Acute pancreatitis

Colin J. McKay, Euan J. Dickson and C. Ross Carter

General description

Acute pancreatitis is a common cause for emergency hospital admission, with approximately 40 cases per year for each 100 000 population in Scotland,¹ Norway² and Sweden.³ There has been a steady increase in the incidence and a slight reduction in case mortality, although not population mortality, over the past 45 years.⁴ In approximately 80% of patients, acute pancreatitis is a rapidly-resolving condition requiring little more than analgesia and a short period of intravenous fluid resuscitation, with the remainder developing a multisystem illness characterised by a systemic inflammatory response with a variable degree of organ dysfunction.

Pathophysiology

The mechanism by which gallstones trigger an attack of acute pancreatitis has not been clearly defined. The bile reflux theory, proposed by Opie in 1901, suggested that obstruction of the common bile duct/pancreatic duct common channel by a gallstone caused reflux of bile into the pancreatic duct resulting in acute pancreatitis. While there is no doubt that passage of and at least transient obstruction by a gallstone is the initial step in biliary acute pancreatitis, there is little evidence that bile reflux is involved.

Experimental models have shed some light on the mechanism by which pancreatic duct obstruction induces acute pancreatitis. Changes in the pattern of enzyme secretion within pancreatic acinar cells, coupled with intracellular zymogen activation, are considered the important early events in the development of acute pancreatitis. Disruption of the paracellular barrier allows release of pancreatic enzymes into the paracellular space. Inflammatory cells and inflammatory mediators may further exacerbate the acinar cell injury.⁴ Research has shown that many of these early events can be triggered by an increase in intracellular calcium.⁵

The mechanism of alcohol-induced acute pancreatitis is less clear, but alcohol has been shown to increase the sensitivity of acinar cells to cholecystokinin hyperstimulation, resulting in enhanced intracellular protease activation.⁶ Alcohol also influences acinar cell calcium homeostasis, but several alternative theories have been proposed.

Natural history

Acute pancreatitis varies from a mild, self-limiting attack to a severe life-threatening illness and, for this reason, patients are often classified as having either mild or severe acute pancreatitis (see Box 13.1). This rather simplistic description ignores the wide variety of clinical behaviour that can be observed in these patients but helps to focus attention on the subgroup of patients who develop complications. Currently, the internationally accepted classification of acute pancreatitis and its complications is set out in the paper arising from the Atlanta Conference.⁷ Improved understanding of treatment concepts and the dynamic nature of the pathophysiology has rendered a number of the concepts outlined in the Atlanta Conference outdated and a revision has recently been published.⁸

Box 13.1 Definitions

Acute pancreatitis

Acute pancreatitis is an acute inflammatory process of the pancreas, with variable involvement of other regional tissues or remote organ systems.

Mild acute pancreatitis

Mild acute pancreatitis is associated with minimal organ dysfunction and an uneventful recovery. The predominant feature is interstitial oedema of the gland.

Severe acute pancreatitis

Severe acute pancreatitis is associated with organ failure and/or local complication such as necrosis (with infection), pseudocyst or abscess. Most often this is an expression of the development of pancreatic necrosis, although patients with oedematous pancreatitis may manifest clinical features of a severe attack.

Systemic inflammatory response syndrome

Response to a variety of severe clinical insults, manifested by two or more of the following conditions:

• Temperature > 38 or < 360 °C

• Heart rate > 90 beats/min

• Respiratory rate > 20/min or PaCO₂ < 32 mmHg (< 4.3 kPa)

• White blood cell count (WBC) > 12 000 cells/mm³, < 4000 cells/mm³ or > 10% immature (band) forms

Multiple organ dysfunction syndrome

Presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention.

An acute pseudocyst is a collection of pancreatic juice enclosed in a wall of fibrous or granulation tissue that arises following an attack of acute pancreatitis. Formation of a pseudocyst requires 4 or more weeks from the onset of acute pancreatitis.

A pancreatic abscess is a circumscribed intra-abdominal collection of pus, usually in proximity to the pancreas, containing little or no pancreatic necrosis, which arises as a consequence of acute pancreatitis.

