controlled trials of vitamin D supplementation in older persons, concluded that both falls and fractures could be prevented. In addition, a dose-response relationship suggested that the optimal supplementation dose is 700 IU to 1000 IU per day.2 Epidemiologic associations between low vitamin D status and various cancers has led some to recommend balancing risk and benefit of moderate ultraviolet light (UV) exposure against complete UV protection for prevention of skin cancer.3 Others have reviewed the epidemiologic evidence for vitamin D supplementation in treatment of hypertension and prevention of cardiovascular disease.4 These epidemiologic studies are tantalizing, yet the evidence is not sufficient to support a causal relationship in making decisions about vitamin D supplementation for the prevention of cancer and cardiovascular disease. I will limit my editorial comments to preventing falls and fractures.

I would suggest looking at potential short- and long-term risks as well as the benefits of any intervention. What evidence do we have for the risks of vitamin D use for prevention? One recent study using a single dose of 500,000 IU of vitamin D daily showed an increased relative risk of fractures,5 but the dose of vitamin D in that study was far higher than other randomized controlled trials. Bischoff-Ferrari et al reviewed documented cases of hypercalcaemia in the randomized controlled trials;2 those authors add that only one trial reported nephrolithiasis, the Women’s Health Initiative.6 It is noteworthy that only the self-reported vitamin D and calcium dose was determined in that study, not the vitamin D status of the subjects. My opinion is that hypercalcaemia is uncommon and its complications are rare.
Many interventions that are routinely recommended for the older person probably have higher risks than the 700 IU to 1000 IU of vitamin D per day suggested by the evidence. Medications for hyperlipidaemia are one case in point; antihypertensives are another. Both are considered relatively safe and effective in primary and secondary prevention of cardiovascular disease. The long-term risks of the supplementation of 700 IU to 1000 IU of vitamin D are not well known compared to those long-term risks associated with lipid-lowering drugs or antihypertensives. On the other hand, some older persons at increased fall risk have more immediate threats to their health from a fall or fracture than any long-term risks of vitamin D supplementation. Given the detrimental consequences of falls and fractures in the elderly, the risks of vitamin D supplementation may be worth it. 




Competing Interests
None declared
Author Details
JOHN AGENS MD, FACP. Associate Professor Geriatrics, Florida State University College of Medicine, 1115 West Call Street Suite 3140- H, Tallahassee, Florida 32306-4300
CORRESSPONDENCE: JOHN AGENS MD, FACP. Associate Professor Geriatrics, Florida State University College of Medicine, 1115 West Call Street Suite 3140- H, Tallahassee, Florida 32306-4300


1.  Yetley EA, Brulé D, Cheney MC et al. Dietary reference intakes for vitamin D: justification for a review of the 1997 values. The Am J Clin Nutr. 2009 Mar;89(3):719-727.

2.   Bischoff-Ferrari HA, Shao A, Dawson-Hughes B et al. Benefit-risk assessment of vitamin D supplementation. Osteoporosis Int. 2010 Jul;21(7):1121-1132.
3.   Zeeb H, Greinert R. The role of vitamin D in cancer prevention: does UV protection conflict with the need to raise low levels of vitamin D? Dtsch Arztebl Int. 2010;107(37):638-643.
4.   Holick MF. The D-bate: do calcium and vitamin D affect cardiovascular health? Menopause. 2010;17(4):667-668.
5.   Sanders KM, Stuart AL, Williamson EJ Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA. 2010;303(18):1815-1822.
6.   Jackson RD, LaCroix AZ, Gass M Women's Health Initiative trial of calcium plus vitamin D supplementation and the risk of fractures. NEJM. 2006;354:669-683.



The impact of the provision of extended laboratory service of Troponin T assay

S.M. Coughlin, I. Walker and W.S. Wassif

Cite this article as: BJMP 2010;3(4):a346
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The impact of extending the cut-off time for the provision of Troponin T assay from 4:00 to 7:00 pm, focusing specifically on same-day patient discharge was studied over a four-month period. The number of patients discharged on the same day, who would have otherwise been admitted overnight, was determined. The fiscal benefit of the extended laboratory service was then calculated. Of the 140 patients included in the study, 36 (26%) patients were discharged on the day of hospital presentation based on a negative Troponin T concentration; all except one had a Troponin T <0.03ug/L. Based on the cost of overnight stay of £657 we concluded that the extended service would save the hospital £70,956 annually.

