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 Chapter 3

Acute Cholecystitis: Diagnostic Pitfall and Timing of

Treatment

Pasquale Cianci,
Pasquale Cianci, Nicola
Nicola Tartaglia,
Tartaglia,Alberto
AlbertoFersini,
Fersini,
Sabino Capuzzolo, Libero Luca Giambavicchio,
Sabino Capuzzolo, Libero Luca Giambavicchio,
Antonio Ambrosi
Antonio Ambrosi and
and Vincenzo
Vincenzo Neri
Neri
Additional information
Additional information is
is available
available at
at the
the end
end of
ofthe
thechapter
chapter

http://dx.doi.org/10.5772/67549

Abstract
Objective: Cholelithiasis represents a very frequent health problem with higher prevalence
in developed countries. The aim of this chapter is to underline, also by submitting our surgi-
cal experience, some diagnostic deceptions and the timing of treatment.
Methods: The presentation of 42 patients admitted in our institution (September 2012/
September 2014) with the diagnosis of acute pancreatitis allows to identify two differ-
ent clinical forms of acute biliary pancreatitis: the pancreatic pattern and biliary pattern.
Moreover, the evaluation of another 42 patients observed in our institution (September
2014/September 2016) with acute cholecystitis should show our treatment program. Also,
we added the analysis of our previous research, regarding acute cholecystitis, already pub-
lished: difficult cholecystectomy, antegrade dissection in laparoscopic cholecystectomy,
postoperative morbidity, laparoscopic approach in cirrhotics, finally the robotic experience.
Results: Clinical features, laboratory, and imaging exams should identify, into acute bili-
ary pancreatitis, two clinical forms as biliary pattern and pancreatic pattern for different
therapeutic approach. The treatment chosen for acute cholecystitis is early laparoscopic cho-
lecystectomy within 24–72 hours. Severe, complicated acute cholecystitis can require urgent
surgical intervention.
Conclusion: Acute cholecystitis encompasses clinical forms with various degree of severity
and several clinical courses. The treatment is focused on early cholecystectomy with various
and different management strategies, suitable to the specific pathological conditions.

Keywords: acute cholecystitis, acute pancreatitis, cholelithiasis, cholecystectomy,

laparoscopic approach

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons
© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,
Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,
distribution, and reproduction in any medium, provided the original work is properly cited.
and reproduction in any medium, provided the original work is properly cited.
24 Updates in Gallbladder Diseases

1. Introduction

Cholelithiasis represents a very frequent health problem. The prevalence of cholelithiasis is

higher in the developed regions such as Europe and North America in comparison to the
developing regions of the world (Africa, Middle East, China, India, Far East). On average,
gallstone disease affects 10–15% of the adulthood population in the age of majority [1, 2]. The
cost of gallstone disease has high social, administrative, and economic impact as interference
with work activities, home care, hospital admission, and so on. Mortality rate for gallstone
disease reaches 0.6%, thanks to the reduction of more than 50% over the last 60 years [3].
Gallstone disease in its evolution involves acute cholecystitis and some risks of complications
such as gallstone-related pancreatitis and cancer [4, 5]. Moreover, cholecystectomy morbid-
ity encompasses various and diversified pathological conditions especially in severe inflam-
matory circumstances. We underline the problems connected with insufficient preoperative
evaluation. Complications can be divided in intraoperative and postoperative. Intraoperative
morbidity includes bile duct injury, gallbladder perforation, bleeding, and bowel perforation.
Postoperative complications consist of infection and dehiscence of surgical incision, subhe-
patic abscess, residual choledocolithiasis, postcholecistectomy syndrome, umbilical hernia.
Currently, cholecystectomy morbidity rate reaches 8.7–9.5% with up 15% in so-called difficult
cholecystectomy. Among these complications is in evidence the bile duct injury which causes
great impact on patient outcomes and requires usually complex and various procedures of
repair: endoscopy, surgery, operative biliary radiology [6].

2. Etiology and pathogenesis of gallstones

Various etiological conditions and risk factors can cause gallstone disease. We can underline
the gender, age, obesity, fast weight loss, alcohol use, diabetes, pregnancy, hypertriglyceride-
mia, and so on. The study of pathogenesis of gallstones can identify all etiological factors. The
majority of gallstones are non-pigmented stones which are composed of cholesterol (75% of
cases). The cholesterol is retained in solution by an unsteady balance among levels of phos-
pholipids, bile acids, and cholesterol (Admirand’s triangle) [7]. This balance can be disrupted
by several factors: cholesterol supersaturation in bile, crystal nucleating factors because choles-
terol supersaturates tends to precipitate and crystallize, impairment of gallbladder functions
as motility, absorbtion, secretion, finally impaired enterohepatic circulation of bile acids that
changes the balance of Admirand’s triangle. In summary, cholesterol stones are caused by cho-
lesterol iperproduction, large cholesterol-phospholipid vesicles, crystal precipitation (choles-
terol monohydrate crystal) [8]; moreover, by calcium nucleation, and other nucleating factors
as mucin glycoproteins, immunoglobulins, and so on. In addition, impairment of gallbladder
functions plays a significant role: decrease of motility with stasis as in prolonged fasting and
parenteral nutrition, diabetic disease, long-term somatostatin therapy, alteration of absorptive,
secretive activity with increase of water reabsorption. Finally, the reduction of intestinal reab-
sorption of bile acids in the entero-hepatic circulation is also in evidence. Crystallizations of
cholesterol within bile form biliary sludge and biliary sludge can be considered a common
precursor of the gallstones. Pigmented stones consist of calcium-bilirubinate. These stones
 Acute Cholecystitis: Diagnostic Pitfall and Timing of Treatment 25
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are due to solubilization of unconjugated bilirubin with precipitation. There are two types:
black and brown. Black stones reach about 15–20% of global biliary stones. They are caused
and occur in several diseases: hemolytic disorders (increased red blood cell destruction), liver
diseases, cirrhosis (abnormal metabolism of hemoglobin), distal ileal resection (reabsorption
of bile salts), and long-term total parenteral nutrition (TPN). Commonly these stones form in
gallbladder. Brown stones, on the contrary, are found in biliary ducts as primary common bile
duct (CBD) stones. These stones are associated with infection in bile ducts. Bacteria (Escherichia
coli, Klebsiella frequently) produce bacterial beta-glucuronidase; consequently deconjugated
bilirubin, not hydrosoluble, forms calcium bilirubinate. Biliary infections are commonly associ-
ated with biliary ducts stenosis, ampullary stenosis, abnormal sphincter of Oddi, sclerosing
cholangitis, cirrhosis.

