See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/312162790

Indications to laparoscopic cholecystectomy or oral dissolution therapy with

UDCA in symptomatic gallstone disease.

Article in Archives of Clinical and Experimental Surgery (ACES) · June 2014

DOI: 10.5455/aces.20140124040946

CITATIONS READS

2 513

5 authors, including:

Andrea Cariati Elisa Piromalli

Azienda Ospedaliera Universitaria San Martino di Genova 24 PUBLICATIONS 142 CITATIONS
141 PUBLICATIONS 678 CITATIONS
SEE PROFILE
SEE PROFILE

Morelli Nicola Enzo Andorno

69 PUBLICATIONS 540 CITATIONS 72 PUBLICATIONS 1,063 CITATIONS

SEE PROFILE SEE PROFILE

All content following this page was uploaded by Andrea Cariati on 17 January 2017.

The user has requested enhancement of the downloaded file.

 Original Article
Original Article

Archives of Clinical
Experimental Surgery

Increased of Langerhans Cells in Smokeless

Tobacco-Associated Oral Mucosal Lesions
Indications for Laparoscopic Cholecystectomy or Oral Dissolution
Therapy with Ursodeoxycholic Acid in Symptomatic Gallstone Disease
Érica Dorigatti
Andrea de Piromalli,
Cariati, Elisa Ávila1, Rafael
NicolaScaf de Giuliano
Morelli, Molon2,Bottino,
Melaine de Andorno
Enzo Almeida Lawall1, Renata Bianco
Consolaro1, Alberto Consolaro1
Department of General Surgery
Abstract San Martino, IST
University Hospital
Unconjugated bilirubin plays an important role in cholesterol gallstone formation. Patients with Genoa, Italy
1
Bauru Dental School
symptomatic gallstone disease who have high bilirubin plasma levels and/or are homozygous for the Received: November 14, 2013
Abstract University of São Paulo
Accepted: January 24, 2014
rs6742078 TT variant of the bilirubin glucuronidating gene UGT1A1 should not undergo oral dissolu- Bauru–SP, Brazil
Arch Clin Exp Surg 2014;3:161-165
Objective:
tion To evaluate
therapy with the changes
ursodeoxycholic acid. in the number of Langerhans Cells (LC) observed in the epithelium of
DOI:10.5455/aces.20140124040946
Asmokeless
large Danish study (SLT-induced)
tobacco has shown that high bilirubin plasma levels and the genetic variant rs6742078 TT
lesions.
2
Araraquara Dental Scho
São Paulo State Universit
Corresponding author:
of the enzyme
Methods: bilirubin glucuronidase
Microscopic sections fromUGT1A1
biopsiesare associated
carried out inwith an increased
the buccal mucosa riskofoftwenty
developing
patients, who were
Andrea Cariati Araraquara-SP, Brazil
symptomatic gallstone disease. Recent reports regarding the significant association between
chronic users of smokeless tobacco (SLT), were utilized. For the control group, twenty non-SLT users16166 bilirubin Via fratelli Coda 67/5 A
of SLT Genoa, Italy
levels and symptomatic gallstone disease open a new chapter about the indication and exclusion crite- Received: February 05, 20
with normal mucosa were selected. The sections were studied with routine coloring and were immunostained andrea.cariati@libero.it
ria for oral dissolution therapy of symptomatic gallstone disease. Accepted: February 29, 2
for S-100, CD1a, Ki-67 and p63. These data were statistically analyzed by the Student’s t-test to investigate the Arch Clin Exp Surg 2012
A highly select subgroup of patients with small, single, radiolucent cholesterol gallstones who received
differences in the expression of immune markers in normal mucosa and in SLT-induced leukoplakia lesions.
oral dissolution therapy with ursodeoxycholic acid (UDCA) had a reported recurrence of sympto-
DOI: 10.5455/aces.2012022

