Definitions and Epidemiology
Inflammatory disorders of the pancreas are classified as acute or chronic. Acute pancreatitis is generally a reversible process with no significant permanent effects on pancreatic histology or function, whereas chronic pancreatitis leads to irreversible changes in the architecture and function of the pancreas. Both are defined clinically. Acute pancreatitis is a distinct event requiring two of the following three features for diagnosis: (1) clinical symptoms consistent with acute pancreatitis, (2) serum amylase or lipase levels or both at least three times the upper limit of normal, and (3) findings of acute pancreatitis on transabdominal ultrasonography or on contrast-enhanced computed tomography (CECT). Chronic pancreatitis is a progressive disease leading to typical histological and morphological changes in the pancreas, usually identified by radiographic methods, or to loss of digestive function or both.
The diagnosis of acute pancreatitis in childhood has increased over the years.1,2 Currently, the incidence in large children’s hospitals may approach 12–15 cases per 100,000 children per year. The reason for the increase remains unsettled, but a recent study suggested that increased awareness of the disease in childhood is the major factor, since increased amylase and lipase testing accounted for the majority of the change at a single institution.
Although a wide range of prevalence in etiologies exists among various reports and the categories often vary among the reports, systemic illness, biliary disease, trauma, and side effects of medications comprise the majority of patients with an identifiable etiology (Table 31–1).3 A sizable portion of patients have no discerned etiology and are classified as idiopathic. Since there is wide variation in prevalence of etiologies among the available reports, any current compilation of these requires some ambiguity in categorization. The overall variation likely reflects the retrospective nature of the studies, the bias or experience of the clinicians, incomplete investigations for etiologies in many patients, and the recognition of new etiologies over time.
|• Choledochal cyst|
|• Biliary sludge|
|• Pancreas divisum|
|• Anomalous junction of the biliary and pancreatic ducts|
|• Annular pancreas|
|• Ampullary obstruction|
|• Crohn disease|
|Drugs (only the most commonly reported are listed)|
|• Hemolytic uremic syndrome|
|• Diabetic ketoacidosis|
|• Collagen vascular disease|
|• Kawasaki disease|
|• Organ transplantation|
|• Sickle cell disease|
|• Anorexia nervosa|
|• Inflammatory bowel disease|
|• PRSS1 mutations|
|• CFTR mutations|
|• Glycogen storage disease|
|• Organic acidemias|
Recurrent episodes of acute pancreatitis occur in about 10% of children. The most common etiologies in these patients are structural abnormalities, genetic pancreatitis, and idiopathic. Some of these patients will eventually develop chronic pancreatitis.
The prevalence of chronic pancreatitis in childhood is unknown, although it is certainly less frequent than acute pancreatitis. Similarly, the frequency of etiologies remains uncertain. As with acute pancreatitis, idiopathic causes comprise a large percentage of the patients with chronic pancreatitis (Table 31–2). Patients with autosomal dominant hereditary pancreatitis or with autosomal recessive familial pancreatitis form another large group.4–6 There are also toxic or metabolic and obstructive causes.
|• Autosomal dominant|
|• PRSS1 mutations|
|• Autosomal recessive/modifiers|
|• CFTR mutations|
|• SPINK1 mutations|
|• See Table 31–1|
|• See Table 31–1|
|• Isolated autoimmune pancreatitis|
|• Syndromic autoimmune pancreatitis|
|• See Table 31–1|
Acute pancreatitis can be separated into two types, interstitial edematous, the most common type, and necrotizing pancreatitis. Both result from injury and inflammation of the pancreas that may extend to peripancreatic tissues and remote organs.7 Current models include at least three phases in the development of acute pancreatitis. Initially, an extrapancreatic factor initiates the onset of pancreatitis. In children, systemic illness, medications, trauma, and bile or pancreatic duct disease secondary to congenital anomalies or gallstones are the common triggers. The mechanism whereby these events cause pancreatitis remains speculative.8 Early events in experimental pancreatitis include influx of calcium into the acinar cell, the co-localization of pancreatic digestive enzymes and lysosomal enzymes as autophagosomes, and altered secretion of the digestive enzymes, in particular increased basolateral secretion. The early events somehow produce the second phase of pancreatitis, acinar cell injury. Current theories for the mechanism of acinar cell injury center on the premature activation of trypsinogen to trypsin within the acinar cell. Once converted, trypsin activates other proenzymes and the combined action of these enzymes leads to acinar cell injury or autodigestion. Other processes may also contribute to, or even dominate, the early events that damage the acinar cell. These include injury by reactive oxygen species, alterations in the microcirculation of the pancreas producing areas of hypoperfusion, changes in the permeability of the acinar cell plasma membrane, and increased endoplasmic reticulum stress.8 The resultant acinar damage produces pancreatic edema and a local inflammatory response. The cytokines and chemokines released during this response mediate a systemic inflammatory response, the third phase of acute pancreatitis. The magnitude of the systemic response largely determines the clinical severity of acute pancreatitis.9 A vigorous response can lead to pancreatic necrosis, inflammation in adjacent tissues and in distant organs, and systemic complications.