3. Epidemiology and pathophysiology of acute cholecystitis

Symptoms or complications of gallstones can develop in 1–2% of the patients for years [9].
Clinical presentation of cholelithiasis can be various: in the majority of cases (60–80%) lithiasis
stay on long asymptomatic or for the patient’s whole life and its detection could be incidental.
Symptoms of different degree, mild or severe for advanced complications occur in the 20–40% of
patients. Acute cholecystitis is the very frequent surgical entity that occurs in 15–20% of patients
with symptomatic disease. Cholecystitis could be caused by obstruction of the cystic duct by a
gallstone with the same pathogenesis of biliary colic. The obstacle of bile outflow from gallblad-
der causes its wall distention and wall inflammation. This pathological condition may develop
in different ways. In the severe cases (10–18%), the prolonged and complete obstruction causes
extension of parietal flogosis resulting in disturbance of blood perfusion and necrosis. In the
favorable cases, which are the majority, the stone moves, obstruction resolves, and inflammation
may regress. In the acute cholecystitis, bacterial superinfection can occur in 50% of cases with
positive bile culture (Escherichia coli, Klebsiella, Enterobacter, etc.) [10]. We can believe that acute
cholecystitis starts as inflammatory disease without bacterial infection. Recently more complex
pathogenesis has been hypothesized in acute cholecystitis. Acute cholecystitis should be pro-
duced with the addition of irritating factors of gallbladder mucosa to the blockage of the cystic
duct. Lysolecithin has been used in experimental setting as irritant; but lysolecithin comes by
catalyzation from lecithin, normal constituent of bile, by phospholipase A. Trauma of impacted
gallstone may cause the release of this enzyme [11]. Moreover, lysolecithin was found in the
gallbladder with acute inflammation [12]. Gallbladder flogosis should be worsened by further
inflammatory mediators such as prostaglandins, which play an important role in functional
activity of gallbladder (motility, fluid absorption, etc.) [13]. In summary, prolonged obstruc-
tion of gallbladder neck leads the increase of intraluminal pressure, with venous congestion,
impaired blood supply, and lymphatic drainage. Damage of gallbladder wall (edema, intramural
haemorrhage) and secondary bacterial infection complete the pathological features. Acalculous
cholecystitis is acute inflammatory disease associated with right upper abdominal quadrant
pain, leucocitosis, thickened wall without gallstones (ultrasonography (US) findings). Most fre-
quently, it happens in patients with severe disease such as severe burns, trauma, major surgery,
long-term TPN; frequently cholecys`titis can develop with high morbidity and mortality [14].
26 Updates in Gallbladder Diseases

In the acute acalculous, cholecystitis probably can play a role of the bile stasis (fasting, narcosis)
causing distension of wall, impaired blood supply, necrosis. Increased viscosity by dehydration
and intestinal dynamic occlusion produces sludge formation and bacterial overgrowth in the
gallbladder. US shows gallbladder wall thickening, sludge, pericholecystic fluid.

4. Clinical presentations of gallstone disease

Gallstones disease can present and develop in the wide clinical range. Asymptomatic disease
can be detected incidentally. The absence of symptoms is linked to the mobility of stones
that will not obstruct the cystic duct. The presence of gallstones, although asymptomatic for
a prolonged time, can develop in symptomatic disease with various clinical entities. Most
simple and frequent presentation is biliary colic characterized by abdominal pain localized in
right upper abdominal quadrant, nausea, vomiting, frequently irradiating to the right shoul-
der. Usually the colic lasts a few hours. Asymptomatic patients can develop symptomatic
disease in 20–30% of cases in the long term (20 years). The clinical developments of gall-
stone disease encompass several presentations: biliary colic, acute cholecystitis (with various
degree of severity such as gangrene, emphysematous cholecystitis, perforation, cholecysto-
enteric fistula, gallstone ileus), choledocolithiasis, cholangitis, biliary pancreatitis, gallblad-
der carcinoma. The significant clinical problem is the surgical indication of cholecystectomy
for patients with asymptomatic gallstone. The overall likelihood of clinical appearance for
asymptomatic patients should be about 30% but we have to insert it and evaluate it in specific
conditions: demographic, pathophysiological, and clinical. Another relevant information for
the surgical indication choice is the incidence of postoperative morbidity of cholecystectomy.
From the literature, overall morbidity (minor and major) of cholecystectomy in the laparo-
scopic era for uncomplicated gallstone disease in patients without comorbidity is very low:
overall complication rate is 1.5% and the mortality rate is less than 0.1% [15]. In summary, sur-
gical treatment is the first choice in the patients with symptoms, cholecystitis, and gallblad-
der stone-related complications. Moreover, nowadays, the surgical indication for patients
completely asymptomatic is debatable and not well defined. We can identify several clinical-
pathological conditions without clear and evident clinical appearance in which laparoscopic
cholecystectomy should be indicated: patients with mild clinical appearance such as intense
discomfort in the right upper quadrant, nausea vomiting, biliary colic because considerable
risk for developing complications, young patients because high likelihood to develop in later
years symptoms or/and complications, patients with pigmented stones caused by hemolytic
disorders (increased red blood cells destruction) because the risks linked to this pathology in
case of gallstone-related complications, patients with clearly established gallbladder dysfunc-
tion that frequently develops symptomatic disease (25–30% of cases) [16], patient with large
stones (>2 cm) for high risk to develop cholecystitis, patients with porcelain gallbladder (cal-
cifications in the wall) because of the risk of gallbladder cancer (5–10%).