Results:
matic Theredisease
gallstone was aofsignificant difference
50% over five years. Thisin isthe immunolabeling
probably ofpersistence
related to the all markersofbetween normal mucosa
other causal Corresponding author
risk factors for gallstones in addition to that of cholesterol suprasaturation. A subgroup of patients a significant
and SLT-induced lesions (p<0.001). The leukoplakia lesions in chronic SLT users demonstrated Érica Dorigatti de Avila
increase in the number of Langerhans cells and in the absence of epithelial
with high plasma bilirubin levels and the UGT1A1 genetic variant rs6742078 have a greater risk ofdysplasia. Departamento de Estoma
da Faculdade de Odontol
Conclusion:
recurrence. The increase
In conclusion, oralindissolution
the number of these
therapy cells
with UDCArepresents the initial
might still stage of leukoplakia.
be appropriate for patients
Bauru
Keyrefuse
that words: Smokeless tobacco,
laparoscopic leukoplakic
cholecystectomy lesions,they
provided cancer,
havelangerhans cells,
small (< 0.5 cm),chewing tobacco.
radiolucent cholesterol Universidade de São Pau
gallstones and a functioning gallbladder, and have mean plasma bilirubin levels below 1.33 mg/dL and Avenida Alameda Octávi
are not homozygous for the UGT1A1 rs6742078 TT genotype. Pinheiro Brizola, 9-75, 17
Introduction contact with the oral mucosa and creates a Bauru–SP, Brasil
Key words: Laparoscopic cholecystectomy, oral dissolution therapy, symptomatic gallstone disease erica.fobusp@yahoo.com
more alkaline environment, its products may
Among tobacco users, there is a false be-
even be more aggressive to tissue [5]. The
lief Introduction
that SLT is safe because it is not burned, can women. This demographic variation is
whichGallstone prevalence
leads many people among the cigarettes
to quit gen- probably percentage of SLT
due to genetic users
factors andisdietary
lower compared
eral
andpopulation
start usingvaries
SLT in[1].
different countries.
However, SLT con- to cigarette
differences users; however,
as a cholesterol usage
and fatty acid-is increasing
Specifically, it is nearly 40% among South rich diet predisposes one to the onset of
tains higher concentrations of nicotine than among young individuals and it is therefore a
American women and Native Americans gallstones. The prevalence among men is
cigarettes and, in addition, nearly 30 carci- significant and disturbing danger [6,7].
[1], 20% among Italian and South Euro- usually one half that of women. Gender dif-
nogenic
pean substances,
women [2] andsuch as among
1-3 % Afri- ferences areInitial
tobacco-specific studies
probably on the
linked effects of SLT on the
to hormonal
N-nitrosamines (TSNA), which is formed oral mucosa demonstrated the formation of
during the aging process of the tobacco, [2-4] white lesions induced by chronic exposure to
 162 Cariati A et al.
factors that act on cholesterol and lipoproteins metab-
olism. The widespread use of ultrasonography has re-
sulted in an increased detection of clinically silent gall-
stones. Several studies found that the annual incidence
of biliary pain among patients with clinically silent gall-
stones ranges from 0.4% to 5% [3, 4], while Gracie and
Ransohoff [5] reported an incidence rate of 1-2%.
The general consensus is that asymptomatic gall-
stones should be managed without any treatment and
that, after the first episode of biliary pain develops, the
gold standard treatment is laparoscopic cholecystec-
tomy or, if it is feasible, oral dissolution therapy [6].
Because laparoscopic cholecystectomy has been the
standard treatment for symptomatic gallstones, all new
methods of gallstone treatment must be compared
against this standard. Oral dissolution therapy with
UDCA and/or chenodeoxycholic acid (CDCA) [7]
has been used with good results in select patients. Clas-
sical selection criteria include: cholesterol type of gall-
stone, functioning gallbladder with patent cystic duct
and gallstone size (best results if size is less than 0.5 cm)
[8]. Recently, several studies reported that bilirubin is a
causal risk factor for symptomatic gallstone disease [9,
10]. Hyperbilirubinbilia is a well-known risk factor for
