Pancreatic diseases

Diabetes mellitus is the most common medical disease associated with pancreatic abnormality and is responsible for significant morbidity and mortality. The mainstay of diabetes care, however, is the remit of the endocrinologist rather than the gastroenterologist, because gastrointestinal manifestations are limited. The major gastrointestinal pancreatic conditions seen in Europe include acute and chronic pancreatitis, and pancreatic cancer. Pancreatic illnesses have diverse aetiologies and affect a broad range of individuals. There is evidence in the medical literature to show that the incidences of these conditions are increasing, while the morbidity and mortality rates, despite recent advances in medical technology, have varied little over the past few decades. As a result, pancreatic conditions, other than diabetes mellitus, are major health issues and represent a significant financial burden to society. Ductal adenocarcinoma is the most common malignant pancreatic neoplasm, accounting for almost 90% of cancers. The peak age of incidence is in the seventh and eighth decades of life; men are affected twice as frequently as women. Ductal adenocarcinoma occurs in the pancreatic head in about 70% of cases, with the remaining cases being distributed evenly between the body and tail. Local infiltration is common, with vascular involvement representing the most common reason for unresectability. Unfortunately, most cancers continue to present at an advanced stage, when curative surgery is not a feasible option. In a recent report of over 100 000 cases presenting to hospitals around America, 83% were considered unsuitable for surgical intervention.1 As such, the overall 5-year survival rates remain very low at 5%, and have not changed in two decades. Islet cell tumours represent the second largest subset of pancreatic neoplasms. In all, 10–80% are malignant and require resection. They tend to affect a younger population than ductal adenocarcinomas, with the peak age of incidence for insulinomas and gastrinomas being in the fifth and sixth decades of life.2 Functioning lesions tend to present early because of symptoms induced by the excess secretion of hormones such as gastrin, insulin, somatostatin, glucagon and vasoactive intestinal peptide. However, 60% of gastrinomas are found to have liver metastases at the time of diagnosis, prohibiting curative resection.3 Nonfunctioning tumours are classically large at the time of presentation and associated with signs of tumour expansion such as bile or pancreatic duct obstruction, with resultant jaundice, gastrointestinal haemorrhage or metastases. Rarely, islet cell lesions may be found in conjunction with neoplasms of other sites, comprising multiple endocrine neoplasia syndrome. Rare pancreatic tumours include cystic lesions, which account for 1% of all pancreatic cancers. Serous cyst adenomas are more common in elderly women and are generally considered benign, although symptoms as a result of their mass effect may require surgical intervention. Mucinous cyst adenomas and adenocarcinomas on the other hand tend to affect younger women and are malignant, although metastases are uncommon at the time of presentation.4 Other rare pancreatic neoplasms have been documented but their scarcity prevents accurate collection of epidemiological data. In addition, it may be difficult to distinguish some peri-pancreatic tumours from those truly arising from pancreatic parenchyma, further hindering analysis of epidemiological factors (Table 1). The aetiology of most pancreatic cancers remains poorly understood. Recognized risk factors include male gender, increasing age, smoking, pre-existing pancreatic conditions (chronic pancreatis) and more recently, inherited genetic syndromes and family history.5 Studies in recent times have shown that 4–16% of patients with pancreatic cancer have a family history of the condition. Only a small minority of familial cases are accounted for by inherited genetic syndromes, such as familial atypical multiple-mole melanoma, Peutz–Jeghers syndrome, hereditary breast–ovarian cancer and hereditary nonpolyposis colorectal cancer.6 Most cases, even if found to have a specific germline mutation associated with familial cancer syndromes, do not appear to have consistent family histories, which makes their identification difficult. Individuals with chronic pancreatitis represent another at-risk group for which surveillance strategies are currently being investigated. A recent report estimated the magnitude of the increased risk at 27 times that of controls.7 The difficulty is developing a reliable means of identifying pancreatic tumours in already abnormal tissue. For these reasons, prevention strategies for pancreatic cancer remain an aspiration rather than a tangible possibility. However, a recent economic model did explore the possible effects of smoking cessation on the prevalence of pancreatic neoplasms in Europe, and showed that cessation of smoking would result in a 15% reduction in the incidence of pancreatic cancer over the next 10 years.8 Control of population smoking habits offers the best currently available strategy for reducing the incidence of this disease. Additional dietary measures could be advised, including reduction in alcohol consumption, maintenance of normal bodyweight and consumption of a well-balanced diet with adequate proportions of vegetables, fruits and antioxidants. Pancreatic cancer has been reported to be the fourth leading cause of cancer-related deaths in the USA, with an estimated annual mortality figure of 28 900.5, 6 Few data are available on the incidence of different pancreatic cancer subtypes. In Europe, recent figures published by the European Commission reported age-standardized incidence rates for men and women of 6.1 and 3.9 per 100 000, respectively, between 1990 and 1995.9 Consequently, pancreatic cancers account for approximately 10% of all digestive cancers, but are