Early in their course, patients with chronic pancreatitis may be difficult to distinguish from those with acute pancreatitis.10 Eventually, the continued inflammation produces enough irreversible morphological change in the gland including fibrosis, acinar cell loss, islet cell loss, and infiltration by inflammatory cells that the diagnosis becomes apparent. The inability to diagnose chronic pancreatitis early in its course and to identify early events has permitted investigators to speculate freely and many theories to explain the pathophysiology of chronic pancreatitis have been proposed over the years. Current knowledge supports the hypothesis that chronic pancreatitis is a progression that begins with an episode of acute pancreatitis followed by ongoing chronic or recurrent inflammation to produce end-stage fibrosis. The sentinel acute pancreatitis event (SAPE) hypothesis was proposed in 1999 and remains the prevailing concept.11 In this model, a metabolic or oxidative stress initiates the first episode of acute pancreatitis, the sentinel event. Activated lymphocytes, macrophages, and stellate cells increase in number within the pancreas. They produce cytokines and deposit small amounts of collagen. Most patients recover uneventfully and the gland returns to normal. In some, due to the continued presence of stress, inflammatory cells and stellate cells remain active and release cytokines and deposit collagen, eventually producing the fibrotic changes characteristic of chronic pancreatitis). Although the process may be started and perpetuated by environmental factors, other factors must be present for chronic pancreatitis to develop in some individuals and not others. Most recent studies have focused on the role of genetic predisposition to chronic pancreatitis.
The symptoms and clinical signs of acute pancreatitis are nonspecific and may vary with age (Table 31–3). Upper abdominal pain and vomiting are the most common symptoms. A review of the literature from 1965 to 2000 concluded that abdominal pain is present in 87% of patients.12 Two subsequent studies reported pain in 95% and 68% of patients.2,13 Some of the variation in reporting may reflect the age range of the patients in the studies. Only 29% of patients under 3 years of age had abdominal pain reported.14 Even if irritability was considered a surrogate for pain, the percentage with abdominal pain was still low, 46%, in this age group. Vomiting occurs in 45–85% of reported cases. It was the most common presenting symptom in patients under 3 years of age. Other less common symptoms and signs include abdominal tenderness, abdominal distention, fever, tachycardia, hypotension, jaundice, and back pain. Blue or green ecchymoses of the flank (Turner’s sign) or blue discoloration of the umbilicus (Cullen’s sign) from extravasation of blood are rare in childhood. In hospitalized patients, acute pancreatitis may present as a change in clinical status or feeding intolerance.
|Acute Pancreatitis||Chronic Pancreatitis|
|Abdominal pain||Abdominal pain|
|Abdominal distension||Recurrent acute pancreatitis|
|Back pain||Upper GI bleeding|
Recurrent acute pancreatitis may dominate the early course of chronic pancreatitis in many patients (Table 31–3). The signs and symptoms are the same as described for acute pancreatitis. Chronic pancreatitis should be considered in a patient with recurrent attacks of acute pancreatitis. Patients may present with pain as the prominent clinical feature. The pain can range from mild to severe and from intermittent to persistent. Typically, the pain is in the upper abdomen. Many adults describe the pain as deep and penetrating, radiating to the back and worse after meals. Children are often not as descriptive, and the pain may be hard for them to describe. At diagnosis, many have had periodic episodes of pain diagnosed as viral or functional. The cause of the pain is likely mulitfactorial and will vary from patient to patient and depend on the length of the illness. Early in the course, the pain often arises from the acute inflammation of pancreatitis. Later, pain may arise from pancreatic duct hypertension, increased pancreatic tissue pressure, tissue acidosis, or perineural inflammation.