black pigment gallstones (which accounts for 10-15%
of all gallstones), but its role in symptomatic cholester-
ol gallstone disease has not been well established.
The aim of this review is to analyze the recent lit-
erature regarding risk factors for the development of
symptomatic gallstone disease to revise the classical
patient selection criteria for the inclusion of oral dis-
solution therapy or laparoscopic cholecystectomy.
Table 1. Indications for laparoscopic cholecystectomy or oral dissolution therapy with UDCA in symptomatic gallstone disease.
Symptomatic gallstone disease
Black or brown pigment gallstones
Calcified cholesterol gallstone
Gallstone in non-functioning gallbladder
Radiolucent cholesterol gallstone with <1.33 mgr/dL plasma bilirubin level
Radiolucent cholesterol gallstone without gene UGT1A1 (rs6742078)
homozygosis
Radiolucent gallstone with bilirubin plasma level >1.33 mgr/dL and/or
gene UGT1A1 (rs6742078) homozygosis
Arch Clin Exp Surg
Materials and Methods
A review of published articles documenting indica-
tions for oral dissolution therapy or laparoscopic chol-
ecystectomy was performed using Pubmed and Google
Scholar using the search term: “indications for oral dis-
solution therapy for gallstone”.
Results
There is a general consensus to follow an expectant
management (no therapy) for asymptomatic patients
also if these are eligible for oral bile acid dissolution
treatment (pure cholesterol single gallstones less than
0,5 cm in diameter) due to the costs of therapy [5]. The
gold standard treatment for symptomatic gallstones
has been laparoscopic cholecystectomy [6] that can be
performed using the three of four trocars technique at
varying times following the onset of symptoms [11].
Oral dissolution therapy with UDCA can be adminis-
tered to patients meeting the classical criteria of pure,
radiolucent cholesterol gallstones in a functioning gall-
bladder, especially if the gallstones are less than 0.5-1.0
cm in diameter (success rates of dissolution are 90 and
40%, respectively, after six months of therapy) [8, 12].
The wider use of statins reduces the annual rate of chol-
ecystectomies [13, 14].
Recent studies reported a higher incidence of
symptomatic gallstones among patients with high
plasma bilirubin levels [9,10]. These studies suggest
a modification of the classical indication criteria for
oral dissolution therapy by restricting its use accord-
ing to the presence or absence of genetic variants of
the enzyme bilirubin glucuronidase UGT1A1 and to
plasma bilirubin levels as reported in Table 1.
Laparoscopic Oral dissolution
cholecystectomy therapy (UDCA)
Yes No
Yes No
Yes No
Yes Yes, feasible
Yes Yes, feasible
Yes No
Year 2014 | Volume:3 | Issue:3 | 161-165
 Oral dissolution therapy with UDCA in symptomatic gallstone disease
Discussion
A large Danish study has shown that high plasma
bilirubin levels are associated with an increased risk
of developing symptomatic cholesterol and pigment
gallstone disease [9]. Cholesterol gallstones account
for 80% of all gallstones and it is the only type of gall-
stone that can be treated by oral dissolution therapy
with UDCA. Recent reports of a significant association
between bilirubin and symptomatic gallstone disease
open a new chapter regarding the indication and exclu-
sion criteria for oral dissolution therapy of symptomat-
ic cholesterol gallstone disease.
In fact, cholesterol suprasaturation in bile is neces-
sary, but not sufficient, to develop gallstones. Pronucle-
ating and antinucleating substances are present in bile.
Unconjugated bilirubin, calcium ions and mucus pro-
teins are pronucleating substances. Stender et al. [9]
demonstrated that the genetic variant rs6742078 TT of
the enzyme bilirubin glucuronidase UGT1A1 is associ-
ated with increased levels of plasma and bile bilirubin.
In addition, it is probably associated with an increased
level of unconjugated bilirubin in bile that, as in Gil-
bert syndrome, is associated with an increased risk of
gallstone disease [9]. Bilirubin metabolites in bile are:
bilirubin diglucuronide and monoglucuronide (98%)
and unconjugated bilirubin (2%). Deconjugation of di-
