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ORIGINAL SCIENTIFIC REPORT
Outcomes of Parathyroidectomy in Patients with Primary
Hyperparathyroidism: A Systematic Review and Meta-analysis
Naykky M. Singh Ospina
1,2
•Rene Rodriguez-Gutierrez
2,3
•Spyridoula Maraka
1,2
•
Ana E. Espinosa de Ycaza
1
•Sina Jasim
1
•Ana Castaneda-Guarderas
2,4
•
Michael R. Gionfriddo
2,5
•Alaa Al Nofal
6
•Juan P. Brito
1,2
•Patricia Erwin
7
•
Melanie Richards
8
•Robert Wermers
1
•Victor M. Montori
1,2
ÓSocie
´te
´Internationale de Chirurgie 2016
Abstract
Background Parathyroidectomy is a definitive treatment for primary hyperparathyroidism. Patients contemplating
this intervention will benefit from knowledge regarding the expected outcomes and potential risks of the currently
available surgical options.
Purpose To appraise and summarize the available evidence regarding benefits and harms of minimally invasive
parathyroidectomy (MIP) and bilateral neck exploration (BNE).
Data sources A comprehensive search of multiple databases (MEDLINE, EMBASE, and Scopus) from each
database’s inception to September 2014 was performed.
Study selection Eligible studies evaluated patients with primary hyperparathyroidism undergoing MIP or BNE.
Data extraction Reviewers working independently and in duplicate extracted data and assessed the risk of bias.
Data synthesis We identified 82 observational studies and 6 randomized trials at moderate risk of bias. Most of
them reported outcomes after MIP (n =71). Using random-effects models to pool results across studies, the cure rate
was 98 % (95 % CI 97–98 %, I
2
=10 %) with BNE and 97 % (95 % CI 96–98 %, I
2
=86 %) with MIP.
Hypocalcemia occurred in 14 % (95 % CI 10–17 % I
2
=93 %) of the BNE cases and in 2.3 % (95 % CI 1.6–3.1 %,
I
2
=87 %) with MIP (P\0.001). There was a statistically significant lower risk of laryngeal nerve injury with MIP
(0.3 %) than with BNE (0.9 %), but similar risk of infection (0.5 vs. 0.5 %) and mortality (0.1 vs. 0.5 %).
Limitations The available evidence, mostly observational, is at moderate risk of bias, and limited by indirect
comparisons and inconsistency for some outcomes (cure rate, hypocalcemia).
Conclusion MIP and BNE are both effective surgical techniques for the treatment of primary hyperparathyroidism.
The safety profile of MIP appears superior to BNE (lower rate of hypocalcemia and recurrent laryngeal nerve injury).
Electronic supplementary material The online version of this
article (doi:10.1007/s00268-016-3514-1) contains supplementary
material, which is available to authorized users.
&Victor M. Montori
montori.victor@mayo.edu
1
Division of Endocrinology, Diabetes, Metabolism and
Nutrition, Department of Internal Medicine, Mayo Clinic,
200 First Street SW, Rochester, MN 55905, USA
2
Knowledge and Evaluation Research Unit in Endocrinology,
Mayo Clinic, Rochester, MN, USA
3
Division of Endocrinology, Department of Internal Medicine,
University Hospital ‘‘Dr. Jose E. Gonzalez’’, Monterrey,
Mexico
4
Department of Emergency Medicine, Mayo Clinic,
Rochester, MN, USA
5
Mayo Graduate School, Mayo Clinic, Rochester, MN, USA
6
Division of Pediatric Endocrinology, Mayo Clinic, Rochester,
MN, USA
123
World J Surg
DOI 10.1007/s00268-016-3514-1
Background
Primary hyperparathyroidism (PHPT) is a common clinical
condition characterized by hypercalcemia in the setting of
elevated or normal (inappropriately) parathyroid hormone
(PTH) levels [1]. The estimated prevalence of PHPT is 176
cases in women and 77 cases in men per 100,000 persons
per year (1995–2010) [2]. The clinical spectrum of this
disease has changed dramatically, given routine biochem-
ical screening that has consequently increased the number
of asymptomatic patients with PHPT [3,4].
Parathyroidectomy is the only curative treatment option
available and current clinical practice guidelines recommend
discussing this treatment option with all patients with PHPT.
Surgical intervention is strongly recommended to correct
hypercalcemia and reduce the risk for further hypercalcemia
complications in young patients (\50 years), those with
history of fracture or osteoporosis, kidney stones, low
glomerular filtration rate (60 mL/min), and hypercalcemia
more than 1 mg/dl above the upper limit of normal. Patients
who do not meet these criteria, however, are also offered
parathyroidectomy as a curative treatment option although
the extent of expected benefits in this group of patients
remains uncertain [1].
Parathyroid surgery has advanced dramatically during
the last few years after the innovation and incorporation
of intraoperative assessment tools (e.g., intraoperative
PTH monitoring) [5]. The most common surgical
approaches for the treatment of PHPT include minimally
invasive parathyroidectomy (MIP) and the bilateral neck
exploration (BNE) approach [5]. The available localiza-
tion techniques and the high prevalence of single
parathyroid adenoma as the cause of PHPT, high cure,
and low complications rates make MIP an appealing
surgical option [5]. Two previous systematic reviews and
one meta-analysis with multiple limitations have sum-
marized the available evidence regarding the safety and
efficacy of these procedures and provided a cost effective
analysis in patients at lower risk for hypercalcemia
complications [5–8]. Since their publication, however,
more studies have become available which justifies a new
qualitative and quantitative synthesis of the available
evidence.
