Early Prediction of Severity in Acute Pancreatitis Using Infrared Spectroscopy of Serum

Review Pancreatology 2007;7:447–450 DOI: 10.1159/000108961

Published online: October 1, 2007

Pancreas and Cystic Fibrosis: The Implications of Increased Survival in Cystic Fibrosis J. Krysa A. Steger Department of Surgery, University Hospital Lewisham, London, UK

Key Words Pancreatitis ⴢ Pancreas ⴢ Cystic fibrosis ⴢ Pancreatic cancer

Abstract Pancreatitis affects 0.5% people with cystic fibrosis (CF) in the UK and 0.01% of the normal population. Why do some with CF get pancreatitis and some not? And does pancreatitis in neonates result in pancreatic failure with no further inflammation or risk of pancreatic cancer? Review of the literature would suggest that 85% of those with CF have pancreatic destruction as children with minimal risk of further inflammatory or neoplastic changes. Those with a functioning pancreas are at risk of developing pancreatitis. There are several case series of pancreatic cancer reported in CF patients, but overall the risk is unknown. As patients with CF and pancreatic sufficiency are living longer, further studies to assess the risk of developing pancreatic cancer in this subgroup should be considered. Copyright © 2007 S. Karger AG, Basel and IAP

Background

Cystic fibrosis (CF) of the pancreas has been recognised as a disease entity since the late 1930s. It is the UK’s most common, life-threatening, inherited disorder, death being mainly due to pulmonary complications. It affects 6,932 alive people in this country. 50% are !15 and 70% © 2007 S. Karger AG, Basel and IAP 1424–3903/07/0076–0447$23.50/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/pan

are !20. The deletion of residue 508 in CF transmembrane regulator gene (CFTR) is the most common mutation causing CF [1, 2]. Patients with CF display a spectrum of pathologies which depend on the level of bicarbonate ion conductance through CFTR [3]. Throughout the body there is a change in the nature of mucous and serous secretions so that the former are abnormally sticky or dry and the latter abnormally concentrated. Much of the clinical pathology results from these characteristics, as secretions block ducts or ductules. Such obstructions are particularly important in the lungs and the pancreas and lead to a progressive obstructive suppurative lung disease together with malabsorption due mainly to an insufficiency of pancreatic digestive enzyme secretion. In the pancreas, secretions precipitate within the lumen of the ducts causing blockage and duct dilatation. Destruction of exocrine pancreatic tissue and replacement with fibrous tissue then occurs. In most cases the alteration of function is already present in the pancreas at birth and therefore clinical evidence of malabsorption is usually, but not always evident from this time. With improved treatments of pulmonary CF, patients are living longer [4]. Because of this it seems timely to review possible pancreatic problems that might occur as a result, that is pancreatitis and pancreatic cancer. In a recent survey we studied the prevalence of pancreatitis in patients with CF in the UK [5]. From the UKCF database, 6,932 living patients with CF were idenJo Krysa University Hospital Lewisham London SE13 6LH (UK) Tel./Fax +44 776 025 5903 E-Mail [email protected]

tified of whom 37 in total had a history of CF and pancreatitis representing 0.5% of all people in the database. In this population of patients with CF there is a higher risk of developing pancreatitis (0.5%) than in the general population (0.01–0.02%) [6]. Other studies have shown the prevalence of pancreatitis, in the USA and Canada, in patients with CF to range between 0.5 and 1.7% [7, 8]. All the patients with pancreatitis in both these studies had pancreatic sufficiency (PS). De Boeck et al. [9] studied 10,071 patients with CF in Europe. The prevalence of pancreatitis in their population was 1.24% and again was much higher among patients with PS (10.3%), but they also reported 15 patients with pancreatic insufficiency (PI) who had a diagnosis of pancreatitis (0.5%). They concluded that the most likely reason for pancreatitis occurring among patients with PI is that some residual pancreatic tissue is present among these patients. They also found that relapses of pancreatitis occurred more frequently among patients with PS than those with PI. Similarly, evolution to chronic pancreatitis was more frequent among patients with PS. In none of these studies is it possible to distinguish recurrent pancreatitis from new attacks and so separate the incidence from prevalence or temporal changes. Longer survivors are more likely to have a history of pancreatitis; 45% of patients with CF and pancreatitis are 135 years of age compared to 7% of all patients with CF [5]. The diagnosis of chronic pancreatitis in this group of patients is important, especially if we consider its potential complication, pancreatic adenocarcinoma. It was postulated over 100 years ago that digestive enzymes play a role in acute pancreatitis and trypsinogen activation plays a central role in pathway that results in acute pancreatitis [10]. The current standard screening test for CF is the immunoreactive trypsinogen (IRT) assay [11]. The rationale for IRT testing is that duct obstruction by protein plugs develops in utero in the CF pancreas, leading to enzyme leakage into the blood. Trypsinogen levels are raised in infants with CF. Serum trypsinogen values in the PI group decline steeply up to 5 years, reaching subnormal values by age 7. There is no age-related decline in serum trypsinogen among the CF group with PS [12]. Trypsinogen levels in the group with PS are similar to those in a random population [12]. These results show that the majority of neonates with CF have changes consistent with pancreatitis (190%). Durie et al. [12] have shown that 95% of infants with PI, by the age of 7, had subnormal trypsinogen values. This is the group with pancreatic failure in childhood who are at low 448