4.1. Common clinical presentation of acute cholecystitis

Patients with mild symptomatic gallstone disease such as recurrent biliary colic or mild
postprandial discomfort can develop in about 20% of cases acute cholecystitis. This path-
 Acute Cholecystitis: Diagnostic Pitfall and Timing of Treatment 27
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ological evolution commonly is connected with obstruction by stones of gallbladder neck

or cystic duct. The time duration of the obstructive condition (short or long time) can lead
to decrease and resolution of inflammatory process or, on the contrary, to wall distension,
impaired blood supply, ischemia, necrosis of gallbladder (severe cases 15–20%). In about
50% of cases, commonly in the prolonged impairment of bile outflow from the gallbladder,
bacterial infection adds to flogistic process. In acute cholecystitis, patients complain of severe
pain in abdominal right upper quadrant and overall the clinical presentation is overlappable
to biliary colic but the characteristic pain is on the contrary prolonged greater than 4–6 hours.
Usually fever, nausea, anorexia, and vomiting join and the pain should be referred to right
shoulder or back. Frequently the patients refer previous episodes of biliary colic, or fatty
food ingestion few hours before the onset of colic. Clinical observation shows the suffering
patient with fever, tachycardia, nausea, emesis, anorexia, and inhibition or diminution of the
respiratory movement of right upper quadrant and epigastric area of abdominal wall. On
physical examination can be seen right upper quadrant tenderness of varying degree and
positive Murphy’s sign with increased discomfort and/or inspiratory arrest while, palpating
right upper quadrant, the patient is invited to make deep inspiration. A positive sign shows
sensitivity of 97% and specificity of 93% [17]. In some cases (about 30%), acute cholecystitis
can develop discrete extension of inflammation outside gallbladder wall causing local perito-
nitis with involvement of omentum and adjacent organs that forms a flogistic mass, palpable
in upper right quadrant. Leukocytosis is an almost constant laboratory finding characterized
by the white cell count increase, connected with the severity of the disease.

4.2. Deceptions of clinical diagnosis of acute cholecystitis

Cholelithiasis is the most frequent cause of acute pancreatitis. Clinical diagnostic difficulties
may arise in the context of acute biliary pancreatitis. The major clinical problem is to dis-
tinguish clinical forms of hyperamylasemia, associated with severe abdominal pain, physi-
cal signs of upper abdominal tenderness and guarding based on acute biliary tract disease
(acute cholecystitis, cholangitis, etc.) from acute biliary pancreatitis with evident pancreatic
involvement. In the context of acute biliary pancreatitis may merge acute abdominal dis-
eases different to each other; but they have in common hyperamylasemia and acute/severe
upper abdominal pain and abdominal wall guarding. The correct diagnosis and distinction
between moderate or severe acute biliary pancreatitis with hyperamylasemia, evident pancre-
atic involvement, severe upper abdominal pain/abdominal wall guarding, and acute biliary
tract disease (cholecystitis, cholangitis, etc.) with hyperamylasemia, severe upper abdomi-
nal pain, abdominal wall guarding, minimal, or mild pancreatitis, allows to follow different
therapeutic program overall in regard to timing of surgery [18]. Our aim is to define clinical
and laboratory differentiation between these two clinical manifestation regarding the choice
of therapeutic program. The presentation of consistent and appropriate experience should
clarify some diagnostic difficulties, within the acute biliary pancreatitis, between two clinical-
pathological forms different but confusable. We have evaluated 42 patients admitted in our
Institution in the period September 2012/September 2014. The admission diagnosis was acute
pancreatitis, based on first basic clinical and laboratory evaluation. Demographic features:
male 26, female 16, mean age 64 years (range: 89–27 years). Signs and symptoms of 42 patients
at the admission are reported in (Figure 1).
28 Updates in Gallbladder Diseases

Figure 1. Frequency (%) of signs and symptoms in patients with diagnosis of acute pancreatitis.

In the first phase of the study, the patients have been divided by etiology of acute pancreatitis.
The majority of cases (30 pts. 71%—Group A) shows biliary etiology, based on the detection
with imaging study (US) of biliary lithiasis. In seven patients (Group B—16.6%), the clinical-
anamnestic criteria show the alcoholic etiology (prolonged alcohol abuse). The other five
patients (Group C—11.9%) have been classified as acute pancreatitis patients with unknown
etiology. The patients subdivided following the etiological criteria (Groups A, B, C) have been
evaluated regarding to severity of disease with Ranson criteria, pancreatic involvement with
CT severity index (Balthazar), and finally likelihood of biliary etiology with Blamey criteria
using clinical and laboratory data (age, sex, amylase, alkaline phosphatase, ALT) [19–22]. The
important section of this study concerns the biliary pancreatitis. Within 30 patients with ini-
tial diagnosis of acute biliary pancreatitis (Group A), we have identified two subgroup: the
first subgroup A1 that encompasses 18 patients with acute biliary pancreatitis with moderate/
severe pancreatic involvement and the subgroup A2 that includes 12 patients with acute biliary
disease and minimal pancreatic involvement based on transient hyperamylasemia. The aim of
this subdivision and comparison is to identify, by laboratory and imaging study, two different
clinical forms of acute pancreatitis: the pancreatic pattern (A1) and the biliary pattern (A2).
The patients have been subdivided in three groups following the etiology criteria: biliary
(Group A), alcoholic (Group B), and undefined pancreatitis (Group C). First, we can evaluate if
there are differences among the groups of patients regarding clinical severity (Ranson score),
degree of pancreatic involvement (CT severity index-Balthazar), and finally the likelihood of
biliary etiology (Blamey score). The evaluation of clinical severity (Ranson score) between the
group A (biliary) and group B (alcoholic) shows no differences with Student’s t-test: t = 0.1375
< t0.05 = 1.6896. Because of the low number of cases in our groups, we have also employed the
Kolmogorov-Smirnov test for the comparison of clinical severity (Table 1).
 Acute Cholecystitis: Diagnostic Pitfall and Timing of Treatment 29
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Group Aa versus Group Bb D = 0.205 < D0.05 = 0.554

Group A versus Group Cc D = 0.634 < D0.05 = 0.640

Group B versus Group C D = 0.429 < D0.05 = 0.800

*
Kolmogorov-Smirnov test.
a
Group A: biliary.
b
Group B: alcoholic.
c
Group C: undefined.

Table 1. Comparison of clinical severity between group A, group B, and group C*.

The results of the severity disease comparison (CT severity index) show that there are not
statistically significant differences between group A versus group B and between group B ver-
sus group C. The comparison between group A versus group C shows also no differences
(empirical p value < theoretical p value) even if in the group C there are mild pancreatitis and
in group A there are severe pancreatitis. The comparison among the three groups of degree of
pancreatic and extrapancreatic damage (CT severity index-Balthazar) demonstrates that, even
in this area, there are not statistically significant differences (Table 2).
Finally the evaluation of the predictive accuracy of biliary etiology based on clinical data
(Blamey score) among the three groups did not provide effective results for the early defini-
tion of the biliary etiology because of no statistical differences (Table 3).