For many patients with PHPT, especially for those with
severe disease, parathyroidectomy will be offered as the
treatment of choice. Clinicians may benefit from a sum-
mary of the best available evidence regarding the cure rate
and the risks associated with this intervention to counsel
their patients accordingly. This information might be more
important in those patients without a strong indication for
surgical intervention in whom the benefits should be
carefully considered in light of the potential risks and each
patient’s values and informed preferences [1]. Therefore,
we conducted a systematic review and meta-analysis to
determine the outcomes associated with these surgical
treatment modalities.
Methods
We performed a systematic review and meta-analysis
evaluating the surgical outcomes associated with parathy-
roidectomy (MIP or BNE approach) in patients with PHPT.
This study followed a predesigned protocol and current
standards for reporting systematic reviews [9].
Eligibility criteria
We searched for observational studies evaluating MIP or
BNE and randomized controlled trials (RCTs) comparing
these surgical strategies in patients with PHPT undergoing
initial surgery, and who had no history of familial causes of
PHPT (e.g., multiple endocrine neoplasia, familial
hypocalciuric hypercalcemia). We excluded studies not
written in English and those with missing data despite
author contact.
Study identification
A comprehensive search of several databases from each
database’s earliest inception to September 2014 was
conducted. The databases include Ovid Medline In-Pro-
cess and Other Non-Indexed Citations, Ovid EMBASE,
Web of Science, and Scopus. The search strategy was
designed by an experienced librarian (PE) with input from
the study’s principal investigator (NSO). Controlled
vocabulary supplemented with keywords was used to
search for studies evaluating the risks and benefits of
parathyroidectomy in patients with PHPT (Appendix 1).
We consulted Mayo Clinic experts and the references
from previous systematic reviews to identify studies
missed by our search strategy.
Selection of studies
Reviewers working independently and in duplicate
reviewed all abstracts and selected full-text manuscripts for
eligibility. Disagreements at full-text screening were
resolved by consensus.
7
Mayo Medical Library, Mayo Clinic, Rochester, MN, USA
8
Division of Endocrine Surgery, Department of Surgery,
Mayo Clinic, Rochester, MN, USA
World J Surg
123
Data collection and management
Working independently and in duplicate reviewers used a
standardized web-based form to collect information from
each eligible study. For each study, baseline clinical
features of the included population such as age, sex,
serum calcium, and serum PTH were recorded. The post-
surgical outcomes of interest were hypocalcemia (tran-
sient and persistent), laryngeal nerve injury (transient and
persistent), postoperative bleeding and infection, periop-
erative mortality, and cure rate. The definition provided
for each of these outcomes, in each study, was accepted
as valid. Thus, definitions of the interventions and out-
comes of interest, as well as the number of patients, in
which MIP was converted to BNE were recorded.
Risk of bias
The risk of bias was assessed by reviewers working inde-
pendently and in duplicate using a modified Ottawa clas-
sification for observational studies or the Cochrane
assessment tool for RCTs [10,11]. Disagreements were
resolved by consensus.
Subgroup analysis
To explain possible inconsistencies across study results, we
planned on conducting the following subgroup analysis:
use of localization techniques, use of intraoperative PTH
monitoring, and definition of outcomes. To explore the
effect of lost to follow-up and conversions of MIP to BNE,
we planned on conducting sensitivity analysis.
Summary measures and synthesis of results
We performed a meta-analysis of the proportion of
patients with each of the outcomes of interest in the
included studies according to type of surgery using a
random-effects model [12]. This analysis was based on an
intention-to-treat principle, using the number of patients
who underwent the surgical procedure as the denominator.
As a result, patients who were assigned to MIP and were
converted to BNE were included in the denominator for
the MIP outcomes. This approach is considered conser-
vative since it includes all the patients assigned to a
specific intervention (intention-to-treat) [13]. We per-
formed indirect comparisons using the pooled estimates
for each of the outcomes according to treatment strategies
[14]. We used the I
2
statistic to assess for inconsistency
across individual studies. I
2
[50 % indicates large
inconsistency across studies (heterogeneity) not explained
by chance [15]. All statistical analyses were performed
using Open-Meta [16].
Results
Study identification
Our literature search (Fig. 1) identified 3,141 abstracts, of
which 82 observational studies and 6 RCTs, published
between 1973 and 2014, were included (Table 1)[17–104].
Most of them were conducted in adults who underwent
surgery for PHPT using MIP (70 studies, 9643 patients) or
BNE (38 studies, 2471 patients). In addition, 93 % of the
included series were from University/Academic Centers. A
clear definition of MIP was provided in 54 of the studies
that evaluated this surgical technique (*77 % of the
included studies) and mostly referred to an intervention
based on preoperative imaging and a limited neck explo-
ration; there were variations in terms of type of anesthesia,
surgical approach, and the use of other operative adjuncts.
Overall, a lack of consistency and clarity in the definitions
of the outcomes of interest was found (especially for cure
and hypocalcemia). The different definitions used for
hypocalcemia and cure rate in the included studies are
listed in Supplementary Table 1.
Risk of bias of selected studies
Overall, the risk of bias was moderate in observational
studies (Table 2) due to lack of or unclear description of
follow-up time and lost to follow-up. For the RCTs, the
overall risk of bias was moderate (Table 3) due to lack of a
clear randomization method, or allocation concealment,
and lack of a clear statement with regard to lost to follow-
up.
