Clinical profile and outcome of choledochal cysts in a pediatric tertiary hospital from 2000 to 2013

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1 International Journal of Gastroenterology, Hepatology, Transplant & Nutrition Original Article Clinical profile and outcome of choledochal cysts in a pediatric tertiary hospital from 2000 to 2013 Odessa C. del Rosario-Bayani, Sarabeth V. de Castro, Randy P. Urtula, Maria Estela R. Nolasco, Mary Ann F. Aison Philippine Children s Medical Center Quezon Avenue corner Agham Road, Quezon City, Philippines Address for Correspondence: Odessa del Rosario-Bayani detdelrosario@yahoo.com Access this article online QR Code Website: ABSTRACT Background: In spite of early surgical intervention of choledochal cysts to prevent adverse outcomes, a few still develop significant morbidity and mortality. Determining which factors affect outcome will aid in the management and care of patients with choledochal cysts. Objective: This study aims to determine the clinical profile of patients with choledochal cyst and determine the factors affecting its outcome. Methodology: A retrospective cohort study of patients with choledochal cysts 0-18years old was done. Clinical data were correlated with the outcome which include immediate postoperative complications, portal hypertension and mortality. Results: A total of 77 patients with choledochal cyst were studied. Majority were >2-5 years old at 31% (n=24/77). The mean age at onset of symptoms was at 2.75 years old. The most common cyst type was type I at 79% (n=61) followed by 16% type IV (n=12), 3% type III (n=2) and 1% type V (n=1). There was no type II cyst. Age had a significant association with the clinical manifestations with jaundice, abdominal distention and hepatosplenomegaly found in less than 2 years old and abdominal pain in 5-7 years old (P 0.05). Classic triad was significantly associated with cyst type III (50%) and IV (20%). 91% underwent surgery (n=70/77) with cyst excision and hepaticoenterostomy being the most commonly used (n=51/77, 66%).17% had immediate postoperative complications (n=12/70) with infection (n=7/12) being the most common complication significantly found in less than 2years old (n=5/7). 13% had portal hypertension (n=10/77) significantly found in those whose onset of symptoms was less than 2 years old (n=9/10) and Type I cysts (n=6/10). 6.5% died (n=5/77) and was significantly highest in those whose onset of symptom was less than 2 years old (n=4/5). Conclusions: Particular attention to diagnose, provide timely intervention and anticipatory care of possible complications should be given to infants with choledochal cysts because they were significantly associated with immediate postoperative complication particularly infection, development of portal hypertension and mortality. Recommendations: It is recommended to include a bigger population size and followup studies to monitor long-term complications of patients with choledochal cysts. Key words: dif Choledochal cysts, Clinical profile, Outcome INTRODUCTION Statement of the problem: What are the factors leading to the outcome of choledochal cysts? The varying clinical manifestations depending on the age of the patient and the limitations of imaging such ultrasound necessitating further sophisticated imaging which lead to a delay in the diagnosis of cheoledochal cysts, the cyst type, presence of preoperative comorbidities and complications, were in some studies, cited to contribute to the outcome of choledochal cysts. However there are no available studies correlating such factors in the outcome of choledochal cysts. SIGNIFICANCE OF THE STUDY This study aims to determine if the different factors such as the age of the patient on presentation and intervention, interval 15

2 between onset of symptom and diagnosis and treatment, cyst type, preoperative comorbidities and complications and type of surgical intervention and liver biopsy findings will affect the outcome of patients with choledochal cysts. REVIEW OF RELATED LITERATURE Choledochal cysts are congenital anomalies of the biliary tract with varying degrees of cystic dilatation occurring at various segments of the biliary tree either extrahepatic or intrahepatic. They are more frequently seen in Asians with with a female predilection. Local studies in the prevalence of the disease are lacking. 1 There are varying clinical manifestations of choledochal cysts according to age at presentation. Some occur and are diagnosed at infancy period, others are diagnosed much later by 20 years of age. The clinical manifestations vary according to the age at presentation. A case cohort study done by de Vries (2002), correlated the age at presentation to the clinical manifestations of patients with choledochal cysts. He grouped the patients into those less than two years old, those 2-16 years old and those more than 16 years old. While jaundice and hepatomegaly are the most common symptoms in patients less than two years old, abdominal pain is most frequently seen in those more than two years of age. Other manifestations observed in this study were nausea and vomiting, weight loss and hepatomegaly. Only one out of the 42 cases presented with portal hypertension. Others presented with sepsis, cholangitis, pancreatitis and gallstones. 1 A similar study by Pereira et al (2000) was done which included pediatric patients and were grouped into <1year old, 1-3 years, 3-5 years, 5-7 years and more than 7 years old in which 56% of the subjects belong to the less than 3 years age group 2 Jaundice was the most common initial symptom occurring in 83% of patients but the study done by Pereira did not specify the common manifestation per age group. Todani classification of choledochal cysts and incidence: Type I: Dilatation of hepatic and common bile duct (40% to 85%) Type IA: Saccular dilatation involving all or most of the extrahepatic bile duct. Type IB: Saccular dilatation involving a limited segment of the bile duct. Type IC: Fusiform dilatation involving all or most of the extrahepatic bile duct. Type II: Diverticulum of the common bile duct (2% to 3%) Type III: Intraduodenal common bile duct dilatation (1.4% to 5.6%); also known as choledochocoele Type IVa: Intra- and extrahepatic bile duct dilatation (18% to 20%) Type IVB: Multiple dilatations involving only the extrahepatic bile ducts Type V: Intrahepatic bile duct dilatation (rare), also known as Caroli s disease 1 In the De Vries study, Type I and Type IVa cyst most commonly occur in less than two years old while type V cyst occurs most commonly in more than 16 years old age group. 1 The presenting symptoms were compared with the type of cyst in a study done by De Vries. Abdominal pain is the most common symptom in most types. Jaundice is mostly seen in Type I and IV (both extrahepatic cysts). Exclusively intrahepatic cysts (Type V), present primarily with both cholangitis and gallstones. 1 The five cyst types used the information from operative and radiographic findings including ultrasonography, computerized tomography scan and cholangiogram and magnetic resonance cholangiopancreatography (MRCP). 3 Ultrasound findings of a choledochal cyst demonstrates a cystic echo-free mass found in the biliary tree. 4 The sensitivity of ultrasound in making the diagnosis of choledochal cyst is 71 to 97%. Unfortunately, ultrasonography may underestimate the size of the cyst. It may also be limited by body habitus, bowel gas and overlying structure. 5 MRCP is now considered to be the gold standard in the diagnosis of choledochal cyst with the sensitivity of sensitivity for diagnosis as high as 90% 100%. 5 Laboratory findings of anemia, elevated levels of transaminase, alkaline phosphatase, bilirubin and coagulopathy were included in the retrospective study by Singhavejsakul. In this study, children younger than 2 years of age had significantly lower levels of hemoglobin and serum albumin with higher levels of alkaline phosphatase, ALT and AST, and bilirubin; This age group has a greater likelihood to develop coagulopathy. 3 Failure to do operative intervention early in the course of the disease result in complications such as cholangitis, cyst rupture leading to peritonitis, pancreatitis, cirrhosis and portal hypertension, upper gastrointestinal bleeding secondary to bleeding esophageal varices. 6,3,1,5 It is not known however, as to what degree these preoperative complications of choledochal cysts adversely affect the outcome. Primary cyst excision coupled with a Roux-en-Y loop or hepaticojejunostomy is the current treatment of choice for choledochal cysts. 4 Palliative cyst drainage increases the risk for cholangiocarcinoma. Liver transplantation is recommended in those with multiple intrahepatic cysts not amenable to cyst excision and hepatic resection. To those who are unstable for surgery, or who refused surgery, medical management in the form of supportive medications for the liver was recommended. 3 The early postoperative complications noted are bleeding, infection like cholangitis, sepsis, wound infection and hematoma, subhepatic abscess, bile leak and bowel perforation. 3,1,7 Median hospital stay is 8.5 days (5-26 days). 6 In the study by Singhavejsakul, patients diagnosed with choledochal cysts with and without intervention were categorized as having one of four possible poor outcomes: 1) 16