Group Aa versus Group Bb t = 0.4345 < t0.05 = 1.609

Group A versus Group Cc t = 0.2884 < t0.05 = 1.6939

Group B versus Group C t = 0.2006 < t0.05 = 1.8595

*
Student’s t-test.
a
Group A: biliary.
b
Group B: alcoholic.
c
Group C: undefined.

Table 2. Comparison of CT severity index between group A, group B, and group C*.

Group Aa versus Group Bb t = 0.0568 < t0.05 = 1.6896

Group A versus Group Cc t = 0.9195 < t0.05 = 1.6924

Group B versus Group C t = 0.8594 < t0.05 = 1.8125

*
Student’s t-test.
a
Group A: biliary.
b
Group B: alcoholic.
c
Group C: undefined.

Table 3. Comparison of Blamey score between group A, group B, and group C*.
30 Updates in Gallbladder Diseases

To identify the two subgroups A1 (pancreatic pattern) and A2 (biliary pattern) within the
group A (acute biliary pancreatitis) have been used clinical features, laboratory, instrumental
tests (imaging), therapeutical procedures employed. We have verified if there are statistically
significant differences between group A1 and group A2 with respect to leukocytosis, amyla-
semia, bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline
phosphatase, clinical severity score (Ranson), modified CT severity index (Balthazar). The
purpose of the study is to identify clinical or instrumental criteria for detection of pancreatic
pattern versus biliary pattern in acute biliary pancreatitis. In the statistical evaluation, leu-
kocytosis, amylasemia, and alkaline phosphatase did not show differences between the two
groups. On the contrary, there are differences for bilirubin, AST, and ALT. The results of com-
parison, among subgroups A1 and A2, of clinical severity score (Ranson) and modified CT
severity index (Balthazar) are different with statistical significance with Student’s t-test but not
following Kolmogorov-Smirnov test (Table 4).

Finally, we have compared the results of clinical severity score and modified CT severity index
respectively within the subgroup A1 (Figure 2) and subgroup A2 (Figure 3).

In the subgroup A1 (pancreatic pattern), the results of two scores are overlappable (covari-
ance = 0.000177 > 0). Otherwise in the subgroup A2, the data of the two scores are discordant.
The results of this section of our study allow several considerations. First, we can identify
in the group A (acute biliary pancreatitis) two subgroups: A1 (pancreatic pattern) and A2
(biliary pattern). In the subgroup A2, the pancreatic involvement (valued with modified CT
severity index) was mild (pancreatic edema); on the contrary, in the subgroup A1, the pan-
creatic damage was moderate/severe or severe (Grade C2, D3); the difference between the
two groups is statistically significant with Student’s t-test not with Kolmogorof-Smirnov test.
The clinical severity (Ranson score) was comparable in both groups and of middle level.
The comparison of bilirubin, AST, ALT shows impairment significant in the subgroup A2;
not significant the differences for amylasemia, leukocytosis, and alkaline phosphatase. The
therapeutic program followed the indication of clinical evaluation. The first approach is
based on medical treatment: fluid-electrolyte replacement, control of pain, nutrition, control
of papillary flow and, if necessary removal of persistent papillary obstacle. Patients (18) with

Student’s t-test Kolmogorov-Smirnov test

White blood cells t = 0.2918 < t0.05 = 1.7011 D = 0.22 < D0.05 = 0.500

Amylasemia t = 0.8754 < t0.05 = 1.7011 D = 0.203 < D0.05 = 0.500

Bilirubin t = 2.0192 < t0.05 = 1.7011 D = 0.72 < D0.05 = 0.500

AST t = 2.1664 < t0.05 = 1.7011 D = 0.67 < D0.05 = 0.500

ALT t = 8.7062 < t0.05 = 1.7011 D = 0.78 < D0.05 = 0.500

Phosphatase t = 0.6253 < t0.05 = 1.7011 D = 0.39 < D0.05 = 0.500

Ranson’s score t = 1.8477 < t0.05 = 1.7011 D = 0.363 < D0.05 = 0.500

Balthazar’s index t = 1.8585 < t0.05 = 1.7011 D = 0.416 < D0.05 = 0.500

Table 4. Comparison within acute biliary pancreatitis between subgroup A1 and A2 with Student’s t-test and Kolmogorov-
Smirnov test.
 Acute Cholecystitis: Diagnostic Pitfall and Timing of Treatment 31
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Figure 2. Correspondence between Ranson’s score (X) and Balthazar’s index (Y) in the A1 subgroup in acute biliary
pancreatitis.

Figure 3. Correspondence between Ranson’s score (X) and Balthazar’s index (Y) in the A2 subgroup in acute biliary
pancreatitis.

pancreatic pattern (subgroup A1), after initial medical treatment, followed by improvement
of general conditions and pancreatic involvement, have been treated 7–10 days after onset
of disease with cholecystectomy (13 pts.). In five patients with cholestatic index and persis-
tent CBD dilation was planned magnetic resonance cholangiopancreatography (MRCP) and
endoscopic retrograde cholangiopancreatography (ERCP)/endoscopic sphincterotomy prior
the cholecystectomy, delayed for few days but in the same hospital stay. All cholecystec-
tomies were performed with laparoscopic approach. On the other hand, patients (12) with
biliary pattern (subgroup A2) because severe damage of general condition, imminent risk
of developing severe sepsis, clinical/instrumental evidence of biliary inflammatory disease
32 Updates in Gallbladder Diseases

within acute biliary pancreatitis, underwent emergency surgery (48 hours from onset). The
intraoperative findings were acute cholecystitis (6), within two cases choledocolithiasis and
cholangitis, in six cases gangrenous cholecystitis. In these patients was present pancreatic
edematous impairment. The conversion rate of these procedures was 16.6% (2/12). In both
subgroups, postoperative morbidity was Grade I and Grade II according to Clavien-Dindo
criteria. In the subgroup A2, mortality rate was 8.3% (1/12) [23]. We can conclude that it
seems possible to identify two types of acute biliary pancreatitis for which the therapeutic
approach should be different. The pancreatic pattern characterized by preeminent pancreatic
involvement requiring conservative treatment following the severity and evolution of pan-
creatitis; not delayed cholecystectomy, control, and treatment of papillary obstacle if present,
prolonged control of pancreatic and peripancreatic fluid-necrotic collections, and so on. The
biliary pattern is characterized by persistent, severe acute biliary tract disease, accompanied
by mild or moderate acute biliary pancreatitis. This clinical-pathological condition should
undergo urgent surgical intervention to treat the septic-inflammatory disease (acute chole-
cystitis, cholangitis, etc.).