Meta-analysis
Cure rate was 98 % (95 % CI 97–98 %) with BNE and
97 % (95 % CI 96–98 %) with MIP. Bleeding rate was
slightly higher for BNE 0.9 % (95 % CI 0.3–1.5 %) when
compared to MIP 0.1 % (95 % CI 0.0–0.3 %). Hypocal-
cemia (including postoperative, short-term and long-term
events) occurred in 13.6 % (95 % CI 10.0–17.1 %) of BNE
cases and 2.3 % (95 % CI 1.6–3.1 %) with MIP
(P\0.001). There was no difference between MIP and
BNE in the rate of infection (0.5 vs. 0.5 %). There was a
statistically significant difference in the rate of laryngeal
nerve injury between BNE and MIP (0.9 vs. 0.3 %,
P=0.01). Mortality was reported in 19 of the 88 studies
and found to be no different between MIP (0.1 %) and
BNE (0.5 %) (Fig. 2).
We performed a sensitivity analysis including only
studies in which a clear definition of MIP was provided for
all our outcomes and in the case of studies reporting cure
World J Surg
123
rate, including only studies in which at least 6 months of
follow-up was provided (these results were comparable to
those of the main analysis) (Supplemental Table 2).
Due to the limitations of the reported data in the primary
studies (i.e., lack of clear definitions of outcomes and
surgical techniques), we were unable to perform any of the
other preplanned subgroup and sensitivity analyses.
Discussion
Summary of the findings
The body of evidence evaluating the surgical outcomes of
patients who underwent MIP or BNE parathyroidectomy
for PHPT comprised mostly of observational studies of
Records identified through
database searching
(n =3141)
Screening
Included Eligibility Identification
Records screened
(n =3141)
Records excluded
(n =2349)
Full-text articles assessed
for eligibility
(n =792)
Full-text articles excluded
(did not meet inclusion
criteria)
(n =704)
Studies included in
qualitative synthesis
(n =88)
Studies included in
quantitative synthesis
(meta-analysis)
(n =88)
Fig. 1 Study selection diagram
World J Surg
123
Table 1 Summary characteristics of the included studies
Study Year Country Type of
surgery
Number of
patients
MIP
Number of
patients
BNE
MIP
definition
provided
Type of MIP % MIP
completed
Outcomes
measured
Pre-op
localization
PTH
monitoring
Aarum 2007 Sweden MIP and BNE 49 50 Yes NA 49 5 Yes No
Adil 2009 USA MIP 305 Yes Radioguided 100 1,2 Yes Yes
Arkles 1996 Australia MIP and BNE 59 46 No NA 100 1,2,4,5 Yes No
Babinska 2012 Poland MIP 35 Yes Open-Mini 100 2 Not clear Yes
Balisky 2005 USA MIP and BNE 52 28 Yes NA 100 2,5 Yes No
Bergenfelz 2005 Germany MIP and BNE 25 25 Yes NA NA 2,3,5 Yes Yes
Bergenfelz 2002 Sweden MIP and BNE 47 44 Yes Video-assisted surgery 62 1,2,5 Yes Yes
Beyer 2007 USA MIP and BNE 111 49 No NA 100 1,5 Yes Yes
Bumpous 2009 USA MIP and BNE 240 82 Yes Intraoperative Tc
99m
sestamibi
with gamma probe
NA 1,2,3,4,5 Yes Yes
Burkey 2003 USA MIP and BNE 87 30 Yes Focused approach through limited
neck incision
80.4 1,2,4,5 Yes Yes
Carneiro 2004 USA MIP 423 Yes NA 97.3 5 Yes Yes
Chau 2010 Canada MIP 74 Yes Different Anesthesia techniques 96 2,4,5 Yes Yes
Chen 1998 USA BNE 184 – NA NA 5,6
Chen 2005 USA MIP 254 Yes Radioguided/gamma probe NA 5 Yes Yes
DeCrea 2013 Italy MIP 124 Yes Video Assisted 100 1,2,5 Yes Yes
Del Rio 2013 Italy MIP and BNE 76 81 Yes Video assisted 95 2,5 Yes Yes
Delbridge 2000 Australia MIP 50 Yes Endoscopically assisted and Direct
Lateral minimal incision
approach
86 2,3,4,5 Yes Yes
Dobrinja 2008 Italy MIP 23 Yes Video Assisted 95.6 1,2,5 Yes No (only half
of the
patients)
Doherty 1994 USA BNE 39 – NA 1,2,5,6
Durkin 2010 USA MIP 18 Yes NA NA 1,2,5 Yes Yes
Fang 2008 Taiwan MIP 19 Yes NA 100 3,4,5 Yes No
Ferzli 2004 USA BNE 34 – NA 1,2,5,6
Flint 2002 New
Zealand
BNE 33 – NA 2,3,5,6
Fouda 1999 Saudi
Arabia
BNE 24 – NA 5
Fouquet 2010 France MIP 200 Yes Totally endoscopic lateral
parathyroidectomy
72 1,2,3,5,6 Yes Yes
Garimella 2012 UK MIP 56 Yes Video Assisted 85.7 2,3,5 Yes No
Gauger 1999 Australia MIP 24 Yes Endoscopically assisted 100 1,2,3,4,5 Yes No
World J Surg
123
Table 1 continued
Study Year Country Type of
surgery
Number of
patients
MIP
Number of