3 survived without residual liver disease,2) survived with cirrhosis or portal hypertension, 3) deceased, or 4) unknown. 3 Mortality and morbidity postoperatively are caused by sepsis, comorbid conditions like congenital heart disease, liver failure and degree of liver fibrosis or biliary cirrhosis documented by intraoperative liver biopsy. 3,8 General Objective: OBJECTIVES OF THE STUDY This study aims to determine the clinical profile of patients with choledochal cyst admitted at Philippine Children s Medical Center from the year 2000 to 2013 and determine the factors affecting the outcome of patients with choledochal cysts. Specific Objectives: 1. To identify the clinical profile of patients with choledochal cysts which will include the following factors: Gender Age at onset of symptoms Age at intervention Clinical manifestations Laboratory tests Diagnostic imaging findings Type of choledochal cyst based on imaging and operative findings Preoperative comorbidities Preoperative complications Interval between onset of symptoms and operative intervention Type of Surgical Intervention Intraoperative liver biopsy histopathology 2. To determine the outcome of patients with choledochal cysts which include the following: Morbidity (Immediate postoperative complications) Presence of portal hypertension Mortality 3. To determine the effect of the following factors on the outcome of patients with choledochal cysts: Age of the patient at surgical intervention Interval between the onset of symptoms and diagnosis/treatment Type of choledochal cyst Type of surgical Intervention Preoperative comorbidities and complications Presence of liver fibrosis / cirrhosis OPERATIONAL DEFINITION 1. Choledochal cysts cystic dilatation of the biliary tree either extrahepatic and/or intrahepatic as seen in imaging and/or intraoperative cholangiogram 2. Severe Malnutrition severe malnutrition to include severe wasting and/or severe stunting or severely underweight. Severe wasting is defined as, weight for length/height below minus 3 SD for patients less than 2 years old and 2-5 years old, respectively and BMI below minus 3 SD for >5 years old. Severe stunting is defined as length/height for age below minus 3 SD for patients below 2 years old and 2-18 years old, respectively Severely underweight: weight for age below minus 3 SD for patients without a length or height recorded in the chart. 3. Moderate malnutrition Moderate wasting is defined as, weight for length/height below minus 2 SD for patients less than 2 years old and 2-5 years old, respectivelyand BMI below minus 2 SD for >5years old. Moderate stunting is defined as length/height for age below minus 2 SD for patients below 2 years old and 2-18 years old respectively. Moderately underweight: weight for age below minus 2 SD for patients without a length or height recorded in the chart. 4. Portal hypertension presence of hematemesis or hematochezia or melena with splenomegaly. 9 In the absence of bleeding, this may be manifested as prominent vascular formation on the abdomen coupled with ascites and hepatosplenomegaly 5. Pancreatitis: if 2 of the following criteria are fulfilled: abdominal pain, elevated amylase and/or lipase and/or imaging findings consistent with pancreatitis. 6. Laboratory tests: Cholestasis direct bilirubin more than 20% of the total if the total bilirubin is >5mg/dL or direct bilirubin more 1 mg/dl if total bilirubin is less than 5mg/dL 10 Elevated SGPT/ ALT >2x the upper limit of normal Deranged prothrombin time Prothrombin time >2 seconds from the control Hypoalbuminemia less than 35 mg/dl Alkaline phosphatase >4x the normal METHODOLOGY A retrospective cohort study was performed on all patients aged 0-18 years old diagnosed with choledochal cysts with and without surgical intervention in Philippine Children s Medical Center seen for the past thirteen years from 2000 to Charts were reviewed and clinical details were analyzed. The following details were gathered: 1. Age at onset of symptoms and surgical intervention stratified as follows: 1 a. 2 years old b. >2-5 years old c. >5-7 years old d. >7 years old 2. Gender: male/female 3. Interval between onset of symptoms and diagnosis 4. Interval between onset of symptoms and treatment 17

