Journal of Services Institute of Medical Sciences

Volume. 06 October - December 2010 No. 03

Patron
Prof. Faisal Masud

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(Principal SIMS & Professor of Medicine)

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Editor -in-chief

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Prof. Aziz-ur-Rehman
(Professor of Medicine)

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Associate Editors

Dr. N. Rehan cu
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(Director PMRC (R))
Prof. Dilawaiz Nadeem
(Orthopaedic Sur ger y)
Prof. Tahira Tasneem
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(Haematolog y)
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Assistant Editors
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Dr. Anjum Razzaq (IPH)

Dr. Muhammad Nasar Sayeed Khan (Psychiatr y)
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Dr. Tayyaba Khawar Butt (Paediatric Medicine)

Dr. Muhammad Saeed Anwar (Patholog y)
Dr. Sajid Nisar (Medicine)
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Dr. Salma Haq (Patholog y)

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Art Director
Abdur Raheem (Esculapio Cr eative Dept.)

Statistician
Muhammad Ghias

Composed by
Ameer Ali
Review Board
Prof. Dr. Iftikhar Ahmad (Lahore)
Prof. Dr. Mumtaz Hasan (Lahore)
Prof. Dr. Humanyun Maqsood (Lahore)
Prof. Dr. Anwar A. Khan (Lahore)
Prof. Tahir Shafi (Lahore)
Prof. Dr. Bashir Ahmed (Lahore)
Prof. Dr. S.A.R. Gerdezi (Lahore)
Prof. Dr. Shamim Ahmad Khan (Lahore)
Prof. Dr. Wasif Mohayudin (Lahore)
Prof. Dr. Iqbal Butt (Lahore)
Prof. Dr. Rashid Latif Khan (Lahore)
Prof. Dr. Tahir Saeed Haroon (Lahore)
Prof. Dr. Farrukh Khan (Lahore)
Prof. Dr. A. H. Nagi (Lahore)
Prof. Dr. Tahir Shafi (Lahore)
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Prof. Dr. Kartar Dhawani (Karachi)
Prof. Dr. Abdul Malik Achakzai (Quetta)
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Prof. Dr. Fareed A. Minhas (Rawalpindi)
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Prof. Dr. Zafar Iqbal (Lahore)
Prof. Dr. Alaf Khan (Peshawar)
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Prof. Dr. Shabbir Nasir (Multan)
Prof. Khalid Bashir (Lahore)
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Prof. Dr. J. P. Long (UK)
Prof. Dr. Harry Minhas (Australia)
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Prof. Dr. Sasleri (UK)
Dr. Zia Farooqi (Lahore)
Maj. Ge. Dr. Naseem-ul-Majeed (Rawalpindi)
Brig. Dr. Mowadat H. Rana (Rawalpindi)
Brig. Dr. Muhammad Ayub (Rawalpindi)
Dr. Zia Farooqi (Lahore)
Editorial Advisory Board
Prof. Matee Ullah Matee (Medicine)
Prof. Rakhshan Shaheen Najmi (Gynae & Obst.)
Prof. Riaz Ahmad Tasnim (Urology)
Prof. Rizwan Masood Butt (Neurosurgery)
Prof. Sohail Khurshid Lodhi (Obst. & Gynae)
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Prof. Saqib Siddique (Obs. & Gynae)
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Prof. Sadaqat Ali Khan (Surgery)
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Prof. Ferdose Sultana (Anatomy)
Prof. Ghazala Jaffary (Pathology)
Prof. Ghulam Qadir Fayyaz (Plastic Surgery)
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Prof. Hamid Javed Qureshi (Physiology)
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Prof. Shahid Mahmood (Community Medicine)
Prof. Javed Raza Gardezi (Surgery)
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Prof. Kamran Khalid Chima (Pulmonology)
Prof. Mehmood Ayaz ( Surgery)
Prof. Muhammad Ali (Paediatric Medicine)
Prof. Mohammad Tahir (Paediatric Surgery)
Prof. Muhammad Amjad (ENT)
Prof. Muhammad Azam Bokhari (Dermatology)
Prof. Muhammad Mujeeb (ENT)
Prof. Muhammad Sarfraz Ahmad (Surgery)
Prof. Muhammad Tayyab (Ophthalmology)
Prof. Naveed Aqbal Ansari (Pharmacology)
Dr. Saeed Akhtar Khan (Histopathology)
Dr. Syed Zia-ud-Din (Forensic Medicine)
Dr. Qamar Sardar (Radiology)
Dr. Kaukab Sultana (Biochemistry)
Dr. Khadija Irfan Khawaja (Endocrinology)
Dr. Sobia Qazi (Infectious Diseases)
Dr. Shoaib Nabi (Thoracic Surgery)
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010
Review Article
Prostate Cancer and Prostate Specific Antigen
Anila Asghar, Arif Rasheed Malik and Khawaja Tariq Feroze
Incidence of Prostate Cancer
Prostate cancer is a major cause of mortality and
morbidity in men. It is the second leading cause of
death due to cancer in men.1 In the United States,
benign and malignant diseases of the prostate are
responsible for more surgery than any other organ
disease in men over the age of fifty.2 In Europe
prostate cancer is the second leading cause of death in
males3. In Netherlands the morbidity and mortality
caused by this tumor are exceeded only by those of
4
lung cancer and in a retrospective study, 1.62 %
incidence of prostate cancer is reported in Lahore,
Pakistan.5
Prostate Specific Antigen
Prostate specific antigen (PSA) is a single chain
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polypeptide distinct from prostatic acid phosphatase.
It is localized in prostatic epithelial lining cells of the
acini and ducts in both primary and metastatic
prostatic carcinoma cells.6 It is shown that PSA is a
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more sensitive marker of low stage disease than
prostatic acid phosphatase. 7 In 1980, PSA
concentrations were first reported to be increased in
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prostate cancer patients and currently tests for PSA
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are widely used to monitor patients with prostate
cancer.8 PSA has better sensitivity than prostatic acid
phophatase. However detection of cancer of prostate
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by PSA measurement alone is restricted by the fact
that increased concentrations are also found in a
significant number of patients with benign prostatic
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hyperplasia (BPH). 9
Since the discovery of Prostate specific antigen (PSA)
Co
by Wang in 1979, it has been an important tool in the
diagnosis of prostate carcinoma and is considered to
be the best marker of disease progression and
10
response to different treatments. The tumor is
adenocarcinoma in more than 90% of cases.11
Chemistry of Prostate Specific Antigen
Prostate specific antigen (PSA) is a 33,000 dalton
neutral serine protease, composed of a single
polypeptide chain of 33 amino acids.12 It is a
chymotryptic like serine protease that belongs to the
human tissue kallikerine family.13 The expression and
secretion of PSA is under the androgen control. PSA
1
usually is released into the blood at low conc.
(<4ng/ml) in healthy individuals.14 Recently using two
site immunometric methods and gel permeation
chromatography it has become possible to
characterize the different forms of serum PSA. PSA
complexed to ACT is the predominant
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immunoreactive form of PSA in serum whereas
<30% of total PSA occurs in the noncomplexed free
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form. Thus PSA-ACT form and free PSA are two
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molecular forms that may be monitored using
15
immunological methods such as immunoassay. In
serum the ratio free PSA : PSA-ACT is about 1:4.16
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Patients with prostate cancer have a lower proportion
of f-PSA than patients with benign prostatic
cu
hyperplasia.17
Chemistry of Prostate Specific Antigen
Prostate specific antigen (PSA) is a 33,000 dalton
neutral serine protease, composed of a single
polypeptide chain of 33 amino acids.12 It is a
chymotryptic like serine protease that belongs to the
human tissue kallikerine family.13 The expression and
secretion of PSA is under the androgen control. PSA
usually is released into the blood at low conc.
(<4ng/ml) in healthy individuals.14 Recently using two
site immunometric methods and gel permeation
chromatography it has become possible to
characterize the different forms of serum PSA. PSA
complexed to ACT is the predominant
immunoreactive form of PSA in serum whereas
<30% of total PSA occurs in the noncomplexed free
form. Thus PSA-ACT form and free PSA are two
molecular forms that may be monitored using
immunological methods such as immunoassay.15 In
serum the ratio free PSA : PSA-ACT is about 1:4.16
Patients with prostate cancer have a lower proportion
of f-PSA than patients with benign prostatic
hyperplasia.17
Role of Prostate Specific Antigen Levels in
Prostate Cancer
Prostate specific antigen is the most useful marker in
the early diagnosis of adenocarcinoma of the
prostate.18 PSA leaks into the systemic circulation due
to the local breakdown of histological barriers
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010
separating the prostatic duct acinar and the systemic
circulation which is associated with the presence of
malignancy.19 Measurement of total serum PSA is
routinely used for early detection and monitoring the
progress of prostate cancer. However early detection
is limited by the fact that increase concentration of
PSA are found also in many patients with benign
prostatic hyperplasia BPH.20 In the past most prostate
cancers were detected at an advanced stage by digital
rectal examination. Now the majority of prostate
cancers are detected early with PSA assay which
increases the lead time for diagnosis.21 PSA
measurement is used in combination with other
diagnostic procedures such as imaging methods and
digital rectal examination for the detection of existing
22
prostate disorder. It has also been suggested that the
use of PSA in monitoring the patients with prostate
carcinoma can reduce repeated bone scan.23 PSA
concentrations are increased not only in patients with
adenocarcinoma prostate but also in patients with
benign prostate hyperplasia or inflammation and
after manipulation of prostate .On the other hand not
all the patients with prostate cancer have an elevated
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serum PSA concentration. 30-40% of men with
organ confined prostate cancer have a normal serum
PSA level.24
To eliminate the interference of factors that reduce diagnostic
@
power of PSA, various concepts are being used such as age
related reference values, PSA density, PSA velocity, and
quantitative determinants of the different molecular forms.
25
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Age specific reference ranges are taken as opposed to
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the single reference range of 0.0-4ng/ml for men of
26
all ages. Use of age specific PSA reference ranges
include age related changes in PSA production and
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secretion as well as prostate growth. In conjunction
with PSA density, the age specific reference ranges
identifies those patients who require biopsy.27
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PSA density (PSAD) is the quotient of the serum
PSA concentration divided by the volume of the
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prostate. It is useful in patients with PSA level
between 4-10ng/ml.It is important to determine the
PSAD in patients with PSA level of 4.1-10ng/ml who
had no abnor mal finding on TRUS and
recommended that a biopsy should only be taken if
the PSAD was >0.15. 28 PSA velocity is the
longitudinal change in serum PSA level over time.
Prostate cancer growth follows a simple exponential
growth curve throughout its natural history. Since
serum PSA is proportional to cancer volume, the rate
of change of PSA with time in untreated patients
29
should follow a similar course. Determination of
free PSA versus complexed serum PSA, which refers
to the ratio of free PSA to PSA complexed to alpha -
2
1 antichymotrypsin in the serum is important to
improve the diagnostic potential and diagnostic
30
specificity of PSA. As f PSA is believed to be
derived mostly from non malignant cells,31 the
measurement of ratio between total PSA and
unbound or free PSA (percent free PSA) has been
introduced as a useful clinical tool for early detection
of clinically localized prostate cancer as prostate
cancer is best cured by surgery when it is organ
confined.32 PSA has been recognized as a sensitive
indicator of recurrent prostate cancer after radical
prostatectomy. Numerous PSA assays with improved
limits of detection have been developed. The rational
k
behind the development of more sensitive PSA
.p
assays (lower limit of detection) is that the relapse of
prostate cancer or the tumor doubling time, after
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radical prostatectomy can be detected much earlier if
patients are monitored with more sensitive assays.33
The measurement of the percentage of free PSA as a
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marker of cancer aggressiveness has been
documented.34 PSA appears to be the single most
cu
efficient primary tool in prostate cancer screening, in
most screening programs PSA greater than 4ng/l or
equivalent is considered abnormal and leads to
further evaluation with digital rectal examination,
transrectal ultrasound and biopsies according to
35
various algorithms. Although PSA screening has not
been demonstrated to reduce prostate cancer
mortality in clinical trials or population settings, the
increase in its use during the early 1990 paralleled a
dramatic increase in national prostate cancer rate.
From 1990 to 1991, the incidence increased
36
approximately 25%.
Serial PSA determinations are especially useful in
annual screening surveys and in following patients
expectantly with potential clinically insignificant
volumes of prostate cancer. 37 Although its role in
monitoring the treatment of known prostate cancer is
well established, its utility along with other tests in
screening men from prostate cancer remains
uncertain .This is largely due to the lack of convincing
data showing reduction in disease specific mortality
by earlier identification of cancer in asymptomatic
population. Nevertheless PSA has been found to be
more sensitive than other markers in identifying gland
contained and presumably curable cancer and in
detecting a preponderance of clinically significant
tumors as opposed to latent indolent micro-
carcinomas.
38
Department of Forensic Medicine
King Edward Medical University / M. H. L
theesculapio@hotmail.com
www.sims.edu.pk/esculapio.html
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010
References
1. France MW and Seneviratne CJ.
Screening for prostate
carcinoma : Case finding is not
the problem. Ann. Clin.
Biochem. 1997; 34: 333-338.
2. Srinivasdn G,Campbell E, Elahi
NB. Androgen , estrogen, and
progestron receptors in normal
and aging prostates. Microscopy
Res Tech 1995; 30 : 293-304.
3. Rietbergen JBW, Kranse R,
Kirkles WJ, Koning DH and
Schroder FH. Evaluation of
prostate specific antigen, digital
rectal Examination, and
transrectal ultrasonography in
population basedscreening for
prostate cancer : Improving the
efficiency of early detection. Br.
J. Urol. 1997;79: 57-63.
4. Pretlow TG, Yang B, Pretlow TP ,
Organ culture of benign , aging
a n d hy p e r p l a s t i c h u m a n
prostate. . Microscopy Res Tech
1995, 30: 271-81.
5. Parvez T. Prevalence of cancer in
different hospitals of Lahore.
The cancer research 1992 ; 1 : 6-
10.
6. Bais R, Huxtable A, Edwards JB.
Human prostatic acid
phosphatase: properties of the
native enzyme and the enzyme
antibody complex. Ann Cli
Ri
7. Armitage TG, Cooper EH,
Newling DWW, Robinson MRG
and Appleyard I. The value of
py
the measurement of serum
prostate specific antigen in
patients with benign prostatic
Co
hyperplasia and untreated
prostate cancer. British Journal
of Urology 1988; 62: 584-589.
8. Haapiainen RK, Permi EJ,
rannikko SAS, Voutilainen PEJ
and Alfthan S. Prostate tumour
markers and differentiation
grade in prostate cancer. British
Journal of Urology 1990;
66:635-638.
9. Y u H , D i a m e n d i s E P.
Ultrasensitive time resolved
immuno fluorometric assay of
prostate specific antigen in
serum and preliminary clinical
studies clinical chemistry 1993 ; 39
: 2108-2114.
10. Mitr unen K, Petterson K,
Pironen T, Bjork T, Lilja H et al.
Dual label one step immunoassay
for simultaneous measurement of
free and total prostate specific
antigen concentration and ratios
in serum. Clin chemistry 1995;41/
8:1115-20.
11. Deliverites C, Alivzitas G
Karayiannis A., Kontothanasism
D, Maksrychontis K.. The role of
prostate specific antigen in the
pio
early diagnosis of prostate cancer:
a greek view . British Journal of
Urology 1995; 75: 637-641.
12. Gilliland FD, Hunt WC and Key
la
CR. Improving survival for
patients with prostate cancer
cu
diagnosed in the prostate specific
antigen era. Urology 1996; 48: 67-
Es
71.
13. Raviv G, Zlotta AR, Janssen T,
Descamps F, Vanegas JP, et al. Do
prostate specific antigen and
@
prostate specific antigen density
enhance the detection of prostate
cancer after initial diagnosis of
ts
prostatic intraepitheltal necplasia
without concurrent carcinoma?
gh
Cancer 1996;77:2103-2107.
14. Romel FM, Agusta VE, Breslin
JA, Huffnagle HW, Pohl CE,
Sieber PR et al. The use of
prostate specific antigen and
prostate specific antigen density
in the diagnosis of prostate cancer
in a community based urology
practice. J. Urol, 1994; 154: 88-93.
15. Petterson K, Piironen T, Seppala
M, et al. Free and complexed
prostate specific antigen: In vitro
stability, epitope map and
d e v e l o p m e n t o f
immunofluorometric assay for
specific and sensitive detection of
free PSA and PSA a1-
antichymotr ypsin complex.
Clinical Chemistry 1995; 41:1480-
1488.
16. Black MH, Grass L, Leinonnen J
Stenman H and Diamandisb EP.
Characteristization of
Monoclonal antibodies for
3
prostate specific antigen and
development of highly sensitive
free prostate specific antigen
assay. Clinical Chemistry 1999:
45: 3. 347- 354.
17. Akdas A, Cevik I, Tarcar T,
Turkeri L, Dalaman G and
Emerk K. The role of free
prostate specific antigen in the
diagnosis of prostate cancer. Br.
J. Urol. 1997; 79: 920-923.
k
18. Paus E, Nilssons O, Bomer OP,
.p
Fossa SO, Otnes B. Stability of
free and total prostate specific
antigen in serum from patients
with prostate carcinoma and
benign hyperplasia . The Journal
of Urology 1998; 159: 1599-
1605.
19. Bunting PS. A guide to the
interpretation at serum prostate
specific antigen levels. Clinical
Biochemistry. 1995; 28: 221-235.
20. Diamandis EP. New diagnostic
applications of prostate specific
antigen. Br. J. Urol. 1997; 79: 87-
91.
21. Jung K, Stephen C, Llein M, et al.
Analytical performance and
clinical validity of two free
prostate specific antigen assays
compared. Clinical Chemistry
1996; 42: 1026-1033.
22. Nixon RG, Meyer GE, Blasé
AB,Gold MH, and Braver MK
.Comparison of the
investigational assay for the free
form of prostate specific antigen
. J Urol 1998; 160: 420-25.
23. Chen YT, Luderer AA, Thiel
RP, Carlson G, Cuny C, Soriano
TF. Using proportion of Free to
total prostate specific antigen,
age and total prostate specific
antigen to predict the probability
of prostate carcinoma. Urology
1996; 47:518-24.
24. Smith DS, Carvalhal GF, Mager
DE, Bullock AD, Catalona WJ.
Use of lower prostate specific
antigen cut off value for prostate
cancer screening in white and
black men. J Urol 1998; 160:
1734-38.
25. Carter HS, Partin AW. Luderer
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010
AA, Metter EJ, Landis P,Chan
PW. Percentage of free Prostate
Specific Antigen in sera predicts
aggressiveness of prostate
cancer a decade before
diagnosis. Urology 1997;49:379-
84.
26. S t o c k R G, S t o n e N N ,
Dewyangaert JK, Lavagnini P,
and Unger PD. Prostate specific
antigen findings and biopsy
result following interactive
ultrasound guided transperineal
brachytherapy for early stage
prostate carcinoma. Cancer
1996; 77: 2386-2390.
27. Lein M, Koenig F, Jung K,
Mcgovern FJ, Skates SJ,Schnorr
D, et al. The percentage of free
Prostate Specific Antigen is an
age- independent tumour
marker for prostate cancer:
establishment of reference
ranges in a large population of
healthy men. The Journal of
Urology 1998; 82: 231-236.
28. Oesterling JE, Kumamoto Y,
Tsukamoto T, et al. Serum
prostate specific antigen in a
community based population of
healthy Japanese men: Lower
values than for similar aged
white men. Br. J.Urol. 1995; 75:
347-353.
gh
Ri
py
Co
29. Barry MJ. Prostate Specific
Antigen testing for early diagnosis
of prostate cancer. N Engl J Med.
2001; 344: 1373-1376
30. Carter HB and Pearson JD.
Prostate Specific Antigen for early
diagnosis of prostate cancer:
For mulation of guideline.
Urology 1999; 54: 780-786.
31. Deliverites C, Alivzitas G
Karayiannis A., Kontothanasism
D, Maksrychontis K. The role of
prostate specific antigen in the
early diagnosis of prostate cancer:
a greek view. British Journal of
Urology 1995; 75: 637-641.
32. Oesterling JE, Kumamoto Y,
Tsukamoto T, et al. Serum
pio
prostate specific antigen in a
community based population of
healthy Japanese men: Lower
la
values than for similar aged white
men. Br. J.Urol. 1995; 75: 347-353.
cu
33. Gillat D, Reynard M. What is the
normal range for prostate specific
antigen? Use of a receiver
Es
operating characteristic curve to
evaluate a serum marker. British
Journal of Urology 1995; 75: 341-
346.
@
34. Gao ZW, Liu G, Sheng BW.
[Changes of serum total PSA and
free PSA in patients with prostate
ts
carcinoma and benign prostate
4
hyperplasia] Ai Zheng. 2004
Jun;23(6):701-3.
35. Petterson K, Piironen T, Seppala
M, et al. Free and complexed
prostate specific antigen: In vitro
stability, epitope map and
d e v e l o p m e n t o f
immunofluorometric assay for
specific and sensitive detection
of free PSA and PSA a1-
antichymotrypsin complex.
Clinic Chemistry 1995; 41:1480-
1488.
36. Black MH, Grass L, Leinonnen J
k
Stenman H and Diamandisb EP.
Characteristization of
.p
Monoclonal antibodies for
prostate specific antigen and
development of highly sensitive
free prostate specific antigen
assay. Clinical Chemistry: 45: 3.
347- 354.
37. Wilson MJ. Proteases in prostate
development, function and
pathology. Microscopy Research
and technique 1995; 30: 305-318.
38. Raffery B, Rigsby P, Rose M,
Stamey T, das RG. Reference
reagents for Prostate Specific
Antigen (PSA): Establishment
of the first international
standards for free PSA and PSA
(90: 10).Clinical chemistry 2000;
46: 1310- 1317.1243-1249.
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

Original Article

Correlation Between Bone Mineral Density and Anthropometric and Glycemic

Parameters in Type 1 Diabetic Children
Amna Tahir and Hamid Javaid Qureshi

Background: The foundation of bone health is established during the pre and postnatal
developmental stages especially childhood and adolescence. During this period the bone
development may be altered by genetic and acquired disorders. Type 1 diabetes mellitus is one of
chronic diseases in children and has great impact on the growth of children.
Objective: To access bone mineral density in type 1 diabetic children of 9-15 years as
compared to age matched healthy subjects and correlate these values with anthropometric and

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glycemic parameters.

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Subjects and Methods: This cross sectional study was carried out in 60 boys 9-15 years old ,
in Department of Physiology, University of Health Sciences, Lahore. The control group consisted

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of 30 healthy boys and diabetic group comprised of 30 boys suffering from type 1 diabetes
mellitus. Weight, height were measured and BMI was calculated. Fasting blood glucose was
determined by glucose oxidase method and HbA1c by affinity liquid chromatography. Bone

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mineral density was measured with bone profiler based on quantitative ultrasound measurement
(QUS).

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Results: There was statistically non significant (p >0.05) difference of bone mineral density in
diabetic and non-diabetic boys. The correlations between bone mineral density and
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anthropometric and glycemic parameters were not significant (p>0.05).A significant negative
(p<0.05) correlation was observed between duration of diabetes and height. Significant (p<0.05)
positive correlations were also observed between age and weight and age and height in diabetic
@

boys.
Conclusion: In type 1 diabetic children, bone mineral density, height and weight are not
significantly affected by glycemic parameters but duration of diabetes has a significant negative
ts

impact on height in children.

Keywords: Type 1 diabetes mellitus, bone mineral density, quantitative ultrasound
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measurement (QUS), body mass index (BMI), fasting blood glucose.

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Introduction density (BMD).

4, 5

Diabetes mellitus (DM) is a heterogeneous group of Children and adolescents with type 1 DM show
syndromes characterized by an elevation of fasting severe impairment of bone metabolism and structure
py

plasma glucose that is caused by a relative or absolute resulting in a higher risk of decreased bone mass and
deficiency of insulin.1 Diabetes mellitus can affect its related complications later in life.6
Co

almost every system in the body.2 Insulin deficiency as
occurs in type 1 diabetes mellitus or tissue resistance
to insulin in type II DM, both are associated with
several deleterious consequences related with skeletal
growth.3
Evidence shows that type 1 DM along with poor
glycemic control disturbs the growth hormone
insulin like growth factor (GH-IGF) axis resulting in
alteration of the levels of bone resorption factors like
parathyroid hormone (PTH), type 1 collagen cross
linked carboxy terminal telopeptide (1CTP) and bone
formation markers such as bone alkaline phosphatase
and osteocalcin resulting in decreased bone mineral
The pathogenesis of osteopenia in type 1 diabetic
patients is not clear.7 Osteopenia is the consequence
of lowered bone formation with predominance of
bone resorption in male patients with insulin
dependent diabetes mellitus.8
Several mechanisms are thought to contribute to
skeletal damage in diabetes mellitus including the
increased urinary excretion coupled with lower
intestinal absorption of calcium, the inappropriate
homeostatic response in terms of parathyroid
hormone and alteration of vitamin D regulation.9
The purpose of this study was to access bone mineral
density in type 1 diabetic children of 9-15 years as

5
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

compared to age matched healthy subjects and
correlate these values with anthropometric and
glycemic parameters.
Material and Methods
This cross sectional study was carried out in
Department of Physiology, University of Health
Sciences, Lahore.
Sixty boys 9-15 years old were selected. The control
group consisted of 30 healthy boys and diabetic
group comprised of 30 boys suffering from type 1
diabetes mellitus. Children having co-morbidity of
other endocrinopathies or history of bone surgery/
Bone mineral density was determined with bone
profiler based on quantitative ultrasound
measurement, Z score was determined according to
WHO criteria.10 All calculations were carried out with
SPSS version 15. Arithmetic mean and standard
deviation (SD) of each parameter were determined.
The significance of differences among the two
groups was analyzed by student's t-test. Pearson's
correlation coefficient was used to determine
correlation between variables of interest. P value
<0.05 was considered statistically significant.
Results

k
malignancy were excluded from the study. Blood No significant differences were observed in the value

.p
sample was drawn after overnight fasting of 12 hours. of weight, height and BMI ( p>0.05) between the type
Weight and height were measured and BMI was 1 diabetics and non-diabetic controls. HbA1c and

pio
calculated. Fasting blood glucose was determined by fasting plasma glucose levels were high significantly
glucose oxidase method and HbA1c concentrations (p<0.01) in diabetic boys as compared to the control
were found out by affinity liquid chromatography. group (Table 1)

la
Table-1: Anthropometric and glycemic parameters of type 1 diabetics and non-diabetics
Parameters Controls (n=30)
cu Type 1 diabetes (n=30) p value
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Chronological age (CA) (years) 12.77±1.77 12.27±1.91 >0.05*
Duration of diabetes (years) - 3.5±2.3 -
Weight (kg) 39.77±11.64 35.23±8.72 >0.05*
@

Height (m) 1.51±0.14 1.47±0.13 >0.05*

BMI (kg/m ) 2
16.83±1.96 16.04±2.4 >0.05*
ts

Fasting blood glucose (mg/dl) 92.5±5.45 261.03±113.75 <0.001**

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HbA1C (%) 5.27±0.23 11.1±3.26 <0.0001**

* Not statistically significant ** Statistically significant

Table-2: Comparison of bone mineral density (Z score) of type 1 diabetics and non-diabetic controls
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Parameters Non-diabetic controls (n=30 Type 1 diabetes (n=30 p value

Bone mineral density (Z-score) -2.68±1.84 -2.66±2.59 >0.05*
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* Not statistically significant ** Statistically significant

Table-4: Correlations between bone mineral density
Co

Table-3: Correlations between duration of diabetes (Z-score) and anthropometric and glycemic
and anthropometric and glycemic parameters in parameters in type 1 diabetics.
type 1 diabetics. Correlation between Pearson’s correlation
p-value
Correlation between Pearson’s Correlation BMD and coefficients (r)
p-value
duration of DM and Coefficient (r) Duration of diabetes -0.057 0.764*
Chronological Age (CA) -0.191 0.313 Chronological age (CA) -0.205 0.278*
Weight -0.346 0.061 Weight -0.185 0.328*
Height -0.390 0.033** Height 0.330 0.103*
BMI -0.130 0.492 BMA -0.047 0.805*
Fasting blood sugar -0.118 0.533 Fasting blood sugar 0.085 0.654*
HbA1C 0.043 0.821 HbA1C -0.154 0.417*

