- Email: [email protected]
Chronic Pancreatitis in the Elderly in Japan
Original Paper Pancreatology 2004;4:223–228 DOI: 10.1159/000078433
Received: July 11, 2003 Accepted after revision: January 18, 2004 Published online: May 12, 2004
Chronic Pancreatitis in the Elderly in Japan Terumi Kamisawa a Masami Yoshiike a Naoto Egawa a Hitoshi Nakajima a Kouji Tsuruta b Atsutake Okamoto b Teruo Nakamura c Departments of a Internal Medicine and b Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo, and of Health Science, Hirosaki University School of Medicine, Aomori, Japan
c Department
Key Words Chronic pancreatitis, elderly Japanese W Elderly Japanese, chronic pancreatitis W Autoimmune pancreatitis, elderly Japanese
Abstract Background/Aim: Although the elderly comprise an increasingly large segment of the population, little has been written about chronic pancreatitis in this age group in Japan. In this study, we analyzed the clinical features of elderly Japanese patients with chronic pancreatitis and compared them with those of late-onset chronic pancreatitis patients in Western countries. Methods: Subjects were 182 patients (162 males and 20 females) with chronic pancreatitis. They were divided into two groups: early-onset group (onset !65 years of age, n = 119) and late-onset group (onset 665 years of age, n = 63). Clinical findings and follow-up data were examined for each group. Results: Alcohol abuse was the most common etiological factor in early-onset pancreatitis patients. In the late-onset group, the frequencies of idiopathic and autoimmune pancreatitis increased. Furthermore, the age at onset of autoimmune pancreatitis was 160 years in 94% of the cases. The late-onset group was more likely to have painless disease, and calcifica-
ABC
© 2004 S. Karger AG, Basel and IAP 1424–3903/04/0044–0223$21.00/0
Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com
Accessible online at: www.karger.com/pan
tion of the pancreas and steatorrhea were rare in this group. Major causes of death were malignancy and malnutrition in each group. Conclusions: Early- and lateonset chronic pancreatitis showed different clinical features. Clinicians should consider autoimmune pancreatitis in the differential diagnosis in elderly patients with obstructive jaundice. Copyright © 2004 S. Karger AG, Basel and IAP
Introduction
Chronic pancreatitis is morphologically defined as an irreversible, irregular sclerosis of the gland with destruction of the exocrine parenchyma and ductal distortion. Chronic pancreatitis, usually related to alcohol abuse, is generally a disease of the young rather than the elderly, perhaps because many patients with alcoholic pancreatitis die earlier in life. Clinically, it is associated with recurrent or persistent abdominal pain, often accompanied by signs of pancreatic exocrine insufficiency. Due to a steadily increasing life span and a diminishing birth rate, the elderly comprise an increasingly large segment of the population. As a result, physicians are being faced more often with the need to treat chronic pancreatitis in patients in this age group. In the West, the incidence
Dr. Terumi Kamisawa Department of Internal Medicine, Tokyo Metropolitan Komagome Hospital 3-18-22 Honkomagome, Bunkyo-ku Tokyo 113-8677 (Japan) Tel. +81 3 3823 2101, Fax +81 3 3824 1552, E-Mail [email protected]
of chronic pancreatitis is 5–10 cases/100,000 in the population as a whole, and many studies on chronic pancreatitis in the elderly have been published [1–4]. In Japan, although the incidence is 5.0–5.9/100,000 [5], there has been relatively little published about chronic pancreatitis in the elderly. We examined the clinical features of elderly Japanese patients with chronic pancreatitis and compared them with those in elderly Western populations.