4 5. Clinical manifestations (jaundice, abdominal mass, abdominal distention, vomiting, abdominal pain, acholic stools or pale yellow stools, bleeding) 6. Physical examination findings (presence or absence of jaundice, icterisia, ascites, visible veins, abdominal tenderness, abdominal mass, hepatomegaly, splenomegaly, digital clubbing, bipedal and/or facial edema) 7. Diagnostic tests and Results/ Findings: a. Biochemical tests (Hemoglobin, bilirubin, SGPT or ALT, albumin, Prothrombin time, GGTP, alkaline phosphatase) 9 b. Imaging (Ultrasound, Abdominal Ct scan, MRCP, HIDA scan) 8. Classification/ Type of Choledochal cyst (I, II, III, IV, V) based on imaging findings and/or intraoperative cholangiogram findings 9. Preoperative comorbidities (malnutrition, sepsis) 10. Preoperative complications (portal hypertension, peritonitis due to cyst rupture, cholangitis, pancreatitis) 11. Operative Intervention performed with intraoperative findings a. Cyst excision with hepaticojejunostomy b. Cyst excision with hepaticoduodenostomy c. Cyst drainage (internal/external) d. Mucosectomy e. Staged procedure: cyst drainage followed by cyst excision and hepaticoenterostomy f. Cyst excision + hepaticojejunostomy + hepatic resection 12. Histopathology results (intraoperative wedge liver biopsy) a. Fibrosis b. Cirrhosis c. Normal findings d. Other findings 13. Outcome a. Operative Outcome i. Morbidity: 1. Immediate postoperative complications a. bleeding at hepaticojejunostomy/ hepaticoduodenostomy (HJ/HD) site, wound dehiscence, infections, bile leak 2. Development of portal hypertension ii. Mortality b. Outcome for those who did not undergo surgery i. Morbidity 1. Development of portal hypertension ii. Mortality ASSOCIATION OF VARIABLES (NON- OUTCOME) The age was correlated with the clinical manifestations, preoperative comorbidities and complications. The cyst type was correlated with the clinical manifestations, preoperative comorbdities and complications and operative intervention. CORRELATION WITH OUTCOME The following data gathered were correlated with the outcome (Immediate postoperative complications, portal hypertension, mortality) 1. Age at onset of symptoms 2. Age at intervention/ admission 3. Cyst type 4. Type of operative intervention 5. Preoperative comorbidities: malnutrition, sepsis and liver function test abnormalities 6. Preoperative complications such as portal hypertension, peritonitis due to cyst rupture, cholangitis, pancreatitis 7. Liver biopsy findings ANALYSIS OF DATA Data were described using means and standard deviations, frequency counts and percentages. For discrete variables, tests of association used were chi- square and Fischer s exact test, whichever was appropriate. For continuous variables, t-test and ANOVA one way were used. For all tests, a 95% confidence level was considered significant. RESULTS Demographic and Clinical Profile A total of 77 patients were diagnosed with choledochal cyst from January 2000 to December 2013 in Philippine Children s Medical Center comprising predominantly of 52 females and 25 males with a 2:1 ratio. Majority of the subjects with choledochal cysts belong to the >2-5 years old at 31% (n=24/77). Infantile choledochal cysts or those less than 2 years old consist of 26% of subjects (n=20/77). (See Table 1 and Figure 1) In this pediatric study, the mean age at onset of symptoms and diagnosis was 2.75 years old (range: birth to 14 years old for onset of symptoms) Clinical Manifestations Clinical manifestations may occur alone or in combination with other manifestations. The most common clinical manifestation is jaundice occurring in 48% (n=37/77). This was followed by abdominal pain which occurred in 41% (n=32/77). The classic triad of abdominal pain, jaundice and abdominal mass, only occurred in 4 patients (5%). (See Table 1, Figure 3) Laboratory tests Table 2 shows the laboratory test results with their median and range. Out of the 77 subjects, the most common abnormal liver test results was cholestasis occurring in 21 (27%). Hypoalbuminemia occurred in 20 subjects (25%). Only 13 (16%) subjects had a deranged PT > 2 seconds from the control. >4x elevated Alkaline phosphatase was found in only 4 subjects (5%). (See Table 1, Figure 4) 18

5 TABLE 1. Demographic and Clinical Profile N PERCENT GENDER M/F 25/ /67.5 AGE DISTRIBUTION, IN YRS : AT SURGERY/ ON ADMISSION or WITHOUT SURGERY 2 16/4 80/20 >2-5 24/0 100/0 >5-7 11/0 100/0 >7 19/3 86/14 All Ages 70/7 =77 91/9 AGE IN YRS: AT ONSET OF SYMPTOMS > > > Total CLINICAL MANIFESTATIONS Jaundice Abdominal pain Vomiting Hepatomegaly Abdominal distention Acholic stools or pale yellow 9 11 stools Abdominal mass 7 9 Splenomegaly 6 7 Others (fever) 5 6 Classic Triad 4 5 Bleeding 3 3 Dark urine 2 2 Ascites 1 1 LABORATORY TESTS N=77 Percent Cholestasis PT> 2 SECS Hypoalbuminemia ALT > 2x elev Alk PO4 > 4x elev 4 5 CYST TYPE I II 0 0 III 2 3 IV V 1 1 No data 1 1 Total PREOPERATIVE COMORBIDITIES Severe malnutrition N PERCENT Moderate malnutrition 7 9 Sepsis No complications Total PREOPERATIVE COMPLICATIONS Portal hypertension 7 10 Peritonitis due to cyst rupture 5 7 Cholangitis 2 3 Pancreatitis 0 0 No complications Total OPERATIVE INTERVENTION Cyst excision with Hepaticojejunostomy (CE-HJ) Cyst excision with hepaticoduodenostomy (CE-HD) Cyst Drainage Internal drainage 9 External drainage 3 Mucosectomy 3 4 Staged procedure 4 5 No OR 7 9 Total LIVER BIOPSY RESULTS Liver fibrosis Liver cirrhosis Other findings Normal liver Not Done Total Imaging Out of 77 patients, 57 patients (74%) had ultrasound done, 26 (34%) had CT scan, only one (1.2%) had MRCP and one HIDA scan (1.2%). 22 (28%) had both ultrasound and CT scan imaging done. The 57 ultrasound findings reviewed showed a mean diameter of 4.8cm ( cm) for type I cyst; 7cm (2-11cm) for type IV cyst; 10cm (8-15cm) choledochocoele or type III cysts. Findings of extrahepatic and intrahepatic dilatation were seen in 4 ultrasound imaging however, were signed out as type I cyst intraoperatively. Other findings seen in ultrasound were hydatid cyst, a nonspecific abdominopelvic mass, hepatic cyst, intrahepatic polyp, pancreatic head pseudocyst and liver abscess. Further imaging such as CT scan and MRCP were done in such patients to confirm the diagnosis of choledochal cysts whereas others were diagnosed through intraoperative cholangiogram. Only one MRCP finding of a type I choledochal cyst was found in this study with an initial finding of 19