6
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010
Table-5: Correlations between chronological age
(CA) and different parameters in type 1 diabetics.
Correlation between Pearson’s correlation
p-value
CA and coefficients (r)
Weight 0.466 0.009**
Height 0.661 0.00**
Table 2 shows bone mineral density (Z-score) of
diabetic boys and of non-diabetic control group and
their difference was found to be statistically non-
significant (p >0.05) .
Table 3 indicates correlations of duration of diabetes
with anthropometric and glycemic parameters in type
1 diabetics. A significant negative correlation
(p<0.05) was observed between duration of diabetes
and height (r= -0.390).
Table 4 shows correlations between BMD (Z-score)
and anthropometric and glycemic parameters in type
1 diabetic boys. No significant correlation was
observed between BMD and other parameters.
Significant (p<0.05) positive correlations were
observed between chronological age and weight
(r=0.466) and also between chronological age and
Es
height (r=0.661) in diabetic boys (Table-5).
Discussion
@
A number of skeletal defects associated with type 1
DM have been reported including diminished linear
bone growth during the pubertal growth spurt,
ts
decreased adult bone density, an increased risk for the
adult osteoporosis, poor healing and regeneration
gh
characteristics.3
A poor metabolic control may expose adolescents
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with long standing type 1 DM to the risk of
developing osteopenia in adult age and optimization
of metabolic control of glucose levels in growing
py
children may prevent osteoporosis in later life.11 On
the other hand a study conducted in Greece suggests
that control of patient's blood glucose levels and
Co
duration of diabetes do not appear to influence
12
BMD. Our study also showed no significant
correlation of diabetic duration and control (HbA1C)
with bone mineral density in diabetic boys. However,
it is also found in a study that longer diabetic duration
and poor metabolic control resulted in reduced bone
turnover which could damage bone health in
IDDM,13 while Heap et al (2004) reported that
metabolic control of diabetes affects the bone
mineral acquisition.14
It was found that boys with IDDM had an increased
height until 1 year before diagnosis and this increased
7
height was followed by a delay in growth just before
15
the onset of IDDM. However it was also found that
children with IDDM have normal height at the time
of diagnosis.16,17 It is also indicated in the present
study that height of diabetic boys was not
significantly affected by the disease when compared
to healthy controls. However the duration of diabetes
had significant negative correlation with the height of
the diabetic boys indicating that with increase in the
duration of disease, height of boys decreases .
It is reported that weight gain by diabetic children is
independent of diabetic duration and weight at the
time of diagnosis but it is positively correlated with
k
HbA1c.18 Our study indicates that weight of diabetic
.p
boys does not significantly differ from non-diabetic
controls and there is also no significant correlation
pio
between weight of diabetic boys and HbA1c.
However weight of diabetic boys showed significant
positive correlation with chronological age and height
la
of diabetic boys showing that even in diabetes, weight
increases with age and height.
cu
The present study showed no significant difference
of bone mineral density (Z-score) between type 1
diabetic children and non-diabetic control children.
In our study bone profiler [which is based on
quantitative ultrasound technique (QUS) ] was used
and measured BMD at the phalanx. Quantitative
ultrasound measurement (QUS) is a useful method
for measuring the physiological bone development in
children and adolescent.
19
Bone metabolism and bone mineral density in
patients with type 1 DM have been extensively
investigated and these patients seem to be at risk of
decreased bone mass.9 Diabetes mellitus is thought to
impair the attainment of peak bone mass and also
increases the risk of osteoporosis with its related
complications in later life.
12,15
Type 1 diabetes mellitus has also been related to
reduced bone mineral density (BMD) in childhood.20
Whether diabetes mellitus is a risk factor for
developing osteoporosis or whether osteoporosis is
one of the long term complications of diabetes,
remains controversial.
21
The present study showed that bone mineral density
(Z-score) of diabetic boys and of non-diabetic
control group did not show significant difference
indicating that type 1 DM has no significant effect on
acquisition of bone mineral density. Our study did
not indicate any significant correlation of bone
mineral density with anthropometric as well as
glycemic parameters in diabetic children.
In contrast to our finding , a number of studies
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

showed that patients of type 1 diabetes mellitus had reference range.

25

reduced bone mineral density indicating that

osteopenia was a common complication in type 1
4,15,22,23
diabetes mellitus. A study conducted on
adolescents of type 1 DM with long term poor
metabolic control found decreased bone mineral
density (Z-score) and negative correlation between
Z-score and age of diabetic subjects.12 Damilakis et al
(2004) evaluated bone status at radius and phalanx in
children and adolescents with type 1 DM by using
QUS. It was found that male and female patients with
type 1 DM did not have significantly different bone
24
mineral density supporting the finding of our study.
Conclusion
The present study concludes that type 1 DM does not
significantly affect bone mineral density, height and
weight. Bone mineral density is not significantly
affected by the glycemic control. However, duration
of diabetes has a significant negative impact on height
in children.
Department of Physiology
Services Institute of Medical Sciences, Lahore
theesculapio@hotmail.com

k
Similarly a study conducted in Germany showed that www.sims.edu.pk/esculapio.html

.p
BMD of children with type 1 DM were within the

pio
References
1. Chanpe PC, Harvery RA, Ferrier status. Eur J Endocrinol 2005; CH, Sacramento M, Moreira A,

la
DR. Diabetes mellitus: In Harvey 153: 879-85. Adan L. Bone metabolism is
RA, Chanpe PC (editors). Bio- 7. Leon M, Larrodera L, Lledo G, linked to disease duration and

chemistry. 3rd ed. New York:
Lippincott Williams and
Wilkins 2005 ; 335-46.
2. Frier BM, Fisher M. Diabetes
mellitus. In: Boon NA, Colledge
NR, Walker BR, Hunter JA
(editors). Davidson's principles
cu
Hawkins F. Study of bone loss in
diabetes mellitus type 1. Diabetes
Res Clin Pract 1989;6:237-42.
Es
8. Kemink SA, Her mus AR,
Swinkels LM , Lutterman JA, Snals
AG. Osteopenia in insulin
dependent diabetes mellitus: pre-
@
metabolic control in type 1
diabetes mellitus. Diabetes Res
Clin Pract 2007;3923:1-6.
14. Heap J, Murray MA, Miller SC,
Jalili T, Moyer LJ. Alterations in
bone characteristics associated
with glycemic control in

and practice of medicine. 20th valence and aspects of patho- adolescents with type 1 DM. J
ed. New York. Churchill physiology. J Endocrinol Invest Pediatr 2004; 144:56-62.
Livingstone 2006; 805-47. 2000;23:295-303. 15. Bloom L, Burden AC. Growth
ts

3. Thrailkill KM, X-Lumpkin CKJ, 9. Carnevale V, Romagnoli E, of children before onset of

Bunn RC, Kemp SF, Fowlkes . Is Erasmo E. Skeletal involvement in diabetes. Diabetes Care 1992;
gh

insulin an anabolic agent? patients with diabetes mellitus. 15:1393-5.

Dissecting the diabetic bones for Diabetes Metab Res Rev 2004; 16. Hoskins PJ, Lesfie RDG, Pyke
clue. Am J Physiol Metab 2005; 20:196-206. DA. Height at diagnosis of
Ri

289:735-45. 10. Netto OS, Coutinho LOL, Souza diabetic children: a study in
4. Jehle PM, Jehle DR, Mohan S, DC. Analysis of the new identical twins. Brit Med J 1985;
Bohm BO. Serum levels of classification of bone densito- 290:279-80.
py

insulin-like growth factors metry reports. Radiol Bras 2007; 17. Leslie RDG, Millward BA,
system component and 40:23-5. Honour J, Pyke DA. Decreased
relationship to bone metabolism 11. Valerio G, del Puente A, Buono P, growth velocity before IDDM
Co

in type 1 and type 2 diabetes
mellitus. J Endocrinol 1998; 15:
297-306.
5. Li G, Mick G, Wang X, Xue J,
McCor mick K. Growth
hormone IGF-1 axis and growth
velocity in Chinese children with
type 1 diabetes mellitus. J Pediatr
Endocrinol Metab 2006; 19:
1313-18.
6. Galluzzi F, Stagi S, Salti R , Toni S,
Piscitelli E, Simonini G.
Osteoprotegerin serum levels in
children with type 1 diabetes : a
potential modulating role in bone
Mozzillo E, Franzese A. The
lumber bone mineral density is
affected by long term poor,
metabolic control in adolescents
with type 1 diabetes mellitus.
Horm Res 2002;58:266-72.
12. Hadjidakis DJ, Raptis AE,
Sfakianakis M, Mylonkais A,
Raptis SA. Bone mineral density
of both genders in type 1 diabetes
according to bone composition. J
Diabetes Complicat 2006; 20: 302-
7.
13. Brandao FR, Vicente EJ, Dlatro
onset. Diabetes 1991; 40:211-6.
18. Elamin A, Hussein Q, Tuvemo
T. Growth, puberty and final
height in children with type 1
diabetes. J Diabetes Complicat
2006; 20:252-6.
19. Wunsche K, Wunsehe B,
Fahnrich H, Montzel H, Vogt S,
Abendroth K et al. Ultrasound
bone densitometry of os calcis
in children and adolescents.
Calcif Tissue Int 2000; 67:39-55.
20. Siman EV, Lozano GB, Maresca
A, Francisca JLR, Perez CF,

8
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010
Tonkin CL. Bone mineral density
in juvenile onset diabetes
mellitus. Anasles Espanolis de
Pediatr 2000; 52:507-15.
21. Piepkorn B, Kam P, Frost T,
Andreas J, Pfutzner A, Bayer J.
Bone mineral density and bone
metabolism in diabetes mellitus.
Horm Metab Res 1997;29:584-
91.
22. Gunczler P, Lanes R, Paolis M,
Martinis R, Illaroel O, Wessinger
JR. Decreased bone mineral
density and bone formation
A 76-year-old woman was seen in OPD. She complained of dizziness and was found to be hypertensive. This is a
photograph of her face.
gh
Ri
py
Co
What is the diagnosis?
markers shortly after diagnosis of
clinical type 1 diabetes mellitus. J
Pediatr Endocrinol Metab
2001;14:525-8.
23. Lopez-IbarraPJ, Pastor MM,
Escobar JF, Pardo MD, Gonzalez
AG, Luna JD. Bone mineral
density at the time of clinical
diagnosis of adult onset type 1
diabetes mellitus. Endocr Pract
2001; 7:346-51.
24. Damilakis J, Galanakis E, Mamo-
ulakis D, Sbyrakis S, Gono-
tsoyiamis N. Quantitative ultra-
Picture Quiz
pio
la
cu
Es
@
ts
9
sound measurement in children
and adolescents with type 1
diabetes . Calcifi Tissue Int 2004;
74:424-8.
25. Bechtold S, Dirlenbach l, Raile
K, Noelle V, Bonfig W, Schwarz
HP. Early manifestation of type 1
diabetes in children is a risk factor
for changed bone geometry: data
using peripheral quantitative
computed tomography. J Pediatr
2006; 118:627-34.
k
.p
See Answer on Page No. 24
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

Original Article

Changes in Organ-Body Weight Relationship After Withdrawal of Chronic

Lithium Administration in Rabbits
Nazreen Sharif, Ansa Rabia and Omar Iftikhar

Background: There is widely increasing use of lithium in psychiatric patients. Its chronic use
has various side effects on the body. These effects are more severe if drug is withdrawn suddenly,
affecting not only body weight but also other organs of the body disturbing hypothalamic-
hypophyseal axis.
Objective: To document changes in organ-body weight relationship after withdrawal of chronic
Lithium administration in rabbits

k
Material and Methods: Thirty adult male rabbits were divided into two groups, control and

.p
experimental. Each group was further divided into three subgroups. Lithium Carbonate powder
34.2 mg per kg body weight was administered daily by oral route in the form of capsule for four

pio
weeks to experimental group whereas control group was given empty capsules and normal diet.
Animal weight and serum lithium levels were measured at the beginning of the experiment and
thereafter checked weekly. After four weeks, one third of the animals in each group were

la
sacrificed and their liver, kidney, thyroid and pituitary were weighed to see the effect of drug.
Second and third groups were sacrificed one and two weeks after lithium withdrawal, respectively.

cu
Results: The mean serum lithium levels gradually dropped after one week and significant fall
was seen after 2 weeks of withdrawal but it did not touch the baseline. After 4 weeks of lithium
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consumption, hypothalamic-hypophyseal axis showed exaggerated response reflected by
statistically significant increase in thyroid weight and statistically significant fall in that of pituitary
along with decrease in weight of animal and kidney.
@

Conclusion
Abrupt withdrawal of drug set hypothalamic-hypophyseal axis at a new level as reflected by
increase in thyroid and pituitary weight. Weight gained by body might be on account of other
ts

reasons.
Key Words: Chronic lithium, abrupt withdrawal, rabbits, hypothalamic-hypophyseal axis.
gh

Introduction sclerosis. 4 Lithium however has a narrow therapeutic

Ri

Affective disorders are extremely common in general
medical practice as well as in psychiatry. It covers an
extraordinarily broad range from normal grief to
py
index of 0.6 to 1.2 meq/lit which makes its blood
serum monitoring absolutely essential to avoid
intoxication. Levels above 2 meq/lit are usually toxic.
5

sometimesfatal psychosis. The lifetime risk of suicide Chronic lithium usage had been shown over the years
in major affective disorders is about 10-15%.1 to produce a number of side effects. A lot of research
Co

Lithium has been used since the late eighteenth
century in different parts of the world for the
treatment of bipolar disease. It was used for the first
time to treat the bipolar patients in the 1870's by Carl
Lange and William Hammond in Denmark and New
York respectively.2 Lithium carbonate lowers up to 7
folds in rate of suicidal acts and 2.7 folds in morbidity,
whereas there is an increase of up to 14 times in
fatalities after its discontinuation in manic depressive
3
patients. Non psychiatric uses are limited, however, it
had been used in prophylaxis of cluster headaches
(trigeminal autonomic cephalgias) and in neuro-
degenerative diseases like amyotrophic lateral
had been focused on studying the harmful effects of
lithium on various organs such as the kidney, thyroid,
brain and liver.6,7 However another common effect of
such use was noticed to be weight gain.8
Lithium is a drug which is concentrated in various
tissues like brain, kidney, thyroid, bone, liver and
muscle cells against concentration gradient, causing
increased lithium ratio. 9 Inside the cell its
concentration may affect various functions and
10
metabolism of the cells so when the drug is
withdrawn, unexpected response occurs.11,12,13 These
effect are more severe with abrupt rather than with
14,15
slow withdrawal. With widely increasing popularity

10
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

Table-1: Lithium therapy given to albino rabbits.

Groups Subgroups Rabbits Treatment Duration Serum lithium level done & Sacrificed
Group “A” A1 5 Normal diet & empty capsule 4 weeks 29th day
A2 5 Normal diet & empty capsule 4 weeks After one week of withdrawal 36th day
A3 5 Normal diet & empty capsule 4 weeks After two week of withdrawal 43th day
Group “B” B1 5 Normal diet & lithium 34.2mg/kg 4 weeks 29th day
B2 5 Normal diet & lithium 34.2mg/kg 4 weeks After one week of withdrawal 36th day
B3 5 Normal diet & lithium 34.2mg/kg 4 weeks After two week of withdrawal 43th day

of lithium being prescribed around the world, the one week of withdrawal in B2 but it was not
present study was designed to highlight its effect not statistically significant when compared with B1(p

k
only on body weight but also on different organs of value=0.732). However, statistically significant
the body especially in relation with hypothalamic- decrease was seen in subgroup B3 when compared

.p
hypophyseal axis. with subgroups B1 and B2 (p values=0.000 and 0.001

pio
respectively) i.e. after 2 weeks of withdrawal of drug;
Material and Methods but it did not touch the baseline. (Figure I).
Chemical: Lithium carbonate powder by Fluka
0.6
Chemic AG. CH-9470 Buchs Company, made in

la
Switzerland was obtained from the medical store of 0.5

cu
Postgraduate Medical Institute, Lahore and was used
for the study. 0.4 Serum Lithium

Animals: Thirty adult male albino rabbits were used

Es
E
meq/lit

0.3
for the experiment. They were kept at the Animal
House of Postgraduate Medical Institute, Lahore and 0.2
were allowed 2 weeks for acclimatization in optimal
@

light and temperature and had free access to water and 0.1

seasonal vegetables. Animals were randomly divided

0
into 2 main groups; control A and experimental B,
ts

Wk4 Wk4 Wk5 Wk5 Wk6 Wk5

each with further subgroups A1, A2, A3 & B1, B2, (C)/A1 (E)/A1 (C)/A2 (E)/A2 (C)/A3 (E)/A3
B3, each having 5 animals. Lithium carbonate powder Weeks
gh

was given orally in a dose of 17 mg/kg calculated Figure I: Graph showing mean serum lithium levels
from chronic oral consumption of 1200 mg/day for with chronic lithium therapy and after its withdrawl in
an average of 70 kg given to man.7 The weighed different experimental groups.
Ri

quantities of Li2CO3 in double the therapeutic dose

34.2 mg/kg body weight, once daily in capsules was Animal/Body ( C ) Animal/ Body (E)
py

given (Table 1). The control group animals were 1800

given empty capsules. Serum lithium levels were 1600

recorded by using FP 10 & IT 20 Flame Photometer
Co

1400
at the beginning of experiment and then weekly till
Weight in grams

1200
m
the end of the experiment (Table 1). The animals g
in 1000
t
were also weighed and sacrificed on different days; h
gi 800
e
their thyroid, liver, pituitary and kidneys were W
600
removed from the body and were weighed (mean 400
weight of both kidneys was used for statistical 200
analysis). The results were analyzed using statistical 0
variance appropriate to the experimental design. Wk 4 Wk 4 Wk 5 Wk 5 Wk 6 Wk 6
(C)/A1 (E)/A1 (C)/A2 (E)/A2 (C)/A3 (E)/A3

Results Week

No serum lithium levels were detected in control

group animals as they did not receive lithium. The Figure II: Graph showing comparison of weight of
mean serum lithium levels gradually dropped after animals in control (C) and experimental (E) groups.

11
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

0.3 There was a statistically significant increase in weight

of liver in subgroup B1 when compared with
0.25 subgroup A1(p value=0.017) i.e. after 4 weeks of
Pituitary Lithium therapy. There was no statistically significant
0.2
change in weight of kidney when subgroups of group
Weight in grams

m
g
in
t 0.15
C B were compared with comparable subgroups A (p
h
ig
e E value=0.736; 0.271 and 0.508 at week 4, 5 and 6
W 0.1 Thyroid respectively ( Figure IV).
C
0.05
Discussion
E In the present study, after 4 weeks of chronic lithium
0
Wk4 Wk4 Wk5 Wk5 Wk6 Wk5
therapy, there was a statistically significant rise in
(C)/A1 (E)/A1 (C)/A2 (E)/A2 (C)/A3 (E)/A3 serum lithium levels in group B1 as was also observed

k
Weeks
by Javaid16 and Sharif.17 Animals gained body weight

.p
Figure III: Graph showing comparison of weight both in groups A1 and B1 but it was more so in group
of thyroid and pituitary in control (C) and A1 as compared to group B1. However, this

pio
experimental (E) groups. difference in weight was not statistically significant.
Individual variation in response to Lithium had been
Kidney & Liver largely reported. 18 Lithium did not affect appetite in

la
normal individuals,19,20 whereas other workers had
8
reported weight gain despite reduced appetite which

cu
7
6 Kidney
might be due to an altered resting metabolic
m C rate. 21 Combining anti-psychotics with mood
Weight in grams

g5
Es
n E
i
t4
h
stabilizers had lead to a greater weight gain than
gi
e3 Liver treatment with one or two mood stabilizers.22
W
2 C Animals belonging to control group A1 showed an
increase in weight of organs like kidney and pituitary
@

1 E
0 but liver and thyroid did not show any rise. There was
WK 4 WK4 Wk 5 WK 5 Wk 6 WK6 a decrease in weight of thyroid and increase in weight
(C)/A1 (E) A1 (C)/A2 (E)/A2 (C)/A3 (E)/A3
of pituitary in animals belonging to control group
ts

weeks
showing that there was normal functioning of
gh

hypothalamic-hypophyseal axis. Not only this, it also

Figure IV: Graph showing comparison of weight explained decrease in BMR which was reflected by
of kidney and liver in control (C) and experimental increase in body weight and decrease in the weight of
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(E) groups. liver. An increase in kidney weight seemed to follow

that of body weight. In experimental group B1, the
Animals gained body weight both in groups A and B. hypothalamic-hypophyseal axis showed an
py

There was a statistically significant weight gain in B3 exaggerated response which was reflected by an
when compared with A3 (p value=0.030) i.e. after 2 increase in thyroid weight with a concomitant
Co

weeks of withdrawal of drug (Figure II). decrease in weight of pituitary, causing an increase in
The weight of thyroid increased both in groups A and BMR reflected by increase in liver weight and a fall in
B. There was a statistically significant increase in body weight. Kidney followed weight change as that
weight of thyroid in subgroup B1 when compared of body. Chatterjee et al (1990) observed marked
with subgroup A1 (p value=0.035) i.e. after 4 weeks weight loss in the experimental animals after three
of Lithium therapy and also in subgroup B3 when weeks of lithium consumption in therapeutic dose.
compared with subgroup A3 (p value=0.043). There Chronic lithium therapy had been reported to cause
was no statistically significant change in weight of mild microscopic changes but no effect on weight of
pituitary when subgroups of group B were compared the kidney 17 whereas functional changes related to
with comparable subgroups of A (p values=0.051; oxidative stress had been reported.24 Lithium is a
0.523 and 0.0223 at week 4, 5 and 6 respectively) as known anti-thyroid drug1 and goiter associated with
shown in (figure III). lithium therapy was suggested to be a compensatory
The weight of liver increased both in groups A and B. 10
reaction to its anti-thyroid effect. Mild to moderately