and mono-glucuronide bilirubin may be catalyzed by
mucosal glucuronidase or bacterial glucuronidase (en-
dogenous beta-glucuronidase activity can be detected
at pH 7.5 or lower, but conjugated bilirubin may also
undergo non-enzymatic hydrolysis to form unconju-
gated bilirubin [15].
Unconjugated bilirubin in normal bile exceeds
its aqueous solubility by 100-1000 fold [15, 16] (the
solubility of unconjugated bilirubin at pH 8.5 in he-
patic bile is 3 mmol/L, and it is 1 nmol/L at pH 7 [16].
When unconjugated bilirubin exceeds its solubility, it
forms a divalent salt with calcium. Calcium bilirubi-
nate can precipitate either in the main lumen or in the
Rokitansky-Ashoff sinuses of the gallbladder [17]. As
assessed by X-ray diffractometry, calcium bilirubinate
is amorphous, as is calcium palmitate. In contrast, cal-
cium phosphate, calcium carbonate, cholesterol and
calcium palmitate rosettes are crystalline [14, 17, 18].
Heterogeneous nucleation of cholesterol crystals on
DOI:10.5455/aces.20140124040946
163
a black pigment calcium bilirubinate nucleus is more
likely than homogenous nucleation and amorphous
calcium bilirubinate acts as a cement between the ir-
regular features of cholesterol crystals, thus promoting
an interaction between crystals [14].
The role of unconjugated bilirubin is as important
as the role of cholesterol in gallstone formation. This
should be taken into account during studies of symp-
tomatic gallstone disease prevention and treatments
[14]. Further in vitro studies also could report the
role of unconjugated bilirubin by adjusting the classi-
cal Admirand and Small triangles as in Figure 1 [19].
Moreover, oral dissolution therapy with UDCA among
a highly select subgroup of patients with small, single,
pure cholesterol gallstones has a reported recurrence
of 50% over five years [8]. These results are probably
related to the persistence of the causal risk factors of
gallstones that are not only represented by cholesterol
suprasaturation, but also by unconjugated bilirubin su-
prasaturation and by gallbladder wall factors (gallblad-
der motility and Rokitansky-Aschoff sinuses) [14, 17].
A study by Stender et al. [9] indicates that a sub-
group of patients with symptomatic gallstone disease
is at increased risk of gallstone recurrence after oral dis-
solution therapy with bile acids. In addition, the indi-
Figure 1: Modified Admirand and Small triangle. CHOL is choles-
terol percentage from 0-100%. LECIT is lecithin percentage from
0-100%. BILIARY SALT is bile salt concentration from 0-100%.
On the y-axis is mucin concrentration (with a top at 1100 micro-
gr/mL). On the z axis is the percentage of unconjugated bilirubin
(UCB) with respect to conjugated bilirubin (usually 2-8%). The
final result is a truncated pyramid volume that contains data of the
five biliary variables in patients with cholesterol gallstones [19].
www.acesjournal.org
 164 Cariati A et al.
cations for oral litholysis with UDCA among patients
with symptomatic gallstone disease should be revisited
in light of these new findings. In fact, oral dissolution
therapy with UDCA might still be appropriate in pa-
tients that refuse laparoscopic cholecystectomy provid-
ed they have small (<0.5 cm), radiolucent cholesterol
gallstones, a functioning gallbladder [9], mean plasma
bilirubin levels <1.33 mg/dL [9] and are not TT ho-
mozygous for the UGT1A1 rs6742078 genotype [9]
(Table 1). Diagnostic tests to select the subgroup of pa-
tients that would benefit from oral dissolution therapy
with UDCA include abdominal ultrasound with the
study of gallbladder contractility, abdominal x-ray (or
abdominal CT scan), plasma bilirubin level determina-
tion and genetic analysis of bilirubin glucuronidating
enzyme UGT1A1 rs6742078. In conclusion, patients
with radiolucent, single small cholesterol gallstones
should not undergo oral dissolution therapy with
UDCA if they have high plasma bilirubin levels (>1.33
mg/dL) or are homozygous for the rs6742078 TT ge-
netic variant in the bilirubin glucuronidating gene.
Conflict of interest statement
We declare that we did not receive funding for this