6 intrahepatic polyps by ultrasound. One patient who had a normal ultrasound and a CT scan done (results of which were not present in the record) underwent HIDA scan showing a consideration of biliary atresia. This patient was subsequently diagnosed as choledochal cyst through an intraoperative cholangiogram, which was used to confirm the diagnosis of choledochal cyst. Cyst Types Out of the 77 subjects studied, only 76 had specific cyst types in the chart. The most common type of cyst found was the type I cyst comprising of 61 out of 77 (79%). Type I cysts was subdivided into 54 type Ia cyst (88%), 1 type Ib cyst (1%) and 6 type Ic cyst (10%). There were only 12 (16%) Type IV cyst. No Type II cyst was found in this study. Only 2 Type III (3%) cysts and 1 (1%) type V cyst were found in this study. (See Table 1 and Figure 5) Preoperative Comorbidities and Complications Preoperative comorbidities such as severe malnutrition was found in 15 (19.5%) of the subjects, followed by moderate malnutrition in 7 (9%). 5 (6.5%) had sepsis. (See Table 1 and Figure 6) The most common preoperative complication is portal hypertension in 7 (10%) followed by peritonitis due to cyst rupture in 5 (7%) patients, and lastly cholangitis in 2 (3%) patients. Pancreatitis was not found in any of the subjects. (See Table 1 and Figure 7) Operative Intervention 70 out of 77 (91%) patients underwent operative intervention. 7 (9%) had no surgical intervention done due to different reasons such as decompensated liver disease, unstable preoperative course, infection or refusal of the caregiver. The most widely used operative intervention is cyst excision with hepaticoenterostomy in 66% of cases (n=51/77). This was followed by 12 (16%) cyst drainage: 9 had external drainage while 3 had internal drainage in the form of cystoduodenostomy or cystojejunostomy. 3 (4%) underwent mucosectomy while 4 (5%) underwent the staged procedure. Cyst excision with hepatic resection was not done in any of the subjects. (See Table 1 and Figure 8) Liver Biopsy Findings Only 11 patients had intraoperative wedge liver biopsy done. Out of the 11 patients with liver biopsy, cirrhosis is found to be more common occurring in 4 patients (36%) than fibrosis in 1 patient (9%). Most of the liver biopsy done had other findings such hepatocyte necrosis and ballooning degeneration, portal traiditis, obstructive cholangiopathy and bile duct proliferation occurring in 5 (45%) subjects. One (9%) of out of the 11 who had an intraoperative liver biopsy done had normal histopathology result. Majority of those who underwent surgery (59 subjects) had no wedge liver biopsy done. (See Table 1 and Figure 9) In our study, 2 patients with cirrhosis had type I cyst, 1 patient had type III cyst, 1 had type IV cyst. Liver fibrosis was found in a type I cyst. Other findings seen were bile duct proliferation and hepatitis seen in Type I and Type IV cysts. In this study, out of the 4 patients with liver cirrhosis, 1 eventually died, while 3 developed portal hypertension. One patient with liver biopsy finding of fibrosis did not develop portal hypertension. Figure 1. Age distribution 26% 2 years old >2-5 years old >5-7 years old Figure 2. Age at onset of symptoms 26% 2 years old Age Distribution (%) 31% >2-5 years old Percent 14% >5-7 years old 29% >7 years od Age at onset of symptoms (%) 33% Percent 15% 26% >7 years old 20

7 TABLE 2. Laboratory test results Laboratory tests Median (range) Hemoglobin 115 g/l (67-156) Total bilirubin 4.55 mg/dl ( ) Direct bilirubin 3.65 mg/dl ( ) ALT 116 U/L (14-459) PT 12.5 secs ( ) PT % 87% ( %) PT INR (0.8-8) Alkaline phosphatase 373 ( ) GGTP None Figure 3. Clinical Manifestations Clinical manifestations (%) 3% 0% 1% 16% Figure 5. Type of Cyst Type of cyst (%) 1% 79% I II III IV V no data 48% 41% 31% 28% Figure 6. Preoperative comorbidities Preoperative comorbidities (%) 16% 11% 9% 7% 6% 5% 3% 2% 1% 66% 21% 6% 7% Severe malnutrition Moderate malnutrition Sepsis No comorbidities Figure 7. Preoperative complications Preoperative Complications (%) Figure 4. Liver function tests 27% Laboratory Tests 25% Percent 16% 14% 5% 10% 7% 3% 0% Portal hypertension Peritonitis due to cyst rupture Cholangitis 80% Pancreatitis No complications 21