12
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010
enlarged thyroid on gross examination with mild to
moderate follicular hyperplasia and increased
vascularity on microscopic examination had been
25
noted earlier. Similar findings suggestive of goiter
had been reported earlier.7 Inflammatory, congestive
changes26 and bile duct proliferation16 had been
reported on histological examination of liver from
animals treated with chronic lithium therapy which
might be responsible for this weight gain. An increase
in hepatic glycogen with such therapy causing a
weight gain had also been observed.27 Chronic lithium
therapy had been known to induce oxidative stress in
liver.
24
At week 5 i.e. one week after withdrawal of chronic
lithium therapy, a fall in serum lithium level was
observed in B2 but it was statistically insignificant
when compared with that of B1. However, a post
withdrawal rise in serum lithium levels, attributed to
redistribution of lithium from its stored tissues like
brain, kidney, liver and thyroid had been reported.28 In
control group A2, there was a fall in weight of thyroid
and pituitary; however, only fall in pituitary weight in
A2 was statistically significant when compared with
Es
that of Al. So it seemed to follow hypothalamic-
hypophyseal axis. But due to decrease in BMR, there
was an increase in body weight followed by kidney
and liver in control group A2. In experimental group
@
B2, hypothalamic-hypophyseal axis was disturbed as
sudden withdrawal of lithium had reset the
hypothalamic-hypophyseal axis to a higher level so
ts
that basal and TRH stimulated response of pituitary
gh
was exaggerated causing central hyperthyroidism
10
which was shown by an increase in weight of both
thyroid and pituitary along with those of body, liver
Ri
and kidney, but no value was statistically significant
when compared with those of A2. So it was observed
that there was a sustained effect of drug on weight of
py
animal and its various organs after one week of
sudden withdrawal of chronic lithium therapy.
Co
Thyroid gland had been reported to be moderately
enlarged with prominent isthmus and mild
congestion after sudden withdrawal of chronic
lithium therapy on gross & microscopic examination
respectively.25 This exaggerated response might be
due to unmasking of anti-thyroid antibodies by
lithium withdrawal leading to rebound phenomenon.
7,29
Mild focal changes in renal architecture without
congestion had been observed but without effecting
17
weight of the organ. This prolonged excretion
pattern of lithium might be related to tissue storage,
particularly in bones30,31 and its gradual release from
there into blood.30
13
Two weeks after withdrawal of chronic lithium
therapy, there was a statistically significant fall in
lithium level (B3). but it did not reach the baseline.
Normally after withdrawal of the drug the serum
lithium levels usually reach baseline in 10-14 days.1
Margo and McMahon and Delva et al observed
similar effect of withdrawal on the serum lithium
levels.11,12 However, such unpredictable responses in
various individuals could be due to genetically
determined lithium ratio, erythrocyte lithium/serum
lithium, which is different even in mono-dizygotic
twins.32 Hypothalamic-hypophyseal axis was normal
as weight of thyroid was increased with significant fall
k
in weight of pituitary, suggesting an increase in BMR
.p
as reflected by fall in body weight, followed by
statistically significant fall in kidney weight. There was
pio
an increase in liver weight suggesting an increased
metabolism. An age-related decrease in pituitary
weight had been reported earlier.33 In experimental
la
group (B3), hypothalamic-hypophyseal axis was set at
a new level. This was suggested by an increase in
cu
weight of pituitary and thyroid when compared with
those of A3. However, body weight and weight of
thyroid in B3 was statistically significant more than
those of A3 which could be supported by Sharif
(2006) who reported thyroid gland to be grossly
enlarged with marked congestion 2 weeks after
withdrawal of chronic lithium therapy on gross and
25
microscopic examinations. It had been reported that
changes appearing one week after lithium withdrawal
17
persisted at week 2. When the drug was
discontinued suddenly, it gave rise to unexpected
results. Regression analysis suggested that there was
dose dependent gradual increase in weight which
became significant after 2 weeks of withdrawal.
Raised erythrocyte ratio in rabbits as compared to
humans, caused sustained effect on various tissues
like muscles, liver and fat cells, leading to increase
4
weight even after the withdrawal. It may be either due
to its insulin like effect on carbohydrate metabolism,
leading to increase in glucose uptake and glycogen
synthesis in muscles, adipose tissue and brain;
accompanied by depletion in liver glycogen
10,35,36
or
due to persisting edema. 28
Conclusions
After 4 weeks of lithium consumption, hypothalamic
-hypophyseal axis showed exaggerated response
reflected by statistically significant increase in thyroid
weight and statistically significant fall in that of
pituitary causing an increase in BMR, leading to
increase in liver metabolism and decrease in weight of
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010
of animal and kidney.
2 weeks after sudden withdrawal of drug,
hypothalamic-hypophyseal axis was set at a new level
as reflected by increase in thyroid and pituitary weight,
but weight gained by body might be on account of
other reasons as explained earlier.
It is suggested that abrupt withdrawal of chronic
lithium therapy could have unexpected side effects.
References
1. Goodman L, Gillman AG.
Thyroid and antithyroid drugs.
In: The Pharmacological Basis
of Therapeutics. 9th Edition.
McGraw Health Professions 12.
Division New York. 1996; 446-
49.
2. Baldessarini RJ, Tondo L,
Davis P, Pompili M, Goodwin
FK, Hennen J.Decreased risk 13.
of suicides and attempts
during long-term lithium
treatment:a meta-analytic
review. Bipolar Disord 2006;8: 14.
625–39.
3. L i t h i u m s l o w s A L S
progression In Study. muscular
dystrophy Assoc-iation. 2008;
ts
Av a i l a b l e f r o m U R L : 15.
H t t p : / / w w w. a l s -
gh
mda.org/research/news/080
204Lithium_slows_
ALS.html. Retrieved 2009.
Ri
4. Groleau G. Lithium toxicity. 16.
Emerg Med Clin North Am
1994;12:511-31.
py
5. Clarke WB, Clarke RM, Olson
EK, Barr RD, Downing RG.
Co
Binding of lithium and boron
to human plasma proteins.
B i o l Tr a c e E l e m Re s 18.
1998;65(3):237-49.
6. Rosser R. Thyrotoxicosis and
lithium. Br J Psych 1976; 128: 19.
61-6.
7. Barbara S, Fleischhacker WW,
K a s c h k a W P. P s y c h o
neuroimmun. 2001. Karger
Publishers, p. 2. ISBN 17.
380557262X.
8. Okusa MD, LIT Crystal.
Therefore, in order to find the level of disturbance of
hypothalamic-hypophyseal axis, we should explore
microscopic picture of pituitary, hypothalamus and
liver alongwith their biochemical analysis.
Department of Anatomy
CMH/Medical and Dental College, Lahore
theesculapio@hotmail.com
www.sims.edu.pk/esculapio.html
Clinical manifestations and rabbit kidney-a histological
management of acute lithium study. Pak Postgr Med J
k
intoxication. Am J Med 1994; 2003; 14(2) :100- 3.
.p
97:383-9. 20. Jensen GL. Drug-induced
Lazarus JH. The effects of hyperphagia: what can we
pio
lithium therapy on thyroid & learn from psychiatric
thyrotropin releasing horm- medications. J Parenter
one. Mary Ann Liebert. Inc Enteral Nutr 2008; 32(5):
la
1998;8:10. 578-81.
Marg o A. McMahon P. 21. Chen Y, Goodal ER,
cu
Lithium withdrawal triggers
psychosis. Brit J Psych
Silverstone T. The effects
of lithium on body weight
Es
1982;141:407- 10. and food intake in normal
Delva NJ, Letemendia FJJ, subjects a pilot study. Int
Prowse AW. Lithium with- Clin Psychopharmacol
@
drawal trial in chronic schizo- 1992;7(l):51-4.
phrenia. Br J Psych 1982; 22. Oerlinghausen BM,
141:401-6. Psychological effects,
Lapierre YD, Gagnon A, compliance and response
Kokkinidis L. Rapid of long-term lithium. Brit J
recurrence of mania following Psychiatry 1982 ;141:411-
lithium withdrawal. Biol Psych 9.
1980; 15:859-64. 23. Ruetsch O, Viala A,
Baldessarini RJ, Tondo L, Bardou H, Martin P,
Floris G. Reduced morbidity Vacheron MN. Psycho-
after gradual discontinuation tropic dr ugs induced
of lithium treatment for weight gain: a review of
bipolar I and II disorders: A the literature concerning
replication study. Am J Psych epidemiological data,
1997; 154:551-3. mechanisms & manage-
Yuce M. Difficulty in stopping ment. Encephale 2005;31
lithium prophylaxis. Br Med J :507- 1 6.
1979; 1020. 24. Correll CU. Weight gain
Javaid S. A study of lithium and metabolic effects of
induced toxicity in rabbit. M. mood stabilizers and
P h i l T h e s i s Pa t h o l o g y antipsychotics in pediatric
Department, University of the bipolar disorder: a
Punjab. Lahore;1985. systematic review and
Sharif N, Hussain N, Raza TA. pooled analysis of short-
Role of chronic lithium term trials. J Am Acad
therapy and its withdrawal on Child Adolesc Psychiatry
14
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010
2007;46(6):6X7-700.
25. Chatterjee S, K Roden, TK
Baner ji. Mor phological
changes in some endocrine
organs in rats following
chronic lithium treatment.
Anat Anz Jena 1990; 170:3 1-
7.
26. Nciri Rr Allagui MS, Vincent
C, Murat JC, Croute F, El
Felki A. The effects of
subchronic lithium adminis-
tration in male Wistar mice on
some biochemical para-
meters. Hum & Exp Tox
2009;2X( 1 0): 64 1 -6.
27. Sharif N. Raza TA. Histo-
logical study on withdrawal
of chronic lithium therapy on
rabbits thyroid. Annals 2006;
12(3): 450-4.
28. Loghin F, Olinic A, Popa DS.
Socaciu C. Leucuta SE.
Effects of long-term
administration of lithium and
hydrochlorothiazide in rats.
Met Based Drugs 1999;
6(2):X7-93.
29. Bosch F, Rodriguez-Gill JE,
Hatzoglou M, Gomez-Foix
AM, Hanson RW. Lithium
inhibits hepatic gluco-
gh
neogenesis and phospho-
enolpyruvate carboxykinase
Ri
py
Co
gene expression. J Biol Chem
1992 Feb 15;267(5):2888-93.
30. Morton AW, Sonne SC,
Lydiard RB. Lithium side
effects in the medically ill. Inf
LJ Psych Med 1993;23(4):357-
X2.
31. Todd J, TC Jerram. Thyro-
toxicosis during lithium treat-
ment. PASTIC 197X;32:201-3.
32. Laurence DR, Bennett PN.
Central nervous system In:
Clinical Pharmacology. 7
th
edition. ELBS with Churchill
Livingstone, Sing apore
1992;293-5.
pio
33. Birch NJ. Metabolic effect of
lithium. Proceedings of the
first British Lithium Congress
la
University of Lancaster,
England In: Johnson FN,
cu
Johnson S editors. Lithium in
medical practice. MTP.
Lancaster, England 1977;X9-
Es
111.
34. Lee CR, C Paschalis. Meta-
bolism as guide to the solution
@
of patients for lithium.
therapy. Proceedings of the
first British Lithium Congress
ts
University of Lancaster
England In: Lithium in
Medical Practice. Johnson FN.
Jo h n s o n S ( e d ) . M T P.
15
Lancaster, England
1977;365-79.
35. Ikram MF, Sajjad Z, Shokh I,
Omair A. Pituitary height on
magnetic resonance imaging
observation of age and sex
related changes. J Pak Med
Assoc 2008 May;58(5):261-5.
36. Laurence DR. Bennett PN.
Central Nervous System In:
Clinical Pharmacology. 7th
Edition. ELBS with Churchill
Livingstone, Singapore 1992;
k
293-5.
.p
37. Plenge P. Lithium effects on
rat brain glucose metabolism
in long term: Lithium treated
rats. Proceedings of the first
British Lithium Congress
University of Lancaster,
England In: Johnson FN,
Johnson S, editors. Lithium
in medical practice. MTP.
Lancaster, England 1977;
145-52.
38. Vendsborg P. Lithium and
Glucose Tolerance. Proceed-
ings of the first British
Lithium Congress University
of Lancaster. England In:
Lithium in Medical Practice
Johnson FN. Johnson S (ed).
MTP. Lancaster, England
1977;153-7.
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

Original Article
Histological Patterns in Gastric Biopsies and their Association with
Helicobacter Pylori Infection
Rakhshindah Bajwa

Background: Helicobacter Pylori (H. Pylori) is recognized as the primary cause of chronic
gastritis and gastric diseases. H. Pylori is associated with increased risk of gastric cancer through
the development of a multi-step carcinogenesis. Multiple biopsies of gastric mucosa are helpful in
making a categorical diagnosis of H. Pylori induced gastric lesions.
Objective: The purpose of the study was to evaluate the morphology of different gastric lesions
associated with H. Pylori.

k
Material and Methods: It was a descriptive study conducted in the Department of
histopathology, Services Institute of Medical Sciences / Services Hospital, Lahore. The study

.p
included 157 endoscopic biopsies from patients undergoing endoscopy for non-ulcer dyspepsia
during a period of one year from January 2008 to December 2008.

pio
Results: A total of 157 gastric biopsies from patients of ages ranging from 5 to 85 years were
included, out of which 6 (3.8%) were normal. Out of 151 remaining patients, 128 (84.8%) were in
the fifth and sixth decade who were found to have chronic gastritis with evidence of H. Pylori in 42

la
(32.8%). 13 (8.6%) had gastric adenocarcinoma with evidence of H. Pylori in 1(7.7%). 77

cu
(60.16%) of the patients with chronic gastritis were males out of which 26 (34%) were positive for
H. Pylori. No evidence of atrophic gastritis or intestinal metaplasia was seen.
Conclusion: Chronic gastritis was predominant diagnosis followed by gastric adenocarcinoma.
Es
Multiple endoscopic gastric biopsies should be taken to rule out the possibility of pangastritis,
atrophic gastritis and intestinal metaplasia which are part of multi-step development of gastric
carcinoma.
@

Keywords: Helicobacter Pylori, Chronic gastritis, atrophic gastritis, gastric adenocarcinoma,

intestinal metaplasia.
ts

Introduction severe.6,7
Helicobacter Pylori (H. Pylori) is recognized as the Infection with H. Pylori has been associated with an
gh

primary cause of chronic gastritis and gastric increased risk of gastric cancer. It has been found that
diseases.1 Profound suppression of gastric acid is precursor lesions like mucosal trophy, IM and
Ri

associated with increased severity of gastritis caused dysplasia are universally associated with H. Pylori
by H. Pylori.2 Chronic gastritis is a histologic entity infection, but it is not directly associated with
characterized by chronic inflammation of the gastric stomach carcinogenesis; instead, it takes the affect
py

mucosa. Gastropathy is a more appropriate term to through the development of chronic atrophic
describe gastric mucosal injury caused by chemicals gastritis (CAG).8,9,10 H. Pylori causes chronic active
gastritis with predominant localization in the gastric
Co

and reflux of bile and pancreatic secretions into the

3
stomach. “Sydney Classifications” of gastritis
classifies gastritis on histo-morphological criteria as
acute, chronic and chronically active,4 depending on
density of H. Pylori infection, the degree of chronic
inflammation, inflammatory activity, gastric atrophy
(GA), intestinal metaplasia (IM) and surface epithelial
damage.5
It is interesting to note that the principal histological
features of acute H. Pylori gastritis, surface epithelial
degeneration and polymorphonuclear leucocytic
infiltration remain the most sensitive indicators of`
activity` of infection in the chronic phase, with
grading of severity as (1) mild, (2) moderate and (3)
antrum. H. Pylori colonization of gastric mucosa
precedes the development of patchy distribution of
chronic active gastritis.11,12
Gastric biopsies giving histologic findings of severe
gastric atrophy, corpus predominant gastritis or IM
are at increased risk for developing carcinoma.13 Risk
of gastric atrophy and IM increases with advancing
age; however in a study atrophic gastritis was not
found to be a normal aging process, instead it is likely
to be the result of H. Pylori infection; IM was,
however, found to be associated with aging process as
well as H. Pylori infection. According to a model of
carcinogenesis of the intestinal type gastric

16
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

adenocarcinoma proposed by Correa, the multi-step
development starts from chronic active gastritis,
followed by glandular atrophy, IM, dysplasia and
gastric adenocarcinoma with increasing risk in
pangastritis and corpus predominant gastritis.14,15,16 It
is pertinent to say that there is a topographical
relationship between H. Pylori, histological response
and gastro-duodenal disease leading to carcinoma.17, 18
H. Pylori plays a decisive role in the pathogenesis of
marginal zone B cell lymphoma of mucosa associated
lymphoid tissue (MALT).19 Endoscopy is an accurate
test for diagnosing H. Pylori as well as the
20
inflammation and ulcers it causes. Pathologists are
mounting medium. The sections were reviewed for
histological assessment, as proposed by the updated
“Sydney Classifications” of gastritis, the findings
were categorized on histo-morphological criteria as
acute, chronic and chronically active, depending on
density of H. Pylori infection, the degree of chronic
inflammation, inflammatory activity, gastric atrophy
(GA), intestinal metaplasia (IM) and surface epithelial
damage.4,5
Statistical Analysis
Data was analyzed using a computer based statistical
analysis software. The mean age and (± SD) of the

k
frequently asked to evaluate endoscopic gastric patients in various groups was calculated and

.p
mucosal biopsy specimens for the presence of H. compared using student’s t test at 5% level of
Pylori infection. The Sydney system combines significance.

pio
topographical, morphological and causative
information for evaluation of gastric biopsy Results
specimens and for providing recommendations A total of 157 formalin fixed gastric endoscopic

la
regarding biopsy site and number.21 biopsies were included in the study; out of 157, 6
(3.8%) were found to be normal in morphology. Out
Objectives
Purpose of this study was to evaluate the morphology cu
Table-1: Distribution of gastric lesions and their
association with H. Pylori in endoscopic biopsies.
Es
of different lesions associated with H. Pylori and its
frequency in different age groups of our patients No of H-Pylori
Lesions %
undergoing endoscopy showing normal or minimal cases Positive
nonspecific changes of gastric mucosa.
@

Acute gastritis 04 2.6 0

Chronic gastritis 128 84.8 42 (32.8%)
Material and Methods
Ulcer 06 4.0 0
ts

It was a descriptive study conducted in the

department of histopathology, Services Institute of Adenocarcinoma 13 8.6 01 (7.7%)
gh

Medical Sciences / Services Hospital, Lahore. The Total 151 100 43 (28.4%)
study included 157 endoscopic biopsies from patients
undergoing endoscopy for non-ulcer dyspepsia
Ri

% of Gastric Morphology
during a period of one year from January 2008 to
December 2008.
Adenocarcinoma Normal
8% 4%

The inclusion criteria were:-

py

Ulcer
Ac. Gastritis 4%
1) Male and female patients of any age, presenting 3%

with non-ulcer dyspepsia.

Co

2) Patients with normal or minimal change gastric

mucosa on endoscopy.
The exclusion criteria were:-
1) Patients already diagnosed to have gastric
carcinoma.
2) Patients known to have gastric or duodenal ulcer,
GI bleeding or upper GI malignancy.
Formalin (10%) fixed gastric biopsies were processed
in an automatic tissue processor; later paraffin
embedded blocks were prepared. Multiple serial Ch. Gastritis
81%
sections 3-5µ thick were made, stained with
Haematoxylin & Eosin and Giemsa stains for
localizing H. Pylori and cover slipped with a Fig-1:Distribution of gastric morphology in
endoscopic biopsies

17
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

Table-2:Range and mean age in gastric lesions categorized using Sydney histo-morphological
Lesions No of case Age (Years) criteria; gastric lymphocytic infiltrate was moderately
n (%) Range Mean±SD prominent, polymorphonuclear leucocytic infiltrate
Ac. gastritis 04 (2.6) 25-50 42±12 was occasional in gastric mucosa.
Age of patients diagnosed to have chronic gastritis
Ch. gastritis 128 (84.8) 05-85 43.8±17.5 ranged between 5 to 85 years with a mean of 43.8 ±
Gastric ulcer 06 (4.0) 35-80 35±18 17.5 years, which was significantly different as
Adenocarcinoma 13 (4.0) 25-75 25± 14.5 compared to patients with gastric adenocarcinoma
(p<0.001) and gastric ulcer (p<0.0001) with mean
35 ages of 25 ± 14.5 and 35 ± 18.4 years respectively
30
31 (Table 2, Fig; 2)

25 24.2 24

k
21
20

.p
18.8
16.4 No.of Cases
15 15
14
%
12

pio
11.7
10.9
10 9.4

5 5
4 3.9
3.1
2
1.6

la
0
0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89
Age Groups

cu
Fig-2:Age distribution in cases of chronic gastritis
Es
Table-3: Sex distribution of chronic gastritis and
its association with H. Pylori.
No of cases No. of cases with No. of case with-
Sex Fig-2:Photomicrograph showing dysplasia
@

n (%) H-pylori (%) out H-pylori (%)

Male 77 (60.16) 26 (34) 51 (66) Out of 128 patients of chronic gastritis 42 (32.8%)
Female 51 (39.84) 16(31) 35 (69) were found to be infected by H. Pylori, whereas only 1
ts

128 (100) 42 (32.8) 86 (67.2)

out of 13 (7.7%) patients of gastric adenocarcinoma
Total
harbored H. Pylori (Table 1).
gh

77 (60.16%) males were found to have chronic

gastritis with a mean age of 42.38±17.4 years with
Ri

evidence of H. Pylori on special stain in 26 (34%)

biopsies. 51(39.8%) females were diagnosed to have
chronic gastritis out of which 16 (31%) were H. Pylori
py

positive ( Table 3, Fig. 3 ). The evidence of atrophic

gastritis (AG) and intestinal metaplasia (IM) was not
found in any biopsy, however, evidence of dysplasia
Co

was found in one biopsy (Fig 4 ).

Discussion
Helicobacter Pylori are gram negative rods that have
the ability to colonize and infect stomach. The
bacteria survive within the mucosal layers that covers
Fig-3:Photomicrograph with H. Pylori (H&E;× the gastric surface epithelium and upper portion of
100). 3,22
the gastric foveolae. Inflammatory cytokines
generated locally within the gastric mucosa could be
of the remaining 151 biopsies, 4 (2.6%) were acute relevant to the gastric physiology of H. pylori
gastritis, 128 (84.8%) were chronic gastritis, 6 (4%) infection.
23

were gastric ulcer and 13(8.6%) were gastric In an international survey an estimated 50% of the
adenocarcinoma (Table 1 Fig. 1). Gastritis was world population is infected with H. Pylori, whereas

18
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

35% of the adult US population is affected by H.
Pylori , a finding consistent with our study where with
an overall incidence of H. Pylori being 43 (28.4%) and
42 out of 128 (32.8%) patients in fifth decade with ch.
gastritis were histologically found to be colonized by
H. Pylori (Table 1 & 2 ). Our study is also compatible
with another study conducted in 3548 patients to find
the prevalence of H. Pylori associated gastritis where
13.8% patients positive for H. Pylori were in the age
range of 45-54 years and 23.1% in the age range of
gastric mucosa in only one case; the prevalence of
gastritis featuring dysplastic changes increases with
age, reinforcing the necessity for the histological
assessment even in the patients with normal
endoscopic appearance.
Our study found no difference in gender frequency
among patients of ch. gastritis, a finding consistent
16
with that of Leodolter et al. Helicobacter Pylori
induced gastritis is associated with an increased risk
of cancer development with increasing age, as
16

54-64 years. shown in our study where 13 of the 151 (8.6%)

Background Helicobacter Pylori infection plays an patients of fifth and sixth decade were found to have
important role in the development of atrophic gastric adenocarcinoma (Table 1); only 1 of these 13

k
gastritis and IM, conditions that predispose patients (7.7%) was positive for H. pylori, a finding consistent

.p
to gastric carcinoma. Our study failed to detect with a study where relatively high risk population
atrophic gastritis. In one study 31 out of 72 patients failed to show an association between H. pylori

pio
with H. Pylori infection treated with fundoplication infection and subsequent risk of gastric cancer.8 This
did not develop atrophic gastritis. The diagnosis is, low frequency of H. pylori association could be due
however, based on histological examination of to short time period of follow up and delay in getting

la
multiple biopsies from several different sites of clinical assistance at an earlier stage.
gastric mucosa. In this study no patient was found to

have IM, a finding consistent with a study including
forty-six patients, 20 with H. Pylori infection and 36
with IM where intestinal metaplasia was missed in
Es
more than 50% of those with confirmed intestinal
metaplasia. No set or site of biopsy specimens was
found that could reliably exclude the presence of
@
cu
Conclusion
Chronic gastritis was the most frequent diagnosis
among adult population followed by gastric
adenocarcinoma. Multiple gastric endoscopic
biopsies must be taken to rule out the possibility of
pan-gastritis, intestinal metaplasia and atrophic

intestinal metaplasia.21 gastritis which are part of multi-step development of

In a study, relationship between H. pylori and peptic gastric carcinoma. Our data clearly indicates that
ulcer was studied and 87.2% were found to have there is a need to obtain gastric specimen in routine
ts

histological evidence of H. pylori infection.17 Our endoscopy, even if the macroscopic appearance is to a
study failed to detect H. pylori in 6 (4%) ulcer cases, a
gh

greater or lesser extent normal.

finding in contrast to the above study; this could be
due to the fact that gastric ulcer was an incidental Department of Pathology
Ri

finding, as endoscopic biopsies were taken from SIMS/Services Hospital, Lahore

patients with non-ulcer dyspeptic patients. theesculapio@hotmail.com
This study was able to detect dysplastic changes in www.sims.edu.pk/esculapio.html
py

References
Co

1- Tran CD, Huynh H, Campbell F,
Coyle P, Butler R. Metallo-
thionein knockout mouse: a
potential model of Helicobacter
Pylori induced gastritis. [online]
2001[cited on 2010 July 9].
Available from: http:// www.
intact.com.au/links/helicobacte
rpylori/hpylori-gastritis-model.
aspx.
2- Kuipers EJ, Lundell L, Klinken-
berg Knol EC, Havu N, Festen
HPM, Liedman B et al. Atrophic
gastritis and Helicobacter Pylori
infection in patients with reflux
esophagitis treated with omepra-
zole or fundoplication. N Engl J
Med 1996; 334(16): 1018-22.
3- Mukherjee S, Sepulveda AR, Dore
MP, Bazzoli F. Gastritis, chronic.
[serial online ] 2009 [ cited on 2010
June 14 ]. Available from URL:
http://emedicine.medscape.com
/article/176156- overview.
4- Freytag A, Deist T. Stomach-
Sydney classification of gastritis.
[online] 2003 [ cited on 2010 June
7]. Available from URL: www.
endoskopischer-atlas.de /m01ae.
htm.
5- Chen XY, Van der Hulst RW,
Bruno MJ, Van der Ende A, Xiao
S D, T y t g a t G N e t a l .
Interobserver variation in the
histological scoring of
Helicobacter Pylori related
gastritis. J Clin Pathol 1999;
52(8): 612-615.
6- Dixon MF. 3 histological
responses to Helicobacter Pylori
infection: gastritis, atrophy and
preneoplasia. Baillére's Clin

19
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010
Gastroenterol 1995; 9(3): 467-486.
7- Hussein NR, Napaki SM,
Atherton JC. A study of
Helicobacter Pylori associated
gastritis in Iraq and their
association with strain virulence.
Saudi J Gastroenterol 2009;
15(2): 125-127.
8- Yuan JM, Yu MC, Xu WW,
Cockburn M, Gao YT, Ross RK.
Helicobacter Pylori infection and
risk of gastric cancer in Shanghai,
China: updated results based
upon a locally developed and
validated assay and further
follow-up of the cohort. Cancer
Epidemiol Biomarkers Prev
1999; 8(7): 621-24.
9- Guarner J, Mohar A, Parsonnet J,
Halperin D. The association of
Helicobacter Pylori with gastric
cancer and preneoplastic lesions
in Chiapas, Mexico. Cancer 2006;
71(2): 297-301.
10-Ohata H, Kitauchi S, Yoshimura
N, Mugitain K, Iwane M,
Nakamura H. Epidemiology-
progression of chronic atrophic
gastritis associated with Helico-
bacter Pylori infection increases
risk of gastric cancer. Intl J
Cancer 2003; 109(1): 138-43.
11-Kuipers EJ, Uyterlinde AM, Peña
AS, Hazenberg HJA, Bloemena
E, Lindeman J et al. Increase of
gh
Helicobacter Pylori associated
corpus gastritis during acid
suppressive therapy: implications
Ri
for long term safety. Am J
Gastroenterol 2008; 90(9): 1401-
6.
py
12-Bayerdörffer E, Oertel H, Lehn
Co
N, Kasper G, Mannes GA,
Sauerbruch T et al. Topographic
association between active
gastritis and Campylobacter Pylori
colonization. J Clin Pathol
1989 ; 42: 834-9.
13- U e m u r a N, O k a m o t o S,
Yamamoto S, Matsumura N,
Yamaguchi S, Yamakido M et al.
Helicobacter Pylori infection and
the development of gastric cancer.
N Engl J Med 2001; 345 (11):
784-9.
14- Fontham ETH, Ruiz B, Perez A,
Hunter F, Correa P. Determinants
of H. Pylori infection and chronic
gastritis. Am J Gastroenterol 2008;
90(7): 1094-1101.
pio
15- Ohkuma K, Okada M, Murayama
H, Seo M, Maeda K, Kanda M et
al. Association of H. Pylori
la
infection with atrophic gastritis
and intestinal metaplasia. J
cu
Gastroenterol Hepatol 2008;
15 (10): 1105-12.
16- Leodolter A, Ebert MP, Peitz U,
Es
Wolle k, Kahl S, Vieth M et al.
Prevalence of H Pylori
associated ' high risk gastritis' for
development of gastric cancer in
@
patients with normal
endoscopic findings. World J
Gastroenterol 2006; 12(34): 5509-
ts
12.
17- Hu PJ, Li YY, Zhou MH, Chen
MH, Du GG, Huang BJ et al.
Helicobacter Pylori associated
with a high prevalence of
duodenal ulcer disease and a low
prevalence of gastric cancer in
developing nation. Gut 1995;
36(2): 198-202.
20
18- Fo r m a n D, N e we l l D G,
Fullerton F, Yarnell JW, Stacey
AR, Waid N. Association
between infection with H. Pylori
and risk of gastric cancer:
evidence from a prospective
investigation. BMJ 1991; 302
(6788): 1302-05.
19- Fischbach W, Goebeler-Kolve
ME, Dragosics B, Greiner A,
Stolte M. Long term outcome of
patients with marginal zone B cell
lymphoma of mucosa associated
l y m p h o i d t i s s u e ( M A LT )
k
following exclusive H. Pylori
eradication therapy: experience
.p
from a large prospective series.
Gut 2004; 53 (1): 34-37.
20- Rehman AU. Diagnosis of H.
Pylori infection [Editorial].
Esculapio 2007; 6(1): 1.
21- El-Zimaity HM, Graham DY.
Evaluation of gastric mucosal
site and number for identification
of Helicobacter Pylori or
intestinal metaplasia: role of the
Sydney System. Hum Pathol
1999; 30(1): 72-77.
22- Kazi JL, Sinniah R, Zaman V, Ng
ML, Jafarey NA, Alam SM et al.
Ultra str uctural study of
Helicobacter Pylori associated
gastritis. J Pathol 2005; 161(1):
65-70.
23- Crabtree JE, Shallcross TM,
Heatley RV, Wyatt JI. Mucosal
tumor necrosis factor alpha and
interleukin-6 in patients with
Helicobacter Pylori associated
gastritis. Gut 1991; 32(12):1473-
1477.
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

Original Article
Role of H.Pylori Eradication Therapy in Alleviation of Symptoms
In H. Pylori Positive Non-ulcer Dyspepsia Patients
Zaheer Iqbal, Dur Muhammad Khan and Muhammad Ashfaq

Abstract: To establish the role of anti H. pylori eradication therapy in alleviation of symptoms in
H. pylori positive non-ulcer dyspepsia (NUD) patients.
Material & Methods: This clinical trial was carried out in the Medical unit II and Medical Special
unit of the Services Hospital, Lahore during the period from 2003 to 2004.100 patients with the
symptoms of dyspepsia without having evidence of peptic ulcer on upper GI endoscopy were
included in the study. Out of these 100 patients 33 were found H. pylori negative on first

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endoscopy & histopathology, whereas, the remaining number of 67 was completed by

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confirmation of H. pylori eradication in initially positive cases. Post treatment six weeks follow up
was performed to confirm outcome.