Within this framework different patterns of disease have emerged. Multicentre trials in acute pancreatitis have enabled prospective study of severe acute pancreatitis and several important points have emerged. Firstly, the majority of patients who develop severe acute pancreatitis have evidence of early systemic organ dysfunction.⁹ It is exceptional for a patient to have no evidence of organ failure in the first week of illness and to subsequently develop a significant late local complication. Secondly, most patients who develop organ failure have evidence of this at the time of admission or very shortly thereafter.¹⁰ Thirdly, while the tendency is for early organ dysfunction to recover without further problems, worsening organ failure is associated with a high mortality.⁹^,¹¹^,¹²

These observations have important implications for patient management. The presence of early organ dysfunction identifies a high-risk group of patients who merit close observation for both early and late clinical complications. In particular, deteriorating organ failure carries a high mortality and should prompt early involvement of the intensive care team and consideration of transfer to a specialist unit if possible. The fact that organ dysfunction is present at, or shortly after, admission in the majority of patients in whom it develops means that efforts should be directed at early recognition of this rather than employing prediction systems of disease severity.

The majority of patients with severe early organ dysfunction will have pancreatic necrosis on computed tomography (CT) scan. A significant proportion (30–40%) of patients with pancreatic necrosis will develop secondary pancreatic infection, usually in the second to third week after admission,¹³ which may be associated with a deterioration in organ failure. Patients who have infected pancreatic necrosis complicated by multiple organ failure represent a formidable management challenge.

Diagnosis

In the majority of patients the diagnosis of acute pancreatitis is relatively easy, characterised by a clinical presentation of sudden severe epigastric pain radiating through to the back. Vomiting within the first 24 hours is very frequently severe and contributes to dehydration. Other signs and symptoms such as tachycardia, tachypnoea and circulatory collapse are dependent on the severity of the attack. A raised serum amylase (at least three times the upper limit of normal) supports the diagnosis in >95% of cases. Serum amylase estimation may be inaccurate in association with hyperlipidaemia, where a raised urinary amylase can be diagnostic. Serum lipase may be marginally more accurate but is not commonly available in routine clinical practice. CT can confirm the diagnosis where doubt exists, or in patients with delayed presentation, and it should therefore be very uncommon for the diagnosis to be made at laparotomy (Fig. 13.1).

Figure 13.1 Extensive fat necrosis in the infracolic compartment in a patient with severe acute pancreatitis.

Aetiology

Obstructive factors

Genetic defects

Genetic familial defects of the cationic trypsinogen gene ¹⁴ (N29I, RII7H) and the cystic fibrosis gene (CTFR) may be associated with recurrent pancreatitis, but severe acute inflammatory changes are uncommon.

Trauma

Hyperamylasaemia may occur after blunt abdominal trauma, usually from a crush injury to the body of the pancreas against the vertebral column, and is suggestive of pancreatic injury. Investigation is by contrast-enhanced CT to determine the extent of pancreatic and associated visceral injury.

Iatrogenic causes

Hyperamylasaemia may follow surgical or endoscopic procedures on the pancreas, and is usually self-limiting. The risk increases following a therapeutic endoscopic retrograde cholangiopancreatography (ERCP; 3%), especially when a sphincterotomy has been performed. Where a patient has significant symptoms or clinical signs, the possibility of iatrogenic duodenal perforation should be considered and where necessary excluded by CT.

Drug-induced acute pancreatitis may occur following ingestion of a number of drugs;¹⁵ those most commonly implicated are valproic acid, azathioprine, L-asparaginase and corticosteroids. However, unless gallstone disease has been excluded with confidence it is unwise to ascribe acute pancreatitis to a particular drug. Repeat exposure to the same drug again causing acute pancreatitis is the strongest evidence of a direct association.