5. Pathological features of acute cholecystitis

Acute cholecystitis can develop some inflammatory complications that give rise to severe patho-
logical conditions, gangrenous cholecystitis, gallbladder empyema, emphysematous cholecysti-
tis, perforation of gallbladder, cholecystoenteric fistula, and gallstone ileus. These complications
are life-threatening with risk of severe sepsis and septic shock evolution, peritonitis, and so on; it
is mandatory urgent surgical procedure. Gangrenous cholecystitis is a very dangerous compli-
cation because of the difficulty of preoperative detection. Gangrene is the development of wall
phlogosis, impaired blood supply, wall ischemia, gangrene; the final development of this compli-
cation can be the perforation. Gangrene is not frequent complication and perforation can occur
in 5–10% of these patients. Gangrene as complication of acute cholecystitis occurs frequently in
patients with compromised clinical conditions: diabetes, trauma, severe burns, prolonged TPN
and stay in intensive care unit, cardiac surgery. Frequently perforation is localized in a circum-
scribed peritonitis, characterized by pericholecystic abscess limited with omentum and surround-
ing organs. Free perforation causes generalized peritonitis, accompanied by severe impairment
of clinical course such as abdominal wall guarding, fever, increase of leukocytosis, start of severe
sepsis and septic shock. Gallbladder empyema results as pus collection in the gallbladder because
of bacterial overgrow. Obviously, the septic site can initiate severe sepsis and septic shock. The
clinical picture is severe with abdominal pain in upper right quadrant, leukocytosis, fever, and
tachycardia. Initial medical treatment with broad-spectrum antibiotics must be followed by
urgent cholecystectomy. In the emphysematous cholecystitis is added the superinfection of gas-
forming organisms (Clostridium Welchii, Escherichia coli, Klebsiella, etc.) [24]. This complication is
uncommon and usually develops in males, old and diabetics patients. The most frequent evolu-
tion of gallbladder wall emphysema (75% of cases) is gangrene and perforation. Clinical course
develops severe sepsis and septic shock. Imagine exams (CT scan) show gas in the gallbladder
wall. Emergency surgery should be the correct treatment.
 Acute Cholecystitis: Diagnostic Pitfall and Timing of Treatment 33
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Cholecystoenteric fistula can be due to dual pathogenesis: long-standing pressure necro-

sis by large stones and flogistic adhesion of gallbladder wall with adjacent hallow organs,
followed by pathological communication. Most frequent communications are with duo-
denum (70–85%) and right flexure of the colon (15–20%) [25]. Cholecystoduodenal fis-
tula allows the passage into the small intestine of gallstones, usually of large size that
cause decubital effect. The stone progress in small intestine and in the narrowest part,
frequently ileum, stops and determines mechanical obstruction, that is gallstone ileus
(about 15% of patients with cholecystoenteric fistula). Clinical course of gallstone ileus
develops as common intestinal obstruction. In the past decades, this clinical condition
appeared in the characteristic way: acute cholecystitis treated with medical therapy,
in 7–10 days improvement of signs and symptoms (decompression of the gallbladder
because the fistula forms), in the following several days appearance of clinical features
of intestinal obstruction (gallstone ileus). In the therapeutic program, the first step is the
resolution of intestinal obstruction by enterotomy and stone removal. The treatment of
cholecystoduodenal fistula should be performed in the same time or delayed for impaired
general conditions of patients.

In the uncomplicated cholecystitis, usually there are no increase of serum total and direct
bilirubin and alkaline phosphatase (cholestasis indexes). If the signs of cholestasis occur,
may be due to choledocolithiasis, cholangitis, or the Mirizzi syndrome. There are two
types of Mirizzi syndrome: in type I, a large stone blocked in the cystic duct and in the
Hartmann’s pouch of gallbladder compresses the common bile duct but without fistula
between gallbladder and common hepatic duct. In the type II, due to necrosis of wall
of common hepatic duct, there is a fistula with various degrees of defect of hepatic duct
wall and presence of stone in hepatic duct. The first type can be treated with “partial”
cholecystectomy and repair of bile duct with T-tube. The type II requires more complex
procedure with complex dissection and hepaticojejunostomy. On the other hand, there are
patients, in course of acute cholecystitis, with mild increase of amylase, AST, ALT, biliru-
bin caused by papillary passage of sludge, pus, and cholesterol crystals [26]. Moreover
in several cases because transient papillary obstruction during transpapillary passage of
small stones, can occur elevation of serum transaminase levels (AST, ALT), so called “gall-
stone hepatitis” [27].

6. Imaging studies in acute cholecystitis

6.1. Plain radiography

Plain radiography is not very useful to confirm the diagnosis of acute cholecystitis. In few
cases, it may detect biliary disease such as biliary stones (only 10–15% of stones contain cal-
cium enough to be radiopaque), gallbladder wall calcified, pneumobilia; but unfortunately,
these findings are not diagnostic for acute cholecystitis. The role of plain radiography remains
crucial in any acute abdomen to rule out some pathological condition such as perforated hol-
low organs (pneumoperitoneum), and intestinal obstruction (air fluid levels).
34 Updates in Gallbladder Diseases

6.2. Ultrasonography

Transabdominal US should be employed as completion of clinical examination in patients with

abdominal pain. It is very important to define accurately the reliable data that the US can pro-
vide in different diseases that can cause an acute abdomen. The US can detect gallstones (acous-
tic shadowing behind to the stones) with sensitivity of 84% and specificity of 99% [28–30]. We
have to remember some features that US can highlight such as mobile gallstones in the gallblad-
der, polyps, small stones attached to the wall, very small stones without acoustic shadow, and
the fluid absence around the gallstones that make difficult their detection. Finally, there are
also some false negative exams with US that range from 5 to 15% in acute cholecystitis [31, 32].
More crucial for the diagnosis of acute cholecystitis are the gallbladder wall edema or pneuma-
tosis (“double wall sign”) and wall thickening; both features of inflammation condition. US can
detect bile duct dilation and also the site of obstacle if present. The US can add some information
about pericholecystic fluid collection or inflammatory mass in upper right abdominal quadrant
but the complete definition of these findings should be obtained by CT scan.

