Endoscopic treatment of chronic idiopathic pancreatitis in children

Endoscopic Treatment of Chronic Idiopathic in Children By L. Perrelli,

L. Nanni, G. Costamagna, Rome, Italy

0 The purpose of this study was to analyze the preliminary results obtained with endoscopic treatment of children with chronic idiopathic pancreatitis. The disease appears to be caused by a deficit of pancreatic stabilizing proteins that leads to precipitation of solutes contained in the pancreatic secretions; these precipitates are the cause of inflammation. The possible role of a congenital malformat(on in the pathogenesis of this disease is being regarded with increasing scepticism. Between October 1991 and April 1994, five cases of chronic pancreatitis were referred to the Division of Pediatric Surgery of the Policlinico “A. Gemelli” of Rome. The age range of the patients (3 boys, 2 girls) was 3 to 14 years (mean, 10.8 years); all had a history of acute attacks and had blood chemistry findings compatible with pancreatitis. None of the patients’ families had a history of pancreatic disease. All diagnoses were confirmed by endoscopic retrograde cholangiopancreatography, and the disease was staged according to the criteria of Cremer et al. Endoscopic pancreatic sphincterotomy, with or without removal of calculi, was performed in four cases (2 in the authors’ hospital, 2 in another institution). Three of the children have had no further symptoms [mean follow-up period, 20 months), and their growth and weight gain have been normal. The fourth child, a 3-year-old girl; has had two episodes of pain since treatment. These attacks, both of which subsided spontaneously, probably were caused by the passage of protein plugs through the sphincterotomy. The fifth patient received no treatment because she had remained asymptomatic since the first examination (28 months ago). The ‘short-term effects observed in these children indicate that endoscopic treatment of chronic idiopathic pancreatitis is associated with a high rate of success with respect to pain control. Because of the short follow-up, the effects on endocrine and exocrine function have not been assessed. No deaths or complications occurred. Conservative treatment of this type can be repeated if pain recurs, an important factor given the chronic nature and early onset of this disease, and it does not preclude the possibility of subsequent surgery. The authors’ experience indicates that this approach should be considered the initial treatment of choice for children with chronic pancreatitis. Copyright o 1996 by W.6. Saunders Company INDEX WORDS: treatment.

T

Chronic

pancreatitis,

childhood;

endoscopic

HE ONSET of idiopathic forms of pancreatitis sometimes occurs during infancy.lT2 It is difficult

From the Division of Pediatric Surgery and the Istituto di Clinica Chirurgica, Policlinico “A. Gemelli, ” Universitri Cattolica de1 Sacro Cuore, Rome, Italy. Address reprint requests to L. Perrelli, MD, Divisione di Chirurgia Pediatrica, Policlinico “‘A. Gemelli, ” Universitd Cattolica de1 Sacro &ore, Large Gemelli 8, I-00168, Rome, Italy. Copyright o 1996 by WB. Saunders Company 0022-3468/9613110-0015$03.OOiO 1396

Pancreatitis

and M. Mutignani

to estimate the frequency of this type of pathology in children and adolescents because most of the studies of this disease have focused on etiologic factors, clinical manifestations, or surgical treatment, and, in the majority of studies, the number of patients has been small. Based on an analysis of 69 adult patients with chronic pancreatitis associated with various causes, Little et al3 found that approximately 14% had had significant symptoms before the age 20 years. Although the incidence of chronic pancreatitis is low, it should always be considered as a possible cause of recurrent abdominal pain in children. The possible role of a congenital malformation in the pathogenesis of this disease is being regarded with increasing scepticism.4J Instead, the origin of this disease appears to be related to a quantitative deficit of pancreatic stone proteins (PSP) that maintain the equilibrium of solutes contained in the pancreatic juice. This deficit, which seems to have a hereditary basis,7 promotes the formation of calcium-protein precipitates within the pancreatic ducts, and this event represents the “prime mover” in the inflammatory process.6,7 PSP are synthesized by pancreatic acinar cells and are co-released with enzymes from zymogen granules. These proteins have a common backbone composed of 144 amino acids, and their molecuIar weights range from 16,000 to 19,000 d, depending on the degree of glycosylation. The original PSP molecule (PSP-S2-5) is hydrolyzed by trypsin to form a short N-terminal glycosylated peptide that is soluble and a long, insoluble C-terminal peptide. Although PSP-S2-5 and its N-terminal peptide prevent calcium precipitation, the C-terminal peptide (known as PSP-Sl) polymerizes to form fibrils. Polymerized PSP-Sl can precipitate even in the absence of calcium to form radiolucent protein plugs.’ Until recently, the therapeutic options available for symptomatic patients were either medical or surgical. Seemingly good results, in terms of pain amelioration and preservation of pancreatic function (both endocrine and exocrine), have been obtained in children with pancreatic-duct diversion procedures.3T8 However, a valid nonsurgical alternative has been provided with the advent of therapeutic endoscopic retrograde cholangiopancreatography (ERCP). In addition to its invaluable role in the diagnosis and staging of chronic pancreatitis, this technique allows JournalofPediarricSurgery,