8 16% 0% 4% 5% Figure 8. Type of Intervention Intervention (%) 9% 31% 35% Figure 9. Liver biopsy findings Cyst excision with Hepaticojejunostomy (CE- HJ) Cyst excision with hepaticoduodenostomy (CE-HD) Cyst Drainage Mucosectomy Staged procedure Cyst excision + hepaticoenterostomy + hepatic resection No OR TABLE 3. Outcomes of Hospitalization OUTCOMES N PERCENT A. IMMEDIATE POSTOPERATIVE COMPLICATIONS Bleeding HJ/HD site Wound dehiscence Infection 7 10 Bile leak 2 3 Cholangitis No complications Total B. PORTAL HYPERTENSION Portal hypertension No portal hypertension Total C. MORTALITY Mortality Discharged Total % 86% OUTCOMES OF HOSPITALIZATION 1. Immediate Postoperative Complications The most common postoperative complication found was infection in 7 (10%). Infections consisted of subcutaneous abscess, drain culture growth of Enterobacter cloacae, Klebsiella pneumonia and Escherichia coli. (See Table 3 and Figure 10) 2. Portal Hypertension Liver biopsy findings (%) 5% 7% 1% Liver fibrosis Liver cirrhosis Other findings Normal liver Not Done Only 10 out of 77 patients (13%) developed portal hypertension. (see Table 3) Out of the 10 patients with portal hypertension, 4 underwent cyst excision and 2 underwent external drainage of the cyst. 2 subjects with portal hypertension who underwent cyst excision were both 3 month old infants with type I cysts and eventually died. One of them died due to a stormy postoperative outcome and subsequently liver failure while the other died on readmission due to cholangitis. One patient who did not undergo any surgical intervention had decompensated liver disease and eventually died. 3. Mortality 5 out of 77 patients died comprising of 6% of the total subjects. The rest (94%) were discharged (See Table 3). The following are the profile of patients who died: 4 out of the 5 patients who died had onset of symptoms at less than 2 years old (range 1month-1year old). One patient with a type I cyst presented with decompensated liver disease and portal hypertension at 3 months old and due to the unstable condition, no operative intervention was done. He later died due to liver failure and septicemia. One patient who had preoperative portal hypertension successfully underwent excision of a type I choledochal cyst with hepaticoduodenostomy at 3 months old, however developed cholangitis and sepsis on the first and 3 rd month after operation leading to her death. Another patient who was a 5-month old female with preoperative portal hypertension underwent excision of an 8cm type I choledochal cyst with hepaticojejunostomy with liver biopsy findings of biliary cirrhosis. She developed wound dehiscence and infection, sepsis, cholangitis and bile leak and perforation of the jejunum postoperatively for which jejunorrhaphy was done. Unfortunately, she developed decompensated liver disease, portal hypertension and overwhelming sepsis which led to her demise. Another patient who underwent internal cyst drainage of a type IV choledochal cyst at 1 year old developed cholangitis at 6 th and 10 th year of age. At his 16 th year of age, he had sepsis and decompensated liver disease which led to his death. The fifth patient who died was a 14 year-old female who had onset of symptoms at 14 years old age with presenting with peritonitis due to rupture of a massive 10x16cm Type I choledochal cyst. She underwent mucocectomy and hepaticoduodenostomy initially but developed massive hemoperitoneum from the breakdown of 22

9 hepaticodudoddenostomy anastomosis necessitating duodenorrhaphy and hepaticostomy. Unfortunately, she died intraoperatively due to massive bleeding. Figure 10. Immediate postoperative complications Immediate Postoperative Complications 83% 1% 1% 10% A. ASSOCIATION OF VARIABLES (NON-OUTCOME) 1. Association of age with clinical manifestations, preoperative comorbidities and complications and immediate postoperative complications (see Table 4) The age is found to have a significant association with some of the clinical presentation (P 0.05). Jaundice, abdominal distention and hepatosplenomegaly are significantly seen in less than 2 years old. Abdominal pain is significantly seen in all 11 patients 5-7 years of age (P 0.05). The classic triad is rarely seen in the pediatric age group occurring only in 5%. The age is not significantly associated with preoperative comorbidities such as malnutrition and sepsis. On the other hand, the age is found to have a significant association with preoperative complications in which portal hypertension most commonly occurs in the 0-2 years age group (6 out of 16 patients aged 0-2years). Infection is the only immediate postoperative complication which is found to have a significant association with age which was commonly seen in less than 2 years of age (5 out of 16 patients) (P 0.05). (See Table 4) 2. Association of cyst type with the clinical manifestations, preoperative comorbidities and complications and operative intervention. (see Table 5) The only clinical manifestations which were found to have a significant association with the cyst type were the classic triad and bleeding. The classic triad is mainly seen in 50% and 20% of type III and type IV cysts, respectively. Although bleeding has a significant association with the cyst type, the small number of patients with bleeding (1 type I cyst and the other type 4 cyst) precludes association. Jaundice, abdominal pain and 3% 1% Bleeding HJ site Wound dehiscence Infection Bile leak Cholangitis No complications distention, and hepatomegaly are most commonly seen in type I cysts although there is no significant association noted (P>0.05) Preoperative comorbidity like severe malnutrition is significantly associated with type IV cyst. The preoperative complications were not significantly associated with any cyst type. There is no significant association between the type of cyst and operative intervention used. (P>0.05) (See Table 5) 3. Association of cyst type with laboratory results Cyst type was significantly associated with total bilirubin showing higher values in Type 4 cysts compared to Type I cyst. (see table 6) ALT and alkaline phosphatase elevation were significantly associated with cyst type. The only two subjects (100%) with type III cysts have elevated ALT than type I cyst (15%). More subjects with type III and V have elevated alkaline phopsphatase than the rest of the cyst types. (See Table 7) B. ASSOCIATION OF FACTORS WITH OUTCOMES 1. Association of Length of hospital stay (LOS), interval between onset of symptoms and diagnosis/treatment and outcome Interval between symptoms and diagnosis had an average of 5.9 months while interval between symptoms and treatment averaged to 7 months both with a range of 1 month to 48 months. No association was found between LOS, interval between symptoms and diagnosis/treatment, and portal hypertension and mortality. Type II error cannot be ruled out (lack of power to show significant difference) (See Table 8 and Table 9). 2. Risk factors for immediate postoperative complications. (See Table 10) In general, the immediate postoperative complications was not found to be significantly associated with the age. However if taken specifically since there is frequency of mention on these data (see Table 4), infection has been found to be significantly associated with the age, most commonly occurring in the less than 2 years age group (26%). The rest of the factors such as cyst type, preoperative comorbidities and complications, operative intervention were not statistically significant risk factors for immediate postoperative complications. 3. Risk factors for the development of portal hypertension. (See table 11) The age at onset of symptoms, the cyst type and the preoperative complications were significantly associated with the development of portal hypertension. Majority of the portal hypertension developed in less than 2 years of age occurring in 9 out 10 patients (90%) (P <0.05). Cyst type is a significant risk factor for the development of portal hypertension wherein 6 out of the 10 patients (60%) with 23