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risk of developing further pancreatitis (82% of all patients with CF). A proportion of the infants with steatorrhoea and reduced duodenal trypsin output have early PI and develop pancreatic failure when older. The mean trypsinogen levels in this group become undetectable when they become teenagers [13]. Therefore, serial measurement of serum trypsinogen is a valuable tool for monitoring the pancreatic status of patients with CF and PS [14]. These findings are also supported by another screening test used in CF. Pancreatitis-associated protein (PAP) is a protein originally identified in rats with pancreatitis. Serum levels are raised in humans with pancreatitis and these increase further in severe pancreatitis. The majority (41/43 = 95%) of babies with CF show high levels of PAP. PAP testing (levels 18 ng/ml) identified all babies with CF (41/202807) except for 2 with mild CFTR mutation and has been recommended as a screening test [15]. Thus the majority of neonates with CF have evidence of pancreatic inflammation and a small proportion a normal pancreas. Both of these screening tests are based on the fact that the vast majority of babies with CF have biochemical evidence of pancreatitis. The majority of adolescents with CF have trypsinogen levels that are undetectable [13], and from these observations it can be suggested that their pancreata are no longer either functioning or inflamed. But why do some with CF get pancreatitis and some not? And does this suggested process lead to pancreatic destruction with no further inflammation or risk of pancreatic cancer? Patients with PI generally have two alleles associated with severe abnormalities, whereas patients with PS have one allele associated with mild disease [16]. There have been over 1,000 mutations reported in the CFTR gene (www.genet.sickkids.on.ca/cftr); these have been grouped into five classes which reflect functional alterations in the CFTR protein [17]. Mutations categorised as I, II and III represent complete loss of chloride-channel function. Homozygosity or compound heterozygosity for these mutations is strongly associated with PI. Class IV and V mutations are associated with PS and a milder clinical phenotype [16]. Since mutations associated with severe disease account for about 92% of known mutations, approximately 84% of patients will have two such alleles and will have PI. On the basis of the above discussion, this group is at low or no risk of pancreatitis. The remaining 16% will have PS and are susceptible to inflammation. In the normal population the risk of pancreatic cancer appears to rise appreciably only after decades of chronic Krysa/Steger

pancreatitis. Lowenfels et al. [18] reported a cumulative risk of pancreatic cancer in subjects with chronic pancreatitis of 1.8% after 10 years and 4% after 20 years. This has been supported by other epidemiological studies [19]. However, the relationship between chronic pancreatitis and pancreatic cancer is most clear in studies of patients with childhood-onset chronic pancreatitis caused by genetic factors. These studies confirm a high risk of pancreatic cancer in subjects with hereditary pancreatitis, regardless of underlying mutation [20]. There are a number of papers which evaluated the risk of pancreatic cancer in patients with CF [21–23]. Sheldon et al. [22] identified 2 cases of pancreatic cancer among 412 people with CF (0.5%). Neglia et al. [23] looked at various cancers in patients with CF and showed an increased incidence of digestive tract cancers including pancreatic cancer. They identified three pancreatic cancers in a cohort of approximately 38,000 CF patients (0.01%) (this is similar to the incidence of 9:100,000 in the normal population of England and Wales [24]). In comparison with their control population, the odds ratio for pancreatic cancer in European patients was calculated as 31.5. They did not specify whether these patients had PS or PI. The majority of patients with a cancer of digestive tract were in their third decade at the time of diagnosis, but the age of those with pancreatic cancer was not specified. One of the treatments to improve survival in people with CF is a lung transplant. This involves immunosuppression which may further increase the risk of developing cancer in those with PS and CF [25]; this however has not been validated elsewhere. Theoretically, all patients with CF are at risk of pancreatitis, but the majority develop pancreatitis in utero or as neonates leading to pancreatic destruction by the time they are about 6 years old. We would suggest that this group is at low or no risk of further inflammatory or neoplastic change. A common misconception is that CF is a risk factor for pancreatic cancer. This is not the case in the vast majority of patients with PI. The second, smaller group (PS) includes those with a functioning pancreas and represents approximately 1,000 people on the UKCF database. They have an increased risk of developing pancreatitis [9] and, as they survive longer, may be at risk of developing pancreatic cancer [23]. This is the subgroup in whom close follow-up or screening could be considered (fig. 1), as is the case with other at-risk groups. Patients with PS ought to be identified early which can be achieved by genetic and biochemical assessment and genotype analysis of patients with CF. The latter will idenPancreas and CF: Implications of Increased Survival in CF

Cystic fibrosis

Pancreatitis

Early: 85–90%

Pancreatic failure in utero or soon after birth

Low risk of pancreatitis or neoplastic change

Late: 10–15%

Functioning pancreas

Risk of pancreatitis and pancreatic cancer Implications Close follow-up versus screening

Fig. 1. Incidence and course of CF and pancreatitis.

tify those with class IV and V mutations which is likely to represent those with a functioning pancreas. The pancreatic function can be further assessed by measuring the serum trypsinogen values or faecal pancreatic elastase-1 concentration. The latter has been shown to be simple, cost-effective and easy to perform [26]. Once the PS group has been identified they could be followed up. The difficulty is that a perfect screening test for pancreatic cancer on the background of chronic pancreatitis is yet to be developed. In other circumstances, multimodality screening using computed tomography and endoluminal ultrasound in combination with molecular analysis of pancreatic juice has been considered [27]. The benefits of screening may not however become apparent for another 2–3 decades and those with CF may well have other medical problems such as poor pulmonary function that would mitigate against major surgery if neoplasia were detected. Whilst stopping smoking is the best way to reduce the risk of pancreatic cancer [28], patients with CF smoke less because of pulmonary complications. In conclusion, the majority of CF patients may well not be at risk of pancreatitis and pancreatic cancer, but a small subgroup may be and can be identified. This, whilst possible, raises ethical and medical concerns which will be difficult to answer but need to be considered and investigated in further population studies. Pancreatology 2007;7:447–450

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