Patients and Methods We identified 182 patients (162 males and 20 females, average age at the time of diagnosis 57.7 B 8.2 years) who had the diagnosis of chronic pancreatitis at the Tokyo Metropolitan Komagome Hospital between 1976 and 2003. The medical records of these patients were analyzed retrospectively. The diagnosis of chronic pancreatitis was made when at least one of the following criteria was positive: pancreatic calcification on computed tomography or ultrasound (n = 82), typical histological changes (n = 47; 37 at surgery and 10 at autopsy), irregular dilation or irregularly narrowing of the pancreatic duct on endoscopic retrograde pancreatography (n = 160), and an abnormally low bicarbonate concentration combined with either decreased enzyme output or decreased secretory volume based on secretin test results (n = 38) [6–8]. Forty-four cases were confirmed only by endoscopic retrograde pancreatography findings. Alcoholic chronic pancreatitis was diagnosed on the basis of typical clinical features in the presence of a history of excessive alcohol intake (usually 1 80 g/day for more than 7 years). Idiopathic chronic pancreatitis was diagnosed in cases having chronic pancreatitis without alcohol abuse, family history, biliary tract disease, hyperparathyroidism, hyperlipidemia, autoimmune etiology, and trauma. Autoimmune pancreatitis was diagnosed in the presence of the following: swelling of the pancreas (n = 15), diffuse narrowing of the main pancreatic duct (n = 16), hypergammaglobulinemia (n = 10), autoimmune antibodies (n = 9), lymphoplasmacytic infiltration with fibrosis on histological examination (n = 8), and effectiveness of steroid treatment (n = 7). Patients with obstructive pancreatitis secondary to pancreatic duct obstruction due to invasion into the pancreas of extrapancreatic tumor or without adequate data were excluded. The patients were divided into two groups by the age at which chronic pancreatitis was diagnosed during the first hospitalization: early onset (! 65 years) and late onset (665 years). Clinical findings and follow-up data were reviewed for each group. In particular, we assessed alcohol consumption with or without smoking (1 20 cigarettes/day) and the presence of abdominal pain (requiring analgesics), diabetes mellitus (requiring insulin or hypoglycemic agent), manifest steatorrhea (fecal fat excretion 1 5 g/day by the Van de Kamer method and/or appearance of fatty stools by naked eyes) [9, 10], and malnutrition (presence of more than two of the following factors: ideal body weight index ! 0.8, serum albumin concentration ! 3.0 g/dl, and serum total cholesterol level ! 120 mg/dl). Statistical analyses were done using Fisher’s exact probability test. The duration of survival was estimated by means of the KaplanMeier method, and the survival curves were established using the generalized Wilcoxon test. p ! 0.05 was considered statistically significant. Values are expressed as mean B SD.
224
Pancreatology 2004;4:223–228
Results
The numbers of the patients in the early- and late-onset pancreatitis groups were 119 and 63, respectively. Males were affected much more frequently than females; however, the male/female ratio gradually decreased with age. Long-standing alcohol abuse was the most common etiological factor in patients with onset before the age of 65 years. Most patients with alcoholic chronic pancreatitis were smokers. In chronic pancreatitis manifesting for the first time in the elderly, the frequency of idiopathic and autoimmune pancreatitis increased and that of alcoholic pancreatitis decreased. 15 of 16 cases (13 males and 3 females) having autoimmune pancreatitis were 160 years old at the time of diagnosis. Five late-onset patients were diagnosed as having biliary chronic pancreatitis, because of the presence of long-term cholecystolithiasis/choledocholithiasis (n = 2) or papillary stenosis with biliary dilation (n = 3). Hereditary chronic pancreatitis was not observed (table 1). Although no significant differences in the incidence of associated diabetes were apparent, the late-onset group was more likely to experience painless disease (p ! 0.01). However, calcification of the pancreas (p ! 0.05) and steatorrhea (p ! 0.01) were rare in the late-onset pancreatitis group. Significantly more early-onset patients underwent pancreatic surgery than late-onset patients (p ! 0.01). Intractable pain or a pseudocyst was the main indication for pancreatic surgery in early-onset patients, but 4 lateonset patients underwent pancreatic surgery for suspicion of pancreatic carcinomas (table 2).
Table 1. Clinical findings in each group of patients having chronic
pancreatitis Early onset
Late onset
n Male/female ratio Age at the time of diagnosis, years Follow-up period, years
119 1/0.06 49.5B8.5 6.5B6.1
63 1/0.26 71.9B6.4 3.5B3.4
Etiology Alcoholic With smoking Without smoking Idiopathic Autoimmune Biliary Trauma Radiation
108 (91%) 69 8 6 (5%) 3 (2%) 0 1 (1%) 1 (1%)
26 (41%) 17 3 19 (30%) 13 (21%) 5 (8%) 0 0
Kamisawa/Yoshiike/Egawa/Nakajima/ Tsuruta/Okamoto/Nakamura
Late-onset patients survived significantly longer than early-onset patients (p ! 0.01; fig. 1). During the follow-up period, 24 patients of the early-onset group and 19 patients of the late-onset group died. Age and period between onset of disease and death were 58.8 B 10.4 and 6.8 B 4.6 years and 74.3 B 16.9 and 3.1 B 2.2 years, respectively. Major causes of death were malignancy and malnutrition in each group. Fifteen patients died of malignancy (pulmonary carcinoma 6 patients, pancreatic carcinoma 3, gastric carcinoma 3, esophageal carcinoma 2, biliary carcinoma 1, urinary bladder carcinoma 1, and leukemia 1 patient). Pancreatic carcinomas occurred in 2 early-onset patients and in 1 late-onset patient (table 3). Fig. 1. Overall survival for patients with early- and late-onset
chronic pancreatitis.
