Asymptomatic Cholelithiasis in Children With Sickle Cell Disease

Abstract

Summary Background Data:

Our study aimed to evaluate the role of elective laparoscopic cholecystectomy (LC) in children with sickle cell disease (SCD) and asymptomatic cholelithiasis and, furthermore, to determine whether the outcome is related to the operation timing.

Methods:

The records of 30 children with SCD diagnosed with cholelithiasis from June 1995 to September 2005 were retraspectively reviewed. All 30 children were asymptomatic at the time of the first visit, and an elective LC was proposed to all of them. The operation was accepted in the period of study by 16 children and refused by 14. During medical observation, 10 of the 14 children who refused surgery were admitted for severe biliary colics. Acute cholecystitis was diagnosed by abdominal ultrasound in 3 cases and in 1 case choledocholithiasis, ultrasonographically suspected, was confirmed by magnetic resonance cholangiopancreatography (MRCP) and treated during endoscopic retrograde cholangiopancreatography (ERCP). All children, emergency admitted, underwent LC after the onset of symptoms. The patients were divided up into 2 groups (A: asymptomatic; B: symptomatic) depending on clinical presentation and operation timing and the respective outcomes were compared.

Results:

Elective LC in asymptomatic children (group A) is safe with no major complications reported. During medical observation in children who refused elective surgery (group B), 6 biliary colics, 3 acute cholecystitis, and 1 choledocholithiasis were observed. Three sickle cell crises occurred in symptomatic children during biliary colics. The correlation between cholecystectomy performed in asymptomatic children (group A) and cholecystectomy performed in symptomatic children (group B) showed significant differences in the outcome. Morbidity rate and postoperative stay increased when children with SCD underwent emergency LC.

Conclusions:

Elective LC should be the gold standard in children with SCD and asymptomatic cholelithiasis to prevent the potential complications of biliary colics, acute cholecystitis, and choledocholithiasis, which lead to major risks, discomfort, and longer hospital stay.

Sickle cell disease (SCD) is the most important cause of cholelithiasis in children. Laparoscopic cholecystectomy (LC) is the standard treatment in symptomatic children, but it is still a source of debate as to what to do in children with clinically asymptomatic disease. A retrospective study was conducted to evaluate the role of elective LC in children with SCD and asymptomatic pigment gallstones.

Sickle cell disease (SCD) is the most important cause of cholelithiasis in children.¹ Pigment gallstones affect 15% of children with SCD younger than 10 years of age and more than 80% of those older than 30 years.² Laparoscopic cholecystectomy (LC) is the treatment of choice in children with clinically symptomatic disease, but the best option for asymptomatic ones is still a source of debate.³ Despite several reports on the safety and efficacy of LC in these children, little information is available about the risk of developing complications as a consequence of delaying the operation in asymptomatic children. Our study aims to evaluate the role of elective LC in preventing potential complications in children with SCD and asymptomatic cholelithiasis and, furthermore, to determine whether the outcome is related to the timing of the procedure.

MATERIALS AND METHODS

We reviewed the records of 30 children with SCD diagnosed with cholelithiasis from June 1995 to September 2005. The cases were labeled as SCD children based on clinical history and hemoglobin electrophoresis. The diagnosis of cholelithiasis was based on abdominal ultrasound scan performed routinely in patients with SCD. All 30 children were asymptomatic at the time of the first visit and an elective LC was proposed to all of them. The operation was accepted by 16 children and refused by 14. During medical observation, 10 of the 14 children who refused surgery were urgently admitted for severe biliary colics. Acute cholecystitis was diagnosed by abdominal ultrasound in 3 cases and in 1 case choledocholithiasis, ultrasonographically suspected, was confirmed by magnetic resonance cholangiopancreatography (MRCP) and treated during endoscopic retrograde cholangiopancreatography (ERCP). All children emergency admitted underwent LC within 72 hours since admission. We divided the patients up into 2 groups depending on clinical presentation and operation timing (Table 1): group A (16 totally asymptomatic children operated on) and group B (10 symptomatic operated on after the onset of biliary colics).

TABLE 1. Clinical, Preoperative and Postoperative Parameters in the 2 Groups

Group A (Asymptomatic)

Elective LC was performed on asymptomatic children who accepted the operation within 15 days since diagnosis using the standard 4-port technique. In this interval, asymptomatic children were invited to have a low-fat diet and received folic acid as usual (1 mg/day). Prophylactic erythrocyte transfusion or partial exchange transfusion was not routinely adopted. Simple transfusion before surgery was considered as beneficial in 2 children of the elective group to raise the hemoglobin above 10 g/dL and to decrease the hemoglobin S below 50%. Upon admission, all elective children were well hydrated, given nothing orally since the night before surgery and had intravenous antibiotics started 2 hours before surgery and continued for 24 hours after the procedure. Intraoperatively and postoperatively children were kept warm, well hydrated, and well oxygenated, and any acid-base imbalance was corrected to prevent any SCD-related complication. Adequate analgesia and early mobilization was also obtained.