Extending the provision of Troponin T assay for 3 hours daily is cost effective and reduces the number of unnecessary hospital admissions of patients presenting with chest pain of non-cardiac origin.
Keywords:  Troponin T, lipid profile, cost-effectiveness, hospital admission


Troponin T is a protein component of cardiac muscle. When death or damage of the myocardium occurs, it is released in to the circulation and can be detected by immunoassays 1. Troponin T is a sensitive and specific marker of myocardial damage when taken at least 12 hours after a suspected cardiac event and can be detected up to 7-10 days after myocardial damage 1,2. When used in conjunction with clinical history, electrocardiograms (ECGs) and cardiac imaging it is effective in excluding acute coronary syndrome (ACS) and myocardial infarction (MI). The cost of a Troponin T assay is £3.75 per sample inclusive of staff time.
Troponin concentrations have been incorporated in up to date definitions of acute MI. One of the criteria for diagnosis of acute MI is the detection of rise and/or fall of cardiac biomarkers (Troponin) with at least one value above the 99th percentile of the upper reference limit (URL) together with evidence of myocardial ischaemia with at least one of the following: ischaemic symptoms, new ischaemic ECG changes, pathological Q waves on ECG, or imaging suggesting loss of viable myocardium or new regional wall abnormality 3. Other criteria include unexpected cardiac death involving cardiac arrest, Troponin concentrations associated with percutaneous coronary intervention (PCI) and coronary bypass grafting (CABG) and pathological findings of acute MI 3. Troponin T is an important component of the risk stratification of patients with acute myocardial ischaemia and can be used to predict 30-day mortality 4,5.
Detection of a rise and/or fall in Troponin T concentration is important when diagnosing acute MI 3,6. It is the rise and fall that differentiates individuals who have sustained myocardial damage from other causes such as chronic kidney disease (CKD) 3, 7. In these other conditions the elevated Troponin T concentrations are sustained. To establish the diagnosis of MI, one elevated value above the decision level is required. The demonstration of a rise and/or fall in Troponin T levels assists clinicians in distinguishing elevated background Troponin T concentrations from elevations in the same patients suggestive of MI.  Detection of rise and/or fall also identifies those patients with re-infarction within a short time period after an acute MI 8.
It is important to remember however that if the patient presents 24 hours after the onset of symptoms this rise and fall of Troponin T concentration is not necessary to make the diagnosis of MI. Troponin T levels must be interpreted in the light of the clinical presentation. An elevated concentration of Troponin T in the absence of clinical evidence of ischaemia should prompt a search for other aetiologies, such as CKD, congestive heart failure, myocarditis, aortic dissection, or pulmonary embolism 3, 6.
Risk stratification also includes the measurement of lipid profile in those presenting with suspected ACS or MI. To ensure that a cholesterol level representative of the patient’s normal baseline the blood sample must be organised within 24 hours of the event. In those with delayed presentation or where cholesterol is omitted on admission clinicians should wait until 3 months after the event to obtain a reliable cholesterol level, although most would be expected to have started lipid-lowering medications 9,10,11.
We studied Troponin T requests made between 4pm and 7pm for a four-month period. Request cards were retrieved and the Troponin T result for each request was obtained. Any other Troponin T results obtained at any time relating to that event were noted as well as any rise and fall of the Troponin T concentrations. Review of the hospital notes for each patient established the working diagnosis, whether any other appropriate investigations had been carried out during admission, co-morbidities that were present and current relevant medications.
The final patient outcome was noted. The number of patients discharged on the same day, who would have otherwise been admitted overnight, based on Troponin T concentration was determined. Those patients with a Troponin T concentration above the 99th percentile of the upper reference limit (URL) used in the local laboratory (Troponin T <0.03ug/L) who were not discharged on the day of Troponin T measurement were identified and the reason for admission determined. The fiscal impact of the extended laboratory service was calculated.
Of 162 Troponin T requests received during the four-month period, 140 (86%) were included in the study; 22 (14%) were excluded (12 haemolysed, 1 unlabelled, 2 not on computer system, 7 clinical notes unavailable).
The study population comprised of 74 (53%) male and 66 (47%) female patients. The age range was 21 – 101 years; mean (±SD) 67.6 (±16.8).