Inflammatory

Autoimmune pancreatitis is a rare condition, considered part of the IgG4-related autoimmune disease spectrum.¹⁶ This presents as abdominal pain associated with homogeneous gland enlargement with a well-defined edge on CT, an increased IgG4/IgG ratio and a periductal lymphoplasmocytic infiltrate on biopsy. This may also be associated with abnormalities in the extrahepatic biliary tree resembling sclerosis cholangitis and a response to steroids is diagnostic. Focal autoimmune pancreatitis may prove difficult to differentiate from carcinoma. There are established associations with other autoimmune diseases (polyarteritis nodosa, systemic lupus erythematosus, vasculitis) and inflammatory bowel disease (Crohn’s and ulcerative colitis), and many are now considered part of the autoimmune spectrum, although only a small proportion appear to have an association with IgG4 serum or tissue abnormalities.

Physiological

Sphincter manometric abnormalities

Type 1 pancreatic sphincter dysfunction ¹⁷ may be associated with hyperamylasaemia and abnormalities on sphincter manometry, as part of a global gut dysmotility spectrum. Managament of sphincter spasm may only partly resolve the patient’s symptoms. Conventional treatment involves endoscopic sphincterotomy, but the risk of post-ERCP pancreatitis in these patients is high (30%).

Assessment of severity

The dynamic nature of organ dysfunction in patients presenting with acute pancreatitis has been well described,⁹ and for over 30 years authors have explored ways of ‘predicting’ those patients with more severe disease. Overall mortality, whether early or late, is also associated with the development and persistence of organ failure.¹⁸ This was indirectly shown, if not recognised, 25 years previously with the development of the predictive multifactorial scoring systems – Ranson,¹⁹ Glasgow²⁰ and APACHE II²¹ – which, rather than predicting the subsequent development of organ failure, more accurately identified established multisystem organ dysfunction. Their principal use is to remind the inexperienced of the multisystem nature of the disease process, or as a method of stratifying patients within a study protocol. Of the multiple factor scoring systems, APACHE II provides the best prediction of mortality but the mainstay of assessment remains repeated, careful clinical observation.²²

Single biochemical measures

Many studies have attempted to find a single biochemical or clinical marker that would allow adequate prediction of severity without the need for cumbersome scoring systems. In addition, the need for an objective marker of severity at the point of hospital admission is well recognised and would greatly facilitate the entry of patients with severe acute pancreatitis into clinical studies.

C-reactive protein (CRP)

The most widely studied single predictive marker is serum CRP. The major advantage of CRP is its routine availability in clinical practice. Patients with clinically severe pancreatitis usually have a CRP > 200 mg/L, with a practical cut-off being 150 mg/L, but its serum peak is not reached for 36–48 h. The positive predictive value of CRP is similar to that of APACHE II ²² but its major use is in monitoring the clinical course during the acute and recovery phase.

Other single predictive markers

Peak levels of interleukin-6 (IL-6) occur within 24 h and this has aroused interest in its use as a predictor of outcome. IL-6 is a pro-inflammatory cytokine induced by stimuli such as tumour necrosis factor (TNF) and interleukin-1 (IL-1). Other single predictive markers that have been studied include trypsinogen activation peptide (TAP), leucocyte polymorph neutrophil (PMN) elastase, TNF and serum procalcitonin. Procalcitonin is the precursor of the hormone calcitonin and is raised in the presence of an inflammatory response, particularly where this is bacterial in origin. Serum procalcitonin is a promising marker of both severe acute pancreatitis and of infected pancreatic necrosis in the later phase.²²^,²³

Intra-abdominal hypertension (IAH)

IAH is recognised as a contributing factor to organ dysfunction in the context of a variety of acute abdominal processes. Most of the literature to date focuses on trauma patients, but there is increasing interest in its role in patients with severe acute pancreatitis (SAP). There are data to suggest that raised intra-abdominal pressure (IAP) may be associated with disease severity,²⁴ organ failure and mortality in SAP.²⁵ There are, however, no data to suggest improved outcome following surgical decompression for raised IAP in acute pancreatitis, and indeed this may be harmful. At present the monitoring of IAP cannot be recommended outside of a clinical trial.