patients
BNE
MIP
definition
provided
Type of MIP % MIP
completed
Outcomes
measured
Pre-op
localization
PTH
monitoring
George* 2009 India MIP 15 Yes NA 100 1,2,5,6 Yes No
Goasguen 2010 France BNE 186 – NA 1,2,4,5,6
Gurnell 2004 UK MIP 50 Yes Focused parathyroid surgery 100 2,3,4,5 Yes Yes
Haciyanli 2009 Turkey MIP 30 Yes NA 100 1,4,5 Yes No
Han 2007 USA MIP and BNE 352 121 No NA 100 5 Yes No
Henry 2008 France MIP 86 No NA 84.4 2,5 Yes Yes
Henry 2001 France MIP 166 Yes Video-assisted 85 2,5 Yes Yes
Henry 2001 France MIP and BNE 80 68 Yes Video-assisted via lateral approach 82 4,5 Yes Yes
Hessman 2009 Sweden/
Denmark
MIP 143 Yes Video assisted and open approach 79.6 1,2,3,4,5 Yes Yes
Hughes 2013 USA MIP and BNE 833 156 No NA 77.7 1,2,4,5 Yes Yes
Kacker 2001 USA MIP and BNE 19 36 No NA 100 5 Yes No
Karahan 2013 Turkey MIP 49 Yes NA 95.9 2 Yes No
Kavanagh 2012 Ireland BNE and MIP 55 60 Yes NA 2,5,6 Yes No
Kelly 2014 Singapore MIP 150 Yes Mini-incision parathyroidectomy
2-2.5 cm
85.3 1,2,4,5 Yes No
Koren 2005 Israel MIP 21 Yes Lateral minimal
parathyroidectomy
100 2,3,4 Yes No
Koskal 2006 BNE 52 – NA 1,5
Kuriloff 2004 USA BNE 35 – NA 5
Li 2012 China BNE 12 – NA 1,2,5
Livingston 2008 USA MIP 79 Yes Radioguided 100 2,3,4,5,6 Yes No
Lo 2003 China MIP 66 Yes Endoscopic-assisted 94 1,2,4,5 Yes Yes
Lorenz 2001 Italy MIP 123 Yes Video-assisted 89 1,2,5,6 Yes Yes
Martin 2000 USA MIP and BNE 59 101 No NA NA 1,2,4,5 Yes No
Mekel 2005 Israel MIP 76 Yes Unilateral Kocher incision under
cervical block anesthesia
NA 1,5 Yes Yes
Melck 2012 USA MIP 220 No NA 205 1,2,3,5,6 Yes Yes
Meurisse 1999 Belgium BNE 31 – NA 5,6
Miccoli 2004 Italy MIP 370 Yes Video Assisted 94 1,2,3,5 NA Yes
Mortier 2004 France MIP 126 Yes Lateral/Conventional cervical
approach
NA 5 Yes Yes
Moure 2008 Spain MIP 136 Yes NA 96 1,5 Yes No
Nottinham 1993 USA BNE 73 – NA 1,2,4,5,6
World J Surg
123
Table 1 continued
Study Year Country Type of
surgery
Number of
patients
MIP
Number of
patients
BNE
MIP
definition
provided
Type of MIP % MIP
completed
Outcomes
measured
Pre-op
localization
PTH
monitoring
Okido 2001 Japan MIP 11 Yes Video-assisted 100 2,5 Yes No
Pang 2007 Australia MIP 500 Yes Focused mini-incision technique 100 2,4,5,6 Yes No
Pitale 2008 UK MIP 24 Yes Short lateral incision 92 1,2,5 Yes No
Prager 2001 Austria MIP and BNE 82 31 Yes Minimally invasive
parathyroidectomy by lateral
approach
83.1 2,5,6 Yes Yes
Pratley 1973 Australia BNE 60 – NA 1
Rajeev 2013 UK MIP 86 Yes NA 100 1,2,3,4,5 Yes No
Rankin 1979 New
Zealand
BNE 38 – NA 1,2,5
Ready 1996 UK BNE 53 – NA 1,2,5,6
Rubello 2006 Italy MIP 22 No NA 100 5 Yes Yes
Russell 2005 UK MIP and BNE 54 46 Yes NA NA 1,2,5 Yes No
Sarfati 1989 France BNE 55 – NA 6
Schneider 2012 USA MIP and BNE 928 155 No NA NA 1,2,3,4,5 Yes Yes
Seving 2010 Turkey MIP 51 No NA 100 1,2,4,5,6 Yes Yes
Shaha 1993 USA BNE 85 – NA 2,5
Shindo 2007 USA MIP 88 Yes Focused lateral approach 87 1,2,4,5 Yes Yes
Sidhu 2003 Northern
Ireland
MIP 184 No NA NA 1,2,5,6 Yes No
Slepavicius 2008 Lithuania MIP and BNE 24 23 No NA 87.5 1,2,5 Yes Yes
Somashekhar 2007 India MIP 15 Yes Radioguided/gamma probe 100 1,5 Yes Yes
Sprouse 2001 USA MIP 47 Yes Conventional and gamma probe
radioguided
100 1,2,5,6 Yes No
Stalberg 2007 Australia MIP 30 Yes Focused lateral mini-incision
technique
2,4,5 Yes No
Stepansky 2010 Israel MIP 108 No NA 100 1 Yes Yes
Sugino 2010 Japan MIP 167 Yes NA 100 2,4,5,6 Yes Yes
Summers 1991 USA BNE 100 – NA 5,6
Tarazi 1984 USA BNE 70 – NA 1,2,3,4
Tibblin 1982 Sweden MIP and BNE 25 75 Yes NA 100 1,2,5 No No
Udelsman 2011 USA MIP 986 Yes NA 100 5,6 Yes Yes
Untch 2012 USA MIP 136 No NA 100 2 Yes Yes
Usmani 2009 Kuwait MIP 9 No NA 100 5 Yes No
World J Surg
123
each surgical modality forcing indirect comparisons and at
moderate risk of bias. Most results are precise and con-
sistent except for the outcomes of cure and hypocalcemia
rates which vary substantially across studies (which could
be due to different outcome definitions). Cure rate was
close to 97 % with both approaches. Hypocalcemia was
more common in patients who underwent BNE 13.6 vs.