study and that we have no conflicts of interest nor any
financial interest in publishing this paper.
References
1. Sampliner RE, Bennett PH, Comess LJ, Rose FA,
Burch TA. Gallbladder disease in pima indians.
Demonstration of high prevalence and early onset
by cholecystography. N Engl J Med 1970;283:1358-
1364.
2. Heaton KW, Braddon FE, Mountford RA, Hughes
AO, Emmett PM. Symptomatic and silent gall
stones in the community. Gut 1991;32:316-320.
3. Comfort MW, Gray HK, Wilson JM. The Silent
Gallstone: A Ten to Twenty Year Follow-up Study
of 112 Cases. Ann Surg 1948;128:931-937.
4. Ralston DE, Smith LA. The natural history of
cholelithiasis. A 15 to 30-year follow-up of 116 pa-
tients. Minn Med 1965;48:327-332.
5. Gracie WA, Ransohoff DF. The natural history of
silent gallstones: the innocent gallstone is not a
myth. N Engl J Med 1982;307:798-800.
6. National Institutes of Health Consensus Devel-
opment Conference Statement on Gallstones
Arch Clin Exp Surg
and Laparoscopic Cholecystectomy. Am J Surg
1993;165:390-398.
7. Fromm H, Roat JW, Gonzalez V, Sarva RP, Farivar
S. Comparative efficacy and side effects of ursode-
oxycholic and chenodeoxycholic acids in dissolv-
ing gallstones. A double-blind controlled study.
Gastroenterology 1983;85:1257-1264.
8. Portincasa P, Moschetta A, Palasciano G. Choles-
terol gallstone disease. Lancet 2006;368:230-239.
9. Stender S, Frikke-Schmidt R, Nordestgaard BG,
Tybjærg-Hansen A. Extreme bilirubin levels as a
causal risk factor for symptomatic gallstone dis-
ease. JAMA Intern Med 2013;173:1222-1228.
10. Greenhill C. Gallbladder: High levels of bilirubin
as a risk factor for symptomatic gallstone disease.
Nat Rev Gastroenterol Hepatol 2013;10:444.
11. Gurusamy KS, Koti R, Fusai G, Davidson BR. Ear-
ly versus delayed laparoscopic cholecystectomy for
uncomplicated biliary colic. Cochrane Database
Syst Rev 2013;6:CD007196.
12. Guarino MP, Cocca S, Altomare A, Emerenziani
S, Cicala M. Ursodeoxycholic acid therapy in gall-
bladder disease, a story not yet completed. World J
Gastroenterol 2013;19:5029-5034.
13. Suuronen S, Niskanen L, Paajanen P, Paajanen
H. Declining cholecystectomy rate during the era
of statin use in Finland: a population-based co-
hort study between 1995 and 2009. Scand J Surg
2013;102:158-163.
14. Cariati A, Piromalli E. Limits and perspective of oral
therapy with statins and aspirin for the prevention
of symptomatic cholesterol gallstone disease. Ex-
pert Opin Pharmacother 2012;13:1223-1227.
15. Spivak W, DiVenuto D, Yuey W. Non-enzymic hy-
drolysis of bilirubin mono- and diglucuronide to
unconjugated bilirubin in model and native bile
systems. Potential role in the formation of gall-
stones. Biochem J 1987;242:323-329.
16. Brodersen R. Bilirubin. Solubility and interac-
tion with albumin and phospholipid. J Biol Chem
1979;254:2364-2369.
17. Cariati A, Cetta F. Rokitansky-Aschoff sinuses of
the gallbladder are associated with black pigment
gallstone formation: a scanning electron micros-
copy study. Ultrastruct Pathol 2003;27:265-270.
Year 2014 | Volume:3 | Issue:3 | 161-165
 Oral dissolution therapy with UDCA in symptomatic gallstone disease 165

18. Cariati A. Blackberry pigment (whitlockite) gall-
stones in uremic patient. Clin Res Hepatol Gastro-
enterol 2013;37:e69-e72.
19. Cariati A. Cholesterol gallstone formation in bile.
Admirand and Small triangle could be modified
reporting the rules of unconjugated bilirubin and
mucin. Comment on Nature 2012 on line num-
bers #53054 and #53127 (figure 1) to: Davis JG,
Gierszal KP, Wang P, Ben-Amotz P. Water struc-
tural transformation at molecular hydrophobic
interfaces. Nature 2012; 491: 582-585. Available
via: http://www.nature.com/nature/report/index.
html?comment=53054&doi=10.1038/nature11570
and Available via: http://www.nature.com/nature/re-
port/index.html?comment=53127&doi=10.1038/
nature11570 (Accessed: November 0, 2013).

DOI:10.5455/aces.20140124040946
View publication stats
© GESDAV
This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial
License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, www.acesjournal.org
distribution and reproduction in any medium, provided the work is properly cited.