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Results: The H. pylori eradication therapy did not show statistically significant improvement in
symptoms of NUD patients.
Conclusion: Routine H. pylori eradication has little role in the alleviation of symptoms in patients

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with NUD.
Keywords: Non-ulcer dyspepsia, H. pylori, Upper G.I endoscopy

Introduction
Es
Non ulcer dyspepsia (NUD) is one of the most
common problems encountered in primary care
practice. NUD is about twice as common as ulcer
peptic disease. Recurrent abdominal pain or
@
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dyspepsia remains uncertain. Results from
population based epidemiological studies have been
conflicting regarding a causal link between H. pylori
6
infection and NUD. According to Joshi et al NUD is
being postulated as one of the gastroduodenal

discomfort, early satiety, bloating and postprandial manifestation of H. pylori infection. H. pylori
fullness are characteristic features. Absence of other infection may result in clinical symptoms as well as
organic diseases like GERD, billiary tract disease and histological changes in NUD.7 As concluded in a study
ts

peptic ulcer are essentials of the diagnosis. The conducted by Veldhuyzen et al there is need to clarify
gh

underlying patho-physiology of non ulcer dyspepsia the role of H. pylori in this disorder. Therefore, there
is not fully understood.1 Probable mechanisms is no evidence of a causal relation between H. pylori
include gastroduodenal hypersensitivity, delayed and NUD.8
Ri

gastric emptying and antral hypomotility, gastric
dysrhythmias, impaired proximal g astric
2
accommodationand small intestinal dysmotility.
py
The annual prevalence of dyspepsia in the USA and
western countries is approximately 25% and it may
account for up to 5% of visits to primary care

The role of Helicobacter pylori (H. pylori) in patients providers.9 Prevalence of H. pylori infection was
with non ulcer dyspepsia (NUD), the relationship of found in 43% to 87% of subjects with NUD in
Co

the virulence of the organism to the occurrence and
severity of NUD and the need for eradication of H.
pylori in alleviating symptoms of NUD remain
3
controversial. There is considerable debate about
whether H. pylori infection is important in causing
NUD. Many studies assessing this relationship have
been performed in selected patient populations.4 It
seems that gastric juice does not play a role in the
5
genesis of NUD. Although H. pylori infection has
been recognized as a major etiological agent for the
development of chronic active gastritis, duodenal
ulcer and benign non-NSAID related GU, its role in
the development of symptoms in patients with
different studies done in the west.10 In a study done by
Schlemper et al, H. pylori positivity was reported to
be 80% in NUD and 68% in all other non-ulcer
subjects.11
Material and Methods
Patients presenting with the features of NUD were
enlisted. Presenting symptoms were recorded on the
proforma. Patients aged more than 15 years, having
no organic pathology to explain dyspepsia and with
normal endoscopy (no ulcer), were included. Biopsy
from the pre-pyloric region of the stomach was taken
using biopsy forceps and the sample was preserved in

21
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

formalin and sent for detection of H. pylori. All
patients were given anti H. pylori treatment
(Clarithromycin 500 mg twice daily and Amoxicillin 1
gm twice daily for 7 days and Omeprazole 20 mg
twice daily for 4 weeks). The initial biopsy report
determined 33 cases as negative which were labelled
as control group. A repeat gastroscopy and biopsy
after completion of treatment was done on patients
who were H. pylori positive to confirm eradication
and cases not confirming eradication were excluded
from the study. A total of 67 such cases were enrolled
to complete a total number of 100. Outcome was
judged by improvement or disappearance of
fullness (64%), bloating (58%), belching (56%) were
also very commonly reported. The least common
complaint was vomiting (5%), whereas, nausea was
reported in 38% of the patients (Table 2).
Among the 100 patients, 67 (67%) were found to be
H. pylori positive (infected) on gastroscopic biopsy
and histopathology, while 33(33%) were H. pylori
negative (not infected).
Among the 67 H. pylori positive patients, 23 (34.33%)
responded to treatment with improvement in
symptoms, whereas, 44 (65.67%) patients did not
show improvement, likewise in the other group i.e. H.
pylori negative 33 patients only 10 (30.31%) were

k
symptoms in the follow-up for six weeks post cured, while 23 (69.69%) had no improvement in

.p
treatment. symptoms after treatment. The Chi square value was
Data analysis was computer based. Data was entered 0.03, df = 1 and P = > 0.8599 (statistically non-

pio
in SPSS version 10.0. Outcome was compared by the significant) (Table 3).
Chi square test. Frequency tables of variables
included in proforma were also made. Table-2: Distribution of symptoms

la
Symtoms Numbers
Numbers Percentage
Results Burning epigastrium 36 36.0%

cu
The study was conducted on 100 patients who
Pain/discomfort epigastrium 67 67.0%
fulfilled the inclusion criteria. They ranged form 20 to
Belching
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60 years of age. The highest number of patients was 56 56.0%
between 20-30 years i.e. 45 (45%) while lowest Nausea 38 38.0%
number of patients was in the age range of more than
50 years, 6 (6%). There were 26 (26%) patients Vomiting 05 05.0%
@

between 31-40 years and 23 (23%) patients were Bloating 58 58.0%

between 41-50 years. Mean age of the patients was
Postprandial fullness 64 64.0%
found to be 34.19±10.7 years.
ts

The percentage of males and females was 41% and

59% respectively. The figures show that among Table-3:Cross table of H. Pylori infection & sympto-
gh

younger age group female were much more matic relief secondary to eradication therapy
predominant in number 31% in 3rd decade and 16% H. Pylori PositiveH. Pylori Negative Total
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in 4th decade, whereas in older age group males were

more in number as compared to their counterparts Symptoms relieved 23 10 33
13% in 5th decade and 4% in 6th decade and above Not relieved 44 23 67
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(Table1).
Total 67 33 100
The most common recorded symptom was
pain/discomfort epigastrium (67%). Post prandial Chi Square=0.03 p=0.8599
Co

Table-1: Age wise distribution of males and females included in the study
Age / Years Male Female
Number Percentage Number Percentage
20 - 30 14 34.1% 31 52.5%
31 - 40 10 24.4% 16 27.1%
41 - 50 13 31.7% 10 16.9%
> 50 04 09.8% 02 03.5%
Total 41 100.0% 59 100.0%
Mean±SD (years) 37.0±11.4 32.24±9.76

22
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

Discussion (range 21-58%).13, 14

In our study the H. pylori positive cases were 67%
which has the same trend as reported in the available
literature although it is a little on the lower side as
expected in the developing countries, where a higher
rate is reported. The possible explanation being
frequent use of antibiotics prescribed by general
practitioners and even self medication by the patient
Blum et al denote there is no significant overall effect
of treatment on quality of life compared with
placebo.13,14
Mc Cobi et al do not support the use of H. pylori
eradication therapy in NUD. A non-significant trend
toward a small benefit with H. pylori therapy was the
outcome of the study.
15

for different ailments which might have led to
eradication of infection among a reasonable number.
Moreover, the overwhelming majority of our study
subjects were of younger age group, who are reported
to have relatively lower infection rate.
In our study two groups of NUD patients were
separated, i.e. H. pylori positive (67%) and H. pylori
negative (33%). The effects of identical treatment on
the two groups were recorded and processed. Among
the H. pylori positive patients, 23 out of 67 (34.3%)

k
Our study reveals that overwhelming number of benefitted as compared to 10 out of 33 (30.33%) in H.

.p
patients recorded belonged to the younger age group, pylori negative group. The Chi Square value (Yates
rd th
45% in 3 decade and 26% in the 4 decade, whereas corrected) was calculated to be 0.03 (df 1) with p

pio
the patients registered for age 50 and above are only value of 0.8599 indicating the effect of eradication
6%. The literature also reports higher rate of NUD in treatment to be non-significant.
younger age groups in contrast to H. pylori infection,

la
which is much higher in older age group. Conclusion
Sex distribution indicates a significantly higher rate of In accordance with the existing updated literature,

NUD among females, 59% as compared to 41%
among the males in our study.
Es
The effects of H. pylori eradication treatment have
been determined in different studies and are
conflicting in conclusion, majority indicating no
statistically significant benefit.
@
cu
this study concludes that a causal relationship
between NUD and H. pylori infection is not
established. Therefore, little support is provided for
the routine H. pylori eradication in the symptomatic
treatment of patients with NUD. Further evaluation
of the etiology of NUD and new therapeutic

Moayyedi and Axon concluded that patients with inter ventions are needed for appropriate
dyspepsia and normal endoscopy gain a modest management.
benefit from H. pylori eradication therapy. It states
ts

that H. pylori eradication is of small but significant

benefit for dyspepsia symptoms of patients with Medical Special Unit
gh

NUD.12 Services Hospital, Lahore

Burley et al state the mean placebo response rate at theesculapio@hotmail.com
Ri

one year was 28% (range 7-51%) and the mean H. www.sims.edu.pk/esculapio.html
pylori eradication treatment response rate was 36%
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References
1. Loh KY, Siang TK. Understan- Lamers CB. Non ulcer dyspepsia dyspepsia and non-ulcer
Co

ding non ulcer dyspepsia. Med J
Malaysia 2008; 63:174-6.
2. Chaudhuri S, Santra A, Dobe PB,
Das AS. Esophageal and gastric
dysmotility in non ulcer
dyspepsia. Indian J Gastro
enterol 2000; 19: 109-11.
3. Babu V, Kate V, Anantha krishnan
N. Role of eradication of Cag A
Helicobacter pylori in non ulcer
dyspepsia. Trop Gastroenterol
2005; 26:211-4.
4. Schlemper RJ, van der Werf SD,
Vandenbroucke JP, Biemond I,
in a Dutch working population
and Helicobacter pylori. Ulcer
history as an explanation of an
apparent association. Arch Intern
Med 1995; 155: 82-7.
5. Cahuayme L, Berrios J, Reca-
varren S, Huerta MJ, Bussalleu A.
Famotidine versus placebo in non
ulcer dyspepsia treatment. Rev
Gastroenterol Peru 2000; 30: 213-
28.
6. Huang JQ, Hunt RH. Eradication
of Helicobacter pylori infection in
the management of patients with
dyspepsia. Yale J Biol Med 1998;
71: 125-33.
7. Joshi A, Gupta SD, Ahuja V,
Sharma MP. Helicobacter pylori
infection in non ulcer dyspepsia.
Trop Gastroenterol 2001; 22:
194-6.
8. Veldhuyzen van Zanten SJ,
Sherman PM. Helicobacter
pylori infection as a cause of
gastritis, duodenal ulcer, gastric
cancer and non ulcer dyspepsia: a
systematic overview. CMAJ
1994; 150: 17-85.

23
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

9. Talley NJ, Silverstein MD, Agreus
L, Nyren O, Sonnenberg A,
Holtmann G. AGA technical
review: evaluation of dyspepsia.
American Gastroenterological
Association. Gastroenterol 1998;
114: 582-95.
10. Clark ML, Silk DB. Gastro-
intestinal disease. In: Kumar P,
Clark M, editors. Clinical
Medicine. 5th ed. London: WB
Saunders, 2002. p. 271-2.
11. Schlemper RJ, van der Werf SD,
B i e m o n d I , L a m e r s C B.
pylori in Japanese employees with
and without ulcer history. J
Gastroenterol Hepatol 1995; 10:
633-8.
12. Moyayyedi P, Axon ATR. Is there
a rationale for eradication of
helicobacter pylori? Cost-benefit:
the case for. Br Med Bull 1998; 54:
243-50.
13. Talley NJ, Vakil N, Ballard II ED,
Fennerty MB. Absence of benefit
of eradicating helicobacter pylori
in patients with non ulcer
dyspepsia. N Engl J Med 1999;
14. Bruley des Varannes S, Flejou JF,
Colin R, Zaim M, Meunie A.
Helicobacter pylori eradication
in non-ulcer dyspepsia: a
randomized, double-blind,
placebo-controlled study with a
12-month follow-up.
Gastroenterol 2000; 118: 468-71.
15. McColl K, Murray L, EI-Omar
E, Dickson A, El-Nujumi A, Wiz
A et al. Symptomatic benefit
from eradicating Helicobacter
pylori infection patients with non
ulcer dyspepsia. N Engl J Med

k
Dyspepsia and helicobacter 341-5. 1998; 339: 1869-74.

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Answer Picture Quiz

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The lesion in the tip of her nose was suspect for a carcinoma of the skin. A punch biopsy was performed under
local anesthesia. The pathology revealed infiltrative basal cell carcinoma. She was referred to plastic surgery to
definitive excision of neoplastic tissue.
cu
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24
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

Original Articles

Effects of Intake of Nitrate, Nitrite and Isosorbid Dinitrate

(ISDN) on Plasma Nitrate/Nitrite Contents in Rabbits
Muhammad Abdul Rehman, Mohammad Ashraf and Muhammad Suleman Khan

Background: The objective of the present study was to demonstrate the changes in plasma
levels of nitrate and nitrite in rabbits after oral (intragastric) administration of inorganic nitrate
(KNO3), inorganic nitrite (NaNO2) and organic nitrate (isosorbide dinitrate, ISDN).
Material and Methods: Twenty eight rabbits were divided into four groups (7 in each group) and
various doses of these solutions were given via intragastric route. Group-I (control) was given 6

k
ml distilled water. Group-II (nitrate) was given 500 mg nitrate, group-III (nitrite) 50 mg nitrite and

.p
group-IV 20 mg ISDN per kg body weight per day. The experiment was conducted for 12 weeks
and blood samples were taken at regular intervals. Plasma nitrate and nitrite levels were

pio
determined as stable metabolites of nitric oxide (NO) formation.
Results: Results indicate 28.2±3.3 µmoles/dL nitrate and 21.24±2.8 µmoles/dL nitrite, a
nitrite/nitrate ratio of 0.75 in all 28 rabbits at zero-day. After 1-day of nitrate intake, an 8.1-fold
increase in nitrate content (from 29.3±3.32 to 238.5±48.9 µmoles/dL, p<0.05) and 2.3-fold

la
increase in nitrite content (from 20.67±2.88 to 48.75±6.36 µmoles/dL) in group-II animals was

cu
seen. No significant change was observed in their levels in group-III and IV animals during this
period. On 2-day, plasma nitrate content decreased to 165.4±18.3 µmoles/dL and nitrite contents
dropped to normal in group-II animals. After 1-week, nitrate content in group-II also decreased to
Es
normal values. However, nitrite content in group-III animals increased 3-fold (from 18.43±3.06 to
57±4.96 µmoles/dL) during 1-week with no increase in nitrate content. No sudden rise or fall in
contents was observed for 12-weeks in all the groups.
@

Conclusion: The results demonstrate that the plasma nitrate and nitrite contents are not
changed significantly in all four groups in 12-weeks duration (except the initial rise in week-1) and
animals may possess some adaptive metabolic mechanisms to normalize these levels.
ts

Key words: Nitrate, Nitrite, Nitric oxide, Rabbits

gh

Introduction 8
some types of cancers. This nitrite is also a source of
Nitric oxide is an important mediator in nervous, 9
NO. L-arginine, another source of NO, is
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immune and cardiovascular systems. Its involvement
has been demonstrated in normal as well as
1,2
pathophysiological states. NO is synthesized by a
py
immediately converted into various stable products
like nitrite and nitrate.10 Because of the gaseous
nature, determination of NO itself is difficult and the

family of three isoenzymes called nitric oxide estimations of plasma nitrate and nitrite are used as a
synthases (NOS).3 Various molecules act as NO measure of the formation of NO radical.11
donors which include nitrate, nitrite, isosorbide
Co

To study the toxic effects of nitrate, Mascher and

dinitrate (ISDN), L-arginine, nitroglycerin etc.
Nitrates and nitrites are ingested with food and water
whilst their endogenous production by intestinal and
oral microbial flora is also reported.4 It has been
estimated that 60-70% of the total oral intake of
nitrate is excreted in urine in the first 24 hours and
remaining is stored in various tissues or re-enters at
5
various points in the gastrointestinal tract. About
25% of ingested nitrate is excreted in saliva where it is
partially reduced to nitrite by oral micro flora. Nitrite
can react with hemoglobin to form methemoglobin
7
or secondary and tertiary amines to form N-nitroso
compounds which are involved in the aetiology of
Marth (1993) gave calcium nitrate to mice over a dose
of zero (control), 100 and 1000 mg nitrate in drinking
water over a period of 18 months. Liver and kidney
functions showed no statistical differences with the
control group and significant differences were found
between individual groups in their body weights, urea
and ammonium levels.12 Similarly, in another study,
rats were given sodium nitrite at 100 mg/kg body
weight in drinking water daily during their entire life
span over three generations and no evidence of
chronic toxicity, carcinogenicity or teratogenicity was
observed.13 Mulsch et al (1995) treated rabbits with
different NO donors like nitroglycerine (NTG, 0.5

25
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010
Mg/kg), ISDN (10 mg/kg) etc. NO formation was
higher in organs like liver, kidney, heart, lungs, spleen
and low levels were detected in blood vessels. ISDN
and NTG formed NO preferentially in the
mesenteric bed.14
These individual studies in different animals and
different laboratories partially demonstrate the
plasma nitrate and nitrite levels and some associated
biochemical or pathological parameters during the
studied period. A comparative study for the
determination of plasma nitrate/nitrite levels with
oral intake (by passing intragastric tube) of inorganic
nitrate, inorganic nitrite and organic nitrate has not
been carried out earlier. This paper demonstrates the
changes in plasma nitrate and nitrite contents in
rabbits in response to these NO donors during a 12-
weeks duration.
Material and Methods
Twenty eight rabbits, 4 males, one in each group and
24 females, 6 in each group (0.85-1.520 kg with a
mean of 1.55 kg/rabbit) of local race were purchased
from the local market and were kept in the animal
Es
house in controlled conditions (23oC; 12h light and
12h dark cycle).
The animals received standard rabbit diet (dry food)
and water ad libitum. Before the start of experiment,
@
animals were acclimatized for one week. Water and
food given to animals was lacking in nitrate and
nitrite.
ts
Rabbits were divided into four groups (7 in each
group). Group-I (control) was given orally 6 ml
gh
distilled water/kg body weight/day. Group-II
(nitrate) was given 500 mg nitrate (KNO3), group III
Ri
(nitrite) 50 mg nitrite (NaNO2) and group-IV 20 mg
organic nitrate (ISDN) per kg body weight per day.
The experiment was conducted for 12 weeks and
py
blood samples from internal jugular vein were taken
at zero-day and after 1, 2 day and then 1 to 12 weeks.
Co
Rabbits were weighed before taking blood samples to
observe changes in their weights. Plasma was
obtained from heparinized blood and stored at -20 C
o given diet had no effect or contribution in the total
until used for analyses.
Plasma nitrate levels were determined by
standardized Cd-Zn reduction column method.
15,16
Briefly, Zn pellets (10g) were mixed with 100-200 ml
saturated solution of cadmium sulphate for 2-3
hours. Cadmium grains deposited on Zn pellets as
sponges were separated, washed with distilled water
(100 ml), washed twice with 0.5N HCl (100 ml x 2) for
30 minutes each followed by washing with water (100
26
ml x 2) and finally with elution buffer (50 mg
ammonium chloride and 20 g sodium chloride in 1L
water; pH 9.6-9.7 was adjusted with ammonium
hydroxide). Cd-Zn grains were packed upto 1-1.5 ml
in a 5ml disposable syringe column. 100 µl plasma was
loaded onto the column.
Elution was carried out with elution buffer, collecting
3 ml eluate in each of the 3 test tubes. 2 ml coupling
reagent (1% Sulphanilamide in 3M HCl and 0.02% N-
ethylenediamine HCl in water in 1:1 ratio) was added
to each of the test tube. Absorbance was read at 540
nm after 20 minutes. Nitrite concentration was
measured from the standard curve. Results were
k
expressed in terms of µmoles/dL plasma.
.p
For the regeneration of columns, pre-used columns
were placed overnight in 0.5N HCl. The next day,
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columns were washed with water, 0.5N HCl, water,
and buffer solution, respectively, as mentioned earlier.
These columns proved as efficient as the fresh
la
columns (80-95% efficiency).
For the determination of plasma nitrite levels, 200 µl
cu
plasma was added to distilled water to make volume
of 3ml followed by the addition of 2ml coupling
reagent. After 20 minutes nitrite contents were
measured at 540 nm.
In some sets of experiments where nitrite levels were
below the detection limit, 10 nmoles nitrite was added
to 100 l plasma as an external standard and assay
performed as mentioned above. Statistical analysis
was carried out by SPSS package using ANOVA test.
Results
1. Control Group
In control group-I rabbits (n=7), mean plasma nitrate
and nitrite contents on zero-day were 24.43±1.38 and
19.43±2.19µmoles/dL respectively. With statistically
insignificant changes (p>0.05) on 12-week, nitrate
and nitrite contents were 21.33±2.85 and 18.17±3.12
µmoles/dL respectively, exhibiting 46% nitrite
contents (Fig- 1 & 2). These results show that the
nitrate+nitrite (NOx) contents (Fig-3) in plasma and
nitrite/nitrate ratio remained consistent, that is, 0.88
and 0.87 (Fig- 4).
2. Effects of Potassium Nitrate
In group-II, plasma nitrate and nitrite contents on
zero-day were 29.33±3.32 and 20.67±2.88
µmoles/dL, respectively. After day-1 of oral intake of
first dose of first dose of nitrate, nitrate and nitrite
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

1600
350 Group-I
Group-II
300 Group-III
Group-IV
250
moles/dL
1400

200

Weight (G)
150
100 1200

50
0
0 0.15 0.3 1 1000
0 2 4 6 8 10 12
W eek
Weeks

k
.p
Fig-1: Changes in plasma nitrate contents. Fig-4: Nitrate/nitrite ratio in plasma.

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80
2.5 I II
70 III IV
2

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N itr ite /N itr a te r a tio
60

1.5

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50
% Nitrite

40 1
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30
0.5
20

0
10
0 5 10 15
@

0
0 2 4 6 8 10 12 14 Weeks
Weeks
ts

Fig-5: Change in body weight of rabbits during the

Fig-2: Changes in percent nitrite levels in plasma. studied period of 12- weeks Values are mean±s.e.m.
gh

Percent nitrite indicates the percent nitrite in the total (n=7 )Rabbits were given distilled water (group-I),
nitrate+nitrite contents (Nox). potassium nitrate (group-II), sodium nitrite (group-
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III) and ISDN (group-IV) by passing through

intragastric tube. Blood was drawn at specified time
and plasma was used for the determination of nitrate
py

240
and nitrite. ANOVA was applied to the data. Values
200 (means.e.m.) are significantly different when
*p<0.05.
Co
Total contents ( moles/dL)

160
contents jumped upto 238.5±48.9 and 48.75±6.36
120
µmoles/dL, respectively (n=4, p<0.01), with just
I
III
II
IV
18.88% nitrite contents (a nitrite/nitrate ratio of 0.20,
80 p<0.05) (Figure 1 & 2). This indicated an 8.1-fold
increase in nitrate and 2.3-fold increase in nitrite
40
contents in these animals. On day-2, nitrate contents
0 decreased to 165.4±18.3 µmoles/dL (p<0.01) and
0 2 4 6 8 10 12 nitrite contents dropped to normal values
W eek s
(21.2±2.65µmoles/dL). No significant changes in the
nitrate/nitrite contents were observed in these
Fig-3: Changes in plasma total nitrate and nitrite animals till week-12 (p>0.05). These results indicate
contents (Nox). that oral intake of potassium nitrate brings about

27
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010
Sudden increase in plasma nitrate and nitrite contents
which reach basal values soon after a week.
3. Effects of Sodium Nitrite
Plasma nitrate and nitrite contents in group-III
animals on zero day were 32.17±2.76 and 21.17±2.80
µ moles/dL (n=7), respectively. These values
indicated 38.75% plasma nitrite contents (a
nitrite/nitrate ratio of 0.658). After day-1 of oral
intake of sodium nitrite, nitrate and nitrite contents
remained unchanged though %nitrite increased from
38.75 to 44.21% (p>0.05). On day-2, a decrease in
nitrate contents from 32±4.44 to 19.43±3.61
µmoles/dL (p<0.05) was observed associated with a
slight decrease in nitrite contents (Figure 1 & 2). NOx
value (Figure 3) decreased from 56.3±4.81 to
37.86±6.46 µmoles/dL (p<0.05). A nitrite/nitrate
ratio (Figure 4) of 0.948 (p>0.05) was observed.
These results indicate that after 48 hours, nitrate and
nitrite contents are almost 50% in plasma though
there was a decrease in total contents. When these
values were monitored after 1-week, nitrate and
nitrite contents were 26.29±3.96 and 57±4.96
µmoles/dL (p<0.05), respectively, with a nitrite
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content of 68.6% and nitrite/nitrate ratio of 2.168
(p<0.05). In further weeks, a slow decrease in total
contents as well as in nitrite contents was observed
@
and a nitrite/nitrate ratio was found 1.248 (2-week),
1.03 (4-week), 0.938 (10-week) and 0.637 (12-week).
NOx contents reached less than the basal values.
ts
4. Effects of Isosorbide Dinitrate
gh
In group-IV animals, basal nitrate and nitrite contents
were 26.86±3.27 and 23.71±1.92 µmoles/dL, (n=7)
Ri
with nitrite/nitrate ratio of 0.883. After 1-day, little
decrease in NOx (from 50.57±4.3 to 43.29±5.38
µmoles/dL) was observed with nitrite/nitrate ratio
py
of 0.757 (p>0.05) (Figure 3 & 4). On 2-day, this ratio
increased to 1.049 (p<0.05) and remained at this
higher level till week-4 with insignificant changes in
Co
total nitrate and nitrite contents. However, on 10-
week and 12-week, basal values of nitrite/nitrate ratio
of 0.87-0.89 was reached. These results indicate that
ISDN action is delayed till 2-day or 1-week and lasts
longer (upto 4-week) compared to other NO donors.
Further, there were no recorded variations in plasma
nitrate and nitrite contents.
5. Change in Body Weight of Rabbits
Change in body weight of animals was monitored
each week for 12-weeks and results are shown in
Figure 5. A consistent increase in weight of animals is
depicted in all four groups; group-II animals had
28
comparatively a higher weight than the rest of the
animals.
Discussion
Plasma nitrate and nitrite contents determinations are
11
used for the synthesis of NO. Some workers prefer
to measure nitrate as the major metabolite of NO in
blood,17 others report only nitrite contents in blood.18
The present paper reports the changes in plasma
nitrate, nitrite, nitrate+nitrite (NOx), %nitrite of total
and nitrite/nitrate ratio.
o
Plasma samples were kept at -20 C and used within a
year for determination since it is already documented
k
that nitrate and nitrite are stable in plasma for 1-year.11
.p
Cd-Zn column method was standardized for the
reduction of nitrate into nitrite and determination by
pio
Griess reaction with or without added nitrite as an
external marker where the plasma nitrite levels were
below the detection limit. Using human plasma, with
la
or without added nitrate as an external marker, the
column showed 80-95% efficiency even after
cu
regeneration (data not included), 87% nitrate and
11
nitrite recovery is also documented. In other sets of
experiments, plasma samples were deproteinized
with 2% sulphosalicylic acid but no effect on the
estimation of nitrate or nitrite was found (data not
shown). Therefore, all values were taken from
deproteinized plasma.
In the present studies, nitrate and nitrite contents
have been expressed in terms of nitrate, nitrite, NOx,
%nitrite and nitrite/nitrate ratio. The presence of
plasma nitrate and nitrite (24.43±1.38 and
19.43±2.19 µmoles/dL, respectively) in control
group exhibits NOx of 43.86±3 µmoles/dL or
43.80% nitrite contents. This makes nitrite/nitrate
ratio of 0.795. On day-1 of oral intake of nitrate,
significant changes in nitrate, nitrite and NOx
contents have been seen in group II animals
compared with other groups (all values are p<0.05).
On day-2, nitrate and NOx contents were
significantly different (p<0.05) in group II animals.
This initial increase in nitrate/nitrite plasma pool
indicates excess of NO formed during the said
period. This study coincides with the findings of
19
Cortas and Wakid (1991) wherein they gave 470
µmoles/kg sodium nitrate (equivalent to 292 mg
nitrate) orally to animals and peak levels of plasma
nitrate (183 µmoles/dL) reached in 40 minutes.
Plasma nitrite contents were not detected in their
experiments. In the present study, animals were given
500 mg nitrate/kg body weight and nitrate levels
reached 238.5±48.9 µmoles/dL in 24 hours. Initial
rise in plasma nitrate contents within day-1 has also
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

Been reported after oral intake of ammonium nitrate
20
or intravenous sodium nitrate.
In group II, these changes disappeared after a week
but appeared in nitrite-fed animals, group III,
wherein nitrite and NOx contents increased
significantly (p<0.05) compared with the other
groups including control. These differences persisted
in group III on week-2 (p<0.05). In group IV, the
increase in nitrate contents was delayed till week-4,
when the nitrate and total NOx contents were higher
than the other groups (p<0.05) while nitrite contents
remained indifferent (p>0.05). No further statistically
different readings were recorded till week-12 which
animals. In the present study, nitrate or nitrites were
given to rabbits according to their body weight via
intragastric tube. The present study therefore reveals
the effects of these chemicals in animals kept in the
similar conditions in a more quantitative way, given
the same food and the environment with different
NO donors. Results reveal that changes in plasma
nitrate and nitrite contents occur till the first week,
later the levels of these anions remain consistently
constant. This suggests that some form of NO
tolerance mechanism is operative to maintain total
nitrate and nitrite contents in plasma. However, it
does not indicate that how much nitrate or nitrite is

k
indicates that ISDN intake causes little change in the present in tissues and how much damage has been