Vol31,No

lO(October),1996:

pp1396-1400

CHRONIC

lDl0PATl-K

PANCREATITIS

1397

the execution of maneuvers aimed at restoring normal pancreatic-duodenal flow in cases of obstruction, such as sphincterotomy, extraction of stones, and even prosthesis placement.9 Endoscopic approaches of this sort have been widely used in adult patients, but they are not often considered for the treatment of children.lO The purpose of the present study was to analyze the short-term results of this approach, in terms of pain control, in pediatric patients with chronic idiopathic pancreatitis. Further studies involving longer follow-up periods will be necessary to determine whether endoscopic treatment is effective in slowing or halting the progression of the disease. MATERIALS

AND METHODS

Between October 1991 and April 1994, five children (2 girls, 3 boys; age range, 3 to 14 years; mean age, 10.8 years) with chronic idiopathic pancreatitis were referred to the Division of Pediatric Surgery of the Policlinico “A. Gemelli.” None of the patients’ family histories were positive for pancreatic disease. All the children had had a history of recurrent attacks of deep abdominal pain, without the typical upper quadrant localization. Most of these attacks, which varied in frequency from patient to patient (five to eight episodes per year), were described by the children and/or their parents (using an arbitrary 3-point scale) as “moderately” painful and not severe enough to require medication. However, two of the patients (cases 1 and 3) also had experienced one or more episodes of “severe” pain necessitating the administration of analgesics. Patient 3 also noted that the majority of his attacks were postprandial and that most of his meals were followed by a certain degree of discomfort (Table 1). In all five cases, laboratory data (elevated serum amylase and lipase levels) and ultrasound findings (calcification, hyperechogenie spots within the parenchyma, dilatation of Wirsung’s duct) were indicative of chronic pancreatitis. Endocrine function, as reflected by results of glucose-tolerance tests (GTT), was normal in all patients. The pancreolauryl test results were normal in for all children except patient 3, who had markedly reduced exocrine function. The fecal chymotrypsin level was normal in all cases. ERCP was performed to confirm the diagnosis and to stage the disease. Because of the young ages, the examinations were performed with the patients under general anesthesia. Standard duodenoscopes (Fujinon Duo-XL5 -EVD-XL, and -ED7-XL2; respective diameters, 12, 12, and 10 mm) were used for ERCP and sphincterotomies. In one case (the 3-year-old girl) a pediatric duodenoscope (Olympus prototype; caliber, 7.5 mm) was used to Table Patient NO.

SW

1

F

2

Age (vr)

3

Age at onset (vr)

1

The diagnostic phase of ERCP was completed successfully for all five patients. Cholangiographic findings were normal in all cases. Pancreatographic findings confirmed the presence of chronic pancreatitis. Four children were considered to have type IV disease; type III pancreatitis was diagnosed in the fifth. Because of their histories of recurrent abdominal pain and findings of distal obsiruction with dilatation of the ducts, the four patients with type IV disease were subjected to endoscopic treatment with sphincterotomies of the main biliary and pancreatic ducts to restore normal drainage (2 in our hospital, 2 in another institution). In one case, minor sphincterotomy also was necessary because of accessory-duct dominance (Fig 1). In two cases, spontaneous expulsion of protein plugs was observed immediately after sphincterotomy. In the remaining two, stones were extracted using Dormia baskets and Fogarty balloon catheters. At the end of the procedure, nasopancreatic drains were positioned and kept in place for 2 to 6 days (mean, 4 days) (Fig 2). None of the procedures was associated with complications or death. The mean follow-up period as of March 1995 was 20 months (range, 9 to 30 months). Because of the short follow-up, our evaluation of these patients has been primarily clinical, with functional assessments planned at a later stage. Three of the children have been symptom-free throughout the follow-up period. The 3-year-old girl (patient 1) has experienced two painful episodes, both of which subsided spontaneously. eepeat ERCP showed no evidence of ductal or sphincter obstruction. Data