Discussion
Table 2. Complications and surgical intervention in each group of
patients having chronic pancreatitis
Pain Calcification Diabetes Steatorrhea Pancreatic surgery
Early onset (n = 119)
Late onset (n = 63)
n
%
n
%
72 60 62 33 34
61** 50* 52 28** 29**
17 22 28 6 5
27 35 44 10 8
* p ! 0.05; ** p ! 0.01.
In Western countries, the clinical onset of chronic pancreatitis tends to be between 30 and 40 years of age, with onset after 60 years of age being rare [1, 11]. Alcohol abuse is the leading cause of chronic pancreatitis, responsible for about 70% of the cases [2]. Alcoholic chronic pancreatitis, however, is not a common problem among older patients, because the mean age of onset is 37 B 10 years, and it rarely develops after age 60 years. Alcoholic chronic pancreatitis usually burns out after a mean duration of 10 years, and the majority of patients do not live beyond age 70 years [1]. During the early phase of most cases of alcoholic chronic pancreatitis, recurrent attacks of upper abdominal pain occur with increasing frequency, but later this pancreatitis is characterized by absence of pain and the appearance of symp-
Table 3. Age and cause of death in each group of patients having chronic pancreatitis
Number of deaths Age at the time of death, years Period between pancreatitis onset and death, years Pancreatic surgery Cause of death (n; %)
Chronic Pancreatitis in the Elderly
Early onset (n = 119)
Late onset (n = 63)
24 58.8B10.4 6.8B4.6 34 (29%) malignancy (8; 33%) malnutrition (7; 29%) portal hypertension (3; 13%) pneumonia (2; 8%) unexplained (2; 8%) hypoglycemia (1; 4%) surgery (1; 4%)
19 74.3B16.9 3.1B2.2 5 (8%) malignancy (7; 37%) malnutrition (3; 16%) cerebral infarction (3; 16%) pneumonia (1; 5%) hypoglycemia (1; 5%) acute myocardial infarction (1; 5%) renal failure (1; 5%) hepatic failure (1; 5%) senility (1; 5%)
Pancreatology 2004;4:223–228
225
toms of diffuse glandular destruction and resultant severe insufficiency. As the proportion of the Japanese population aged 165 years was 17.5% [12], we separated two groups at the age of 65 years. In this study, the number of patients in the late-onset group was as large as 63, and alcoholic chronic pancreatitis manifesting for the first time after the age of 65 years was observed in 26 patients. In the early-onset group, 91% of the patients had alcoholic pancreatitis, and pain was observed in 61% of them, but most patients in the late-onset group had painless disease. On the other hand, the incidence of steatorrhea was less among Japanese patients than among those in Western countries. Healthy Japanese individuals consume fat ranging from 50 to 77 g/day [13, 14] which is almost half the European and American levels. Also, Japanese patients with chronic pancreatitis consume much smaller amounts of fat, ranging from 37 to 45 g/day [13, 14], about half that consumed by healthy Japanese individuals and one third of that consumed by European and American patients with chronic pancreatitis. The lower fecal fat excretion in Japanese patients with chronic pancreatitis is attributable to the lower fat consumption as compared with European and American patients. Many patients with late-onset disease fall into the idiopathic category. Ammann [15] proposed that ‘idiopathic senile chronic pancreatitis’ should be recognized as a distinct clinical entity. Generally, these patients are males, 65 years old or older, who present with some combination of steatorrhea, diabetes, weight loss, pancreatic calcification, and abdominal pain, with or without hyperamylasemia. In this study, 20 patients (12 males and 8 females) were diagnosed with late-onset idiopathic chronic pancreatitis, and associated calcification, diabetes, steatorrhea, and pain were observed in only 30, 20, 5, and 20% of them, respectively. Most cases of idiopathic chronic pancreatitis of late onset in Japan, therefore, appeared to differ from those having ‘idiopathic senile chronic pancreatitis’. On the other hand, in the experience of the Mayo Clinic [16], 66 patients with idiopathic chronic pancreatitis were divided into two groups: early onset (n = 25, !35 years old) and late onset (n = 41). In the early-onset idiopathic pancreatitis group, severe pain frequently occurred initially, whereas patients with late-onset pancreatitis had a mild and often a painless course. Although this study was performed in a specific health care center and could be subject to selection and/or referral bias, we experienced only 3 patients with chronic pancreatitis (alcoholic 2, autoimmune 1) whose ages at the time of diagnosis were !35 years.