Half of Troponin T requests were received from the Acute Assessment Unit (AAU), 20% from the Emergency Department, 14% from inpatients, 8% from the Critical Care Complex (CCC) and 8% from the Coronary Care Unit (CCU).
Clinical notes indicated that 97 (69%) of Troponin T requests were taken appropriately at least 12 hours after the onset of the event, 19 (14%) were taken less than 12 hours after the event, in the remaining 24 (17%) the time of sample in relation to the event was not known. Interestingly only 30% of request cards had documented that sample was taken at least 12 hours after the event.
The indication documented on each request card is detailed in Figure 1. Indications detailed under other included: trauma, sepsis, collapse, cold & clammy, oesophageal cancer with hypercalcaemia, poor complex tachycardia, post-operative after abdominal aortic aneurysm repair, respiratory infection, sweating, palpitations, fall and repeat bleed because of previously unsuitable sample.
Figure 1: Indication noted on request card for Troponin T. ACS: acute coronary syndrome, MI: myocardial infarction, SOB: shortness of breath, LVF: left ventricular failure, CCF: congestive cardiac failure.
One hundred and two (73%) patients had a non-elevated Troponin T concentration of <0.030ug/L and 38 (27%) had an elevated Troponin T concentration >0.03ug/L. Only 5 (4%) patients had the rise and fall of Troponin T documented.
Eighty-three (59%) patients had no lipid profile measured during the attendance/admission. Of the remaining 57 patients, 31 (54%) had cholesterol assayed within 24 hours of the event, in 16 (28%) the cholesterol was taken between 2 and 17 days after the event and in 10 (18%) patients the time of cholesterol assay in relation to the event was not known. Overall only 1 in 5 patients had a lipid profile obtained within 24 hours of the event.
Interestingly of the 38 patients with raised Troponin T concentration of >0.03ug/L only 13 (34%) had a lipid profile organised. Only 7 of the 13 (54%) were obtained within 24 hours of the event, 4 were taken between 2 and 10 days after the event and in 2 patients it was not known when the lipid profile was obtained in relation to the event.
Overall no correlation was noted between cholesterol and Troponin T concentrations in all patients who had an elevated Troponin T concentration and cholesterol measured. Interestingly in those where cholesterol was measured within 24 hours of the suspected cardiac event there was some correlation, but the numbers involved were small.
The working diagnosis as stated in hospital notes is documented in Table 1.
Table 1: Working Diagnosis
Working Diagnosis
Number (%)
62 (44.3%)
8 (5.5%)
Fast AF/atrial flutter
  6 (4.3%)
  5 (3.6%)
 1 (0.7%)
Musculoskeletal chest pain
  7 (5.0%)
Respiratory complaint
18 (12.9%)
GORD put in legend
  4 (2.9%)
11 (7.9%)
No diagnosis
 18 (12.9%)
          140 (100%)
ACS, acute coronary syndrome; MI, myocardial infarction; AF, atrial fibrillation; CCF, congestive cardiac failure; LVF, left ventricular failure; GORD, gastro-oesophageal reflux disease.
Table 2: Reason why those patients with non-elevated Troponin T concentration of <0.03 (ug/L) were not discharged on the same day by the clinician.
Reason for admission
Number of patients
Trop T assayed <12hrs
5 (8%)
Ongoing chest pain
10 (15%)
ECG changes
3 (5%)
High CAD risk patient
2 (3%)
Monitoring and cardiology review
2 (3%)
Already inpatient
7 (10%)
Repeat attendance in 24hrs
1 (1%)
Other medical (non-cardiac) problem
28 (42%)
No reason documented
6 (9%)
Outcome not available
1 (1%)
Self discharge
2 (3%)
67 (100%)
All of the 36 (26%) patients except one who were discharged on the day of Troponin T assay had a negative Troponin T concentration of <0.030ug/L. This patient had CABG one month previously and presented with chest pain and associated cough, although his Troponin T was 0.14ug/L, this was deemed not significant in view of a previous Troponin T concentration of 0.16ug/L assayed two days earlier.
Sixty three (45%) patients remained in the AAU or were admitted to a medical ward, 15 (11%) were admitted to CCU, 4 (3%) to CCC and 18 (13%) were already inpatients. Of the remaining 3 patients, 2 self-discharged and in 1 the final destination was not available.
Of those patients with a raised Troponin T concentration of >0.03ug/L 5 died during this attendance.
The majority (60/102) of patients in whom Troponin T was not raised (<0.030ug/L) still required hospital admission (Table 2). Another 6 patients with a non-elevated Troponin T concentration had no obvious reason for admission documented.
Based on an overnight stay cost of £657 we conclude that the laboratory’s extension of Troponin T service of 3 hours would save the hospital £70,956 annually. No additional manpower was required to provide the extended laboratory service as Biomedical Scientists are already providing urgent out of hour on-call service for other biochemical analysis. No additional laboratory costs were incurred, as the same number of samples would have been analysed during working hours the following day.