; Symptoms

TYPO

IV

Ill

Treatment

Attacks of acute diffuse abdominal pain, shock,

and

vomiting Recurrent acute abdominal Recurrent upper quadrant

pain pain

3

11 13

10 4

IV

4

M

13

5

IV

that resolved spontaneously Spontaneously resolving postprandial abdominal pain

5

M

14

12

IV

Recurrent

biliary

sphincterotomy;

EBS, endoscopic

RESULTS

1. Clinical

F M

Abbreviations:

perform sphincterotomies of both the major and minor papillae. Endoscopic accessories commonly used for adult patients were used in the diagnostic and treatment phases of the procedure. On the basis of pancreatographic findings, the form of the disease was claSsified according to the system of Cremer et al,” which distinguishes five types of pancreatitis on the basis of morphological criteria (Table 2).

acute abdominal

pain

EPS, endoscopic

Results

EBS plus EPS (major and minor) plus extraction of calculi

2 episodes of abdominal (follow-up, 23 mo)

None

Asymptomatic Asymptomatic

(follow-up, (follow-up,

28 mo) 30 mo)

EBS plus EPS

Asymptomatic

(follow-up,

10 mo)

EBS plus EPS

Asymptomatic

(follow-up,

9 mo)

EBS plus EPS plus extraction calculi

pancreatic

sphincterotomy.

of

pain

1398

PERRELLI

Table 2. Classification

of Chronic

ET AL

Pancreatitis

Type 1

Minor

Type II

Moderate irregularity of the main pancreatic duct Dilatation of some of the secondary ducts (type IA) Abnormality of all visualized ducts (type IB) Focal pancreatitis

pancreatitis

Macrocystic dilatation (> 10 mm) of one or more of the secondary ducts localized in one segment of the gland:

Type

Ill

Head of pancreas-type

IIH

Body of pancreas-type Tail of pancreas-type Diffuse pancreatitis

IIB IIT

Single (type IIIB) or multiple (type IIIA) stenoses of the main duct without significant proximal dilatation; Type IV

abnormality of ail secondary ducts Segmentary pancreatitis of the head

Type V

Stenosis of the main duct within the head of the pancreas, with significant dilatation of all ducts proximal to the stenosis Pancreatitis with a stop in the head of the pancreas Occlusion of the main duct within the head of the pancreas secondary to fibrotic stenosis or calculi

NOTE.

Classification

is according

to Cremer

et aI.”

The fifth patient, who was found to have type III chronic pancreatitis, received no treatment because she had remained asymptomatic since the first examination (28 months ago). DISCUSSION

The later stages of chronic pancreatitis are characterized by spontaneous remission of abdominal pain and the appearance of signs of full-blown insufficiency of both the exocrine and endocrine pancreasy12-r4Before the disease reaches this stage, treatment is aimed at producing stable remission of painful symptoms (that respond poorly to medical treatment), prevention of complications (cystic lesions, stenosis of the main bile duct), and hahing or

Fig 1. Case 1. Diagnostic ERCP. The catheter (small arrow) has been inserted within the duct of Wirsung; noncalcific plugs (large arrow) are visible within the accessory duct and one of its lateral branches.

Fig 2. Case 4. Follow-up pancreatography shows a reduction in the caliber of the duct of Wirsung (small arrow) with respect to the pretreatment exam and an unobstructed flow of the contrast medium into the duodenum. The medium is injected via the nasopancreatic drainage tube (large arrow) left in place after the sphincterotomy.

slowing the progression of the disease. These objectives are particularly important when the disease appears early in life because it can interfere with the psychophysical development of the child. In a growing child, suspension of oral feedings prescribed during acute attacks or refusal to eat because of the possibility of pain can have effects that are much more serious than in adults. Given the nonmalignant nature of this disease and the risks associated with pancreatic resection (ie, 12% to 62% incidence of secondary diabetes, depending on the source of the report15J6), most surgeons currently prefer diversion procedures, which carry a much lower risk for endocrine complications (10%” to 23%16) in the treatment of patients with dilatation of the main pancreatic duct. When performed by experienced surgeons, both pancreatic resection and enteropancreatic anastomosis are associated with a mortality rate that is close to zero.r6-l9 However, the incidence of complications after pancreaticqjejunostomy is only S%,i8 as opposed td the figure of 14% reported by Izbicki et alzOafter duodenum-preserving resection. Apart from the higher rate of complica-