6.3. Abdominal computed tomography

CT scan has limited role in the diagnostic confirmation of uncomplicated acute cholecystitis
because the same information and sensitivity of US (presence of gallstones, gallbladder wall
thickening, dilation of CBD). On the contrary, CT scan is crucial in the diagnostic definition of
complications such as pericholecystic fluid, gallbladder empyema, emphysematous gangrene,
perforation, limited peritonitis with inflammatory mass, intrahepatic and extrahepatic bile
duct dilation, choledocolithiasis, concomitant pancreatitis, hepatic lesions.

6.4. Magnetic resonance imaging

Magnetic resonance imaging (MRI) as CT scan is of little help in the diagnosis of simple acute
cholecystitis. On the other hand, MRI is very sensitive in detecting the morphology of biliary
tract, gallstones, and bile duct stones. Moreover, it is a noninvasive technique in the study of
intra- and extrahepatic biliary ducts [33, 34]. Cholescintigraphy, noninvasive test, allows ana-
tomic and functional evaluation of liver, gallbladder, bile duct. This nuclear medicine exam
uses intravenous injection of hepatic 2, 6-dimetyl-imidodiacetic acid (HIDA) that is rapidly
excreted in the bile. Cholescintigraphy allows the functional evaluation of hepatic ability to
extract the radionuclide, the flow into the biliary ducts and gallbladder and finally the passage
into the duodenum within 30–60 min. In the acute cholecystitis, cystic duct obstruction by
stones prevents to visualize the gallbladder; also, stones in the common bile duct or papillary
obstacle prevent the passage of radionuclide into the duodenum. The sensitivity and specific-
ity of HIDA test in detecting acute cholecystitis reach 90–95% [35]. In our experience, we do not
have used this exam that nowadays is less frequently used.

7. Treatment

The first approach in patients with acute cholecystitis includes fluid resuscitation, analgesia,
suspension of oral intake, nasogastric tube, broad-spectrum antibiotics. This therapeutic scheme,
 Acute Cholecystitis: Diagnostic Pitfall and Timing of Treatment 35
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while widely shared, may subject to small variations in timing of each therapeutic measures
and in the choice of the antibiotic. Should be discussed the use of nasogastric tube if it can be
employed widely at the onset of the disease or selectively in case of nausea, vomiting, abdominal
distention. Control of abdominal pain is an essential therapeutic target. For this purpose, nonste-
roidal anti-inflammatory drugs are widely used for analgesia. These drugs inhibit the activity of
cyclooxygenase 1 and 2 (COX-1 and COX-2) with critical reduction of prostaglandins formation.
Prostaglandin E2 plays protective role on epithelial cells of gallbladder by secreting mucin; its
reduction decreases this mucin production and consequently the distention of gallbladder wall.
The therapy with a single broad-spectrum antibiotic can be correct for mild or moderate acute
cholecystitis. In the severe cases should be used more selective antibiotics such as imipenem/
cilastatine, third-generation cephalosporine and metronidazole. Bacteria present in acute cho-
lecystitis are frequently Escherichia coli, Enterococcus, Klebsiella, and so on. In the treatment of
acute cholecystitis, cholecystectomy plays the central role as standard management. This state-
ment seems seemingly plain and without controversies. There are in the literature several points
of wide discussion in which we will report also our experience. The timing of the intervention is
very important topic: the choice between early and delayed cholecystectomy with various opera-
tive outcomes. The first item to make is to define “early intervention.” Within acute cholecysti-
tis, there are several clinical pathological conditions that are the evolution of the inflammatory/
septic process, from mild to severe, life-threatening forms. The reasonable options, always in
urgent approach, can vary from emergency to intervention within 24–48–72 hours (early proce-
dures). Another consideration adds uncertainty in the choice of timing of intervention because
the dissection difficulties of inflamed operative site, with the possible increase of intraoperative
morbidity that can be very severe in both approaches, laparoscopic and open [36].
In our experience about cholecystectomy morbidity, in the group which includes also the acute
cholecystitis, we have compared the outcomes in two following periods: first period 2006–2008
and second period 2009–2011. Total morbidity in the second following period was markedly
reduced from 18.5 to 9.96% (p = 0.009). With regard to morbidity by incomplete preoperative
evaluation and surgical error, we have defined some criteria to increase the control and pre-
vention: acceptable general anesthesia, clear visibility of surgical site, optimal exposition of the
hepatic hilum and its structure, control of possible anatomical variations, finally convertion to
open cholecystectomy if necessary [37]. Employing, since 2002, of antegrade dissection in lapa-
roscopic cholecystectomy as standard technique allows reduction in intervention time (mean
operative time 40 min) and decrease of the conversion rate (from 3.4 to 0.8%) in the comparison
with common retrograde approach [38]. Minor postoperative morbidities as wound infections
can be prevented following correct criteria of medications. In our experience, topical antibiotic
application may reduce surgical wound infection in umbilical site after laparoscopic cholecys-
tectomy [39]. Concerning the subhepatic collections, in our opinion, the common use of sub-
hepatic drainage after cholecystectomy for acute cholecystitis enables the correct drainage of
serous and/or serohematic secretions usually present in the first days in inflamed surgical site.