responsible for a much higher proportion of digestive cancer-related mortality. Survival rates in Europe remain poor and are comparable to American data, with Eurostat reporting a 5-year age-standardized survival rate for the same period of 4.2%. This would rank pancreatic cancer as the sixth and seventh leading cause of cancer-related death in Europe for men and women, respectively. Even for the minority of patients who undergo curative resection, 5-year survival rates remain low, reported as 19–25%.10 Currently, relatively few studies that present economic analysis of treatment and follow-up of patients with pancreatic cancer exist. What information there is usually relies on specific charge data and fails to capture the indirect costs, which result from significant morbidity and premature mortality. Despite evidence to show that patients with pancreatic cancer have high mean anxiety and depression scores, even compared with other oncology patients, there is almost no information regarding the impact of pancreatic cancer on quality of life.11 A reliable disease-specific quality-of-life questionnaire has been developed in Europe, which should enable the impact of pancreatic cancer to be assessed, but until then, the so-called intangible costs remain essentially unaccounted.12 General cost evaluations have been reported in the USA. The total cost of cancer care in the USA in 1999 was reported by one group to be about US$146 billion and it was estimated that pancreatic cancer accounted for approximately 1.8% (US$2.6 billion) of the overall cost, while another estimate suggested the total cost could be as high as US$4.9 billion, the latter including some indirect costs.13, 14 The total cost of treatment depends on the disease stage, the diagnostic strategy used, duration of survival, and the treatments employed (resection, chemotherapy, radiotherapy). Recent studies exploring the effect of palliative chemotherapy show that it greatly affects the overall cost of care per patient. One recent study from the USA reported longitudinal cost data at 6 months, 1 year and total lifetime of US$37 327, US$42 218 and US$48 803, with a median survival of 7 months, and confirmed that the above factors greatly affect economic analysis.15 Similarly a Swedish study reported that employing palliative chemotherapy (gemcitabine) increased the total treatment cost per patient by €17 100.16 Although specific European costs are not available, extrapolating the American data would imply that the direct costs alone of pancreatic cancer in Europe are in the order of €1.54 billion. Acute pancreatitis is an acute inflammatory process of the pancreas with variable involvement of other regional or remote organ tissues. Clinical presentation may be diverse; a history of upper abdominal pain with vomiting and abdominal tenderness are characteristic. Defining pancreatitis has been problematic and several classifications have been devised. The most recent, the Atlanta classification developed in 1992, is based on clinical characteristics, and defines pancreatitis as mild or severe, oedematous parenchymal or necrotizing and includes pancreatic abscesses and pseudocysts.17 The cause of an attack may also be difficult to determine, as there are a large number of possible aetiologies (Table 2).The most frequent causes in Europed include morbid illnesses, and patients with infected necrosis are most at risk. Despite recent advances in diagnostics and therapeutics, mortality rates have not varied substantially in recent times. Initial recognition of its association with multiple organ failure and improvement in resuscitation and intensive care of these individuals did result in a fall in case-related mortality from approximately 30 to 10%, where it has remained stable.18 The true burden of pancreatitis is probably underestimated. There is evidence to show from autopsy studies that many cases remain undiagnosed even in the hospital setting. Consequently, it is important to differentiate between overall mortality rates and percentage case mortality, the latter being most frequently described in the literature.19 Acute pancreatitis affects a wide spectrum of society and may have serious and life-threatening complications, which often require multidisciplinary management in an intensive-care setting, which represents a significant financial and social burden. However, in up to 10–15% of cases, the cause remains unknown despite intensive investigations. Severe cases associated with a systemic immune response syndrome or pancreatic necrosis are fortunately rare, approximately 5% of all cases, but are associated with significant morbidity and mortality.20 Epidemiology: The true incidence of acute pancreatitis remains difficult to ascertain, primarily because of descriptive anomalies as previously stated, but also because of aetiological, diagnostic and geographical variations. This has led to a wide range of reported incidences throughout Europe from 2.1 to 42 per 100 000.21, 22 There is evidence to suggest that the overall incidence is increasing and may reflect population changes in alcohol consumption and dietary habits.23 A large epidemiological study involving 1068 cases from five countries in Europe over 4 years reported similar incidence and mortality rates between the participating countries, but found regional variations in the underlying causes. Alcohol was the most frequent aetiology in northern, and gallstones in southern countries. The overall mortality rate was 7.8%.24 A follow-up study from this group demonstrated that up to 27% of patients would develop recurrent attacks, which results in significant morbidity and is associated with an increased risk of mortality. The mortality rate for patients with recurrent attacks was found to be 12%. A Swedish group has published confirmatory data. They reported an overall incidence of 38.2 per 100 000, of which 15 per 100 000 were recurrent attacks.25 Both studies highlighted the