2.3 % with MIP. Mortality, bleeding, infection and laryn-
geal nerve injury rates were \1 % with both surgical
approaches.
Limitations and strengths
Our search strategy was conducted by an experienced
medical librarian, which increases our confidence in an
extensive search and identification of relevant literature.
However, articles could still be missed [105,106]. We
excluded articles not written in English which could
potentially affect the reported estimates [107]. The identi-
fication of 88 studies and over 11,000 patients, however,
makes unlikely the estimates will change significantly.
Reporting bias is also a concern, since outcomes for which
there were no events might have not been reported in the
original studies. In addition, publication bias may be a
concern, given that case series or cohorts from low volume
centers are less commonly reported and surgeons who
preferred the MIP approach might be more likely to publish
their positive results [108,109].
One limitation of the literature is the broad range and lack
of clear definitions in the outcomes of interest, especially for
cure rate and hypocalcemia (See Supplemental Table 1). For
example, for cure, different endpoints at different timelines
were used as definition (e.g., serum calcium levels vs PTH
levels vs. need for calcium supplementations and postoper-
ative measurements vs. 1-year follow-up). Moreover, the
assessment of outcomes was variable in the included reports.
For example, recurrent laryngeal nerve injury was assessed
only by symptoms in some series, while in others, complete
functional evaluation was carried out after the surgical pro-
cedure. In addition, the definition of the surgical procedure
itself is controversial as it could be argued that a procedure
that does not employ intraoperative PTH is not an MIP,
rather a focused surgical approach based on imaging. This
was also illustrated by a recent study that found 75 different
definitions for MIP. In fact, a standardized scheme for
reporting the different components of MIP is urgently nee-
ded [110]. Even though we planned and tried to perform
subgroup analysis—that may be clinically helpful—this was
not possible for all outcomes due to this inconsistency (i.e.,
limitations of how surgical techniques and outcomes are
defined). However, including studies with a clear definition
of MIP did not result in significant changes in the overall
pooled estimates.
Table 1 continued
Study Year Country Type of
surgery
Number of
patients
MIP
Number of
patients
BNE
MIP
definition
provided
Type of MIP % MIP
completed
Outcomes
measured
Pre-op
localization
PTH
monitoring
Vaid 2011 USA MIP 111 Yes NA 100 5 Yes No
Venkat 2012 USA MIP 200 Yes NA 100 5 Yes Yes
Wong 2011 UK MIP 100 Yes NA 100 5 Yes No
Wong 2009 Hong Kong MIP 65 No NA 100 2,5 Yes No
Outcomes: 1, Hypoparathyroidism; 2, Recurrent Nerve Injury; 3, Infection; 4, Bleeding; 5, Cure Rate; 6, Perioperative Mortality * Included children and adolescents
World J Surg
123
Table 2 Risk of bias observational studies
Study Year Representativeness
of the exposed
cohort
Selection of the
non-exposed
cohort
Ascertainment
of exposure
Demonstration that the
outcome of interest was
not present at baseline
Comparability of
cohorts on the basis
of design or analysis
Assessment
of the
outcome
Was follow-up
enough for
outcomes to
occur?
Adequacy of follow-
up of cohorts
Adil 2009 Somewhat
representative
NA Secure record Yes NA Record
linkage
No No statement
Arkles 1996 Somewhat
representative
NA Secure record Yes NA Record
linkage
Yes Complete follow-up
Babinska 2012 Somewhat
representative
NA Secure record Yes NA Record
linkage
No/Not clear No statement/Not
clear
Balisky 2005 Somewhat
representative
NA Secure record Yes NA Record
linkage
No Complete follow-up
Beyer 2007 Somewhat
representative
NA Secure record Yes NA Record
linkage
No Lost to follow-up rate
more than 20 % or
no description of
lost to follow up
Bumpous 2009 Somewhat
representative
NA Secure record Yes NA Record
linkage
No No statement
Burkey 2003 Somewhat
representative
NA Secure record Yes NA Record
linkage
No Complete follow-up
Carneiro 2004 Somewhat
representative
NA Secure record Yes NA Record
linkage
Yes Complete follow-up
Chau 2010 Somewhat
representative
No description Secure record Yes NA Record
linkage
No/Not clear No statement/Not
clear
Chen 1998 Somewhat
representative
NA Secure record Yes NA Record
linkage
No Complete follow-up
Chen 2005 Somewhat
representative
NA Secure record Yes NA Record
linkage
Yes Complete follow-up
DeCrea 2013 Somewhat
representative
NA Secure record Yes NA Record
linkage
Yes Complete follow-up
Del Rio 2013 Somewhat
representative
NA Secure record Yes NA Record
linkage
No No statement
Delbridge 2000 Somewhat
representative
Drawn from
same
community
Secure record Yes NA Record
linkage
Yes No statement
Dobrinja 2008 Somewhat
representative
NA Secure record Yes NA Record
linkage
Yes Complete follow-up
Doherty 1994 Somewhat
representative
NA Secure record Yes NA Record
linkage
No Complete follow-up
Durkin 2010 Somewhat
representative
No description Secure record Yes NA Record
linkage
Yes No statement/Not
clear
World J Surg
123
Table 2 continued
Study Year Representativeness
of the exposed
cohort
Selection of the
non-exposed
cohort
Ascertainment
of exposure
Demonstration that the
outcome of interest was
not present at baseline
Comparability of
cohorts on the basis
of design or analysis
Assessment
of the
outcome
Was follow-up
enough for
outcomes to
occur?