There are in the literature several reviews regarding the timing of early or delayed cholecystec-
tomy and the comparison of its operative morbidity. Tokyo guidelines suggest a therapeutic
program for acute cholecystitis based on precocious severity assessment as guide for treatment
choices. Mild acute cholecystitis should undergo early laparoscopic cholecystectomy, within
72 hours from onset with possible improvement of other medical problems. For moderate
36 Updates in Gallbladder Diseases

forms also should be performed early cholecystectomy with laparoscopic or open approach
(conversion to open following difficult dissection). Severe acute cholecystitis can show, in
addition, damage of general conditions (organ dysfunction) which needs to treat. For these
clinical-pathological conditions, urgent surgery is necessary: the type of surgical procedures
is connected with pathological findings such as gangrenous or perforated cholecystitis, local
or generalized peritonitis, involvement of adjacent organs. The urgent procedures vary from
cholecystecyomy to cholecystostomy, percutaneous gallbladder drainage, and so on. The revi-
sion of Tokyo guidelines [40] confirms the first choice of laparoscopic early cholecystectomy
but without the exact definition of time of precocious intervention. We can underline that in
the Tokyo guidelines is reported also the elective cholecystectomy, in all degree of severity,
after improvement of the acute inflammatory process [41–43]. Nevertheless, another confir-
mation of the validity of early cholecystectomy, within 24 hours, regarding minor morbidity
and lower cost, has been presented by Gutt CN [44]. More selective criteria have been used in
order to bind the study of patients with acute cholecystitis excluding very severe forms (need
of intensive care admission, urgent cholecystostomy, etc.) by Canadian Researchers. They
employed a population-based analysis (20,000 patients—period 2004–2011) for comparison of
operative outcomes of early and delayed cholecystectomy [45].

This study showed, in the comparison of delayed cholecystectomy, that early cholecystectomy
in the treatment of acute cholecystitis was associated with a lower risk of major bile duct injury,
of operative mortality, of postoperative (30 days) mortality (respectively 1.36 and 0.46%) and
finally a shorter hospital stay. It is also demonstrated almost same conversion rate between
early and delayed laparoscopic cholecystectomy. Obviously early cholecystectomy put in a
safe place for risk of recurrent gallstone disease. Similar results have been reported from other
studies: early laparoscopic cholecystectomy (performed within 48 hours) is associated to bet-
ter postoperative outcomes with lower morbidity and hospital stay [46, 47]. A very interesting
French study evaluated the choice for optimal timing for early cholecystectomy [48]. Patients
with acute cholecystitis from the French National Health Care database have been studied:
42,452 patient—507 hospitals—period 2010–2013. The exam of the literature shows the thera-
peutic indication of early laparoscopic cholecystectomy as standard procedure for acute chole-
cystitis. Nevertheless, with exception for urgent surgery indications (sometimes with various
procedures) in case of very severe cholecystitis as perforated, gangrenous forms with local or
generalized peritonitis, the time of “early surgery” is not well defined. Polo et al. in this study
show that the optimal time for laparoscopic cholecystectomy in acute cholecystitis is between
the first and third day after hospital admission. In this time interval is recorded lower risk
of mortality and lower morbidity: common bile duct injury, reoperation rate, postoperative
sepsis, conversion rate, and finally minor length of hospital stay and cost. The definition of
best time for surgical procedure always has an element of uncertainty because it is very dif-
ficult to report the onset of the symptoms and is instead reported the hospital admission. To
assess the significance of this inaccuracy is very difficult. Moreover, this study report also not
negligible morbidity and mortality (range from 0.8 to 1.4%) for the patients treated within
the first 24 hours. This particular result, in our opinion, proves the need, also in the program
of early cholecystectomy, of a brief time interval for supportive therapy, and resuscitation to
improve the general condition in patients with severe cholecystitis and septic complications.
 Acute Cholecystitis: Diagnostic Pitfall and Timing of Treatment 37
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It is evident in the recent literature that the first, preferred choice for acute cholecystitis is the
laparoscopic approach with conversion rate ranging from 10 to 15%. The first choice of the
open approach should be limited to peritonitis, perforated chilecystitis but always as personal
choice, that cannot be standardized. In the setting of the therapy of acute cholecystitis, we can
propose the presentation of a series of consistent clinical cases, observed and treated in our
Institution in the period September 2014–September 2016, to show our treatment program. In
the chosen period, we have treated 42 patients with acute cholecystitis. Demographic data are
the following: male 45.2% (19/42), female 54.7% (23/42), mean age 59.6% (range: 20–87 years).
Furthermore, we have recorded the pathological features of the patients (Table 5).

Therapeutic program in severe cholecystitis with complications, characterized by severe

morbidity and mortality, demands ready surgical intervention. In our patients with severe
acute cholecystitis (38%), prompt surgery was performed few hours after hospital admis-
sion; two patients needed preoperative intensive care and they were treated within 24 hours.
The patients with acute cholecystitis were treated with laparoscopic early cholecystectomy
performed within 72 hours (range: few hours–72 hours) based on the needs of preoperative
treatments related to comorbidities. All these interventions start with laparoscopic approach
and the conversion rate was 21% (9/42). Postoperative outcomes were characterized by minor
morbidity, no mortality and the postoperative hospital stay was in mean 4.2 days (range: 2–14).

Laparoscopic cholecystectomy for acute cholecystitis, because of the inflammation and severe
pathological involvement in the operative site, can be in most cases a “difficult cholecystec-
tomy.” Our experience and other from the literature have shown that laparoscopic difficult
cholecystectomies for acute cholecystitis are safe and effective and are associated with lower
incidence of minor and major postoperative complications, moreover with several advan-
tages as less respiratory infections, shorter postoperative course, and shorter hospital stay.
Laparoscopic approach decreases some complications of laparotomy as infections, dehiscence,
and laparocele [49–51].

There is an impending risk of lesions of common bile duct during cholecystectomy for acute
cholecystitis. The adoption of an operating procedure that puts at minor risk biliary duct
lesions should be proposed. Gallbladder antegrade dissection is an operative procedure
employed also in the past for open cholecystectomy. This well-known type of dissection has
been proposed in the laparoscopic approach. Several data from the literature demonstrate the

Acute cholecystitis 26

Severe cholecystitis 16

Hydrope (2/16)

Emphysematous (3/16)

Gangrene/perforation (7/16)

Patients 42

Table 5. Pathological features in acute cholecystitis (September 2014–September 2016).

38 Updates in Gallbladder Diseases

frequent use of this operative procedure in difficult cholecystectomy because of acute flogosis
and the decrease in conversion rate to open with antegrade dissection [52, 53].
In our study, we have compared postoperative results of two groups of patients submitted
to antegrade dissection and retrograde dissection in laparoscopic approach [54]. This study
shows that antegrade dissection in laparoscopy for acute cholecystitis with phlogosis of
Calot’s triangle is safer procedure in comparison to retrograde approach, seems to reduce the
operative time, and should significantly decrease the risk of intraoperative complications such
as common bile duct injury and hemorrhages. In our opinion, confirmed by more recent expe-
rience, antegrade dissection may be proposed as a standard procedure of cholecystectomy and
not only for interventions in the acute cholecystitis [38].