.p
plasma nitrate, nitrite or NOx contents. done to the body systems/organs when their plasma
Moshage et al (1995)11 found no relationship in the levels reach peak levels.

pio
plasma nitrite or nitrate contents as measured by
%nitrite of NOx which varied from 3.9-88% in Conclusion
plasma samples. They found that in whole blood, Plasma nitrate and nitrite levels did not change

la
>95% nitrite is converted into nitrite within an hour significantly in all four groups in 12-weeks duration
and suggested that nitrite determination alone was (except the initial rise in week-1) probably because the

cu
meaningless. The present study reveals that the NOx animals possess some adaptive metabolic
contents and amount of nitrate are good indicators mechanisms which normalize these levels.
and results should be expressed in terms of these
Es
configures. Department of Pathology
In the previous studies by Guy (1998),13 rats were Sheikh Zayed Hospital, Rahimyar Khan
allowed to drink nitrite containing water for the entire theesculapio@hotmail.com
@

life and no carcinogenic effects were observed. This www.sims.edu.pk/esculapio.html

study did not tell how much nitrite was taken in by the
ts

References
gh

1 Bredt DS, Snyder SH. Nitric nitrite in saliva. Oncology 1980; Jansen PL. Nitrite and nitrate
oxide: A physiologic messenger 37: 227-31. determination in plasma. A
Ri

molecule. Ann Rev Biochem 7. Kross BC, Ayebo AD, Fuortes LJ. critical evaluation. Clin Chem
1994; 63: 175-95. Methemoglobinemia. Nitrate 1995; 41: 892-6.
2. Davis KL, Martin E, Tarko IV, toxicity in rural America. Am 12. Mascher F, Marth E. Metabolism
py

Murad F. Novel effects of nitric Family Phys 1992; 46: 183-8. and effect of nitrates. Central
oxide. Ann Rev Pharmacol 8. Steindorf K, Schlehofer B, Eur J Publ Health 1993; 1: 49-52.
Toxicol 2001; 41: 203-36. Becher H, Horing G, Wahrendorf 13. Guy R. Nitrites. In
Co

3. Knowles R.G, Moncada S. Nitric
oxide synthases in mammals.
Biochem J 1994; 298: 249-58.
4. Walters CL. The exposure of
humans to nitrite. Oncology.
1980; 37: 289-96.
5. Witter JP, Balish E, Gatley SJ.
Distribution of N12 from
labeled nitrate and nitrite in
germfree and conventional
f l o ra -ra ts. A p p l E nv i ro n
Microbiol 1979; 38: 870-8.
6. Eisenbrand G, Spiegelhalder B,
Preussmann R. Nitrate and
J. Nitrate in drinking water. A case
control study on primary brain
tumors with an embedded drink
water survey in Germany. Int J
Epidemiol 1994; 23: 451-7.
9. McKnight GM, Duncan CW,
Leifert C, Golden MH. Dietary
nitrate in man: friend or foe? Br J
Nutr 1999; 81: 349-58.
10. Boger RH, Bode-Boger SM. The
clinical pharmacology of L-
arginine. Ann Rev Pharmacol
Toxicol 2001; 41: 79-99.
11. Moshage H, Kok B, Huizenga JR,
'Encyclopedia of Toxicology
(Ed., P. Wexler), Academic Press,
1998; 420-421 San Diego, USA.
14. Mulsch A, Bara A, Mordvintcev
P, Vanin A, Busse R. Specificity
of different organic nitrates to
elicit NO formation in rabbit
vascular tissues and organs in
vivo. Br J Pharmacol 1995;116:
2743-9.
15. AOAC. Association of Official
Methods of Analysis. 24th
edition., 1984; Virginia.
16. Ashraf M, Nasim FH, Ahmad E,

29
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

Unis M, Rehman MA, Akhtar S.
Naz N et al. Determination of
serum nitrate and nitrite content
by Cd-Zn reduction method. J
Chem Soc Pak 2006;28(5):501-4.
17. Evans T, Carpenter A, Silva A,
Cohen J. Inhibition of nitric
oxide synthase in experimental
gram-negative sepsis. J Infect
Dis 1994; 169: 343-9.
18. Horton RA, Ceppi ED, Knowles
RG, Titheradge MA. Inhibition of
hepatic gluconeogenesis by nitric
oxide: a comparison with
endotoxin shock. Biochem J 1994;
299: 735-9.
19. Cortas NK,Wakid NW. Pharma-
cokinetic aspects of inorganic
nitrate ing estion in man.
Pharmacol Toxicol 1991;68:192-
5.
20. Ellen G, Schuller PL, Bruijns E,
Froeling PG, Baodenhuijsen
HU. Volatile N-nitrosamines,
nitrate and nitrite in urine and
saliva of healthy volunteers after
administration of large amounts
of nitrate. IARC Sci Publ 1982;
41: 365-78.

Medical News

k
Changes in HbA1- C Units

.p
International changes have been announced for the units for reporting HbA1c results. There was an agreement
that it was necessary for glycated haemoglobin to be standardized to the IFCC Reference Measurement

pio
procedure but there was a concern regarding the introduction of a dual reporting system including new units with
which patients and clinicians were unfamiliar. It was felt that there was a real risk that patient control would
deteriorate due to lack of understanding, particularly with an unheralded change to IFCC units. It was agreed that

la
dual reporting would be necessary for a considerable period until both unitary systems were understood.
However, this should only occur after extensive educational programmes had been performed. Moreover, it must

cu
be ensured that these programmes will reach all the appropriate health-care professionals as well as patients.For a
period of about two years, results will be reported in both old and new units.
Es
Comparative Values
DCCT- HbA1c IFCC-HbA1C
@

(%) (mmol/mol)
6.0 42
6.5 48
ts

7.0 53
7.5 59
gh

8.0 64
9.0 75
Ri
py
Co

30
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

Original Article

Efficacy of Ultrasound-guided Fine Needle Aspiration Cytology (FNAC)

of Abdominal, Pelvic and Retroperitoneal Lymph Nodes
Fareeha Asghar and Sabiha Riaz

Objective: To evaluate the efficacy of ultrasound-guided FNAC of abdominal, pelvic and retro-
peritoneal lymph nodes. Study Design: Cross sectional analytical (comparative study).Setting:
Department of Histopathology, Sheikh Zayed Hospital, Lahore. Study period: One year.
Material & Methods: A total of 36 lymph nodes including 12 abdominal, 10 pelvic and 14 retro-
peritoneal were submitted to FNAC from January 2001 to December 2001. Adequate aspirates

k
were obtained in all these cases. The smears were stained with Haematoxylin and Eosin (H & E),

.p
papanicolaou staining (PAP) and May-Grunwald Giemsa stain (MCG). Results of FNAC were
categorized as malignant (group-I) and non-neoplastic/ inflammatory (group-II). Excision

pio
biopsies from the same 36 cases were also obtained, processed and stained with routine H & E
staining. Histology was taken as the gold standard.
Results: On histological examination 24 of the total 36 cases were categorized as malignant,

la
and 12 as non-neoplastic/ inflammatory lesions. FNAC picked up 20 cases as malignant with 4
false negative diagnoses, including 2 cases of Hodgkin's lymphoma and 2 cases of non-Hodgkins

cu
lymphoma. No false positive diagnosis was obtained. The most common malignancy was diffuse
non-Hodgkin's lymphoma, while granulomatous lymphadenitis was the commonest inflammatory
lesion. Malignant tumours revealed 83.3% sensitivity and 88.89% diagnostic accuracy, while
Es
non-neoplastic/ inflammatory lesions showed a 100% sensitivity and diagnostic accuracy.
Conclusion: Majority of the malignant tumours can be categorized on FNAC with a high degree
of accuracy while lymphomas, specially of the mixed large and small cell type and Hodgkin's
@

lymphomas pose maximum diagnostic problems. Non-neoplastic/ inflammatory lesions can be

correctly diagnosed on FNAC.
Keywords: FNAC, malignant, non-neoplastic.
ts
gh

Introduction The effect of FNAC on lymph nodes is minimal &

Fine needle aspiration cytology (FNAC) has become rarely interferes with subsequent histological
Ri

a well accepted procedure for diagnosis and interpretation.11,12

management of breast masses, cold nodules of
thyroid and lymphodenopathy all over the world
1-3
Material and Methods
py

including our country.4-6 It is rapid, safe, well A total of 36 lymph nodes, including 12 abdominal,
tolerated, easily repeatable, accurate and efficacious 10 pelvic and 14 retro-peritoneal lymph nodes were
for deep nodes, as small as 1 cm in diameter, in subjected to FNAC and excision biopsies from the
Co

abdomen, pelvis and retro-peritoneum.7 It not only
offers a tissue diagnosis, but also serves as a
preliminary screening procedure for a number of
clinical considerations e.g., tuberculosis, lymphoma,
leukaemia, metastatic diseases, fibrosis and
lymphadenopathy (NOS).8,9 Its major role is in
documentation of whether the lymph node is benign
or malignant and also helps in diagnosis of infectious
disease, second malignancy and recurrent disease in
already diagnosed lymphoma patients. The
identification of progression from a known low grade
lymphoma to a high grade lesion is another
advantageous use of FNAC of lymph nodes.10
same 36 cases were then obtained, without any
discrimination of age and gender. The study period
extended from January 2001 to December 2001. A
clinical proforma was filled in each case, to document
the particulars of the patient, clinical and radiological
details, including the size, site and extent of the mass.
Aspirates were then obtained with a 21 or 22 guage
needle attached with a 10 ml syringe. When adequate
material appeared in the hub, the needle was
withdrawn after releasing the suction pressure and 5
smears prepared including a clot, after fixation in 10%
neutral buffered formalin. Two of the smears were air
dried for Giemsa staining, 1 smear each for

31
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

papanicolaou (PAP) and Haematoxylin and Eosin (H
& E) staining after wet fixation in 95% ethyl alcohol.
After screening the results were categorized into 2
groups, malignant (group-I) (including primary and
metastatic tumours) and non-neoplastic/
inflammatory lesions (group-II). Biopsy specimens
from all these cases were also received and fixed in
10% formalin. These specimens were thoroughly
examined by naked eye and representative sections
were taken which were processed in an automatic
tissue processor (Auto processor, model 2LE,
Shandon Germany). After processing the tissue was
embedded and paraffin blocks were made. Section
inflammatory lesions. These 24 malignant cases
included 12 non-Hodgkin's lymphoma, 2 Hodgkin's
lymphoma, 6 metastatic adenocarcinoma and 2 cases
each of malignant round cell tumours and
undifferentiated malignant tumours. Out of 12 cases
of non-Hodgkin lymphoma, 10 were correctly
diagnosed on FNAC. The remaining 2 cases
diagnosed as mixed small and large cell lymphomas
on histological examination were reported as reactive
hyperplasia (false negative) on FNAC. Both the cases
of Hodgkin’s lymphoma were mis-diagnosed as
reactive hyperplasia (false negative) on FNAC. All the
6 cases of metastatic adenocarcinoma, 2 cases each of

k
cutting was done by rotary microtome (Model RM malignant round cell tumours and undifferentiated

.p
2125, Leica, Germany). H & E staining was done in malignant tumours were correctly diagnosed on
each case. Results of FNAC and histological FNAC. All the 12 non-neoplastic/ inflammatory

pio
diagnosis were then correlated. Histology was taken lesions were correctly diagnosed on FNAC, including
as gold standard. The statistical analysis was done. 8 cases of granulomatous lymphadenitis and 2 cases
The diagnostic efficacy/ accuracy was ascertained by each of reactive hyperplasia and non-specific abscess

la
calculating the sensitivity, specificity, positive (Table-I). No false positive diagnosis was made.
predictive values and negative predictive values, in Diagnostic accuracy of FNAC was calculated taking

cu
accordance with the methods employed by Galen and histological diagnosis as the gold standard. The
13
Gambino. statistical analysis showed 83.33% sensitivity and
88.89% diagnostic accuracy with 100% specificity
Es
Results
During the period from January 2001 to December Table-2: Indices indicating diagnostic reliability of
2001, a total of 36 patients of abdominal, pelvic and ultrasound guided FNAC of malignant tumours of
@

retro-peritoneal lymph nodes underwent FNAC and lymph nodes.

tissue biopsies. All these patients had adequate Malignant Group-I) Non-Neoplastic/inflammatory
aspirates. Cytological examination showed 24 cases lesions (group-II)
ts

(66.67%) to be malignant (group-I) and 12 cases Specificity 100% 100%

(33.33%) to be non-neoplastic/ inflammatory lesions
gh

Sensitivity 83.33% 100%

(group-II). Twenty four of the total 36 cases were
reported as malignant and 12 as non-neoplastic/ Diagnostic accuracy 88.89% 100%
Ri

Table-1: Comparison of FNAC with histology (n=36)

Cytological Histological
py

Lesions False Negative

Diagnosis Diagnosis
Malignant Group-1)
Co

Non Hodgkin’s Lymphoma 10 12 2 (Reactive Hyperplasia)

Hodgkin’s Lymphoma 0 02 2 (Reactive hyperplasia)
Metastatic adenocarcinoma 06 06 _

Undifferentiated malignant tumour 02 02 _

Malignant round cell tumour 02 02 _

Non Neoplastic /Inflammatory Lesions (Group-II)

Tuberculous lymphadenitis 08 08 _

Reactive hyperplasia 02 02 _

Non-specific abscess 02 02 _

Total 32 36 04

32
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010
and positive predictive value for malignant tumours,
while for non-neoplastic/ inflammatory lesions a
100% sensitivity, specificity, diagnostic accuracy,
positive and negative predictive value was achieved
(Table-II).
Discussion
On FNAC, a definite diagnosis was made in 32
(88.89%) of patients, with 4 false negative diagnoses
for malignant tumours, but no false positive diagnosis
was made. FNAC can usually diagnose high grade
non-Hodgkins lymphomas and most cases of
14
Hodgkin's lymphomas. It can also distinguish
between low grade and high grade non-Hodgkin’s
lymphomas.15,16
The malignant tumours in our study comprised 12
cases of non-Hodgkin's lymphomas, 10 of which
were of large cell type, all of which were correctly
diagnosed. These 10 cases included 3 cases in which a
differential diagnosis between a large cell
undifferentiated carcinoma and malignant melanoma
was also given for which an excision biopsy was
suggested and to aid diagnosis, immunohisto-
Es
chemistry was recommended.
Cytologic diagnosis of malignant lymphoma can be
made and it has been indicated by Usten et al that this
can be achieved in 50-75% of the cases, the accuracy
@
being greatest in high grade lymphomas.17 Diagnosis
of low grade lymphomas can sometimes be difficult
particularly for those that have a conspicuous non-
ts
malignant component (false negative).14 Also there
may be a diagnostic gray zone between low and
gh
intermediate grade lymphomas, because architectural
growth pattern usually cannot be assessed
Ri
cytologically.18-20 In our series two cases of mixed large
and small cell lymphoma were mis-diagnosed as
reactive hyperplasia (false negative) on FNAC which
py
were cytologically difficult to distinguish from benign
reactive conditions. Although large cell lymphomas
Co
are typically easy to recognize, mixed large and small
cell lymphomas and well differentiated lymphocytic
lymphomas can be difficult to distinguish from
benign reactive conditions. Furthermore, non-
haematolymphoid malignancies such as small
undifferentiated carcinoma and malignant melanoma
can be misinterpreted as lymphoma.9 Two cases
reported as reactive hyperplasia on FNAC were
found to be Hodgkin's lymphoma (nodular sclerosis)
on histology. This false negative diagnosis was
probably because of poor yield due to background
fibrosis of the lymph node, thus making it difficult to
diagnose. Also no definite Reed-Sternberg cells were
identified on FNAC. Classic Reed-Sternberg cells are
33
required for the primary diagnosis of Hodgkin's
lymphoma and they must be found in the
characteristic background.
21,22
The background of
Hodgkin's lymphoma tends to be polymorphic,
similar to benign hyperplasia.
All the 6 cases of metastatic adenocarcinomas were
correctly diagnosed on FNAC. Two cases were
reported as undifferentiated malignant tumours. The
differentials of these 2 cases included large cell
lymphoma, anaplastic carcinoma and malignant
melanoma on FNAC. The diagnosis of malignant
melanoma was confirmed on histology and tumour
markers. The remaining 2 cases were reported as
k
malignant round cell tumours, with possibilities of
.p
lymphoma, Rhabdo-myosarcoma, Ewings sarcoma/
PNET and neuroblastoma on FNAC, while a
pio
histological diagnosis of lymphoma was given, which
was also confirmed by tumour markers.
FNAC is useful for the documentation of metastatic
la
carcinoma, diagnosis of recurrent lymphoma, for
staging the extent of disease, and for monitoring the
cu
treatment in lymph nodes with a significantly low risk
of complications, including tumour recurrence, as
compared to excisional biopsy.23,24 More than 90% of
lymph node metastases are diagnosed by an initial
23
aspiration and can also give clues regarding the
nature and origin of the primary tumour.24 The
sensitivity and diagnostic accuracy for malignant
tumours was 88.33% and 88.89% respectively.
Diagnostic sensitivity was generally found to be
significantly lower for lymphomas than for metastatic
15
malignancy, as also seen in our study. In general there
is a good correlation between the subclassification of
lymphoma by FNAC cytology and that obtained by
histologic examination, and cases that are difficult to
sub-classify by FNAC cytology are also difficult to
sub-classify by examination of biopsy specimens.10
Although the diagnostic sensitivity of metastatic and
recurring malignancy varies, it is usually above 95%.26-
29
Diagnostic specificity on the other hand is high.
False positive diagnosis are rare,30-31 as also seen in our
study. Our results are favorably comparable with
9
other studies in diagnosing lymph node neoplasms. A
100% correct cytologic diagnosis was achieved for all
the non-neoplastic/ inflammatory lesions, including
8 cases of granulomatous lymphadenitis, all of which
were due to tuberculosis, confirmed on Ziehl-
Neelson staining and 2 cases each of reactive
hyperplasia and non-specific abscess (Table-I). A
100% sensitivity, specificity, and diagnostic accuracy
was achieved for non-neoplastic/ inflammatory
lesions.
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

Relatively high diagnostic accuracy achieved in our
study can be attributed to adequate/ diagnostic
material, blood clot, processing and examination,
thorough screening of the smears, with relevant
clinical and radiological information. Also majority
of non-Hodgkin's lymphomas were large cell type,
which are relatively easier to recognize on cytology.
Conclusion
Both tuberculosis and lymphomas are common in
our patient population. FNAC is reliably safe in the
diagnosis of tuberculosis lymphadenitis and in
differentiating it from lymphoma and other
the tissue architecture is not available. However
special techniques like conventional special stains,
electron microscopy, immunochemistry, cytogenetics
and molecular methods when applied can increase the
diagnostic accuracy. In patients with a negative
cytologic finding, a search for a definite diagnosis
should be pursued by a combined cytohistological
correlation and ancillary technique. FNAC is simple,
safe, and cost effective procedure, and should be
considered as the first line of investigation for
lymphadenopathy, specially in our country, with
limited resources in secondary care hospitals.

k
malignancies. The diagnosis of mixed large and small

.p
cell lymphomas, well differentiated lymphomas and Department of Histopathology
Hodgkin’s lymphomas can pose diagnostic problems SIMS/Services Hospital, Lahore

pio
on FNAC because of the overlapping cytological theesculapio@hotmail.com
features with benign reactive conditions especially as www.sims.edu.pk/esculapio.html

References
1. Langumuir VK, Crammer SF,
Hood ME. Fine needle aspiration
cytology in the management of
palpable benign and malignant
breast disease. Acta Cytol 1989;
33:93-6.
la
cu
Efficacy of sonography as a
guidance technique for biopsy of
enlarged superficial lymph nodes
by FNA. Acta Cytol 1993;
Es
abdominal pelvic and retro- 37:853-66.
peritoneal lymph nodes. Am J 15. Das DK, Gupta SK, Datta BN.
Roentgenol 1996;167:957-62. FNA cytology of non-Hodgkins
8. Daskd. Lymph nodes. In: Bibbo lymphoma. Its sub typing under
@

2. Dugo. D, Persiani R, Pende V, Med. Comprehensive cyto- working formulation of 175

Corso E, Rausel S, Picciocchi A. pathology. 2nd ed. Philadelphia: cases. Diag Cytopathol 1991;
The impact of fine needle WB Saunders company 1997:703- 7:487-98.
ts

aspiration in the management of 29. 16. Daskalopoulou D, Harhalakis N,

thyroid nodules. Miresva 9. Al-Mofleh IA. Ultrasound guided Maouni N. Fine needle aspiration
gh

Endocrinal 2000;25:5-10. fine needle aspiration of retro cytology of non-Hodgkin's

3. Frables WJ, Kardos TF. Fine peritoneal, abdominal and pelvic lymphomas: A morphologic and
needle aspiration biopsy: lymph nodes; diagnostic reliability. immunotype study. Acta Cytol
Ri

applications in the diagnosis of Acta Cytologica 1992;36:413-5. 1995;39:180-6.

lymphoproliferative diseases. 10. Carter TR, Feldman PS, Innes DJ, 17. Ustun M, Kisberg B, Davidson
Am J Surg Pathol 1988;12:62-72. Frierson HF, Frigy AF. The role of B, Berner A. Cystic charge in
py

4. Ahmed M, Rafi CM, Mushtaq S, fine needle aspiration cytology in metastatic lymph nodes: A
Mamoon N, Rashid M. Fine the diagnosis of Lymphoma. Acta common diagnostic pitfall in
needle aspiration biopsy in Cytologica 1988; 32:848-53. Fine Needle Aspiration
Co

clinical practice: a review of 350
cases. Pak Armed Forces Med J
1992;42:12-5.
5. Mamoon N, Mushtaq S, Rashid
M, Rafi CM, Khan AH. The value
of fine needle aspiration biopsy
in the management of breast
disease. J Pak Med Assoc
1993;43:120-2.
6. Mamoon N, Mushtaq S, Muzaffar
M, Khan AH. The use of fine
needle aspiration biopsy in the
management of thyroid disease. J
Pak Med Assoc 1997;47:255-8.
7. Memel DS, Dodd GD, Esolacc.
11. Beham FG, O' Dowd GJ, Frable
WJ. Fine needle aspiration effects
on benign lymph node histology.
Am J Clin Pathol 1984; 82:195-8.
12. Tsang WYW, Chan JKC. Fine
needle aspiration cytologic
diagnosis of kikuchi's lymph-
adenitis: a report of 27 cases. Am J
Clin Pathol 1994;102:454-8.
13. Gallen RS, Gambino SR. Beyond
normality: the positive value and
efficacy of medical diagnosis.
New York: John Wiles Sons;1975.
14. Pillotti S, Dr Palma S, Alasiol et al.
Diagnostic assessment of
Cytology. Diagn Cyto Pathol
2002;27:387-92(s).
18. Orell SR, Skinner JM: The typing
of non-Hodgkin's lymphoma
using fine needle aspiration
cytology. Pathol 1982;14:389-94.
19. Pitts WC, Weiss LM. Fine needle
aspiration biopsy of lymph
nodes. Pathol Annis 1988;
23(2):329-60.
20. Russell J, Orell S, Skinner J, et al.
FNAC in the management of
lymphoma. Aust NZ J Med
1983;13:365-8.
21. Butler JJ. The histologic diagnosis

34
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010
of Hodgkin’s disease. Semin Di-
agn Pathol 1992;9:252-6.
22. Dorfman RF, Colby TV. The
pathologists role in management
of patients with Hodgkin’s
disease. Cancer Treat Rep
1982;66:675-80.
23. El Hag IA, Chiedozi LC, al Reyees
FA, Kollur SM. Fine needle
aspiration cytology of head and
neck masses. Seven years
gh
Ri
py
Co
experience in a secondary care
hospital. Acta Cytol 2003 May-
Jun;47(3):387-92(s).
24. Chinoy RF, Baguan IN, Kane SV.
Cytologic evaluation of enlarged
neck node: FNAC utility in
metastatic neck disease. Internet J
Pathol 2007;6 (2):7.
25. Martelli G, Pilotti S, Lepera Pet al:
Fine needle aspiration cytology in
superficial lymph nodes: an
la pio
cu
Es
@
ts
35
analysis of 266 cases. Eur J Surg
Oncol 1989;15:13-16.
26. Cardillo MR. Fine needle
aspiration cytology of superficial
lymph nodes. Diagn Cyto Pathol
1989; 5:166-73.
27. Kline TS, Kannan V, Kline IK.
Lymphadenopathy & aspiration
biopsy cytology. Review of 376
superficial nodes. Cancer 1984;
54:1076-81.
k
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Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

Original Article

Women with Breech Presentation in Previous Cesarean Section.

The Controversy Continues
Lulu Abdullah Al Nuaim

Objective: The study was undertaken to evaluate the outcome of offering a trial of vaginal
delivery to women with breech presentation in women with a previous cesarean section (CS). .
Material and Methods: All women who attended the obstetric unit at the King Khalid University
Hospital (KKUH) Riyadh, with a history of one CS and breech presentation in the current
pregnancy were enrolled in this prospective study. Trial of vaginal delivery was allowed as per the
selection protocol including mother's request. Outcome of pregnancies were compared among

k
those who ended in vaginal delivery and emergency CS or elective CS.

.p
Results: Of the 172 women with a history of one previous CS and a breech presentation in
the current pregnancy, 115 (66.9%) were allowed a trail of vaginal delivery and the remaining

pio
57(33.1%) underwent elective repeat CS. In the trial group, vaginal delivery was achieved in 44
(25.6 %) and 71 (41.3%) ended in emergency CS. The success rate for vaginal delivery was
25.6%. Maternal morbidity was significantly higher in elective CS group (77.2%) compared with

la
vaginal delivery (2.3 %) and emergency CS groups (56.3 %). The Apgar score of < 7 at 1 and 5
minutes respectively did not differ significantly between the babies born by vaginal route and

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those born by CS. Corrected neonatal morbidity also did not differ significantly among the three
groups. There was no maternal or neonatal mortality.
Es
Conclusion: The favorable outcome of vaginal delivery in women with a previous CS and a
current breech in this study suggests that a trial of vaginal delivery can be safely offered to women
who meet the protocol criteria. However, the sample size will have to be expanded in future
@

studies for firm conclusion to be drawn.

Keywords: Breech presentation, previous cesarean section, vaginal birth after cesarean
section (VBAC), trial of labor, breech delivery.
ts

Introduction overall improvement in outcome of breech in labor

gh

There has recently been a renewal of interest in and this has resulted in a modern approach to the
vaginal births in both cephalic and breech breech fetus.9,10 Numerous studies have shown that
Ri

presentation after one previous caesarean delivery. planned vaginal delivery of singleton breech fetuses is
Numerous studies support the contention that a trial a safe clinical option in selected group of women.11 - 15
of vaginal delivery in cephalic presentation is an Since women and obstetricians are increasingly
py

appropriate option for women with a previous
1-6
caesarean section (CS). These reports show that a
policy of vaginal birth after caesarean delivery in
Co
interested in vaginal birth in cephalic presentation
after a previous caesarean section (VBAC), the
obvious question of whether management

selected women will result in decreased maternal
morbidity, shorter hospital stays and less of a burden
on blood bank and nursing facilities7 without an
increase in perinatal morbidity.1-6
The preferred mode of delivery for breech
presentation has been in debate for many years and is
still controversial even today. The first prospective
report on the mode of delivery of a breech fetus
without prior CS was published in 1978. It concluded
that it seems reasonable to allow vaginal delivery in
carefully selected cases of term frank breech
presentation.8
Many other investigators have contributed to the
alternatives should be extended to women with
breech presentation and a previous CS has arisen.
For women who arrive in labor with a breech
presentation and have a scarred uterus from a
previous CS, the consensus has been that these
16
women should have a repeat CS. VBAC however, in
a woman with a breech presentation is a controversial
issue in contemporary obstetrics, since little data
exists on the safety and success of this procedure.
The objective of this study was to assess the impact
of vaginal breech delivery after a prior CS, especially
when a trial of vaginal delivery is desired by some
women.