10 portal hypertension had type I cyst. Only 2 (20%) patients with portal hypertension had type IV cyst. The one and only type V cyst in this study also had portal hypertension. Preoperative complications were found to have a significant association with the development of portal hypertension. Those with preoperative portal hypertension (6 out of 10 or 60%) had persistence of the portal hypertension even after intervention (P<0.05). Those with peritonitis and cholangitis were not risk factors for the development of portal hypertension. Preoperative comorbidities such as malnutrition and sepsis were not risk factors for the development of portal hypertension. TABLE 4. Association of age with clinical manifestations*, preoperative complications and comorbidities and immediate postoperative complications CLINICAL MANIFESTATIONS 2 YO N=20 >2-5YO N=24 >5-7 YO N=11 >7YO N=22 P VALUE (<0.05 is considered significant) Jaundice 17 (85%) 12 (50%) 3 (27%) 5 (23%) Hepatomegaly 13 (60%) 2 (8%) 3 (27% 4 (18%) Abdominal distention 9 (45%) 2 (8%) 2 (18%) Splenomegaly 5 (25%) (4%) Abdominal mass Abdominal pain 0 12 (50%) 11 (100%) 9 (41%) < Classic Triad Acholic stools or pale yellow stools Dark urine Vomiting Bleeding (borderline) Ascites Others(fever) (borderline) PREOPERATIVE COMORBIDITIES 0-2 YO 2-5YO 5-7 YO >7YO P VALUE N=20 N=24 N=11 N=22 Severe malnutrition Moderate malnutrition Sepsis PREOPERATIVE COMPLICATIONS 0-2 YO N=20 2-5YO N= YO N=11 >7YO N=22 Portal hpn 6 (30%) Peritonitis due to cyst rupture 2 (10%) Cholangitis 1 (5%) (4%) Pancreatitis None IMMEDIATE POST OP COMPLICATIONS* 0-2 YO N=20 2-5YO N= YO N=11 >7YO N= ** Bleeding HJ site Wound Dehiscence Infection 5 (26%) (10.5%) Bile leak Cholangitis * Frequency of mention **there is only one p value for the whole set because this is not freq of mention means total is 100% or those with portal hypertension do not have peritonitis etc. 24

11 Operative intervention was not a statically significant risk factor for the development of portal hypertension. Although 3 (30%) patients with portal hypertension had cirrhosis with a P value of <0.05, the liver biopsy finding was not a reliable statistic because of the small number of patients with liver biopsy. (See Table 11) 4. Risk factors for mortality. (see Table 9, 12) Age at onset of symptoms is found to be a risk factor for mortality. 4 out of 5 (80%) patients whose onset of symptoms was at less than 2 years old died. Statistically speaking, age at intervention, interval between onset of symptoms and intervention, cyst type, preoperative comorbidities and complications and type of operative intervention, postoperative complications and liver biopsy findings were not significantly associated with mortality. TABLE 5. Association of cyst type with clinical manifestations, preoperative complications CLINICAL MANIFESTATIONS and comorbidities and operative intervention I N=60 II N=0 CYST TYPE III N=2 IV N=10 V N=1 P VALUE Jaundice Abdominal mass Abdominal distention Abdominal pain Classic Triad (20%) (50%) Hepatomegaly Acholic stools or pale yellow stools Dark urine Splenomegaly Vomiting Bleeding 1 (1.7%) (10%) Ascites Others(fever) PREOPERATIVE COMORBIDITIES I N=60 II N=0 III N=2 IV N=10 V N=1 Severe malnutrition (20%) (3.3%) Moderate malnutrition Sepsis PREOPERATIVE COMPLICATIONS I II III IV V Portal hypertension Peritonitis due to cyst rupture Cholangitis Pancreatitis OPERATIVE INTERVENTION I N=60 II N=0 III N=2 IV N=10 CE-HJ CE-HD Cyst drainage Mucosectomy Staged V N=

12 TABLE 6. Association of Type I and IV cyst with laboratory results Type 1 Type 4 P value Hgb / / Total Bilirubin 4.7+/ / Direct Bilirubin 4.1+/ / ALT / / ALT ELEVATED (NO. OF TIMES) 2.8 +/ / ALBUMIN / / PT Patient / / PT INR 1.30+/ / ALK PHOS / / (only cyst types I and IV have sufficient number of subjects for statistical analysis) TABLE 7. Association of cyst type with laboratory results I N=60 II N=0 III N=2 IV N=10 V N=1 P VALUE CHOLESTASIS PT> 2 SECS Hypoalbuminemia ALT > 2x elev 9 (15%) 0 2 (100%) Alk PO4 > 4x elev 3 (5%) 0 1 (50%) 0 1 (100%) TABLE 8. Association of portal hypertension with length of hospital stay, interval between onset of symptoms and diagnosis/treatment WITHOUT PORTAL HTN N=46 WITH PORTAL HTN N=4 P VALUE LOS, IN DAYS 11.9+/ / INTERVAL 5.6+/ / BETWEEN SYMPTOMS AND DIAGNOSIS, IN MOS INTERVAL BETWEEN SYMPTOMS AND TREATMENT, IN MOS 7.2+/ =/ TABLE 9. Association of mortality with length of hospital stay, interval between onset of symptoms and diagnosis/treatment INTERVAL BETWEEN SYMPTOMS AND DIAGNOSIS, IN MOS INTERVAL BETWEEN SYMPTOMS AND TREATMENT, IN MOS DIED DISCHARGED P VALUE N=3 N= / / / /

13 BLEEDING HJ SITE (n=1) Table 10. Risk factors for immediate postoperative complications. WOUND DEHISCHENCE (n=1) INFECTION (n=7) BILE LEAK (n=2) CHOLANGITIS (n=1) P VALUE AGE IN YRS > > > CYST TYPE I II III IV V PREOP COMORBIDITIES Severe Malnutrition (n=15) (borderline) Moderate malnutrition (n=7) *no conclusions can be made because of singularity (i.e., all entries are zero) Sepsis (n=5) BLEEDING HJ SITE (n=1) WOUND DEHISCHENCE N=1) INFECTION (N=7) BILE LEAK N=2) CHOLANGITIS (N=1) PREOP COMPLICATION S Portal HTN (n=6) Peritonitis (n=5) Cholangitis (n=2) None (n=64) BLEEDING WOUND INFECTION BILE CHOLANGITIS HJ SITE DEHISCHENCE (N=7) LEAK (N=1) (n=1) N=1) N=2) OPERATIVE INTERVENTION CE HJ (n=27) CE HD (n=24) Cyst drainage (n=12) Staged (n=4) Mucosectomy (n=3) P VALUE P VALUE