role of alcohol in recurrent acute pancreatitis. The body of available evidence does support an increasing incidence in Europe, which will have major implications for healthcare providers (Table 3). Financial and social implications. Acute pancreatitis represents a small but significant percentage of presentations to acute hospitals throughout Europe. It has been estimated that pancreatitis accounts for 3% of all cases of abdominal pain admitted to hospitals in the UK.29 The majority of patients do not have so-called severe disease, but despite this the mean length of stay for all cases has been reported to be 11 days, almost double the average length of stay for acute medical admissions. Accurate costs are, however, not available. Severe pancreatitis almost by definition requires multidisciplinary management in an intensive-care setting. Apart from adequate supportive measures and intravenous treatment for infective complications, many patients require repeated radiological, endoscopic or surgical intervention. Consequently, the mean length of stay in hospital is longer and has been reported to be as high as 74 days.30 The financial burden on institutions is substantial. The cost of treating a patient in intensive care has been calculated to be £1500 per day.31 Figures for the USA are US$3000–4000 per patient per day, and have been estimated to account for almost 1% of gross domestic product.32 The actual cost of treatment of such patients has varied in the literature from £9296 to £33 796. The mean cost has been estimated at £18 441.30 When including quality of life measurements, the total cost of caring for such cases has been calculated to be £2157 per quality-adjusted year of life, with a mean of 8.6 years gained. The long-term outcome for the majority of patients who undergo treatment is good. As a result of effective management, most return to normal daily activity and report a normal quality of life.33 Chronic pancreatitis is a progressive inflammatory disorder. A key characteristic of the condition is severe recurrent abdominal pain that is often intractable, necessitating the use of opiates. There are two main pathophysiological hypotheses for the pain: ductal hypertension and terminal nerve damage. Pain may be a direct result of pancreatic inflammation or a consequence of local complications. Inflammatory pain tends to be variable in intensity and duration over time as more pancreatic tissue becomes destroyed and replaced by fibrous tissue and calcification. Pain appears to be particularly intense in the first 5–8 years following diagnosis and to gradually diminish from then on. Despite this, there is evidence to show that up to 50% of patients still report significant episodes of pancreatic pain 10 years after diagnosis.34 Local complications including biliary, pancreatic and duodenal obstruction are also associated with pain. A recent paper reported as many as 46% of patients to have obstructive complications over 10 years.35 Interventional endoscopic and surgical therapeutic strategies have been developed with varying success. Studies focusing on the effective treatment of pain have reported success rates for surgical drainage procedures of up to 70%, with the benefits appearing to be durable.36, 37 In addition, the progressive nature of the condition often results in various degrees of pancreatic endocrine and exocrine insufficiency as well as various local complications. Many patients become malnourished, which severely impedes their ability to work and to partake in an active lifestyle. Diabetes is a frequent complication of late-phase chronic pancreatitis, developing in up to 35% of patients, and adds significantly to the burden of the disease. The onset of diabetes has been recently confirmed to negatively impact on a patient's quality of life.38 Epidemiology. The incidence of chronic pancreatitis, like that of acute pancreatitis, is thought to be increasing in Europe.39 Although less common than the acute form of the disease, the protracted nature of the condition implies that an increasing incidence is likely to have a major impact on prevalence rates in the future. Several studies have reported epidemiological data for chronic pancreatitis in individual European countries. Incidence rates varied widely depending on region. The lowest rate was for Switzerland at 1.6 per 100 000 inhabitants, while Finland has reported the highest incidence at 23 per 100 000 individuals.40-42 These variations may reflect local patterns of alcohol consumption, as the majority of reports confirmed alcohol to be the prime aetiological agent in 70–80% of cases. Apart from significant morbidity, chronic pancreatitis is associated with an increased risk of premature death. Mortality rates have been reported to be in the order of 21–35% at 10 years. The majority of patients die as a result of extrapancreatic malignancy or cardiovascular disease, reflecting the association of both smoking and excessive alcohol consumption with the disease.43, 44 Social implications. Unfortunately the protracted and variable course of this illness, coupled with a lack of specific quality-of-life measurement tools, has made quantifying direct and indirect costs difficult, and accurate data are not available. However, unlike acute pancreatitis, this disease often induces long-term disability and is associated with significant complications and comorbidities. This has a major impact on a person's quality of life as well as carrying a significant risk of mortality, with devastating social consequences. The apparent increasing incidence of chronic pancreatitis has major implications, both for healthcare providers and society in Europe. The changing trends in alcohol consumption, particularly among the young in many European countries, must be considered the major aetiological factor behind these epidemiological trends. With increased exposure, many young Europeans are at risk for this disabling and chronic illness.