Adequacy of follow-
up of cohorts
Fang 2008 Somewhat
representative
NA Secure record Yes NA Record
linkage
No Complete follow-up
Ferzli 2004 Somewhat
representative
NA Secure record Yes NA Record
linkage
No No statement
Flint 2002 Selected group
(survey
responders)
NA Secure record Yes NA Record
linkage
No Complete follow-up
Fouda 1999 Selected group
(survey
responders)
NA Secure record Yes NA Record
linkage
No No statement
Fouquet 2010 Somewhat
representative
No description Secure record Yes NA Record
linkage
No/not clear No statement
Garimella 2012 Somewhat
representative
No description Secure record Yes NA Not
description
Yes Complete follow-up
Gauger 1999 Selected group
(survey
responders)
NA Secure record Yes NA Record
linkage
No No statement
George 2009 Somewhat
representative
NA Secure record Yes NA Record
linkage
No Lost to follow-up
unlikely to
introduce bias
Goasguen 2010 Somewhat
representative
No description Secure record Yes Size of adenoma Record
linkage
Yes No statement/Not
clear
Gurnell 2004 Somewhat
representative
NA Secure record Yes NA Record
linkage
No No statement
Haciyanli 2009 Somewhat
representative
NA Secure record Yes NA Record
linkage
No/not clear Not clear/no statement
Han 2007 Somewhat
representative
NA Secure record Yes NA Record
linkage
No No statement
Henry 2008 Somewhat
representative
NA Secure record Yes NA Record
linkage
No Complete follow-up
Henry 2001 Somewhat
representative
NA Secure record Yes NA Record
linkage
Yes Complete follow-up
Henry 2001 Somewhat
representative
NA Secure record Yes NA Record
linkage
Yes Lost to follow-up
unlikely to
introduce bias
Hughes 2013 Truly
representative
No description Secure record Yes NA Record
linkage
Yes Complete follow-up
World J Surg
123
Table 2 continued
Study Year Representativeness
of the exposed
cohort
Selection of the
non-exposed
cohort
Ascertainment
of exposure
Demonstration that the
outcome of interest was
not present at baseline
Comparability of
cohorts on the basis
of design or analysis
Assessment
of the
outcome
Was follow-up
enough for
outcomes to
occur?
Adequacy of follow-
up of cohorts
Kacker 2001 Somewhat
representative
NA Secure record Yes NA Record
linkage
No Complete follow-up
Karahan 2013 Somewhat
representative
No description Secure record Yes NA Record
linkage
Yes No statement
Kavanagh 2012 Somewhat
representative
No description Secure record Yes NA No
description
No Lost to follow-up
unlikely to
introduce bias
Kelly 2014 Somewhat
representative
NA Secure record Yes NA Record
linkage
No Complete follow-up
Koren 2005 Somewhat
representative
NA Secure record Yes NA Record
linkage
No Complete follow-up
Koskal 2006 Somewhat
representative
NA Secure record Yes NA Record
linkage
Yes No statement
Kuriloff 2004 Somewhat
representative
NA Secure record Yes NA Record
linkage
Yes No Statement
Li 2012 Somewhat
representative
No description Secure record Yes NA Record
linkage
Yes Complete follow-up
Livingston 2008 Somewhat
representative
NA Secure record Yes NA Record
linkage
No No statement
Lo 2003 Somewhat
representative
NA Secure record Yes NA Record
linkage
No Lost to follow-up rate
more than 20 % or
no description of
lost to follow up
Lorenz 2001 Somewhat
representative
NA Secure record Yes NA Record
linkage
No No statement
Martin 2000 Somewhat
representative
NA Secure record Yes NA Record
linkage
No Complete follow-up
Mekel 2005 Somewhat
representative
NA Secure record Yes NA Record
linkage
No Complete follow-up
Melck 2012 Somewhat
representative
No description Secure record Yes NA Record
linkage
Yes Lost to follow-up
more than 20 % or
no description of
lost to follow up
Meurisse 1999 Somewhat
representative
NA Secure record Yes NA Record
linkage
Yes Not statement
Miccoli 2004 Somewhat
representative
NA Secure record Yes NA Record
linkage
Yes Lost to follow-up
unlikely to
introduce bias
World J Surg
123
Table 2 continued
Study Year Representativeness
of the exposed
cohort
Selection of the
non-exposed
cohort
Ascertainment
of exposure
Demonstration that the
outcome of interest was
not present at baseline
Comparability of
cohorts on the basis
of design or analysis
Assessment
of the
outcome
Was follow-up
enough for
outcomes to
occur?