There was sufficient demand for Troponin T assay to justify extension of the laboratory service for 3 hours each day. As expected most requests for Troponin T came from the AAU and the Emergency Department where the majority of patients with chest pain of potential cardiac origin would initially present. In those patients presenting with suspected myocardial damage 3 out of 4 had chest pain of non-cardiac origin.
In those patients where the time of event was known the majority had an appropriate Troponin T assay taken at least 12 hours after the event suggesting that most of the medical and nursing staff were well informed. In contrast it appears that only few of the medical profession were aware of the need to measure lipid profile soon after admission as only 1 in 5 patients had their lipid profile organised within 24 hours of the event.
The majority of requests had appropriate clinical details to justify Troponin T request. However one in four requests were deemed inappropriate (Fig. 1). Since Troponin T may be raised in other conditions the assay should be reserved for those patients where myocardial damage is suspected. Inappropriate testing is potentially hazardous and may expose patients to further unnecessary invasive investigations e.g. cardiac catheterisation with associated morbidity and mortality.
In patients presenting with chest pain, Troponin T assayed appropriately >12 hours after onset of the event can be used effectively to exclude myocardial damage and discharge can be made on the basis of this result without the need for admission. A small proportion (6%) of patients with non-elevated Troponin T concentrations who had no obvious reason for admission, were deemed unnecessary.
Dyslipidaemia plays an important role in the risk stratification of patients with suspected ACS or MI, yet only one in five patients with myocardial damage had a lipid profile organised within 24 hours of the event. Cholesterol measurements organised between 2 and 17 days after the event would not have been representative of the true concentration and were deemed inappropriate. Too few lipid profiles were assayed within 24 hours of the event in patients with an elevated Troponin T concentration to determine whether there is any correlation between cholesterol and Troponin T concentrations.
Similarly only a small number of patients had the rise and fall of Troponin T documented. The lack of serial measurements of Troponin T concentrations may have resulted in failure to recognise some patients with other conditions, which may cause elevated Troponin T concentrations and potentially subject them to unnecessary further invasive investigations.
The provision of the extended laboratory service had a positive impact; it enabled earlier discharge of patients with chest pain of non-cardiac origin, resulted in fewer unnecessary overnight hospital admissions and reduced the demand on hospital beds. Extending the service did not result in extra work for junior doctors, on the contrary by improving the efficiency of the process has not only speeded the patient journey but has improved junior doctors’ time-management.
We have shown that extending the provision of Troponin T assay for 3 hours daily has both fiscal and management benefits and reduces the number of unnecessary hospital admissions. Further extension to incorporate a 24-hour laboratory service for this assay would potentially reduce hospital admissions further with more potential savings.
Extending the provision of Troponin T assay for 3 hours daily has fiscal and management benefits and reduces the number of unnecessary hospital admissions of patients presenting with chest pain of non-cardiac origin.
Learning Points
• Extending Troponin T service has a fiscal benefit.
• Rise and fall of Troponin T values should be documented.
• Lipid profile should be organised within 24 hours in all patients presenting with chest pain of potentially cardiac origin.
• Measuring Troponin T where myocardial damage is not clinically suspected is potentially hazardous and may expose patients to further inappropriate and invasive investigations with associated morbidity and mortality.
• In the current climate of litigation detailed documentation is necessary.


Competing Interests
None declared
Author Details
S.M. COUGHLIN MBBChir DRCOG I. WALKER Chief Biomedical Scientist, Bedford Hospital W.S. WASSIF MB ChB MSc CSci MD FRCPath FRCP.Consultant Chemical Pathologist, Bedford Hospital Departments of Emergency Medicine and Clinical Biochemistry, Bedford NHS Trust, Kempston Road, MK42 9DJ, UK.
CORRESSPONDENCE: Stephanie Coughlin GPVTS ST3, Lower Clapton Health Centre, 36 Lower Clapton Road, London, E5 0PD



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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


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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


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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.


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