Moreover, there are some specific problems related to urgent cholecystectomy in cirrhotic
patients. Cholelithiasis in cirrhotics occurs twice as often in the general population with a
reported incidence of 9–13% versus 5% in non-cirrhotic patients [55]. Major incidence of cho-
lelithiasis is due to several factors with various pathogenesis: hypersplenism, increased level
of estrogen, increased intravascular hemolysis, reduction in gallbladder emptying, and motil-
ity. In our experience, published some years ago [56], this epidemiologic characteristic was
confirmed. In this study, we have evaluated 65 cirrhotic patients with symptomatic gallstone
disease treated with laparoscopic cholecystectomy in the decade 2002–2012. This group of
patients has been compared with 81 non-cirrhotic patients with symptomatic gallstone dis-
ease, no significant morbidity and no significant differences in demographic data, and under-
went laparoscopic cholecystectomy in the period October 2011–May 2012. Within the group
of non-cirrhotic patients, the incidence of acute cholecystitis was 13.5% (11/81) and there are
not further complications; on the contrary, in the cirrhotic group, the incidence of acute cho-
lecystitis reached 27.6% (18/65) with several complications such as 1 cholangitis, 2 gallbladder
hydrops, 2 gallbladder empyema, 3 gangrenous cholecystitis. The cohort of cirrhotics evalu-
ated by Child-Pough classification shows 43 patients in A score (66.2%), 19 in B score (29.2%),
and three patients in C score, medically treated preoperatively and reclassified in B8 score.
Cirrhotic patients have undergone cholecystectomy: six with open approach as first choice,
59 with laparoscopic procedure with conversion rate 20.3%. The comparison of the results
between the two cohorts of patients has been evaluated (Table 6).

In this experience, laparoscopic cholecystectomy morbidity in cirrhotic patients is slightly

increased compared to non-cirrhotics. Moreover, postoperative morbidity in cirrhotic patients
is minor on the whole with laparoscopic approach than open procedure. Cholecystectomy
in cirrhotic patients is associated with non-negligible rate of morbidity and mortality. The
more frequent complications are blood loss, postoperative liver failure, and sepsis [57, 58].
Postoperative liver failure is due to the anesthetic agent’s action, which decrease hepatic arte-
rial blood flow (the ability of cirrhotic patients to compensate for this ischemia is impaired) [59].
Diminished Kupffer cell function leads to reduced clearance of the enteric organisms, endo-
toxinemia, and risk of infection in cirrhotic patients. The increased risk of bleeding is related
to reduced prothrombin time, thrombocytopenia, and portal ipertension. Finally, patients
can have a gallbladder with a significant intrahepatic component due to atrophy of the right
hepatic lobe and a hypertrophic left lobe with more difficulties for intervention [55, 60–62].
 Acute Cholecystitis: Diagnostic Pitfall and Timing of Treatment 39
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VLC (47) Open (6) Converted (12)

Operative time (minutes) 88.9 141 149 85

Hospitalization (days) 4.8 9.1 8.1 3.2

Conversion rate 20.34% - - 3 (3.7%)

Mortality - - - -

Blood transfusion in peri-operative time 2 (4.2%) 1 (16.6%) 2 (16.6%) -

Blood products transfusion in peri- 7 (14.9%) 1 (16.6%) 4 (33.3%) -

operative time

Hemoperitoneum 1 (2.12%) - - -

Reintervention 1 (2.12%) - - -

Pleural effusion - - 2 (16.6%) -

Pulmonary condensation - - 1 (8.33%) -

Trombocytopenia - - 1 (8.33%) -

Atrial fibrillation - - 1 (8.33%) -

Incisional hernia on umbilical port site 4 (8.51%) - - 2 (2.46%)

Table 6. Peri- and postoperative morbidity outcomes in cirrhotics (65) and in control group (81).

The last evolution in the surgical treatment of acute cholecystitis is the robotic approach. On
the whole, the main advantages of robotic surgery can be realized in some phases of complex
laparoscopic procedures requiring high dexterity and best visualization. In this perspective,
robotic approach for cholelithiasis and later for acute cholecystitis should be the start of valu-
able learning curve for robotic advanced skills in general surgery. Our experience in the field
of gallbladder lithiasis confirms the safe feasibility of robotic approach that requires the use
of standardized procedures. The obvious purpose of this approach, however, in the chole-
cystectomy, is the improvement of the technical skills in advanced and more complex robotic
assisted surgical procedures [63]. The comparison of the results of laparoscopic versus robotic
cholecystectomy proves the complete equivalence between both the procedures regarding of
safety and feasibility in all types of gallbladder’s pathology. In particular, acute cholecystitis
can be treated with robotic-assisted approach showing postoperative overlapping outcomes
with symptomatic gallstones disease [64]. On the contrary, the data from a study based on
the literature search with randomized controlled trials and population-based analyses shows
that the advantages of current use of robotic surgery in cholecystectomy are not provable [65].

8. Conclusions

Acute cholecystitis encompasses clinical forms with various degree of severity and several
cases (8–10%) present pathological findings that can make the operative site a surgical chal-
lenge, very difficult to treat. Indeed the laparoscopic approach, worldwide more common
40 Updates in Gallbladder Diseases

choice in the treatment of acute cholecystitis, presents significant conversion rate to open pro-
cedure (10–15%). Furthermore, besides more common clinical, laboratory, and instrumental
features of acute cholecystitis, there are some diagnostic pitfalls, such as the biliary pattern that
should be distinguished from the pancreatic pattern in the field of acute biliary pancreatitis.
The treatment is focused on early laparoscopic cholecystectomy well defined usually within
24–72 hours. Nevertheless, severe, complicated acute cholecystitis can require urgent surgical
intervention. Finally should be evaluated some particular components of a complex clinical
problem such as laparoscopic antegrade dissection in acute cholecystitis to allow minor risk
of biliary duct lesions, the control of the specific problems related to urgent cholecystectomy
in cirrhotic patients, and finally the possible future increased use of robotic approach in the
treatment of acute cholecystitis.

Author details

Pasquale Cianci, Nicola Tartaglia, Alberto Fersini, Sabino Capuzzolo, Libero Luca Giambavicchio,
Antonio Ambrosi and Vincenzo Neri*

*Address all correspondence to: [email protected]

Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy

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