Adequacy of follow-
up of cohorts
Mortier 2004 Somewhat
representative
NA Secure record Yes NA Record
linkage
No Lost to follow-up
unlikely to
introduce bias
Moure 2008 Somewhat
representative
NA Secure record Yes NA Record
linkage
Yes No statement
Nottinham 1993 Somewhat
representative
NA Secure record Yes NA Record
linkage
No Complete follow-up
Okido 2001 Somewhat
representative
NA Secure record Yes NA Record
linkage
No Complete follow-up
Pang 2007 Somewhat
representative
NA Secure record Yes NA Record
linkage
No No statement
Pitale 2008 Somewhat
representative
NA Secure record No NA Record
linkage
Yes Complete follow-up
Prager 2001 Selected group
(survey
responders)
NA Secure record Yes NA Record
linkage
No Complete follow-up
Pratley 1973 Selected group
(survey
responders)
NA Secure record Yes NA Record
linkage
No No statement
Rajeev 2013 Somewhat
representative
No description Secure record Yes NA Record
linkage
Yes Complete follow-up
Rankin 1979 Somewhat
representative
NA Secure record Yes NA Record
linkage
No No statement
Ready 1996 Somewhat
representative
NA Secure record Yes NA Record
linkage
No Complete follow-up
Rubello 2006 Somewhat
representative
NA Secure record Yes NA Record
linkage
No Complete follow-up
Sarfati 1989 Somewhat
representative
NA Secure record Yes NA Record
linkage
Yes Complete follow-up
Scheneider 2012 Somewhat
representative
No description Secure record Yes NA Record
linkage
Yes No statement
Sevinc 2010 Somewhat
representative
NA Secure record Yes NA Record
linkage
No Complete follow-up
Shaha 1993 Selected group
(survey
responders)
NA Secure record Yes NA Record
linkage
No No statement
Shindo 2007 Somewhat
representative
NA Secure record Yes NA Record
linkage
No Complete follow-up
World J Surg
123
Table 2 continued
Study Year Representativeness
of the exposed
cohort
Selection of the
non-exposed
cohort
Ascertainment
of exposure
Demonstration that the
outcome of interest was
not present at baseline
Comparability of
cohorts on the basis
of design or analysis
Assessment
of the
outcome
Was follow-up
enough for
outcomes to
occur?
Adequacy of follow-
up of cohorts
Sidhu 2003 Somewhat
representative
NA Secure record Yes NA Record
linkage
Yes Complete follow-up
Somashekhar 2007 Somewhat
representative
NA Secure record Yes NA Record
linkage
Yes Lost to follow-up
unlikely to
introduce bias
Sprouse 2001 Selected group
(survey
responders)
NA Secure record Yes NA Record
linkage
No Complete follow-up
Stalberg 2007 Somewhat
representative
NA Secure record Yes NA Record
linkage
No No statement
Stepansky 2010 Somewhat
representative
No description Secure record Yes NA Record
linkage
Yes Complete follow-up
Sugino 2010 Somewhat
representative
No description Secure record Yes NA Record
linkage
No No statement
Summers 1991 Selected group
(survey
responders)
NA Secure record Yes NA Record
linkage
No Complete follow-up
Tarazi 1984 Somewhat
representative
NA Secure record Yes NA Record
linkage
No No statement
Tibblin 1982 Somewhat
representative
NA Secure record No NA Record
linkage
Yes Complete follow-up
Udelsman 2011 Somewhat
representative
No description Secure record Yes NA Record
linkage
No/Not clear No statement
Untch 2012 Somewhat
representative
No description Secure record Yes NA Record
linkage
Yes Complete follow-up
Usmani 2009 Somewhat
representative
NA Secure record Yes NA Record
linkage
Yes Complete follow-up
Vaid 2011 Somewhat
representative
Same community Secure record Yes NA Record
linkage
Not clear/No Not clear/no statement
Venkat 2012 Selected group
(survey
responders)
No description Secure record Yes NA Self report Yes Lost to follow-up
more than 20 % or
no description of
lost to follow up
Wong 2011 Somewhat
representative
No description Secure record Yes NA Record
linkage
No Complete follow-up
Wong 2009 Somewhat
representative
NA Secure record Yes NA Record
linkage
Yes Complete follow-up
World J Surg
123
For our analysis, we followed the intention-to-treat prin-
ciple which would provide conservative estimates since the
denominator includes all patients assigned for MIP, without
excluding conversions to BNE and patients lost to follow-up
(i.e., will dilute the MIP results because patients are likely to
have been allocated to this technique). In addition, patients
who underwent BNE could have had more parathyroid
glands removed which could also impact the surgical out-
comes rates; we tried to perform a sensitivity analysis to
account for this finding; however, it was not possible due to
the lack of the required information in the primary sources.
We relied on published descriptions to identify studies in
which intraoperative PTH was measured and did not adjust
for different definitions of cure based on PTH measurement,
which can also affect the results (the number of patients
considered ‘‘cured’’ will change when different threshold are
used). In addition, we focused on pooled estimates of the
frequency of each outcome based on series evaluating only
one surgical modality (BNE or MIP) and provided indirect
comparisons of these estimates [111]. Because of the low
probability of complications and failure to cure with both
treatment techniques (BNE and MIP), differences between
these groups could have been difficult to detect.