Group B (Symptomatic)

In children presented with persistent right hypochondrial pain, the diagnosis of acute cholecystitis was confirmed or excluded by abdominal ultrasonography. Distended gallbladder, thickened gallbladder wall, and presence of gallstones were considered typical findings of AC. Selective preoperative ERCP was performed for therapeutic purposes in 1 case where raised direct bilirubin, jaundice, and dilated common bile duct were present. Emergent LC was performed within 72 hours since occurrence of biliary symptoms using the standard 4-port technique. Prophylactic erythrocyte transfusion or partial exchange transfusion was adopted in all emergent children considering the higher risk of intraoperative bleeding and hypoxia. Hemoglobin S less than 50% and hemoglobin above 10 mg/dL with a hematocrit of 30% were considered beneficial. Upon admission, children were well hydrated, given nothing orally, and had intravenous antibiotics started soon after admission and continued for 48 to 72 hours after the procedure depending on clinical and laboratory tests. The intraoperative and postoperative management was the same of that of the elective group.

In both groups, the gallbladder was sent to the pathologist for examination. The outcome was correlated with the treatment chosen and the operation timing. Both groups used t test and χ² test to compare their preoperative and postoperative characteristics. P values of <0.05 were considered statistically significant. The 4 children who refused surgery and are still asymptomatic were excluded from the correlation.

RESULTS

No major complications were reported in all 16 elective LC (group A). No conversions to open were necessary. One child developed wound infection and another child had fever for 2 days. No transfusions were necessary postoperatively. The mean postoperative stay was 3 days (range, 2–4 days) (Table 1). During medical observation, 10 of the 14 children who refused surgery were admitted for severe biliary colics and among them 3 cases of acute cholecystitis and 1 case of choledocholithiasis were observed. Emergency admission for biliary colics occurred in children who refused surgery after a mean time of 38 months (range, 12–80 months) since first diagnosis of cholelithiasis. An endoscopic sphincterotomy with gallstones extraction was necessary in 1 child and a LC was performed within 72 hours since admission in all 10 complicated cases (group B). One conversion to open was carried out because of adhesions from acute cholecystitis. Three sickle cell crises were observed postoperatively and exchange transfusion was necessary in all cases. Two wound infections occurred and 3 children developed fever postoperatively for 1 and 2 days (2 children), respectively. The mean postoperative stay was 7.4 days (range, 4–10 days) (Table 1).

Histopathologically, cholecystitis was found in 2 of 16 asymptomatic children and in 8 of 10 symptomatic children. Four of 14 children who refused surgery are still asymptomatic after a mean time of 40 months (range, 14–52 months) and they still refuse the operation.

The correlation between cholecystectomy performed in asymptomatic children (group A) and cholecystectomy performed in symptomatic children (group B) showed significant difference in the outcome. Significant differences were found in operative time, morbidity rate, postoperative stay, and total hospital stay between children operated on before the onset of symptoms (group A) and children operated on after the onset of symptoms (group B) (Table 1). The risk of emergency admission in children with cholelithiasis and SCD awaiting surgery was found to be high (71% of our children admitted in emergency after a mean time of 38 months (range, 12–80 months).