14 TABLE 11. Risk factors for portal hypertension + PORTAL HYPERTENS ION N=10 (-) PORTAL HYPERTENS ION N=67 P VALUE AGE IN YRS (borderli ne) 0-2 (n=20) 7 13 >2-5 (n=24) 0 24 >5-7 (n=11) 1 10 >7 (n=22) 2 20 AGE AT < ONSET OF SYMPTOMS, IN YRS 0-2 (n=19) 9 (90%) 10(15%) >2-5 (n=23) 0 23 >5-7 (n=11) 0 11 >7 (n=19) 1 18 No data (n=5) 0 5 CYST TYPE I (n=60) 6 (60%) 55 (82%) II (n=0_ 0 0 III (n=2) 0 2 IV (n=10) 2 (20%) 10(14%) V (n=1) 1 0 No data 1 0 PREOP COMORBIDI TIES + PORTAL HYPERTENS ION N=10 (-) PORTAL HYPERTENS ION N=67 P VALUE Severe malnutrition (n=15) Moderate malnutrition (n=7) Sepsis (n=5) PREOP < COMPLICATI ONS Preop Portal 6 (60%) 0 Hypertension (n=6) Peritonitis 0 5 (n=5) Cholangitis (n ) None 4 53 OPERATIVE INTERVENTI ON CE-HJ (n=27) 3 24 CE-HD (n-24) 1 23 Cyst Drainage 3 9 (n=12) Staged( n=4) 0 4 Mucosectomy 0 3 (n=3) No OR 3 4 LIVER BIOPSY FINDINGS Cirrhosis (n-3) 3 (100%) 0 Fibrosis (n=1 0 1 Others (n=5) 0 5 Normal (n-1) 0 1 Not done 7 53 TABLE 12. Risk factors for mortality DIED N=5 DISCHARGED N=72 P VALUE AGE IN YRS (n=20) 3 16 >2-5 (n=24) 0 24 >5-7 (n=11) 0 11 >7 (n=22) 2 21 AGE AT ONSET OF SYMPTOMS IN YRS 0-2 (n=19) 4 15 >2-5 (n=23) 0 23 >5-7 (n=11) 0 11 >7 (n=19) 1 18 No data (n=5) 0 5 DIED N=5 DISCHARGED N=72 P VALUE CYST TYPE I (n=61) 4 56 II (n=0) 0 0 III (n=2) 0 2 IV (n=12) 1 9 V (n=1) 0 1 No data (n=1) 0 1 PREOP COMORBIDITIES Severe malnutrition

15 (n=15) Moderate malnutrition (n=7) Sepsis (n=5) PREOP COMPLICATIONS Preop Portal 3 3 Hypertension (n=6) Peritonitis (n=5) 1 4 Cholangitis (n-2) 0 2 None (n=64) 1 63 DIED N=5 DISCHARGED N=72 OPERATIVE INTERVENTION CE-HJ (n=27) 1 26 CE-HD (n-24) 1 23 Cyst Drainage 1 11 (n=12) Staged( n=4) 0 4 DIED DISCHARGED N=5 N=72 Mucosectomy (n=3) 1 2 No OR (N=7) 1 6 POST OP COMPLICATIONS Bleeding HJ site (n=1) Wound Dehiscence (n=1) P VALUE P VALUE Infection (n=7) Cholangitis (n=1) Bile leak (n=2) None (n=72) 3 68 LIVER BIOPSY FINDINGS Cirrhosis (n=4) 1 3 Fibrosis (n=1) 0 1 Others (n=5) 0 5 Normal (n-1) 0 1 Not done (n=66) 4 62 Incidence DISCUSSION Choledochal cysts are diagnosed in infants and children 11 and is more common in the in Asia. 1,2 In this present pediatric study, the mean age at onset of symptoms and diagnosis was at 2.75 years old nearly similar to a pediatric study done by Singhavejsakul et al in Thailand whose mean age at diagnosis was at 4 years old. 3 Although majority of the patients had onset of symptoms at 2 to 5 years old, a significant number of subjects also had onset at 2 years age group (26%) similar to a study done by Wong Ho She et al in Hongkong. 7 Its increased incidence in infants and children emphasizes the importance of including choledochal cyst in the differential diagnosis of infants with cholestasis. There was a 2:1 female: male ratio in this study which was similarly seen in other studies. 1,2,7,3,11 Clinical Manifestations This age related difference in the presentation of choledochal cysts is similar to other studies. Infants less than 2 years old most commonly present with jaundice, abdominal distention either due to the cyst or due to hepatosplenomegaly. On the other hand, abdominal pain is most commonly seen in the older age group probably due to the chronic reflux of pancreatic juice from the abdnormal pancreatobiliary duct union that is a predisposing factor for the development of choledochal cyst. 1,7 Jaundice as the main presenting symptom of type I cyst, although not statistically significant (P 0.05) is seen in this study which is similar to others in literature. 1 The reason why jaundice is the main presenting symptom of Type I cyst is due to the extrahepatic biliary obstruction caused by the cyst. On the other hand, cholangitis and gallstones are the usual presenting symptoms of intrahepatic cysts such as in type IV and V cysts. However, this was not seen in our study possibly because of the small number of type IV and type V cysts in our study. The classic triad is mainly seen in type III and type IV cysts with P<0.05. No studies could be found correlating the incidence of Type III and IV cysts with the classic triad. Type of cyst and Imaging Similar to other studies written, the most common type of choledochal cyst found in this study is Type I and type IV occurring in 82% and 14% respectively. Only one type V cyst was seen in this study which is also rarely encountered in literature. Ultrasound is the initial study of choice. 11 However, the presence of intrahepatic dilatation warrants further imaging to delineate whether it is a type I or Type IV cyst. It is important to take note that not all cysts with intrahepatic dilatation are type IV cysts because according to the American College of Surgeons, type I cysts can be associated with mild dilatation of the intrahepatic bile ducts which maybe secondary to biliary stasis. 12,5 In fact, in our study, findings of intrahepatic duct dilatation on ultrasound were actually just type I cysts as confirmed by intraoperative cholangiogram. On the other hand, some intrahepatic dilatation may not be seen on ultrasound hence CT scan is recommended to visualize the IHD and distal bile ducts which was the case in our patient who had a type I cyst on ultrasound, but turned out to be a type IV cyst on CT scan. 5 Further imaging such as CT scan, MRCP or intraoperative cholangiogram (IOC) are important to visualize the cyst s continuity with the biliary tree and rule out pancreatic pseudocysts, hydatid cysts and other hepatic cysts and abdominal mass which were could be confused with 29