CHRONIC

IDIOPATHIC

PANCREATITIS

1399

tions, the rationale for partial resection has been questioned seriously. l&l9 True focal disease is exceedingly rare (unless associated with trauma), and removal of “dominant” disease is illogical because abnormal tissue is left that will undergo progressive deterioration as the disease evolves. Seventy-five percent of patients subjected to side-toside pancreaticojejunostomy experience complete remission of pain during the first 2 years after surgery, but subsequent progression of disease reduces this rate to only 50% at 5 years.19 Because of the low number of pediatric cases reported in the literature, these figures are based primarily on experience with adult patients. The largest study conducted thus far on the effects of surgical treatment on the deterioration of pancreatic endocrine and exocrine functions is that of Nealon and Thompson,21 who examined 143 adults who had chronic pancreatitis. Based on ERCP morphology and exocrine and endocrine function, the patient’s disease was classified as mild-to-moderate (M-M) or severe (S). Eighty-seven underwent surgical drainage of the main pancreatic duct (modified Puestow procedure), and the rest were treated nonsurgically. Regardless of the severity of the disease, none of the surgical or nonsurgical patients experienced any significant functional improvement during the follow-up period (mean, 47.3 months). However, within the M-M group, baseline pancreatic function was preserved in 87% of the patients who were treated surgically, as opposed to only 22% of those of the nonsurgical group. These findings indicate that early drainage of the main pancreatic duct (ie, before advanced functional disease is present) can delay the development of outright pancreatic insufficiency. Endoscopic management is now a common firstline approach for the treatment of adults with chronic pancreatitis. Because of the experience gained in these cases and a greater understanding of the mechanisms underlying the pain experienced by children who have this disease, endoscopic approaches are now being used to treat pediatric patients as welLlo The painful symptoms experienced by adults with chronic pancreatitis generally are caused by a more-or-Iess fixed obstruction within the main pancre-

atic duct (stenosis or calculi) that leads to its proximal distension. In contrast, the pain experienced by children with chronic idiopathic pancreatitis appears to be more commonly caused by the transient occlusion of the sphincter of Oddi by protein plugs that form within the pancreatic juice as a result of the PSP deficit. In these cases, the most effective approach to restore the flow within the duct is to reduce the resistance to the passage of these plugs by sphincterotomy. Although the number of cases reported herein is low, the success achieved in both the diagnostic and therapeutic phases of ERCP indicate that, with appropriate precautions, the use of this procedure in children should be associated with few complications and a low mortality rate. The short-term results are highly encouraging; all the children treated have experienced significant weight gain and good overall growth. In the only case in which endoscopic sphincterotomy did not lead to complete remission of symptoms (patient l), both painful episodes resolved spontaneously. Given the dimensions of the duct of Wirsung in a child of this age (3 years old), the episodes probably can be attributed to temporary obstruction by protein plugs at the level of the duct itself. Prospective studies have not been performed to assessthe effect of endoscopic drainage of the pancreatic duct on the progression of the disease, but the above-mentioned findings of Nealon and Thompson21 suggest that this approach should be capable of slowing the process of functiona deterioration. Because it is less invasive, endoscopic drainage can be repeated if symptoms do recur, and because it does not alter the integrity of the gastrointestinal tract, it does not preclude the possibility of subsequent surgery. In fact, successful resolution of pain with endoscopic drainage of the pancreatic duct is an indicator that the child will benefit, with respect to pain relief, from more definitive surgical procedures to divert the flow of the pancreatic juice. We believe that characteristics make endoscopic drainage the initial treatment of choice for children with chronic pancreatitis.

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PERRELLI

ET AL

chronic pancreatitis, in Beger HG, Buechler M, Malfertheiner P (eds): Standards in Pancreatic Surgery. Berlin, Germany Springer, 1993, pp 385-391 16. Kestens PJ: Traitment chirurgical de la pancreatite cronique: Amelioration des techniques de drainage. Ann Chir 42:241247,198s 17. Morel P, Rohner A: Surgery for chronic pancreatitis. Surgery 101:130-1351987 18. Bradley EL: Long term results of pancreatojejunostomy in patients with chronic pancreatitis. Am J Surg 153:207-213,1987 19. Moossa AR: Surgical treatment of chronic pancreatitis: An overview. Br J Surg 74:661-667,1987 20. Izbicki JR, Bloechle C, Knoefel WT, et al: Duodenumpreserving resection of the head of the pancreas. A prospective randomized trial. Am Surg 221:350-358, 1995 21. Nealon WH, Thompson JC: Progressive loss of pancreatic function in chronic pancreatitis is delayed by main pancreatic duct decompression. Ann Surg 217:458-468,1993