Even though maldigestion is a feature of advanced gland destruction, symptoms of malabsorption may provide the first clue to chronic pancreatitis. These patients usually present with weight loss or fatty stools. Diarrhea may be present, but significant steatorrhea can occur even in patients having a single daily stool. A few may present with extrahepatic biliary obstruction from fibrosis in the head of the pancreas or from a pseudocyst. These patients frequently have jaundice, and may have an unexplained elevation of serum alkaline phosphatase. Rarely, a patient may present with gastrointestinal bleeding secondary to venous thrombosis, often in the splenic vein. Subcutaneous or intramedullary fat necrosis has been described in children as the initial sign of chronic pancreatitis.
Diabetes mellitus may develop late in the course of chronic pancreatitis, and rarely, if ever, do patients present initially with symptoms of diabetes mellitus. Both insulin-producing cells and glucagon-producing cells are destroyed in chronic pancreatitis. Consequently, the diabetes is fragile and blood sugar control is difficult.
Because the symptoms of acute pancreatitis are quite nonspecific, usually abdominal pain or vomiting or both, the differential diagnosis is broad. In general, there is little in the history or exam that can clearly distinguish acute pancreatitis from these other entities. The most common diagnosis for these symptoms is infectious gastroenteritis, usually viral. Other considerations include celiac disease, peptic ulcer disease, gastritis, gallbladder disease, and Crohn disease. If the presentation is acute, abdominal distension is present, or peritoneal signs are present, then appendicitis and causes of partial or complete bowel obstruction should be considered.
The differential diagnosis of chronic pancreatitis includes recurrent acute pancreatitis and the common causes of chronic pain in childhood. Some patients will have repeated episodes of acute pancreatitis but they do not have irreversible changes in the anatomy of the pancreas or diminished exocrine function. Although many of these patients will eventually meet criteria for a diagnosis of chronic pancreatitis, they are properly classified as recurrent acute pancreatitis until they do not meet the definition of chronic pancreatitis. Peptic ulcers, gastritis, gallbladder disease, and Crohn disease are all considerations as they are for acute pancreatitis. In addition, functional abdominal pain, lactose intolerance, and depression can present with recurrent or constant abdominal pain.
The differential changes if malabsorption dominates the clinical picture. Developmental defects of the pancreas, severe enteropathies, cholestatic liver disease, and isolated enzyme deficiencies should all be considered.
Since the signs and symptoms of acute pancreatitis are nonspecific, the physician must keep acute pancreatitis in mind in any child with gastrointestinal complaints. The accepted clinical definition of acute pancreatitis in adults requires at least two of the following features: (1) abdominal pain consistent with acute pancreatitis; (2) serum amylase or lipase levels (or both) at least three times the upper reference limit; and (3) findings of acute pancreatitis on radiological studies. Although this definition generally holds true in pediatrics, the physician must remember that a number of children may not present with abdominal pain or the pain may be minimal and other symptoms may predominate as discussed above. A suggested algorithm to approaching the diagnosis is given in Figure 31–1.
In practice, the likelihood of acute pancreatitis is generally assessed by measuring the serum levels of lipase and amylase in patients with compatible symptoms.15 The reliability of these measurements to diagnose acute pancreatitis remains uncertain. All studies to define the sensitivity and specificity of serum amylase and lipase for acute pancreatitis suffer from the lack of a method to separately and definitively diagnose acute pancreatitis. In particular, no studies on the sensitivity and specificity of these enzyme levels in pediatrics are available. Both can be normal when there is clear clinical and radiological evidence of acute pancreatitis. In turn, both can be elevated in other conditions where there is no other evidence for pancreatitis. Importantly, the level of elevation is not diagnostic although the higher the level the more likely there is to be pancreatic inflammation.
In general, other conditions such as renal failure rarely if ever raise levels three times above the upper reference limit. Two exceptions are worth discussion since both can give serum enzyme levels in large excess of three times the upper reference limit. Both are benign and their recognition will prevent unnecessary investigations and therapies. In each case, the patients have elevated pancreatic enzyme levels in their serum at a time when they do not have symptoms. Often the patients present with abdominal pain, have elevated amylase or lipase and normal radiographic studies, and are diagnosed with acute pancreatitis. During follow-up the enzymes remain elevated even though the patient is asymptomatic. Other times the amylase or lipase is part of a test panel and the patient does not have symptoms consistent with pancreatitis.