Repeated clinical assessment

In the absence of clinically useful predictive systems, our own practice is to monitor patients for the development of systemic organ dysfunction by repeated clinical and biochemical assessment. The presence of a systemic inflammatory response syndrome (SIRS; defined as two or more of the following: fever, tachycardia, tachypnoea or leucocytosis) identifies patients at risk of multiple organ dysfunction syndrome (MODS), particularly when three or four SIRS criteria are present or when SIRS persists for 48 h or more after admission. Patients without SIRS at admission are at very low risk. The development of systemic organ dysfunction (usually clinically manifest as hypoxaemia) mandates careful monitoring in a high-dependency or intensive care unit environment.

Imaging

Role of ultrasound (US)

All patients with acute pancreatitis should have an ultrasonic assessment of the biliary tree within 24 h of admission.²⁶

All patients with acute pancreatitis should have an ultrasonic assessment of the biliary tree within 24 h of admission.²⁶ In those with gallstones, the majority will have mild disease, and this will facilitate definitive treatment of cholelithiasis prior to discharge. In the emergency situation, ultrasonography can be difficult due to a number of factors, including the presence of intraluminal bowel gas or lack of patient cooperation. Therefore, in patients with a negative initial US, and no other obvious aetiological factor, the US should be repeated prior to discharge before excluding gallstones as a potential aetiological factor.

Role of CT

The main role of CT in the early phase of acute pancreatitis is to clarify the diagnosis in cases where there is diagnostic uncertainty. In patients with severe acute pancreatitis, particularly when complicated by MODS, early CT helps to exclude other pathology such as intestinal perforation, gut ischaemia or dissecting aortic aneurysm. Dynamic contrast-enhanced CT can also be used to assess disease severity (Fig. 13.2) and predict the potential for complications.²⁷ Although not widely used for this purpose clinically in the UK, it is routinely used in many other countries, and can be useful for stratification of patients in clinical trials. The CT Severity Index (CTSI)²⁷ combines a score for the radiological pancreatic and peripancreatic abnormalities with a weighting for the extent of necrosis. More recently there are reports of perfusion CT, which may be a useful modality for detecting early, subclinical ischaemic changes in the pancreas that then lead to pancreatic necrosis.

Figure 13.2 CT scan showing acute pancreatitis with necrosis (a) and retroperitoneal gas (b).

Role of magnetic resonance (MR)/magnetic resonance cholangiopancreatography (MRCP)

Magnetic resonance imaging (MRI) offers a realistic alternative to contrast-enhanced CT ²⁸ in the assessment of patients with acute pancreatitis. The avoidance of cumulative radiation exposure, potentially nephrotoxic iodinated contrast media, and the excellent contrast sensitivity and spatial resolution would make it an attractive alternative. Axial T1- and T2-weighted scans produce images analogous to those of CT. Gadolinium contrast enhancement can infer viability and improve anatomical definition. Heavily T2-weighted image acquisition, using a single breath hold and long repetition (TR) and echo (TE) times, results in little signal being produced by solid tissue, and a high signal from static fluid in the biliary and pancreatic ducts, enabling images anatomically comparable to those of ERCP to be produced.

Whilst technically feasible in most centres, the MR environment is unsuitable for patients requiring significant circulatory or respiratory support, and at present few centres have the capability to perform MR-guided intervention. Contrast-enhanced CT therefore remains the imaging modality of choice for assessment and intervention in severe acute pancreatitis. However, MR has a role in the follow-up of acute inflammatory collections, where it is superior to CT in determining the extent of solid material within a collection (Fig. 13.3), and in excluding choledocholithiasis in selected patients.

Figure 13.3 MRI scan showing extensive necrosis (arrowed) within a post-acute fluid collection (FC).

Endoscopic ultrasound (EUS)

EUS has rapidly emerged as an important tool in diagnostic and therapeutic algorithms for patients with acute pancreatitis. Its main areas of use are in the diagnosis of microlithiasis in patients with idiopathic pancreatitis and for linear EUS-guided drainage of peripancreatic collections, as discussed in the relevant sections below.

Management

Initial management

Management of acute pancreatitis in the UK is still based on two key guideline documents, now 7 ²⁶ and 10²⁹ years old, respectively. The initial management of patients presenting with acute pancreatitis should be directed at the early identification and management of organ failure, most frequently renal and respiratory dysfunction.