226
Pancreatology 2004;4:223–228
One of the characteristics of late-onset chronic pancreatitis in Japan is the high incidence of autoimmune pancreatitis. Autoimmune pancreatitis is a recently described clinical entity, in which autoimmune mechanisms are involved in the pathogenesis. It is characterized clinically, histologically, and morphologically as follows: increased levels of serum gamma globulin or IgG and the presence of autoantibodies, fibrotic changes with lymphoplasmacytic infiltration, diffuse enlargement of the pancreas, diffusely irregular narrowing of the main pancreatic duct, sometimes association with other autoimmune diseases such as Sjögren’s syndrome, sclerosing cholangitis, and retroperitoneal fibrosis, and responsiveness to steroid therapy [17, 18]. Autoimmune pancreatitis frequently occurred in elderly men, being associated with obstructive jaundice due to stenosis of the bile duct and swelling of the pancreas. Consequently, pancreatic carcinoma is sometimes suspected, and pancreatectomy is performed in some cases. To avoid unnecessary pancreatic resections, autoimmune pancreatitis should be considered in the differential diagnosis in elderly patients with obstructive jaundice. The incidence of pancreatic carcinomas during the course of chronic pancreatitis is reported to range from 1.1% [19] to 1.9% [20] in Western countries. Ammann et al. [1] reported that of 86 patients who died with chronic pancreatitis, death resulted from malignancy in 16 (19%) of them. In this study, of 43 deaths among patients with chronic pancreatitis, 15 (35%) resulted from associated malignancies. The incidence of associated pancreatic carcinomas in the present study was 1.6%, similar to that observed in Western countries. Clinicians should thus be aware of the risk of associated malignancies, particularly in the treatment of elderly patients with chronic pancreatitis. The other common cause of death was malnutrition. To increase the quality of life in this condition, it is necessary to maintain adequate caloric intake with adequate supplementation of pancreatic enzymes [4]. In conclusion, early- and late-onset chronic pancreatitis showed different clinical features. In patients having late-onset chronic pancreatitis, the frequencies of idiopathic and autoimmune pancreatitis increased, and the frequency of alcoholic pancreatitis decreased. Clinicians should consider autoimmune pancreatitis in the differential diagnosis in elderly patients with obstructive jaundice. In the treatment of elderly patients with chronic pancreatitis, it is necessary to be aware of the possibility of associated malignancies.
Kamisawa/Yoshiike/Egawa/Nakajima/ Tsuruta/Okamoto/Nakamura
References 1 Ammann RW, Akovbiantz A, Largiadèr F, Schueler G: Course and outcome of chronic pancreatitis: Longitudinal study of a mixed medical-surgical series of 245 patients. Gastroenterology 1984;86(5 Pt 1):820–828. 2 Ammann RW: Chronic pancreatitis in the elderly. Gastroenterol Clin North Am 1990;19: 905–914. 3 Gullo L, Sipahi HM, Pezzilli R: Pancreatitis in the elderly. J Clin Gastroenterol 1994;19:64– 68. 4 Cohen SA: Pancreatic diseases in the elderly; in Gelb AM (ed): Clinical Gastroenterology in the Elderly. New York, Marcel Dekker, 1996, pp 213–226. 5 Lin Y, Tamakoshi A, Matsuno S, Takeda K, Hayakawa T, Kitagawa M, Naruse S, Kawamura T, Wakai K, Aoki R, Kojima M, Ohno Y: Nationwide epidemiological survey of chronic pancreatitis in Japan. J Gastroenterol 2000;35: 136–141. 6 Homma T, Harada H, Koizumi M: Diagnostic criteria for chronic pancreatitis by the Japan Pancreas Society. Pancreas 1997;15:14–15. 7 Lankish PG: Progression from acute to chronic pancreatitis: A physician’s view. Surg Clin North Am 1999;79:815–827. 8 Etemad B, Whitcomb DC: Chronic pancreatitis: Diagnosis, classification, and new genetic developments. Gastroenterology 2001;120: 682–707.