16 choledochal cysts as seen in our study. A review by Singham noted that MRCP is to be now considered to be the gold standard in the diagnosis of choledochal cysts with sensitivity of % and specificity of %. Because it s a new imaging modality emerging nowadays, the present study was only able to record one patient who had an MRCP done to confirm the diagnosis of choledochal cyst after the findings of intrahepatic polyps versus choledochal cyst in ultrasound were initially seen. 5 The HIDA scan helps to differentiate a choledochal cyst from biliary atresia wth a sensitivity of 100% for type I cyst and 67% for type IV cyst. 5 In our study, a three month old with cholestasis who had a normal ultrasound, a HIDA scan suggestive of biliary atresia, had an intraoperative cholangiogram showing a type I choledochal cyst. Ultimately, intraoperative liver biopsy showed biliary atresia with cirrhosis. It is important to note that there is a type of biliary atresia called cystic biliary atresia (CBA) where the cysts are smaller, with an atretic gallbladder (GB) with less dilated intrahepatic ducts (IHD) as opposed to choledochal cyst where IHD maybe seen with a normal or distended gallbladder. Extrahepatic biliary atresia associated with choledochal cyst should also be a consideration in such cases. A HIDA scan finding of biliary atresia should be confirmed with an intraoperative cholangiogram (IOC), which is the gold standard in the diagnosis of biliary atresia. On the other hand, an IOC that is done meticulously to visualize the continuity of the cyst with the biliary tree establishes diagnosis of a choledochal cyst and rules out cystic biliary atresia. Differentiating the one from the other is crucial since they differ in management and prognosis. 11 Ultimately, the decision whether further imaging is warranted should be made early to avoid delay in the diagnosis and management of choledochal cyst. Laboratory values In this study, cyst type was significantly associated with total bilirubin showing higher values in Type 4 cysts compared to Type I cyst. 1 Although an elevated bilirubin manifesting as jaundice increases in patients with cholestatic liver diseases such as choledochal cysts, the magnitude of its increase does not distinguish intrahepatic from extrahepatic disorders like Type I cyst (extrahepatic biliary dilatation) from intrahepatic disorders like Type IV (intra and extrahepatic biliary dilatation). 9 Even though a higher proportion of subjects showing > 4x elevation of Alkaline phosphatase (AP) was significantly found in Type III and V cysts, compared to Type I cyst, the extent of elevation of AP does not differentiate intrahepatic (type V) from etxrahepatic obstruction (type I). 9 To further confirm an association of the elevated AP in the cyst types, it is important to note and interpret the AP with an elevated GGTP which is more specific for biliary diseases. However, no GGTP results were found in the charts reviewed. Preoperative comorbidities and complications Preoperative complication is significantly associated with the age on intervention. The most common preoperative complication is portal hypertension which commonly and significantly occurred in less than 2 years old (10%) This is followed by peritonitis then cholangitis. This is in contrast with a study done by Singhavejsakul in Thailand where the most common preoperative complications were biliary tract infections such as cholecystitis and cholangitis. 7,3 In this study, peritonitis occurred in 6% of cases similar to a a review done by Singham et al, where peritonitis due to spontaneous rupture of cyst occur in 1-12% of cases. Spontaneous rupture is thought to occur due to mural fragility of the cyst wall from chronic inflammation, increased ductal pressure from distal obstruction, or raised intraabdominal pressure. 5 Diagnosis is confirmed via an intraoperative finding of bilious peritoneal fluid or peritoneal entry of contrast seen in HIDA scan. In this pediatric study, the 5 cases of peritonitis (6%) was due to rupture of a type I cyst confirmed intraoperatively when a bile-stained peritoneal fluid was seen. The smallest cyst measured 1.6cm while the largest 7 cm. According to a review by Singham et al, the most common site of rupture is the junction between the cystic duct and the common bile duct where the blood flow is poorest. One intraoperative finding mentioned a perforation at the distal common bile duct but did not mention its proximity with the cystic duct. The preoperative complications were not significantly associated with any cyst type in contrast to the study done by Congo et al wherein cholangitis and pancreatitis commonly occur in Type IV cyst possibly due to intrahepatic dilatation. In this study, cholangitis occurred in type I cysts. This maybe due to the small number of type IV cysts in this study. 11,6 Operative intervention Majority of cases seen in this study underwent cyst excision with hepaticojejunostomy or hepaticoduodenostomy which is the surgical procedure of choice. 60% of the type I cysts underwent cyst excsion with bilioenteric anastomoses with a comparable distribution between hepaticoduodenostomy (31%) and hepaticojejunostomy (35%). There was no significant difference in the incidence of postoperative complications between hepaticojejunostomy and hepaticoduodenostomy according to Todani et al. 13 But in another review by Soares et al, 11 hepaticoduodenostomy is associated with a higher risk of long term complications such as gastric cancer due to bile reflux and biliary cancer. Hence, a wide anastomosis is recommended to allow free flow of bile into the intestine. This study did not include long-term followup of the cases hence the occurrence of gastric cancer in patients who underwent hepaticoduodenostomy could not be studied. In some cases, initial external biliary drainage, to be followed by cyst excision 1-2 months later, is the procedure of choice for whom cyst excision will be difficult to perform due to bile peritonitis from a ruptured cyst, severe cholangitis or poor general condition, complicated cysts or large cysts. 14 Indications for biliary drainage on our subjects were peritonitis due to a ruptured cyst, large cysts (10-15cm) which bled while attempts 30