Selection bias is an important limitation of the included
studies given that the MIP cohorts are based on a selected
group of patients that has been preoperatively screened by
imaging. On the other hand, patients undergoing BNE
might represent patients with more severe disease or with
higher suspicion for multi-glandular disease. Ideally, to
provide direct comparisons between the expected surgical
outcomes of these procedures, randomization will be
required (which might not be appropriate for same
patients). We did not explore the effect of incidence of
multi-glandular disease or severity of disease (serum cal-
cium levels, serum PTH levels, parathyroid gland weight)
on the reported outcomes.
Despite these limitations related to the available evi-
dence itself, we provide a summary of the available evi-
dence after an extensive and systematic literature search,
allowing us to report the outcomes based on a large number
of patients who have undergone these surgical procedures.
Implications for practice
The most common cause of PHPT is a single parathyroid
adenoma that can be identified preoperatively in the
majority of the cases [5]. MIP is a safe surgical strategy
that in these cases is associated with a high cure rate and
low rates of postoperative bleeding, hypocalcemia, infec-
tion, mortality, or laryngeal nerve injury. BNE appears
similar to MIP except for higher rates of postoperative
hypocalcemia and laryngeal nerve injury that could be
expected given the larger extent of this surgical approach.
In clinical practice, the estimates for cure and compli-
cation rates reported here represent best estimates and as
such can help clinicians counsel patients as to whether they
should undergo parathyroidectomy for the treatment of
PHPT. Patients receiving care in practices with low volume
of endocrine surgery may experience more complications
and a lower cure rate than estimated here [112,113]. While
not an outcome of this study, we could note that patients
facing out-of-pocket costs may consider MIP as an option
possibly associated with lower costs due to a briefer
postoperative hospital stay [114,115].
Implications for research
We encountered a significant number of definitions for each of
the outcomes that we evaluated (hypocalcemia, recurrent
laryngeal nerve injury, infection, bleeding, and cure). Ideally,
guidelines for reporting outcomes of endocrine surgical
interventions will allow researchers to measure outcomes
more consistently. For example, the definition of cure inclu-
ded different combinations of biochemical measurements and
times of assessment. Similarly, the definition for hypocal-
cemia included different cutoffs based on serum calcium
levels, timing of calcium assessment, and measurement of
other biochemical parameters and are affected by different
Table 3 Risk of bias of randomized control trials
Study Year Randomization
method
Was the allocation
concealed?
Who was blinded during
the study?
Were there any imbalances
at baseline?
% of lost to
follow-up
Aarum 2007 Unknown Yes No blinding No Unknown
Bergenfelz 2005 Simple randomization Unclear Unknown No Unknown
Bergenfelz 2002 Unknown Unclear No blinding No Unknown
Hessman 2009 Unknown Yes Patients No Unknown
Russell 2005 Unknown Unclear Unknown Unknown Low
Slepavicius 2008 Double randomization
principle
Unclear No blinding No Low
World J Surg
123
Fig. 2 Summary of meta-analysis for surgical outcomes of parathyroidectomy according to surgical technique
World J Surg
123
institutional protocols in terms of calcium and vitamin D
supplementation after parathyroidectomy. These variable
definitions add inconsistency to the reported outcomes and in
clinical practice limit our confidence in the estimates.
Conclusion
Based on evidence at moderate risk of bias and indirect
comparisons, both MIP and BNE are associated with high
cure rates and low rates of complications (bleeding,
infection, mortality, laryngeal nerve injury) in patients with
PHPT. MIP appears to be associated with a lower rate of
hypocalcemia and recurrent laryngeal nerve injury when
compared to BNE. Standards for reporting clinical out-
comes and surgical technique are needed to further clarify
the surgical outcomes of patients with PHPT.
Acknowledgments This publication was made possible by CTSA
Grant Number UL1 TR000135 from the National Center for
Advancing Translational Sciences (NCATS), a component of the
National Institutes of Health (NIH). Its contents are solely the
responsibility of the authors and do not necessarily represent the
official view of NIH.
Authors contributions NSO, RRG, SM, and VMM served as
overall principal investigators, designed the study, wrote the protocol,
extracted the data, made statistical analysis, interpreted the data, and
wrote and reviewed the manuscript. SJ, AEEY, and ACG helped with
the extraction, statistical analysis, made a critical review of manu-
script, and assisted with protocol adaptations and submissions. MRG,
AAN, and JPB helped with the extraction, analyzed the data, made a
critical review of the manuscript, and assisted with protocol adapta-
tions and submissions. PE helped with the search strategy, made a
critical review of the manuscript, and assisted with protocol adapta-
tions and submissions. MR and RW interpreted the data, made a
critical review of the manuscript, and assisted with protocol adap-
tations and submissions. NSO and VMM are guarantors. All authors
read and approved the final manuscript.
Financial disclosures MRG was supported by CTSA Grant Num-
ber TL1 TR000137 from the National Center for Advancing Trans-
lational Science (NCATS). The contents of this manuscript are solely
the responsibility of the authors and do not necessarily represent the
official views of the NIH. This publication was made possible by
CTSA Grant Number UL1 TR000135 from the National Center for
Advancing Translational Sciences (NCATS), a component of the
National Institutes of Health (NIH). Its contents are solely the
responsibility of the authors and do not necessarily represent the
official view of NIH.
Compliance with ethical standards
Conflict of interests The authors declare no conflict of interest.
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