36
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

Material and Methods rate and uterine contractions was done on a

All women in this prospective evaluation were
delivered at the King Khalid University Hospital
(KKUH), a tertiary centre which is the teaching
institution of the King Saud University in Riyadh. All
women who presented to the delivery unit with a
history of a previous CS and a breech presentation in
the current pregnancy were recruited in the study.
Antenatal selection for offering a trial of vaginal
breech delivery after one CS was based on the
following inclusion criteria: mother's request,
singleton pregnancy, frank or complete breech
presentation, adequate pelvimetry. Radiological
continuous basis in labor. The total number of
women studied was categorized into three groups
based on the actual mode of delivery for analysis,
namely vaginal delivery, emergency cesarean section
and elective cesarean section groups. Data was
analyzed using goldstat statistical analysis software
package. The t test and Chi square tests were used to
determine the significance of the difference between
the groups. A p value of < 0.05 was considered
significant.
Results

k
pelvimetry (erect lateral) was used routinely in the During the nine years; between 1990-1998, there were

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second gravida (first labor after caesarean section), 34,954 deliveries, of which there were 3788 (10.8%)
but only selectively in parous women. A clinical or cesarean sections and 1497 (4.3%) breech

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ultrasonographic estimation of fetal weight of not presentations. One hundred and 72 (0.5%) women
more than 3500 gms and the flexed attitude of fetal were with singleton breech and a previous cesarean
head should also be known. Exclusion criteria section at 26 to 41 weeks of pregnancy. Table 1 shows

la
included previous classical CS if known, inadequate the maternal characteristics of the 172 women
pelvic dimensions, grade II-IV hypertension, intra- included in the study. Of the 172 women, 115 (66.9%)

uterine growth restriction (IUGR) and fetal head
extension diagnosed by ultrasound. Induction of
labor was performed for obstetric indication, mainly
Es
post-term pregnancies. Syntocinon augmentation
was used sparingly in labor. Monitoring of fetal heart
@
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underwent trial of vaginal delivery (figure 1) and 57
(33.1%) had elective repeat CS. Of the trial group 44
(25.6%) delivered vaginally and the remaining 71
(41.3%) had emergency CS.

Table-1: Maternal characteristics of 172 women with singleton breech presentation and previous cesarean section.
Vaginal delivery group Emergency CS group Elective CS group
Characteristics (III) N=57 P-value
(I) N=44 (II) N=71
ts

Age (Years): Mean±SD 31±6.0 31.2±6.2 30.9±5.1 0.9639

154.5±6.0 0.6450
gh

Age (cm) : Mean±SD 154.3±5.1 155.2±4.7

Parity : Mean±SD 31±2.5 4.0±5.1 3.4±2.7 0.0913
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GA at delivery (Weeks): Mean±SD 36.4±4.9 37.6±3.1 38.4±1.4 0.0121*

Unbooked 6 (13.6%) 7 (9.9%) 0(0.0%) 0.0232*

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Bad Obstetric History 5 (11.4%) 14 (19.7%) 7 (12.3%) 0.3657

Medical Complications 6 (13.6%) 6 (8.5%) 6 (10.5%) 0.6771

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Pelvimetry
Adequate 6(13.6%) 16 (22.5%) 7 (12.3%)
Inadequate 2 (4.5%) 4 (5.6%) 3 (5.3%) 0.5625

Not Known 36(81.9%) 51 (71.9%) 47 (82.4%) df=4

Labour at Presentation
Early Labor 318(40.9%) 44 (62%) 19 (33.3%)
Advanced Labour 24 (54.5%) 19 (26.8%) 1 (1.8%)
Not in labour 2 (4.6%) 8 (11.2%) 5 (8.8%) <0.001 * †
Came Electively 0 (0.0%) 0 (0.0%) 32 (56.1%) df=6
* = Significant (p < 0.05)† = χ2 test was used df = degrees of freedom

37
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

Indications for emergency CS are shown in Table 2. of infants among the three groups respectively.
The success rate of vaginal delivery was 25.6%. However this difference was not statistically
The distribution of the outcome of pregnancies in significant (p = 0.2189).
relation to the various breech presentations in the
two groups of women is presented in Table 3. Table-2: Indications for cesarean section in emerge-
Evaluation of the success of vaginal delivery in ncy cesarean section group (group II)
relation to the type of breech is presented in Table 3.
Indications Number (%)
The morbidity experiences of the 172 women
included in the study are presented in the Table 4. Failure to progress 32(45.0)
Vaginal deliveries did not result in any morbidity
except for the case of one woman who received Prolonged rupture of membranes 1 (1.4)
blood transfusion. On the other hand, both Fetal distress 38 (53.6)
emergency CS and elective CS cases resulted in Total 71 (100.0)

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excessive blood loss that needed blood transfusion.

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Febrile morbidity and administration of antibiotics
for infection were required; in addition to this, 2 Table-3a: Type of breech in 100 women delivered

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women in emergency CS group sustained bladder vaginally and by emergency cesarean section.
injury while one other woman underwent Type of delivery
hysterectomy for hemorrhage. Type of breech No (%)
Vaginal delivery Emerg. CS

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Maternal morbidity showed statistically significant
Frank (Extended) 15 (36.6%) 10 (17.0%) 0.0313 *
difference among the three groups (p < 0.001).

cu
The mean ( ± SD) maternal hospital stay in hospital Complete (Flexed) 20 (48.8%) 46 (77.9%) 0.0028 *
was shortest in the vaginal delivery group (2.0 ± 0.0) Footling 6 (14.6%) 3 (5.1%) 0.1546
compared with emergency CS (6.8±4.1) and elective
Es
Total 41 (100%) 59 (100%)
CS groups (6.9±1.6). This difference in hospital stay
was statistically significant among the three groups * =Significant (p < 0.05)
delivered by different modes (p < 0.001).
@

Neonatal outcome and morbidity is shown in Table Table-3b: The success of the Trial-of-Labor in 100
5. Newborns in the vaginal delivery group had women in relation to the type of breech.
significantly lower mean birth weights (2688 gms)
ts

than the newborns in emergency (2961gms) and Type of delivery

Type of breech Total
Vaginal delivery Emerg. CS
elective CS groups (3209 gms) (p = 0.0027),
gh

corresponding to the difference in the gestational age Frank (Extended) 15(60.0%) 10(40.0%) 25(100%)
at delivery in weeks . Complete (Flexed) 20(30.3%) 46 (69.7%) 66(100%)
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An apgar score of < 7 at 1 minute was found to be in

similar proportions in the three groups, and 5- minute Footling 6(66.7%) 3(33.3%) 9(100%)
apgar score of < 7 was found in 4.5%, 1.4% and 1.8% Total 41(41.0%) 59(59.0%) 100(100%)
py

Table-4: Maternal morbidity in women with breech fetuses and previous cesarean delivered by different modes.
Co

Hospital stay and Type of delivery

maternal morbidity Veginal delivery n=44 group-I Emergency CS n=71 group-II Elective CS n=57 group-III
Hospital stay(days): § (mean±SD ) 2.0 ± 0.0 6.8± 4.1 6.9 ± 1.6
Excessive blood loss (anemia) 0(0.0 %) 12(17.0%) 10(17.5%)

Blood transfusion 1(2.3%) 3(4.2%) 2(3.5%)

Antibiotics for infection 0(0.0%) 13(18.3%) 28(49.1%)

Fever 0(0.0%) 9(12.7%) 4(7.0%)

Bladder injury 0(0.0%) 2(2.8%) 0(0.0%)

Hysterectomy 0(0.0%) 1(1.4%) 0(0.0%)

ΨTotal maternal morbidity * 1 40 44
§ = p < 0.001 (significant) Ψ = χ2 test was used; degrees of freedom = 2; * =p < 0.001 (significant)

38
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

Table-5: Neonatal outcomes in the vaginal delivery and the CS groups

Vaginal delivery group Emergency CS group Elective CS group
Characteristics (III) N=57 P-value
(I) N=44 (II) N=71
Birth Weight (gm): Mean± SD 2688.3±874.6 2961.2±795.0 3209.1± 538.6 0.0027*
Apgar Score at 1 min [as n (%)]
1-6 (<7) 316(36.4) 23(32.4) 19(33.4) 0.9089 †
7-10 (> 7) 28(63.6) 48(67.6) 38(66.7)
Apgar Score at 5 min [as n (%) ]
1-6 (<7) 2(4.5) 1(1.4) 1(1.8)
7-10 (> 7) 42(96.5) 6 (8.5%) 56(98.2) 0.2189 †

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NICU Admission:

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Neonatal Morbidity (n = 25) 11(25.0%) 13(18.3) 1(1.8%) 0.0085 *†

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Corrected Neonatal Morbidity (n=4) 2(4.5%) 2(2.8%) 0(0.0%) 0.3184 †

Reasons for NICU Admission

la
1- Prematurity 8 8 0

2- IUGR 0 1 1
3-Neonatal sepsis 0
cu 1 0
Es
4- Cyanosed foot 1 0 0
5- Respiratory distress 1 0 0
6- Hyaline membrane disease (HMD) 0 1 0
@

7- Congenital anomlies 1 2 0
IUGR= Intrauterine growth retardation. †= χ2 test was used; degrees of freedom =2 . * = Significant (p< 0.05)
ts

Table-6: Summary of studies of Trial of Labor in patients with previous CS, and breech presentation in current pregnancy.
gh

Total No of breech
Reference No. In TOL NO. Of VBAC Success Rate%
with previous CS
1. Clark et al 1984 63 63%
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08 05
2. Paul et al 1985 72 13 06 46%
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3. Dhal et al 1987 590 16 15 94%

4. Ophir et al 1989 71 47 37 78.7%
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5. Samo et al 1989 137 27 13 48%

6. El Gammal et al 1990 86 33 33 100%

7. Al Nuaim 2007 172 115 44 38.3%

Compared to babies born by CS, babies born vaginally
had an estimated risk of having a low apgar score 1 of
< 7 equal to 1.29 (95% CI, 0.60 - 2.78) and the
estimated risk of a low apgar score 5 of <7 equal to
1.46 (95% CI , 0.7 - 1.46). Therefore, the risk of
having a low apgar score of < 7 at 1 and 5 minutes did
not differ significantly between the babies born via
vaginal route compared to those born by CS.
With regard to NICU admissions, it was observed that
significantly higher proportion (25%) of the
newborns from vaginal delivery group were admitted
to NICU compared to 18.3% from emergency CS and
1.8% from elective CS group (p = 0.0085).
Discussion
Vaginal birth after a caesarean delivery in a woman
with a cephalic presentation has received much
attention over the last several years and has been

39
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010
found to be an acceptable option in carefully selected
groups of women.1-6 On the other hand, management
of breech presentation in such cases and which
occurs in 3-4 % of pregnancies, has been and still is a
debatable issue. In the study of the term breech trial
which was conducted in a large randomized study
(Hannah et al) has shown that the neonatal risks
associated with term breech births are much higher
among planned vaginal deliveries, and therefore
recommended that cesarean deliveries should be
planned for all such women.17 Several other studies
published later have reported that vaginal breech
delivery may be justified in carefully selected groups
of women and should be an option for those women
who wish to avoid a repeat CS.
11-15
Breech presentation in a prior CS, however, has
become a virtual indication for elective repeat CS. The
rate now approaches 100% in some centers. The
justification for the liberal use of CS in breech
presentation has been the relatively high mortality
and morbidity rates associated with vaginal breech
delivery in these and which could be lowered.
However, the delivery of breech presenting fetuses
Es
by elective CS has not been shown to be a sure way of
avoiding these fetal problems.
Some authors have attempted to broaden the
acceptance criteria for VBAC to include breech
@
presentation in current pregnancy. Few small series
have been reported, of women with previous CS and
current breech presentation who delivered vaginally
ts
with an acceptable success and low complication
rates.19-24 It was proposed that with a specific protocol
gh
the management of breech presentation in women
with a previous CS some could be delivered vaginally
Ri
without an increase in perinatal mortality and
morbidity.
19
Clark et al reported on 63 women with a scarred
py
uterus and breech presentation at term in the current
pregnancy. In their retrospective study, of the 8
Co
women who had a trial of vaginal delivery, this was
achieved in 5 ( 63 % ) and the other 3 underwent
20
repeat CS for other indications. Paul et al had 72
women with scarred uterus in their prospective series,
13 of which were allowed trail of vaginal delivery,
6(46%) delivered vaginally without complication. In
the study by Dhall et al 21 , 590 cases with previous CS
were allowed a vaginal delivery, of which 16 were
breech presentation, of which 15 (94%) delivered
vaginally without any complications. Ophir et al 22
retrospectively reviewed 71 cases of breech
presentation with scarred uterus. Of the 47 women
allowed a trail of vaginal delivery, 37(78. %) gave birth
40
vaginally. Neonatal morbidity did not differ for
women who were delivered vaginally or by CS and
maternal febrile morbidity was reported to be higher
in the CS group than in the vaginal delivery group.
23
Sarno et al described a prospective series of 137
women with breech presentation and previous CS, of
whom 27 women were selected for trail of vaginal
delivery based on their protocol criteria. Thirteen of
these women (48 %) had a successful vaginal delivery
with no increase in fetal morbidity. The fetal outcome
was comparable to that in women who underwent a
repeat CS and that failed trail of vaginal delivery did
not increase adverse fetal and maternal outcomes.
k
Hence they proposed that a trail of vaginal delivery is
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reasonable in carefully selected cases of breech
presentation after a previous CS.
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El Gammal et al24 had 86 women in their retrospective
study who were with scarred uterus and breech
fetuses, of whom all 33 (100%) selected for trail of
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labor, delivered vaginally, with slightly higher neonatal
morbidity though, but lower maternal morbidity than
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those delivered by CS. They advocated that breech in
previous cesarean can be safely delivered vaginally if
attended by a senior obstetrician, with pelvimetry,
ultrasound assessment of fetal weight, in addition to
other necessary prerequisites of safety which should
be met prior to attempting any vaginal breech
delivery with cesarean section scar. There are still
some doubts, however, as to whether pelvimetry
selects cases accurately for vaginal delivery or whether
knowledge of pelvic adequacy gives the obstetrician
confidence in allowing a woman a trial of vaginal
breech delivery.25 Some regard X-ray measurements
as unnecessary but a view still prevails that pelvimetry
may have a role as part of the selection process for the
mode of delivery for women with breech
26
presentation.
The present study comprises of the largest number
of women with previous CS and current breech
presentation, (n=115) who were allowed trial of
vaginal delivery. This has demonstrated a success rate
of trial of vaginal delivery of 25.6% in selected
women with breech presentation and a previous CS,
and maternal morbidity was significantly higher in the
elective CS group compared to vaginal delivery group.
The corrected neonatal morbidity did not show any
significant difference between the vaginal delivery
and CS groups. The reason for higher rate of NICU
admissions from vaginal delivery group could be
attributed to higher proportion of premature infants
in this group. When the premature infants, IUGR and
congenitally malformed neonates were excluded
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

From each of the three sub groups to compute the
neonatal morbidity that could be attributed to the
mode of delivery, no significant difference was found
among the three groups (p= 0.3184). There was no
neonatal mortality in any of the three groups
however.
Lack of experienced staff in delivering the fetus
presenting by the breech, is now so widely recognized
by the obstetricians and the pregnant women alike,
that an increasing number of units are opting for
elective CS. Many consultants are now advising
elective CS at 38 weeks in every case and insisting that
their junior staff should do the same.
literature. The opinion of many has been polarized by
their personal experiences, good or bad, and there
have been no prospective randomized trials of
sufficient size to resolve this issue. In the absence of
such information, obstetricians have to rely on data
derived from retrospective analyses which are few in
this context, as individual series do not contain a
sufficient number of women to gain a true estimate
of neonatal risks.
Lack of a prospectively randomized trial with
adequate size had perpetuated the controversy just as
the author's opinion was influenced by her own
experiences as well as by several retrospective and

k
Younger staff will then have less opportunity to gain small prospective studies. The data of this study

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experience and are less confident, and consequently suggests that approximately 26% of women with an
so are the pregnant women. We must face the reality earlier caesarean and a current breech fetus who meet

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that breech delivery will continue to occur. It may not protocol criteria can be expected to deliver vaginally.
be possible to pursue a policy of no vaginal breech The trial seems justified since in this study, the fetal
delivery. The basic skills required for the proper outcome was comparable to that in women who

la
selection and the skills in delivering fetuses presenting underwent a repeat caesarean section. The favorable
by the breech will be lost. In addition, this policy fails outcome of the neonates who were delivered

to take into account some points: first, from time to
time, women with breech presentation will arrive at
full cervical dilation, and there is no sufficient time to
Es
perform CS; second, the second twin is often
delivered as breech, and third, there are some women
who would want to have vaginal breech delivery and
@
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vaginally, and the established maternal risks
associated with caesarean section, support the
concept that in selected group of women with breech
presentation after a previous CS, a vaginal delivery
can be performed without increased risks to either
mother or infant. However, careful obstetrical

will not agree to a CS. The net result is that an assessment is required to reach a decision to offer
increased rate of CS for singleton or twin breech will vaginal delivery.
inevitably result in there being no one left capable of
ts

delivering a breech vaginally. Department of Obstetrics & Gynaecology

King Khalid University Hospital
gh

Conclusion Riyadh, Saudi Arabia

The optimal management of breech presentation at theesculapio@hotmail.com
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term remains a lively debating issue in graduate www.sims.edu.pk/esculapio.html

examinations, on the labour ward, and in the obstetric
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References
1. Pridjian G. Labor after prior Van Roosmalen J. Trial of labor Eglinton GS, Phelan JP. Maternal
Co

cesarean section. Clin Obstet
Gynecol 1992; 35 (3): 445-56.
2. Miller DA, Diaz FG, Paul RH.
Vaginal birth after cesarean: a 10
year experience. Obstet Gynecol
1994; 84: 255-8.
3. Flamm BL. Vaginal birth after
caesarean section. In: Flamm
BL, Quilligan EJ, eds. Caesarean
Section: Guidelines for
appropriate utilization. New
York: Springer - Verlag, 1995:p-
51- 64.
4. Spaans WA, Vander Velde FH,
after previous cesarean section in
rural Zimababwe. Eur J Obstet
Gynaecol Reprod Biol 1997; 72: 9-
14.
5. S O G C c l i n i c a l p r a c t i c a l
guidelines. Guidelines for vaginal
birth after previous cesarean birth.
Number 155. Int J Gynaecol
Obstet 2005; 89: 319-31.
6. Ghaffari Z, Bener A, Ahmed B.
Safety of vaginal birth after
cesarean delivery. Int J Gynaecol
Obstet 2006; 92: 38-42.
7. Boucher M, Tahilramaney MP,
morbidity as related to trial of
labor after previous cesarean
delivery: A quantitative analysis. J.
Reprod Med 1984: 29: 12-16.
8. Collea JV, Rabin SC, Weghorst
GR, Quillig an EJ. T he
randomized management of
term frank breech presentation.
Vaginal delivery vs. caesarean
section. Am J Obstet Gynecol.
1978; 131: 186-95.
9. Collea JV, Chein C, Quilligan EJ.
The randomized management of
term frank breech presentation:

41
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010
A study of 208 cases. Am J Obs-
tet Gynecol 1980; 137: 235-44.
10. Gimovsky ML, Wallace RL,
Schifrin BS, Paul RH. Random-
ized management of the non-
frank breech presentation at
term: A preliminary report. Am
J Obstet Gynecol 1983; 146: 34-
40.
11. Doyle NM, Riggs JW, Ramin SM,
Sosa MA, Gilstrap LC.
Outcomes of term vaginal
breech delivery. Am J Perinatol
2005; 22: 325-8.
12. Ismail MA, Nagib N, Ismail T,
Cibils LA. Comparison of
vaginal and cesarean section
delivery for fetuses in breech
presentation. J Perinat Med
1999; 27 : 339-51 .
13. Goffinet F, Carayol M, Foidart
JM, Alexander S, Uzan S, Subtil
D et al. Is planned vaginal
delivery for breech presentation
at term still an option? Results of
an observational prospective
survey in France and Belgium.
Am J Obstet Gynecol 2006; 194:
1002-11.
14. Wolf H, Schaap AH, Bruinse HW,
Smolders-de Haas H, Van
Ertbruggen I, Treffers PE.
Vaginal delivery compared with
cesarean section in early preterm
Ri
py
Co
breech delivery: a comparison of
long term outcome. Br J Obstet
Gynecol 1999; 106: 486-91.
15. Hellsten C, Lindqvist PG,
Olofsson P. Vaginal breech
delivery: Is it still an option? Eur J
Obstet Gynecol Reprod Biol
2003 ; 111 : 122-8.
16. C r u i k s h a n k D P. B r e e c h
presentation. Clin Obstet Gynecol
1986; 29: 255-63.
17. Hannah ME, Hannah WJ,
Hewson SA, Hodnett ED, Saigal
S, Willan AR. Planned cesarean
section versus planned vaginal
birth for breech presentation at
term: a randomized multicentre
trial. Term Breech Trial Colla-
pio
borative Group. Lancet 2000; 356
(9239): 1375-83.
18. Nelson KB, Ellenberg JH.
la
Antecedents of cerebral palsy :
multivariate analysis of risks. New
cu
Engl J Med 1989; 315: 81-6.
19. Clark SL, Eglinton GS, Beall M,
Phelan JP. Effect of indication for
Es
previous cesarean section on
subsequent delivery outcome in
patients undergoing a trial of
labor. J Reprod Med 1984;29:22-5.
@
20. Paul RH, Phelan JP, Yeh SY. Trial
of labor in the patient with a prior
cesarean birth. Am J Obstet
ts
gh
42
Gynecol 1985; 151: 297-304.
21. Dhall K, Mittal SC, Grover V,
Dhall GI. Childbirth following
primar y cesarean section-
Evaluation of a scoring system.
Int J Gynecol Obstet 1987; 25:
199-205.
22. Ophir E, Oettinger M, Yagoda
A, Markovits Y, Rojansky N,
Shapiro H. Breech presentation
after caesarean section: Always a
section? Am J Obstet Gynecol
1989; 161: 25-8.
23. Sarno AP Jr, Phelan JP, Ahn MO.
k
Strong TH Jr. Vaginal birth after
caesarean delivery. Trial of labor
.p
in women with breech present-
ation. J Reprod Med 1989; 34:
831 - 3.
24. El Gammal NM, Jallad KB,
O'Deh HMS. Breech vaginal
delivery after one caesarean
section: a retrospective study.
Int. J Gynecol Obstet 1990; 33:
99-102.
25. Walinshaw S. Pelvimetry and
breech delivery at term. Lancet
1997; 350: 191-2.
26. Ikhena SE, Hallingan A,
Naftallin NJ. Has pelvimetry a
role in current obstetric practice?
J Obstet Gynecol 1999; 19(5):
463-6.
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

Original Article

Surgical Management of Dermatofibrosarcoma Protuberans

Muhammad Ali Rarifique Mirza and Abdul Hameed

Background:Dermatofibrosacoma protruberans (DFSP) is a rare, low to intermediate grade

cutaneous sarcoma, with recurrence rates as high as 60%.
Material & Methods:11 patients were treated over a period of 5 years in Sheikh Zayed Hospital
Lahore .
Results: The tumors presented as asymptomatic nodule in 63.6% cases. Average size of tumor
at the time of presentation was 8.5x6.6cm. Wide Local Excision (more than 3 cm) was done to
reduce the chances of recurrence. Reconstruction of the excised lesions was carried out in the

k
same sitting after frozen section examination of the tumor and margin clearance. 10 patients

.p
(90.1%) were free from recurrence after a follow up of 24 months.
Conclusion: Dermatofibrosarcoma protuberans is a rare, indolent tumor that presents as a local

pio
problem. Wide excision of margins has a favorable impact on recurrence free life interval. Frozen
section analyses, margin clearance and reconstruction should be carried out during one
operation. Fibrosarcoma variant of DFSP may behave more aggressively and radiation therapy

la
may have a role in controlling recurrence of this sub group of tumor. We advocate wide local
excision as an effective measure to control local recurrence of the indolent tumor.

cu
Keywords: Dermatofibrosacoma protruberans; Wide Local Excision; Recurrence; Soft tissue
Es
Introduction protuberans along with literature review. Study also
Dermatofibrosarcoma protruberans (DFSP) is a recommends wide excision as it effectively reduces
variant of soft tissue sarcoma of the skin that the local recurrence.
@

originates in the dermis and accounts for less than 1%

of skin tumors.1 It was first described by Darrier and Material and Methods
Ferrand2 in 1924 but currently accepted term was The study was carried out at the Department of
ts

3
coined by Hoffman when he reported three cases in Plastic and Reconstructive Surgery, Shaikh Zayed
1925. The cellular origin of DFSP is not clear at this
gh

Hospital, Lahore from January 2005 to December

time. Evidence exists that supports the cellular origin 2009. All the patients with diagnosis of DFSP on
being fibroblastic histiocytic or neuroectodermal. It is histological findings and confirmation with CD34
Ri

known for its locally aggressive growth and high rate tumor marker were included in the study.
4
of local recurrence. Demographic data of the patients, site and size of the
DFSP is characterized by its progressive, locally tumor, presenting features, time since noticing the
py

infiltrative behavior, and if left untreated, these lesion, tumor size, tumor recurrence, surgical
tumors continue to grow slowly, with invasion into findings, excision margins and mode of
Co

surrounding tissues like fat, fascia, muscle and bone
including neurovascular bundles.5 The time interval
from apparent onset to initial resection may exceed 10
6
years in more than 50% of cases.
Primary therapy for DFSP is surgical excision.
Inadequate resection of margins with conservative
intent leads to very high recurrence, reported rates
being 26-60%.4,5 To improve local control after
excision many authors have recommended wide
excision with more than 2cm grossly involved margin
of skin and underlying deep fascia. In present paper
we discuss our experience with dermatofibrosarcoma
reconstruction were recorded. All the lesions were
excised with gross resection margins of 3 cm and
excision of one layer deep to the involved area.
Frozen sections were sent for tumor clearance before
reconstruction. The excised tissues were sent for
frozen section margin clearance and later on for
histological evaluation and immunohistochemical
staining for CD34 tumor marker assessment.
Radiotherapy was administered to those cases that
had close clearance margins or patients with DFSP-
FS variant of the tumor. All these cases were followed
up every three months for first two years. They were
advised follow up visits every six months for next two

43
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

years. Cases that needed radiotherapy were referred and excision of pectoralis major muscle (Fig 1b). The
only after their suture lines had healed and flaps were defect was covered with split skin graft after
stable and healthy. All the patients were regularly confirmation of margin clearance with frozen section
checked up for any recurrence at the follow up visits. (Fig 1c). Final fixed section showed 3 mm deep
margin clearance. The patient was free of tumor at 40
Results: months follow up.
A total of 11 cases were treated during five years. The
mean age of patients at the time of surgery was 37.7
years (range 17-53 years). Male to female ratio was
5.5:1 (9 males: 2 females). Most common site of
tumor was the trunk (n=5), followed by head and
neck and extremities (3 cases each). Most of the
tumors (63.6%) presented as painless nodules (n=7).

k
Two patients (18.2%) presented with pain on

.p
movement and other two (18.2%) with itching on the
previously excised tumor site which was then

pio
mistakenly diagnosed as hypertrophic scar. The size
of tumors ranged from 1.2x1.2 cm to 28x23 cm
(average 8.7x6.6 cm). Four patients were referred

la
after incomplete excision/recurrence from other
institutions. The average reporting time between the

cu
development of lesion and seeking medical advice Figure 1a
was 4½ years (range 1-10 years). Various
reconstruction methods were used for wound
Es
coverage. Split skin grafting in 5 cases (45.4%) (Fig.
1), coverage with pedicle flap in 4 cases (36.4%) (Fig.
2), ray amputation in one case (9.1%) and local flap
@

was used in one case (9.1%) to cover the residual

defect. Two patients (Fig.3) showed the DFSP-FS
variant of the tumor (18.2%) while rest of the
ts

patients had less aggressive variant of DFSP. Three

patients (27.3%) received radiation therapy after
gh

excision, 2 with DFSP-FS and one whose biopsy had

shown involvement of margins on permanent
Ri

microscopic analysis of resection margins. The mean

follow up was 27 months (range of 3 months-60
months). Ten patients were disease free whereas one
py

patient, diagnosed as DFSP-FS, presented with tumor Figure 1b

recurrence and lung metastasis within three months
after primary excision and reconstruction at the
Co

subclavicular region. The patient died after one

month in the radiotherapy department.