DISCUSSION

Gallstones are a frequent complication in children with hemoglobinopathies because of the recurrent episodes of hemolysis leading to an increase in bilirubin excretion and pigment gallstones formation. The incidence of gallstones in children with SCD increased in these last years due to both the regular use of the noninvasive detection technique (ultrasonography vs. cholecystography) and the longer survival of these patients.^4–6 The development of pigment gallstones in patients with SCD is age dependent: 15% under 10 years of age, 22% between 10 and 14 years of age, and 36% between 15 and 18 years of age, with a reported prevalence of 50% by the age of 22.⁷ Walker et al³ claim that the place of surgery for asymptomatic gallstones in children with SCD must be determined by the risk of developing complications and that in their series these risks were not so high to justify routine surgery. Nevertheless, our results as well as those of others showed that in children awaiting surgery the risk of developing complications is high and that their occurrence affects significantly the preoperative and postoperative course.^8–12 The mean number of hospitalizations and ambulatory visits for children with SCD and cholelithiasis is twice as high as that of children with SCD without cholelithiasis. It has been calculated that 50% of patients with asymptomatic stones experience complications within 3 to 5 years.³ Parez et al⁹ found that children with SCD develop clinical manifestations in 28% of cases in a maximum delay of 2.5 years after the diagnosis. In our series, the emergency admissions were due to severe biliary colics and 3 cases of acute cholecystitis and 1 case of choledocholithiasis were observed. These children are at high risk when operated on in emergency. Miltenburg et al¹³ reported 52 cholecystectomies of 128 performed on children with chronic hemolytic anemia and found an incidence of 16% of postoperative complications when cholecystectomy was performed in emergency as compared with 6% when performed electively. Suell et al⁷ compared 34 SCD children who underwent elective LC with 17 SCD children operated on urgently finding a significant difference in outcome between the 2 groups. Morbidity rate and mean total hospital stay were significantly higher in children who underwent emergency cholecystectomy. These results are similar to ours. In the past, cholecystectomy has often been thought of as a controversial surgical procedure for children with SCD because these children usually experience asymptomatic gallbladder disease. We think that elective cholecystectomy is appropriate for asymptomatic individuals suffering from a chronic illness and exposed to a higher risk of developing symptomatic gallstones. In our opinion, the onset of symptoms in this particular population is itself a complication that should be avoided. We actually observed 2 sickle cell crises during biliary colics in children who had refused surgery. Moreover, all removed gallbladders were sent to the pathologist for examination and a chronic inflammatory condition (chronic cholecystitis) was found in most symptomatic patients. On the other hand, gallbladders of asymptomatic children were normal in most cases, apart from the presence of pigment gallstones. It is well known that infections may precipitate a sickle cell crisis or a hemolytic crisis by inducing the release of inflammatory factors (IL-1, IL-6, TNF), which have been proved to play a role in shortening red blood cells survival.⁸ A number of different infections are implicated, including viruses (parvovirus B 19, Epstein-Barr virus) and bacteria (Salmonella species, pneumococci, and streptococci). Furthermore, infections may also precipitate a hemolytic crisis in children with SCD by inducing dehydration, hypossia, and metabolic stress.⁸ We think that the outcome observed in children operated on in emergency is worse than the one concerning elective LC due to the inflammatory state of the gallbladder (cholecystitis). These children live with an unstable hematologic equilibrium, which can be broken also by a simple biliary colic (pain, vomit, fever which lead to dehydration, hypossia, and metabolic stress) or, even more, by an acute inflammation (cholecystitis). The primary goal of elective cholecystectomy in these children is to prevent complications associated with emergency operations and to reduce the number of hospitalizations. Potential complications in this particular population are associated with general anesthesia and the inability to implement recommended preoperative care such as red blood transfusion, exchange transfusion, and proper hydration and therapy. The most important clinical factors involved in red cell sickling that need to be addressed when undertaking the perioperative management of a SCD patient are dehydration, deoxygenation, vascular stasis, low temperature, acidosis, and infection.⁸ The mainstays of perioperative management of SCD children are the avoidance of complications and their treatment when they arise. Because of the renal papillary necrosis, these children have difficulty reabsorbing water and are susceptible to dehydration. To prevent SCD-related complications as sickling or painful crises, therapy consists of well hydration, keeping the patient warm, and the use of oxygen. Infections should be treated promptly when they occur using broad-spectrum antibiotics with care not to allow pyrexial patients to become dehydrated.¹⁴ Chronic transfusion therapy has been used in the past to decrease the frequency of crises and may be useful in some severely affected patients. However, actually, this approach has been changing to prevent, over the long term, iron overload. When considering preoperative transfusion practice, each case should be decided on individual merit. The patient’s past medical history, risk factors for complications, and the planned surgical procedure should all be taken into account.^8,14 Considering all these issues in SCD children, it is clear the importance of elective LC when cholelithiasis is ultrasonographically detected. The number of hospitalizations for children with SCD and cholelithiasis is twice as high as that of children with SCD without cholelithiasis. Frequent hospitalizations or more hospitalizations in the year before surgery are significant independent predictors of perioperative vasoocclusive in patients with SCD.¹⁴ It is well known that good hydration and oxygenation with proper acid-base balance decrease the incidence of perioperative SCD-specific complications.¹⁴ These children benefit from a shorter general anesthesia and operating on them as long as they are still asymptomatic can reduce the operative time.⁸ The presence of an inflammatory state of the gallbladder makes gallbladder dissection, cystic duct, and artery exposure more difficult with subsequent longer operative time. Children with SCD are at high risk of developing postoperative complications (sickle cell crisis) when emergency cholecystectomy is performed.¹¹ The safety and feasibility of LC also in children with SCD are well documented. The advantages of decreased postoperative pain, better postoperative lung function, shorter hospital stay, and faster recovery are particularly beneficial for patients with hemolytic disorders.¹⁵ When cholecystectomy is performed electively in asymptomatic children with pigment gallstones, the morbidity rate is very low and the recovery faster.

Elective LC should be the gold standard in children with SCD and asymptomatic cholelithiasis to prevent the potential complications of cholecystitis and choledocholithiasis which lead to major risks, discomfort, and longer hospital stay.