Patient 1:
A 35 years old male was referred with history of
painless multi-lobulated swelling, measuring 10x15
cm on left side of chest and 8x10 cm on right side,
progressively increasing in size for the last 10 years
(Fig 1a). Incisional biopsy revealed dermatofi-
brosarcoma protuberans. MRI showed encapsulated
swelling without infiltration in the pectoralis major
muscle. Excision of tumor was performed with
resection of 3 cm of macroscopically clear margins Figure 1c

44
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

Patient 2:
A 45 years female presented with multiple non tender
swellings in right inguinal region, measuring 10x6 cm,
for the last 4 years (Fig 2a). Wide local excision with 3
cm margins and reconstruction with pedicle tensor
fascia lata flap was done. The patient was tumor free
after 30 months of follow up (Fig 2b).

k
.p
Figure 3a

la pio
Figure 2a
cu
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ts

Figure 3b
gh
Ri
py

Figure 2b
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Patient 3:
A 16 years old male presented with recurrent DFSP-
FS on the nape of neck three months after primary
excision at another hospital (Fig 3a). Wide Local
Excision with 3 cm margins was done. Frozen section
revealed involvement of superior margins. Re-
excision with further 1cm margin was done (Fig 3b). Figure 3c
The wound was covered with split thickness skin graft
(Fig 3c). The patient was also given radiation therapy Discussion
postoperatively. The patient was disease free for last Dermatofibrosarcoma protuberans represents less
18 months and was under regular surveillance at three than 0.1% of all malignancies. It is the head & neck
month intervals.

45
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

Table-1: Sociodemographic and tumour related factors of studied patients

Age Sex Size of lesion Site of lesion Reconstruction Histopathological Analysis
16 M 2×2cm Nape of neck Ststg DESP:FS
28 M 12×6cm R. Subscapular region L.D mycutaneous flap DESP
35 M 10×15cm &8×10cm Chest Ststg DESP
53 M 7×6cm R. Infradavicular region LD mycutaneous flap DESP:FS
33 F 1.2×1.2cm Right ring finger Ray amputation DESP
42 M 7×3cm L. Gluteal region L.D myocutaneous flap DESP
45 F 10×6cm L. Foreheaddddd TFL myocutaneous flap DESP

k
23 M 10×7cm R. Submandibular region Stsg DESP

.p
29 M 3×2cm DESP:FS Stsg DESP

pio
27 M 7×5cm R. Thigh posteromedical aspect Stsg DESP
51 M 3×4cm L. Subcostal region Local transpostion flap DESP

la
7
region where 10-15% of these lesions originate. The 317 patients who underwent conservative excision of

diagnosis of DFSP is confirmed after microscopic
evaluation and CD34 tumor marker. The multifocity
of the tumor in conjunction with its paucity of
Es
symptoms contributes to the difficulty in correct
diagnosis on the basis of clinical findings alone.
Although growth of the tumor is predominantly
@
cu
DFSP, a mean local recurrence rate of 43% was
reported.7 A similar analysis of 489 patients with
“wide” or larger than 2 cm resection margins
demonstrated a decreased rate (43%) of local
7
recurrence. Incomplete initial resection can lead to

horizontal, deep facial, muscular and bone invasion
can be seen with neglected, long-standing or locally
8,9
recurrent lesion. In our series, the mean time
ts
uncontrolled, potentially fatal, locally invasive
recurrence; therefore adequate initial resection is
important because multiple local recurrences

interval between the onset of the lesion and its 11

predispose to distant disease spread. Overall 5-year
presentation was 4 ½ years which corroborates to the 4
survival rates are 93% to 100% . In our series, 10
gh

1
obser vations by Alexander Stojaddinovic. patients (90.9%) were alive after a mean follow up of
Approximately sixty three percent patients in our
24 months. The only patient who died after
Ri

study presented with asymptomatic nodules while

similar results were observed by Hin-Lun Liu10 who recurrence and metastasis had the fibrosarcoma
have mentioned 62.5% asymptomatic patients. The variant of the DFSP. Above all he had a margin free
py

late presentation leads to larger size of tumor and histopathological report. Seven of the patients had a
therefore requires use of different modalities to cover tumor free interval of more than 36 months while the
the post-ablative soft tissue defects. In none of our 3 had less than 3 years of follow up. The duration of
Co

cases primary closure was possible. This is in contrast
to study by Hin-Lun Liu et al where the authors could
achieve primary closure in 40.6% cases.10 However,
they reported one month time interval between the
noticing of the growth and reporting for treatment in
contrast to 4½ years (range 1-10 years) in present
study. This very fact speaks of the importance of
early diagnosis of the disease as it is going to dictate
the tumor size and later reconstruction modality. This
also demands of increased level of suspicion for this
lesion to have an early diagnosis and treatment.
The most significant factor that predicts outcome for
DFSP is extent of resection. In a literature review of
follow up is important because 50-75% tumor
recurrence is noted within 3 years after operation.4
Mohs micrographic surgery (MMS) may be a useful
option for maximum conservation of uninvolved
tissue. The documented local recurrence rate after
MMS ranges from 0-7%.12 This technique allows
precise histological mapping of all lateral and deep
margins that may not be captured by standard
histological vertical step sectioning. This can lead to
false- negative paraffin section interpretation.7,12
Large and recurrent tumors may need exorbitant
number to be examined before getting clear

46
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010
margins.13 Surgery requires experienced Mohs
surgeons, histo-pathologists and laboratory
technicians. This facility is not available in most
institutions of the country. We have to rely on wide
local excision, which has given comparable
international results in our series.
Conclusion
Dermatofibrosarcoma protruberans is a rare,
indolent tumor that presents as a local problem. Wide
excision of margins has a favorable impact on
recurrence free life interval. Frozen section analyses,
References
1. A l e x a n d e r S t o j a d d i n o v i c ;
Howard M. Karpoff; Cristina R.
Antonescu et.al: Dermatofibro-
sarcoma protuberans of head
and neck: Ann Surg Oncol 2000;
7(9): 696-704.
2. DarrierJ, Ferrand M. Dermato-
fibromes Progressifs et Recidi
vants on Fibrosarcomes dela-
Peau. Ann De Dermat Et Syph
1924; 5:545.
3. Hoffmann E. Uber das knollen-
treibende firbosarkon der haut
(dermatofibrosarkoma protu-
berans). Dermat Ztschr. 1925;
43:1.
4. Mark RJ, Bailet JW, Tran LM.
Dermatofibrosarcoma Protu-
berans of head and neck: a report
of 16 cases. Arch Otolaryngeal
Ri
Head Neck Surg 1993;119:981-6.
5. Koh CK, Chung BK, Bury HPR;
Dermatofibrosarcoma Protube-
py
Co
margin clearance and reconstruction should be
carried out during one operation. Fibrosarcoma
variant of DFSP may behave more aggressively and
radiation therapy may have a role in controlling
recurrence of this sub group of tumor.
Department of Plastic Surgery
Federal Postgraduate Medical Institute
& Shaikh Zayed Hospital, Lahore
theesculapio@hotmail.com
www.sims.edu.pk/esculapio.html
k
.p
pio
rans; Int J Dermatol 1995; 256-60. 11. Connelly JH, Evans HL.
6. Burkhardt BR, Soule EH, Dermatofibrosarcoma Protu-
Winkelmann RK, Ivans JC. berans: a clinico pathogical
Dermatofibrosarcoma Protu- review with emphasis on fibro-
la
berans: study of 56 cases. Am J sacomatous areas. Am J Surg
Surg 1966; 111: 638-44. Pathol 1992; 16:921-5.
cu
7. Gloster HM. Der matofibr- 12. Gloster HM Jr, Harris KR,
osarcoma Protuberans. Am J Acad Roenigk RK. A comparison
Dermatol 1996; 35:355-74. between Mohs micrographic
Es
8. Tamoney HJ. Der matofib- surgery and wide surgical
rosarcoma Protuberans: a review excision for the treatment of
of twelve cases. Conn Med 1971; Dermatofibrosarcoma Protube-
@
35:674-9. rans: Am J Acad Dermatol 1996;
9. Gutierrez G, Opisna JE, de Barez 35:82-87.
NE, et al. Dermatofibrosarcoma 13. Joerg Wacker, Benjamin Khan-
Protuberans. Int J Dermatol 1984; Durani,Wolfgang Hartschuh.
ts
23:396-401. Modified Mohs micrographic
10. Hin-Lun Liu, Ramond Waai-Man surgery in the therapy of
gh
Ng. Dermatofibrosarcoma Pro- Dermatofibrosarcoma Protu-
truberans: a review of 10-year berans: Analysis of 22 patients.
experience on wide local excision: Ann Surg Oncol 2004; 11(4):438-
Eur J Plast Surg; Published on line: 44.
26 Jan 2010.
47
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

Original Article

First Dorsal Metacarpal Artery Flap For Soft Tissue Defects of Hand
Saeed Ashraf Cheema

Objective: To highlight the various uses of flap based on first dorsal metacarpal artery in various
soft tissue defects of hand.
Material and Methods: Twelve cases of various soft tissue defects of hand, of various
etiologies, falling within the arc of rotation of the first dorsal metacarpal artery were selected to be
covered by the flap based on this artery.
Results: This flap provided cover for soft tissue defects of thumb in seven cases. Three of these

k
cases had defects on dorsal aspect of thumb, three on the volar aspect and in one case it provided

.p
the pulp of the distal phalanx. It covered defects at palm, thenar eminence and dorsum of hand in
one patient each. Soft defect at first web space were covered in two cases.

pio
Conclusion: This local flap is a good option for the smaller soft tissue defects at the base of
index finger, palm, and various aspects of thumb which are within the arc of rotation of the first
dorsal metacarpal artery.

la
Key Words: Reconstruction, First metacarpal artery, Flaps.

Introduction
Hand trauma is quite common and may arise from a cu
of the fingers and defects at wrist and carpal joints.7-10
Present series of cases describes the utilization of this
Es
number of etiologies including mechanical injuries, flap for defects of various regions.
fireworks trauma, burn injuries and road traffic
accidents. Variety of local flaps is utilized to cover the Material and Methods
@

soft tissue defects of smaller scale. These include
cross finger, reverse digital, thenar, hypothenar,
1-4
metacarpal artery and variety of other flaps. The
ts
This study was carried out at the department of
Plastic Surgery, Services Hospital Lahore. Study
period was from January 2004 to June 2008. Various

first dorsal metacarpal artery flap was first described cases of hand trauma or soft tissue defects as a result
by Colema and Holevich.5 However, this flap was of release of contractures where soft tissue cover was
gh

popularized by Lie and Posch and later modified by provided with flap based on first metacarpal artery
Foucher.6 He incorporated the neural structures into were considered for this study. (Fig1-4).
Ri

the composite flap tissue and termed it as the Kite

flap.
This flap is raised from the dorsal aspect of the
py

proximal phalanx of the index finger. It is based on

the first dorsal metacarpal artery which is a constant
Co

branch of the radial artery. On the dorsum of the

hand, radial artery first gives a branch to the dorsal
carpal arch and then sends another branch, first
dorsal metacarpal artery, before diving between the
two heads of the first dorsal interosseous muscle to
reach the palm. Second, third and fourth dorsal
metacarpal arteries are branches of dorsal arch while
fifth metacarpal artery is branch of the dorsal carpal
branch of ulnar artery. Flaps raised on this artery have
great significance due the anatomic location of the
flap and hence utilized to cover the defects on the Fig-1: Severe post burn flexion contracture
volar and dorsal aspects of the thumb, tip of the involving index finger, palm at the base of the index
thumb, first web space, metacarpophalangeal joints finger and second web space.

48
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

k
Fig-2: Contracture at base of the finger released and

.p
z plasty marked to release the contracture of finger
and web.

la pio
cu
Es
@

Fig-5-6: Four months postoperative results at the

donor and recipient sites showing acceptable
appearance
ts

Study included patients of all ages and both sex. Bio-

gh

Fig-3: First dorsal metacarpal artery flap has been data of the patients including their name, age, sex,
raised etiology of the soft tissue defect, area and extent of
Ri

the defect and the flap utilized was recorded. Choice

of the reconstructive option depended on the site and
size of the defect. Flap was tunneled to the defect site
py

in all the cases. Flap donor site was covered with split
thickness skin graft and tie over dressing was done in
all cases routinely. No occlusive dressing was done on
Co

th th
the flap. Sutures were removed on 7 or 8 post
operative day. Patients were advised regular massage
of the grafted area on dorsum of the index finger to
get good cosmetic results (Fig.5).

Fig-4: First dorsal metacarpal artery flap has been
inset and z plasty flaps also can be seen.
Discussion
Hand is actively involved in almost every physical
activity and as a result is quite commonly involved in
traumatic incidences as well. Variety of local and
regional flaps is available for reconstruction of the
soft tissue defects of the hand. It is a fact that a flap
with long arc of rotation would be quite helpful in

49
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

Table-1: Etiologies of the defects, age of the patients, and various areas of hand covered by the first dorsal metacarpal artery flap.
Age / Sex Etiology Location of defect Area
23 M RSA Dorsum hand - base of thumb at 1st metacarpal Dorsum
19 M M tr Palm - Base of index finger Index finger
25 M FWT 1st web space 1st web
48 M B 1st web space 1st web
22 M Eb Thumb - Dorsal aspect of MCP joint Thumb
33 M Eb Thumb - Dorsum of thumb Thumb
50 M Eb Thenar eminence Palm
27 M M tr Thumb - Dorsum thumb Thumb
28 M Br Thumb - Volar thumb Thumb

k
08 M Thumb - Pulp thumb Thumb

.p
17 F Thumb - Nail area Thumb

providing cover to all the areas within the arc of
rotation. Similarly it is also quite evident that a flap with
a longer arc of rotation would be better able to reach
pio
compared with both the above mentioned flaps.
Similarly the donor site has far less morbidity as
13
compared to these flaps. The sensation of the first

la
the areas wide apart. dorsal metacarpal artery flap, as assessed by 2PD,
First dorsal metacarpal artery is a branch of the radial rivals other modes of thumb reconstruction.13 The

artery which arises just before this vessel dips into the
two heads of the first interosseous muscle. The pedicle
of the flap can be mobilized to the point before radial
Es
artery leaves the dorsum. It provides the flap with an
arc which reaches both the ulnar and radial borders of
the dorsum of hand on a line across the
@
cu
skin from the dorsum of the index finger has 3-7
mm 2PD.15
Although flap has disadvantage of grafted skin on
the dorsal aspect of index finger, proper post
operative care of the grafted area usually leaves this
area supple and soft which is cosmetically

metacarpophalangeal joints of the fingers. This arc acceptable as well. More over studies have described
would also cover the volar and dorsal areas of the the skin of this flap as wear and tear resistant when
thumb. It also means that soft defects of dorsum lying transferred to the volar thumb surface.16,17 At the
ts

in vicinity of the metacarpophalangeal joints, along the same time studies do suggest neuro-vascular flap
unlar and radial borders of the dorsum, and those on
gh

for larger skin defects of thumb.18

the volar and dorsal surfaces of the thumbs may be There was loss of flap in one case where it was used
covered with this flap.6,11,12 to cover the thumb. Failure might have been due to
Ri

The results achieved in this study show that flap any inadvertent pressure at the subcutaneous
effectively covered various defects of hand which are tunnel. Patient was 8 years of age and usually the
otherwise situated wide apart. This included defects at compliance is poor in this age group.
py

first web space, defects on thumb, both on volar and Although it was a series of limited cases but variety
dorsal aspects, base of the index finger, thenar of areas were covered with this flap due to its long
eminence and dorsum of hand.
Co

arc of rotation. It is easy to raise and grafted index

It is also evident that flap was quite often used to
reconstruct the soft tissue defects of the thumb. The
armamentarium to reconstruct the soft tissue defects
1-3, 13,14
of the thumb is quite a big one but this flap has its
own advantages.
It would be a better choice than Moberg flap for such
defects if the thumb tip defect is bigger than 1.5 cm. It
may be preferred choice when compared with Littler
flap for sensate resurfacing of the thumb as dissection
is far more easier in case of first dorsal metacarpal
artery flap and also it contains reliable venous drainage.
The skin paddle is more reliable and larger when
finger is also acceptable in the long run, both
functionally and cosmetically. If the sensory supply
to the skin is included in the flap it provides a
reliable sensory flap. It provides single stage
solution as compared to the cross finger flaps and
also morbidity is less when compared with Moberg
and Littler flaps.
Department of Plastic Surgery
Services Institute of Medical Sciences, Lahore
theesculapio@hotmail.com
www.sims.edu.pm/esculapio.html

50
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010
References
1. Xarchas KC, Tilkeridis KE,
Pelekas SI, Kazakos KJ, Kakagia
DD, Verettas DA. Littler's flap
revisited: an anatomic study,
literature review, and clinical
experience in the reconstruction
of large thumb pulp defects. Med
Sci Monit 2008;14: 568-73.
2. Guelmi K, Barbato B, Maladry D,
Mitz V, Lemerle JP. Reconst-
ruction of digital pulp by pulp
tissue transfer of the toe.
Apropos of 15 cases. Rev Chir
Orthop Reparatrice Appar Mot
1996;82:446-52.
3. Woon CY, Lee JY, Teoh LC.
Resurfacing hemipulp losses of
the thumb: the cross finger flap
revisited: indications, technical
refinements, outcomes and long-
term neuro-sensory recovery.
Ann Plast Surg 2008;61:385-91.
4. Smith RJ, Albin R. Thenar "H-
flap" for fingertip injuries. J
Trauma 1976;16(10): 778-81.
5. Holevich J. A new method of
restoring sensibility to the
thumb. J Bone Joint Surg
1963;45B:496502 .
6. Foucher G, Braun JB. A new
island flap transfer from the
gh
Ri
py
Co
dorsum of the index to the thumb.
Plast Reconstr Surg 1979; 63:344-
9.
7. Chang SC, Chen SL, Chen TM,
Chuang CJ, Cheng TY, Wang HJ.
Sensate first dorsal metacarpal
artery flap for resurfacing
extensive pulp defects of the
thumb. Ann Plast Surg 2004; 53:
449- 54.
8. Sherif MM. First dorsal meta-
carpal artery flap in hand
reconstruction. Anatomical study.
J Hand Surg Am 1994;19: 26-31.
9. El-Khatib HA. Clinical exper-
iences with extended first dorsal
pio
metacarpal artery island flap for
thumb reconstruction. J Hand
Surg Am 1998;23:647-52.
la
10. Tr ä n k l e M , S a u e r b i e r M ,
Heitmann C, Germann G. Restor-
cu
ation of thumb sensibility with the
innervated first dorsal metacarpal
artery island flap. J Hand Surg
Es
2003; 28(5):758-66.
11. Earley MJ. The arterial supply of
the thumb, first web and index
@
finger and its surgical application. J
Hand Surg 1986;11B:163-74.
12. Ratcliffe RJ, Regan PJ, Scerri GV.
First dorsal metacarpal artery flap
ts
51
cover for extensive pulp defects
in the normal length thumb. Br J
Plast Surg 1992;45:544-6.
13. Henderson HP, Reid DA. Long
term follow up of neuro-vascular
island flaps. Hand 1980; 12(2):
113-22.
14. Littler JW. The neuro-vascular
pedicle method of digital
transposition for reconstruction
of the thumb. Plast Reconstr
Surg 1953;12:303-19 .
k
15. Gellis M, Pool R. Two-point
.p
discrimination distances in the
normal hand and forearm. Plast
Reconstr Surg 1977; 59:57-63.
16. McFarlane RM, Stromberg WB.
Resurfacing the thumb following
major skin loss. J Bone Joint Surg
1962; 44A(7): 1365-75.
17. May JW Jr, Chait LA, Cohen BE,
et al. Free neurovascular flap
from the first web of the foot in
hand reconstruction. J Hand
Surg Am 1977; 2(5): 387-93.
18. Bunnell S. Plastic problems in
the hand. Plast Reconstr Surg
1946; 1(3): 265-270.
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

Original Article

Laparoscopic Cholecystectomy as Day Case Surgery

Aleem Ullah Butt and Muhammad Tauseef Asghar
Objective: To assess the feasibility of performing Day Case Laparoscopic Cholecystectomy (Lc)
in selected cases at Shalamar Hospital Lahore by one surgeon.
Material & Methods: Patients having gall stones, chronic cholecystitis were admitted under
care of one surgeon in this study at 8 am in the morning. Selection criteria for this study included
(ASA) American Society of Anesthesiologists grade of I or II, age below 40 years, well counselled
about operation and post operative care, responsible career at home, contact number for advice.
All patients were advised to attend out patient clinic 3 days post op. All patients were discharged

k
about 8pm to 10 pm same day.

.p
Results: From February 2005 to February 2009 (4 years period) 70 patients were admitted for
Laparoscopic cholecystectomy as a day case. All were discharged home at night. Two patients

pio
required an overnight stay (2.8%); there was no conversion to open procedure. One patient was
re-admitted after midnight for pain and one patient was re-admitted next day for vomiting (2.8%).
68 patients were fully satisfied with day case procedure. (%)

la
Conclusion: Day case laparoscopic cholecystectomy is a safe procedure in fit, sensible,
educated patients if they have responsible care-giver at home.
Key Words: Laparoscopic Cholecystectomy
cu
Es
Introduction surgeon. No drain was used in any case. Single dose
Laparoscopic cholecystectomy is now considered prophylactic antibiotic was given I/V at anesthetic
treatment of choice for symptomatic gall stones. induction. All patients were given I/V anesthesia;
@

Laparoscopic cholecystectomy as a day case was first nalbin with antiemetic was used as post op
performed and recognized in 1990.There are very few analgesia.
true day case surgery reports as some units do 23 hour One hour before discharging home I/V analgesia
ts

Laparoscopic cholecystectomy with overnight stay. In was given to patient and then discharged with oral
this study true day case Laparoscopic cholecystectomy analgesia. Patients were advised oral fluids 6 hrs
gh

is performed as the patient stays in the hospital only 12 after operation or some soft, light diet before
to 14 hours. In this study feasibility of true day case discharge.
Patient were sent home once fully conscious,
Ri

Laparoscopic cholecystectomy is done.

ambulant, having no nausea or pain. On discharge,
Material and Methods patient’s attendants were given information about
py

A prospective study was carried out on selected pain control and other complications and were
patients for Laparoscopic cholecystectomy, between advised to discuss with surgeons on phone. If no
February 2004 to February 2009. Indications for problem at home, patents were advised to see the
Co

surgery were symptomatic gall stones, confirmed on
ultrasonography. All patients were selected by one
surgeon. Patients with age of 40 years and below,
absence of jaundice, normal LFTs, normal PT, APTT,
normal pulmonary function, controlled hypertension,
absence of morbid obesity and no acute cholecystitis
were selected. All patients were admitted in either
private rooms or ward on morning of the operation.
Patients requiring Lc were placed first case on list. Only
one day case LS were done on one list. Operation was
performed using standard 4 ports technique with CO2
peritoneal insufflation of abdominal pressure 14-15
mm Hg. All procedures (Lc) were performed by one
surgeons at clinic 3 days post op.
Results
A total of 70 patients were considered and operated
for Lc over 4 years period. F:M ratio was 4:1. The
median age of patients was 30 yrs (20-40yrs). No
patients required an overnight stay. There was no
conversion to open.
No peritoneal drain was used in any case. One
patient (1.4%) was readmitted same night with pain
& discharged next morning. One patient was
readmitted (1.4%) next day with pain and was
discharged same day.

52
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

Reason for Readmission ischemia heart disease, COPD, morbid obesity or

Pain 1(1.4%)
Nausea and vomiting 1(1.4%)
All patients except 2 (2.85%) were satisfied and were
happy with day case LC.
Discussion
This study supports that LC is safe and useful even if
done as a day case. But this study is done on very
selective patients. There are lot of studies on Day Care
LC where patients are kept overnight and discharged in
23 hrs. If the benefits of day case LC in Pakistan are
considered, it does not make any difference whether
acute cholecystitis. Age is not a factor if patient is
ASA I or II. These are high risk patient and it is
better not to include them for Day Case Surgery.
However present study has proved that true Day
Care Surgery (LC) can be performed in selective
number of patients (urban not rural) without any
danger.
Conclusion
Day case laparoscopic cholecystectomy is a safe
procedure in fit, sensible, educated patients if they
have responsible caregiver at home.

k
patient is kept overnight or discharged as a true day Department of Surgery

.p
case. It does not effect the cost of operation for day Services Institute of Medical Sciences, Lahore
case. All patients cannot be considered for day case theesculapio@hotmail.com

pio
surgery especially those with uncontrolled DM, HTN, www.sims.edu.pk.esculapio.html

la
References

1. Nathanson IK, Fsater DW,
Cuschieri A. Laparoscopic
repair/peritoneal toilet of
perforated duodenal ulcer. Surg
Endosc 1990; 4: 232-233.
2. Mouret P, Francois Y, Vignal J,
Brath X, Lombard-Plater R.
cu
perforated peptic ulcer. J R Coll
Surg Edinb 1997;42:92-4.
7. Chung SC, Li AK. Helicobacter
Es
pylori and peptic ulcer surgery. Br
J Surg 1997;84:1489-90.
8. Koo J, Ngan YK, Lam SK. Trends
in hospital admission, perforation
@
steroidal anti-inflammatory
drugs. Br J Surg 1996; 83: 1779-
81.
13. Cuschieri A. Whither minimal
access surgery: tribulations and
expectations. Am J Surg 1995;
169: 9-19.

Laparoscopic treatment of and mortality of peptic ulcer in 14. Darzi A, Cheshire NJ, Somers
perforated peptic ulcer. Br J Surg Hong Kong from 1970 to 1980. SS, Super PA, Guillou PJ,
1990;77:1006. Gastroenterol 1983;84:1558-62. Monson JR. Laparoscopic
ts

3. lau WY, Leung KI, Kwong KH, 9. Crofts TJ, Prk KGM, Dtrrl RJC, omental patch re pair of
Davery IC, Roberston C, Chung SS, Li AKC. A randomized perforated duodenal ulcer with
gh

Dawason JJ et al. A randomized trial of non-operative treatment an automated stapler. Br J Surg

study comparing laparoscopic for perforated peptic ulcer. N 1993;80:1552.
versus open repair of perforated Engl J Med 1989; 320: 970-3. 15. Costalat G, Dravet F, Noel P,
Ri

peptic ulcer using suture or 10. Lanas A, Serrano P, Bajador E, Alquier Y, Vernhet J. Coelio-
sutureless technique. Ann Surg Esteva F, Benito R, Sainz R. scopic treatment of perforated
1996;224:131-8. Evidence of aspirin use in both gastro-duodenal ulcer using the
py

4. Druart Mi, Van Hee R, Etienne J, upper and lower gastrointestinal ligamentum teres hepatic. Surg
Cadiere GB, Gigot JF, Legrand perforation. Gastroenterol 1997; Endosc 1991;5:154-5.
M et al. Laparoscopic repair of 112: 683-9. 16. Pescatore P, Halkic N, Calmes
Co

perforated duodenal ulcer. A
prospective multi center clinical
trial. Surg Endosc 1997;11:1017-
20.
5. Siu WI, Leong HT, Law BKB,
Chau CH, Li CAN, Fung KH et
al. Laparoscopic repair for
perforated peptic ulcer a
randomized conrolled trial. Ann
Surg 2002;235:1313-9.
6. Sui WT, Leong HT, Li MKW.
Single stitch laparoscopic
omental patch re pair of
11. Ng EK, Lam YH, Sung U, Yung
MY, To KF, Chan AC et al.
Eradication of Helicobacter
pylori prevents recurrence of
ulcer after simple closure of
duodenal ulcer perforation:
randomized controlled trial. Ann
Surg 2000; 231: 153-8.
12. Ng EK, Chung SC, Sung JJ, LM
YII, Lee DW, Lau JY et al. High
prevalence of helicobacter pylori
infection in duodenal ulcer
perforations not caused by non-
JM, Blum A, Gillet M. Combined
laparoscopic-endoscopic meth-
od using an omental plug for
therapy of gastro-duodenal ulcer
perforation. Gastrointest
Endosc 1998;48:411-4.
17. Lagoo SA, Pappas TN. Laparo-
scopic repair for perforated
peptic ulcer AM Surg
2002;235:320-1.

53
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

Original Article
Lithium Toxicity
Nasim Akhtar, Khalida Khanum and Samina Karim

Background: Lithium is used for acute mania or prevention of the recurrences of bipolar manic-
depressive illness in adults. There is a close relationship between toxicity and blood levels of
sodium and potassium.
Material & Methods: This study was carried out on 30 rabbits of mixed breed weighing 1-2 kg. A
lithium dose of 5mg/kg body weight/ day was given to rabbits for 22 days. Three blood samples
were collected on 8th, 16th and 22nd days. Serum was separated and analyzed with flame
photometer for lithium, sodium and potassium levels.

k
Results: The level of serum lithium, sodium and potassium was significantly increased at 15th
and 22nd day of administration of lithium carbonate.

.p
Conclusion: It is therefore concluded that concentration of lithium, sodium and potassium in

pio
serum must be determined. It is most important for family physicians who regularly treat patients
receiving lithium as to how to monitor the safe use of drug.
Keywords: Lithium, electrolytes, rabbits

la
Introduction patients with acute lithium intoxication had mild

Lithium therapy is widely accepted as efficacious
treatment for bipolar affective disorder. However,
Es
long term usage of lithium raises concern of side
effects involving multiple organ systems, particularly
renal function.1
Lithium ions are absorbed readily and completely
@
cu
symptoms, independent of the serum lithium levels.
In patients with chronic lithium intoxication, the
frequency of severe symptoms was higher than in
those with acute intoxication. Patients with
concomitant medications, older age, and existing
neurological illness may have an increased

after oral ingestion. Complete absorption occurs in
about eight hours. After absorption it is distributed to
different parts and tissues of the body. Penetration of
ts
6
susceptibility to lithium toxicity. There is a close
relationship between toxicity and blood levels of
sodium and potassium.7 This study would help in

lithium in the extra cellular compartment is slow and finding ways to adjust the serum level of lithium,
gradually accumulates in tissues to a variable degree. sodium and potassium during lithium therapy.
gh

Lithium is not metabolized and virtually the kidney

excretes 95% and its clearance is about 20% of Material and Methods
Ri

creatinine and is lower in the elderly.2 This study was carried out on 30 rabbits of mixed
Lithium metal shares some chemical characteristics breed weighing 1-2 kg each. A lithium dose of
with salts of sodium and potassium. Lithium ions 5mg/kg body weight/ day was given to rabbits for 22
py

mimic some of the biological properties of both days. Three samples of blood were collected on 8th,
extra cellular sodium and intracellular potassium ions. 16th and 22nd days. Serum was separated and
Co

In biological fluid, lithium acts more like sodium than
any other ion. It can replace sodium in isolated nerve
3
tissue, muscle and erythrocytes. Lithium used for
acute mania or prevention of the recurrences of
bipolar manic-depressive illness in adults. The exact
mechanism of anti-manic action of lithium is not well
understood. The postulated mechanism of action of
lithium is that it affects neurotransmitters and their
release, such as noradrenaline, dopamine, serotonin
etc. Lithium is a toxic drug and not metabolized in the
4
body. Lithium toxicity is closely related to serum
levels of lithium, and can occur with doses of lithium
carbonate close to those used in therapy.5 Most
analyzed using flame photometer for lithium, sodium
and potassium levels. Statistical analysis: Mean,
standard error was calculated for each series of
samples. Student 't' test was used to calculate the p
value.
Results
Table 1 shows mean serum lithium level was
0.41mmol/l at 7th day of lithium administration. At
16th and 22nd day it increased to 0.62 and then 0.86
mmol/l (p<0.001). Mean serum sodium level was
136.6 mmol/l at 7th day. At 15th and 22nd day it
increased to 140.16 & 146.33 mmol/l (p<0.001).

54
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

Table-1: Levels of Serum Lithium, Sodium and Potassium on 7, 15 and 22 Days of Lithium administration in Rabbits
(values expressed as mean±s.e.m).
Duration of Administration Lithium (mmol/1) Sodium (mmol/1) Potassium (mmol/1)
7 days 0.41± 0.01 136.6± 0.76 4.1± 0.05
17 days 0.62± 0.02** 140.16±1.95 4.8± 0.1**
22 days 0.86± 0.02** 146.33± 0.5 4.7±0.06**

Mean serum potassium level was 4.1 mmol/l on 7th
day of lithium administration. At 15th and 22nd day
it was increased to 4.8 and then 4.7 mmol/l
(p<0.001).
at 15th and 22nd day of administration of lithium,
when compared with potassium level of 7th day. A
12
group of workers concluded that prolonged
lithium administration interferes with selective renal
excretion of potassium. Another study reported that

k
Discussion lithium is capable of causing a major disturbance in

.p
Lithium has toxicity manifests itself with changes in water balance, which manifests itself as polyuria and
serum electrolytes like sodium and potassium. secondary polydipsia.
13

pio
Results of present study show that the level of serum
lithium was significantly increased at 15th and 22nd day Conclusion
of lithium administration. Mean percentage increase It is therefore concluded that serum lithium level

la
during these days was 50.02 and 38.65% respectively, monitoring is mandatory and must be carefully
whereas overall increase was 107.77%. It has been

9
reported in literature that chronic lithium
intoxication starts insidiously with silent affliction of
Es
10
kidney followed by prodromal symptoms.
Mean serum sodium level was significantly increased
at 15th and 22nd day of lithium administration as
@
cu
maintained between 0.5-1.8 mmol/l. As there is a
close relationship between toxicity and blood level
of lithium and other ions, concentration of lithium,
sodium and potassium in serum must be determined
to facilitate the safe use of drug. Knowing about
lithium intoxication and how to avoid it is most

th
compared to sodium level of 7 day. A group of important for family physicians who regularly treat
workers observed that at 4-5th day of lithium
11
patients receiving lithium.
therapy, there is sodium retention and in some cases
ts

pretibial oedema. Another worker found that

12
Department of Pharmacology
sodium and lithium are reabsorbed at the same loci in Fatima Jinnah Medical College,
gh

proximal renal tubules. They observed that Services Institute of Medical Sciences
prolonged lithium treatment suppresses sodium and Allama Iqbal Medical College, Lahore
theesculapio@hotmail.com
Ri

transport in the collecting ducts of renal tubules.

Mean level of potassium was significantly increased www.sims.edu.pk/esculapio.html
py

References
Co

1. Hicks D. Lithium induced renal 4. Sourami RL, Moxham J. Text- 9.

toxicity-a review of the literature.
S D J Med 1991 Dec;44(12):343-
5.
2. Thornkill DP. Serum levels and
pharmacokinetics at ordinary
and sustained release lithium
carbonate in manic patients
during chronic dosage. Int J Clin
Pharmacol Ther Toxicol 1986;
24:504-7.
3. Coffaan NB, Fernandee JJ. Thera-
peutic drug monitoring lithium
levels. J Am Osteopath Assoc
1992; 92:907-9.
book of Medicine: Drug
interaction. 1990; Churchill Living
Stone Edinburgh. p 41-44.
5. Ide N, Gotou S, Mori M.
[Hospital pharmacists prevented
advance of lithium intoxication
through pharmaceutical inter-
ventions] Yakugaku Zasshi 2009
Aug;129(8):1007-11.
6. Chen KP, Shen WW, Lu ML. Imp-
lication of serum concentration
monitoring in patients with
lithium intoxication. Psychiatry
Clin Neurosci 2004 Feb;58(1):25-
7. Saxena P, Varshney V, Sexena
PN. Effect of lithium carbonate
on central thermoregulation in
rabbits. Indian J Med Res
1988;88:363-70.
8. Amideen A. Clinical features and
management of lithium poison-
ing. Med Taxol Adverse drug
Exp 1988; 3:18-32.
9. Schroeder SA, Krupp MA,
Tierney LM, Mcphee SJ. Current
Medical Diagnosis & Treatment.
3rd ed. 1991; Practice Hall Int
Inc. U.S.A. p739-39.

55
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

9. Schroeder SA, Krupp MA, 11. Cogan E, Noriter J, Abramow H. m a n i c d e p r e s s ive i l l n e s s.

Tierney LM, Mcphee SJ. Current
Medical Diagnosis & Treatment.
3rd ed. 1991; Practice Hall Int
Inc. U.S.A. p739-39.
10. Delva NJ, Hawken ER. Prev-
enting lithium intoxication.
Guide for physicians. Can Fam
Physician 2001 Aug;47:1595-600.
Impaired hydro osmotic resp-onse
to vasopressin of cortical
collecting tubules from lithium
treated rabbits. Oflugers Arch
1990; 416:446-73.
12. Noyes JR, Ringdhal IC, Andresen
NJC. Effects of lithium carbonate
on adreno-cortical activity in
Compreh Psychiat 1971;12:337-
347.
13. Walker RG. Lithium nephro-
toxicity. Kidney Int Suppl 1993
Jul;42:S93-8.

k
.p
la pio
cu
Es
@
ts
gh
Ri
py
Co

56
Esculapio - Volume 06, Issue 03, Oct. - Dec. 2010

Guidelines

AACE/ACE Diabetes Algorithm for Glycemic Control

LIFESTYLE MODIFICATION

A1C 6.5-7.5% A1C 7.6-9%

Mono therapy Dual therapy

MET TZD DPP4 AGI GLP-1 or DPP4

k
MET + or TZD
2-3 Months

.p
SU or Glinide
Dual therapy

pio
2-3 Months
GLP-1 or DPP4
Triple therapy

la
TZD
MET + SU or Glinide
TZD + GLP-1 or DPP4
Colesevelam cu
GLP-1 +TZD
Es
or DPP4
MET +
GLP1 MET GLP-1 or
+
DPP4
+Su
@

TZD
2-3 Months
ts

Triple therapy
2-3 Months
gh

MET + TZD
GLP-1 or +
Ri

DPP4
SU or Glinide

Insulin & other

Agent(s)
py

2-3 Months A1C > 9.0%

Drug naive Under treatment
Co

Dual therapy
Symptoms No symptoms
Insulin & other
Agent(s)

GLP-1 ± Su
or DPP4
Insulin & + Insulin & +
Agent(s) MET + TZD Agent(s)

GLP-1 ±TZD
or DPP4

57
 Case Report

Biliary Cystadenoma: A Case Report With Review Of Literature

Abdul Rehman Alvi

Abstract: A rare case of mucinous biliary cystadenoma presented as an upper abdominal mass
and progressively increasing jaundice in a 45 years old female. A free lying component of the
cystadenoma producing obstruction was present in the common bile duct. Marsupialization of
outer cyst with electro-coagulation of its epithelium and excision of inner cysts was performed as a
palliative procedure. Diagnosis was confirmed on histopathology with positive estrogen receptors.
Postoperative treatment with 20 mg Tamoxifen produced good results without any evidence of
recurrence or progression even 30 months after the surgery.

k
Keywords: Cystadenoma, Biliary tumors, Obstructive jaundice,

.p
Introduction been on any hormonal treatment including oral

pio
Mucinous biliary cystadenomas are extremely rare contraceptives at any stage of her life. On physical
multilocular benign neoplasms. These tumours examination, she was a medium built female with
usually involve hepatic parenchyma and occasionally deep jaundice. A large, firm, non tender smooth mass

extrahepatic biliary tract. Their true incidence in
different areas of the world is unknown. Eighty to
85% of tumours occur in females with peak incidence
between 30-50 years of age. The exact etiology of
Es
these tumours remains unknown. The resemblance
of embryonic structures originating from foregut
suggests their possible origin from ectopic remnants
@
la
was palpable in the epigastrium that moved with
respiration. There was no ascities. Laboratory
cu
investigations revealed her serum bilirubin
21.1mg/dl, Alkaline phosphatase 1033U/l, ALT 37
U/l, INR 1.2, urine was positive for bilirubin.
Haemagglutination test for hydatid disease was
negative and X-ray chest was unremarkable.
Ultrasound reported a large mulitlocular cyst

of Von Meyenberg complexe,1,2 other possibilities

includes origin from peribiliary endocrine cells.3 occupying the left lobe of liver and reaching
Environmental factors may play a role. Marked portaheptis. Intrahepatic biliary ducts were dilated,
while common bile duct could not be defined.
ts

female preponderance suggests a role for hormonal

influence. Some of these tumours are positive for Computed tomography (CT) confirmed the
gh

4
estrogen receptors. Different therapeutic options
including aspiration and sclerotherapy 5 , 6 , 7
fenestration, partial excision masupialization and
Ri
ultrasound findings and also reported that cysts close
to portahepatis having connection with the biliary
channels, however commo

8, 9,10
epithelial electro-coagulation
However complete surgical resection appears to be
py

the only possible mean to cure the disease. Liver

transplantation is also a valid option in cases with
extensive or bi-lobar lesions. Presence of estrogen
Co

receptors in some of these tumours may warrant

treatment with Tamoxifen after palliative resection
with possibility of cure or long term effective disease N bile duct again could not be identified (Fig 1 & 2).
control.

Case Report
A 45 years old female was referred by a local G.P with
epigastric mass and progressively increasing jaundice.
On presentation she had deep yellow sclera, passing
dark urine, clay colored stools and complained of
marked itching. She had lost some weight in the past
few weeks with decreased appetite. She had eight Fig-1: CT scan prior to surgery in Feb. 2004 showing
issues, last child birth five years back. She had never large bilobar biliary cystadenoma

58
 removed from common bile duct, (Note the black
calcium billirubinate deposits on the distal tapering
end of cystadema impacted in distal common bile
duct)

Fig-2: Larger outer cyst and smaller inner cysts,

k
resembling hydatid cyst.

.p
A provisional diagnosis of Biliary cystadenoma was

pio
made with a differential diagnosis of hydatid cyst.
Surgical exploration was performed under general
anesthesia in supine position through upper

abdominal midline incision. A large cyst occupying
almost whole of the left lobe of liver was
encountered. Bile stained mucinous fluid was
aspirated and cyst opened for palliative procedure as
Es
the lesion was involving the region of portahepatis,
with extension into right lobe of liver as well,
complete surgical resection was not possible. Unlike
echinococcus cyst no germinal layer found instead
@
la
Fig-4: Mucinous cystadenoma showing a dilated
cystic space lined by mucus secreting columnar
cu
epithelium and surrounded by vascularized
fibrocollagenous tissue. (H&E x 40)
Wall of outer cyst de-roofed with electrocoagulation
of its epithelial lining. On histopathological
examination, multi-locular cystic lesions, lined by

smooth inner lining and multiple cysts, extending to mucous secreting benign columnar epithelium.
portahepatis with intervening hepatic parynchyma at Intervening stroma composed of collagenous fibrous
places. Common bile duct was enormously dilated. tissue, congested blood vessels and focal chronic
ts

Cysts were excised in toto except close to hepatic inflammatory cells (Fig.4&5).
gh

confluence where small cysts removed piecemeal.

Choledochotomy was performed and a separate cyst
of 4cmx8cm (Fig.3) removed, bile duct then closed
Ri

over T-tube.
py
Co

Fig-5: Multiloculated cysts lined by benign

exfoliated epithelium and containing
eosinophlic secretions(HE10X)

A diagnosis of mucinous biliary cystadenoma was

Fig-3: Large free component of biliary cystadenoma made. Estrogen receptor status was then requested

59
 that turned out to be positive. Post operative course
was uneventful. Patient was discharged on the 5th
post operative day with a T-tube in position. On 12th
day T-tube was removed after a normal T-tube
cholangiogram. Patient was prescribed Tamoxifen 20
mg daily.
Patient was last examined 18 months after surgery
with no clinical signs of recurrence and patient
symptom free. However ultrasound scans at six
months intervals revealed small 2.5x3 cm area of
residual cysts with areas of fibrosis. This area of
residual disease/ recurrence is static in a recent follow
up scan (Fig.6).
Es
@
Fig-6: Recent CT scan showing small residual cyst
with thick fibrous walls
ts
Discussion
gh
Biliary cystadenoma is a rare condition with an overall
incidence of less than 0.05% for the cystic tumours
of the liver (11). The condition predominantly affects
Ri
females after their fourth decade of life (12). The
exact etiology of the condition remains unknown
though; its origin has been attributed to aberrant bile
py
ducts (1). Presence of estrogen receptors in some
reported cases and marked female preponderance
Co
may also suggest hormonal influence as a possible
etiological factor (4,13). Immunohistochemistry and
microscopic studies have ruled out the possible origin
from an ectopic ovarian tissue (14). Biliary
cystadenomas usually present as multilocular (rarely
unilocular) cystic lesions lined by cuboidal or
columnar epithelium surrounded by thick fibrous
capsule and an outer layer of loose connective tissue.
They have variable vascularity and true connections
with bile ducts are rare (8,15). Most cysts contain
serous, clear transudate with electrolyte composition
similar to that of serum (5,16). Rarely bile stained
fluid is encountered (8, 9, 10). Some of the biliary
60
cystadenomas usually asymptomatic are discovered
incidentally after ultrasound scan done for some
other reason. Pain, nausea, upper abdominal fullness
and palpable mass are the common symptoms at
presentation. These symptoms appear usually when
the cyst is more than 5cm in size (11). Obstructive
jaundice, cyst rupture, portal vein compression and
intracystic hemorrhage are rare and may lead to
unusual presenting features (17). Ultrasonography,
CT scan and MRI are all very sensitive investigations
to diagnose the condition. ERCP can be helpful in
establishing the cause and site of obstruction in
biliary cystadenomas presenting with obstructive
k
jaundice (external compression/direct involvement
.p
or communication). FNAC and cytology of aspirated
fluid is reasonably accurate to differentiate from other
pio
similar lesions (18). CA 19-9 in serum or cyst fluid
may be helpful in diagnosis of cystadenocarcinoma
though this test is not 100% reliable.
la
Other cystic lesions of the liver that are to be
differentiated from biliary cystadenoma include
cu
simple cysts, echinococcal cysts, necrotic neoplasms,
abscesses, embryonal sarcoma, polycystic liver and
cystic metastases.Conservative medical treatment is
not effective. Different surgical treatments have been
attempted including aspiration and sclerotherapy
with ethanol (19,20,21), doxycycline (7) and
minocycline (22), partial excision, epithelial
electrocoagulation, marsupialization, fenestration
and omentopexy (23-28). The recurrence remains
high after these procedures (29-30) Complete surgical
resection is required to avoid local recurrence. For
smaller lesions enucleation and for larger lesions or in
case of associated malignancy complete lobectomy is
the procedure of choice (13,17,18,24,31). Hepatic
transplantation may be required in some patients with
extensive bilobar disease (32-35). Biliar y
cystadenomas have 2-4% risk of malignant
transformation (36, 37). Benign to malignant ratio of
biliary cystadenoma and biliary cystadenocarcinoma
is 57-1, it is not clear whether cystadenocarcinoma
starts de novo or as a result of malignant
transformation in an already present biliary
cystadenoma (36, 38-40). The case under discussion is
unique in many ways. Communication with the biliary
channels is rare and this may be the cause of bile
stained mucinous fluid instead of serous fluid in the
cyst cavity in this patient. Presence of large 8cmx4cm
size cyst adenoma within common bile duct has not
been reported previously. As this segment of cyst
adenoma most probably would have come from the
parent cystadenoma in left lobe of liver. The presence
of calcium billirubinate salts on the distal tapering
end indicates its presence in common bile duct for
more than few weeks. The size of the cystadenoma in
common bile duct indicates that it might have been
growing in the bile duct and later got detached from
the parent cystadenoma in the left lobe the liver.Role
of Tamoxifen in estrogen receptor positive biliary
cystadenomas has not yet been investigated. Post
operative treatment with Tamoxifen in our case
brought good clinical results and its role in such cases
needs to be further evaluated. As no medical
treatment has been effective in the treatment of
biliary cystadenoma, possible role of Tamoxifen in
biliary cystadenoma merits further evaluation.
Summery
Biliary cystadenoma is a rare benign cystic disease of
the liver which predominantly affects women.
References
1- Moschcowitz E. Non parasitic
cysts (congenital) of the liver
with a study of aberrant bile
ducts. Am J Med Sci
1906;131:674-699
2- Von Meyenburg H: Ueber die 8-
cystenleber. Beitr Pathol Anat.
1918;64:477-531
3- Marcial M, Hauser S, Cibas E et al.
Intrahepatic biliary
gh
cystadenoma. Dig Dis Sci 9-
1986;31:884-889
4- Suyama Y, Horiey Y, Suou T,
Ri
H i r ay a m a C e t a l . O r a l
contraceptives and Intrahepatic
biliary cystadenomas having an 10-
py
increased level of estrogen
r e c e p t o r s .
Hepatogastroenterology
Co
1988;35:171-174
5- Liu TY, Chen CC, Wong SM.
Treatment of non parasitic cystic 11-
disease of liver: a new approach
to therapy with poly cystic liver.
Ann Surg 1968;168:921-927
6- Kairaluoma MI, Leinonen A, 12-
Stahlberg M, et al. Percutaneous
aspiration and alcohol
sclerotherapy for symptomatic
h e p a t i c c y s t s. A n n S u r g 13-
1989;210:208-215
7- Tokunag a K, Teplick SK,
Banerjee B. Simple hepatic cysts:
Patients usually present in the fourth decade of their
life with symptoms due to its size or complications.
Treatment of cystadenoma is complete surgical
resection to prevent recurrence. Extensive disease
especially involving both lobes of the liver may not be
possible to eradicate with routine surgical measures.
Liver transplantation may have a place for such
patients. Some of the cystadenomas are estrogen
receptor positive. The role of Tamoxifen need to be
further explored for such patients. In our case
palliative resection in an estrogen receptor positive
cystadenoma followed by Tamoxifen treatment
produced good clinical results.
k
.p
Department of Surgery
DHQ Hospital, Gujranwala
pio
theesculapio@hotmail.co
www.sims.edu.pk/esculapio.html.
la
cu
first case report of 14- Devaney K, Goodman ZD,
Es
percutaneous drainage and Ishak KG. He patobiliar y
sclerosis with doxycycline, with a c y s t a d e n o m a a n d
review of literature. Dig Dis cystadenocarcinoma a light
m i c r o s c o p y a n d
@
Sci 1994;39:209-214
Longemire WP, Mandiola SA, immunohistochemical study of
Gordon HE. Congenital cystic 70 patients. Am J Surg Path
disease of the liver and biliary 1994;18:1078-1091
ts
system. Ann Surg 1971;174:711- 15- Gaviser D. Solitary non parasitic
72412 cysts of the liver. Minn Med
Arimtage NC, BlumgartLH. 1953;36:831-839
Partail resection and fenestration 16- Van erpecum KT, Janssens AR,
in the treatment of polycystic Terpsta JL, et al. Highly
liver disease. Br J Surg symptomatic adult
1984;71:242-244 polycystic disease of the liver. J
Litivin DEM, Taylor BR, Greig P, Hepatol 1987;5:109-117.
et al. Non parasitic cysts of the 17- Teoh AY, Ng SS, Lee KF, Lai PB.
liver: the case for Biliary cystadenoma and other
complicated cystic lesions of
conservative surgical
management. Ann Surg the liver : diagnostic and
1987;5:407-411 therapeutic challenges. World J
Andrew WK, Robert J, Ampudia. Surg 2006;30(8):1560-6
Christine E et al. Biliary 18- T h o m a s K T, We l c h D,
Cystadenoma South Med J Trueblood A, Sulur P et al.
2000:93(7); 690-702 Effective treatment of biliary
Vanthey JN. Maddern GJ, c y s t a d e n o m a . A n n S u r g.
Blumgart LH. Adult polycystic 2005;241(5):769-73
disease of the liver. Br J Surg 19- Saini S, Mueller PR, Ferrucci JT,
1991;78:524-527 et al. Percutaneous aspiration of
Florman SS, Slakey DP. Giant hepatic cysts does not provide
biliary cystadenoma: case report d e f i n i t i v e t h e r a p y. A J R
and literature review. Am Surg 1983;141:559-560
2001;67(8):727-732 20- Bean WJ, Rodan BA. Hepatic
61
 Cysts: Treatment with alcohol. AJR
1985;144:237-241
21-Kairaluoma MI, Leinonen A,
Stahlberg M et al. Percutaneous
aspiration and alcohol
sclerotherapy for symptomatic
h e p a t i c c y s t s. A n n S u r g
1989;210:208- 215
22-Cellier C, Cuenod CA, Delandes P
et al. Symptomatic hepatic cysts:
treatment with single shot
injection of Minocycline
hydrochloride. Radiology 1998;
206:205-209
27- Klingler PJ, Gadenstatter M,
Scmid T et al. Treatment of
hepatic cysts in the era of
laparoscopic surgery. Br J Surg
1997;84:438-444
28- Krahenbuhl L, Baer HU, Renzulli
P et al. Laparoscopic management
of non parasitic symptom
producing solitary hepatic cysts. J
Am Coll Surg 1996; 183:493-
498
29- Iwatsuki S, Starzl TE. Personal
experience with 411 hepatic
resections. Ann Surg
34- Starzl TE, Reyes J, Tzakis A et al.
Liver transplantation for
polycystic liver disease. Arch
Surg 1990;125: 575-577
35- Madariaga JR, Iwatsuki S, Starzl
TE, et al. Hepatic resection for
cystic lesions of the liver.
Ann Surg 1993;218:610-614
36- Ishak KG, Willis GW, Cummins
SD et al. Biliary cystadenoma
and cystadenocarcinoma,
report of 14 cases and review of
the literature. Cancer
1977;38:322-338

k
23-Peltikallio V. Non paracytic cysts 1988;208:241-432 37- S i r e n J , P a r k k a i n e n P,
of the liver, a clinical study of 30- Thomas KT, Welch D, Trueblood Luukkonen P, et al. Case report

.p
117 cases. Ann Chir A Sulur P et al. Effective of biliary cystadenom and
Gynaecol 1970;59:1-63 treatment of biliary cystadenocarcinoma.

pio
24-Turnage RH, Eckhauser FE, cystadenoma. Ann Surg Hepatogastroenterology
Knol JA et al. Therapeutic 2005;241:769-773 1998;45:83-89 38- Akawari OE,
dilemmas in patients with 31- Vo gt DP, Henderson JM, Tucker JA jr, Seigler HF, et al.

la
symptomatic polycystic liver Chmielewski E. Cystadenoma and Hepatobiliary cystadenoma with
disease. Am Surg 1988;54:365- cystadenocarcinoma of the mesenchymal stroma. Ann Surg

372
25-Hensen SW jr, Gray HK,
Dockerty MB. Benign tumours
of the liver. Surg Gynaecol
Obstet 1957;104:63-67
26-Albrink MH, McAllister EW,
Rosemerg y AS et al.
cu
liver: a single centre experience. J
Am Coll Surg 2005;200:727-33
32- Newman KD, TorresVE, Rakala J
Es
et al. Treatment of highly
symptomatic polycystic liver
disease. Ann Surg 1990;212:30-37
33- Soravia C, Mentha G, Giostra E et
@
1990;211:18-27
38- 39- Wheeler DA, Edmondson
HA. Cystadenoma with
mesenchymal stroma in the
liver and bile ducts. Cancer
1985;56:1434-1445
39- 40- Adam YG, Nonas CJ.

Laparoscopic management of a.: Surgery for adult polycystic Hepatobiliary cystadenoma.

cystic disease of the liver. Am liver disease. Surgery South Med J 1995;88:1140-1143
Surg 1994;60:262-277 1995;117:272-275
ts
gh
Ri
py
Co

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