9 Nakamura T, Takebe K, Kudoh K, Ishii M, Imamura K, Kikuchi K, Kasai F, Tandoh Y, Yamada N, Arai Y, Terada A, Machida K: Steatorrhea in Japanese patients with chronic pancreatitis. J Gastroenterol 1995;30:79–83. 10 Nakamura T, Tando Y, Terada A, Watanabe T, Kaji A, Yamada N, Suda T: Can pancreatic steatorrhea be diagnosed without chemical analysis? Int J Pancreatol 1997;22:121–125. 11 Gullo L, Costa PL, Labo G: Chronic pancreatitis in Italy. Rendiconti Gastroenterol 1977;9: 97–104. 12 Bureau of Statistics, Ministry of Public Management, Home Affairs, Posts and Telecommunications: Population of Japan,1950–2000. Tokyo, Japan Statistical Association, 2003. 13 Nakamura T, Kikuchi H, Takebe K, Ishii M, Imamura K, Yamada N, Kudoh K, Terada A: Correlation between bile acid malabsorption and pancreatic exocrine dysfunction in patients with chronic pancreatitis. Pancreas 1994; 9:580–584. 14 Nakamura T, Takebe K, Yamada N, Arai Y, Tando Y, Terada A, Ishii M, Kikuchi H, Machida K, Imamura K: Bile acid malabsorption as a cause of hypocholesterolemia seen in patients with chronic pancreatitis. Int J Pancreatol 1994;16:165–169.
15 Ammann RW: Idiopathic senile chronic pancreatitis and pancreatic lithiasis in the aged. Gastroenterology 1984;87:253. 16 Layer PL, Yamamoto H, Kalthoff L, Clain JE, Bakken LJ, DiMagno EP: The different courses of early- and late-onset idiopathic and alcoholic chronic pancreatitis. Gastroenterology 1994; 107:1481–1487. 17 Okazaki K, Uchida K, Ohana M, Nakase H, Uose S, Inai M, Matsushima Y, Katamura K, Ohmori K, Chiba T: Autoimmune-related pancreatitis is associated with autoantibodies and Th1/Th2-type cellular immune response. Gastroenterology 2000;118:573–581. 18 Kamisawa T, Funata N, Hayashi Y, Tsuruta K, Okamoto A, Amemiya K, Egawa N, Nakajima H: Close relationship between autoimmune pancreatitis and multifocal fibrosclerosis. Gut 2003;52:683–687. 19 Malka D, Hammel P, Maire F, Rufat P, Madeira I, Pessione F, Levy P, Ruszniewski P: Risk of pancreatic adenocarcinoma in chronic pancreatitis. Gut 2002;51:849–852. 20 Talamini G, Falconi M, Bassi C, Sartori N, Salvia R, Caldiron E, Frulloni L, Francesco VD, Vaona B, Bovo P, Vantini I, Pederzoli P, Cavallini G: Incidence of cancer in the course of chronic pancreatitis. Am J Gastroenterol 1999; 94:1253–1260.
Editorial Comment Chronic Pancreatitis in Aged Patients – Not of Common Origin K. Kiehne, U.R. Fölsch Department of Internal Medicine, Universitätsklinikum Schleswig-Holstein, Kiel, Germany
Chronic pancreatitis commonly is envisaged as a sequel of alcohol abuse. Despite recent increasing knowledge of the various potential aetiologies, the majority of those with chronic pancreatitis consist of patients with former alcohol abuse. Their life expectancy is limited, and severe comorbidity exists. However, 20 years ago, distinct aetiologies especially for the aged patients have been postulated [1]. Only a few studies have been published on patients with late-onset chronic pancreatitis. Most of these patients have been diagnosed as having alcoholinduced chronic pancreatitis with a mild course or simply were identified late in their life because of minor symptoms. In the paper by Kamisawa et al. [2] in this issue of Pancreatology, 182 patients in a tertiary referral center in
Tokyo, Japan, are analyzed for symptoms, aetiology, and clinical course of their chronic pancreatitis. A major finding is the different aetiology found in relation to the age of onset of chronic pancreatitis. If a cutoff of 60 years at first presentation of symptoms is chosen, a high probability is given for this group of patients to have auto-immune chronic pancreatitis. The description of auto-immune pancreatitis has boosted clinical research similar to the identification of genes as causes of hereditary pancreatitis. Auto-immune pancreatitis should be suspected, if patients present with an enlarged pancreatic gland without calcifications, elevated immunoglobulin levels, especially of the IgG4 subfraction, a suggestive pancreatic duct picture on endoscopic retrograde pancreatography,
Chronic Pancreatitis in the Elderly
Pancreatology 2004;4:223–228
227
and, if performed, typical changes in the pancreatic biopsy specimen [3]. These patients should furthermore respond rapidly to treatment with glucocorticoids which might be a hallmark for a reliable diagnosis of autoimmune pancreatitis. The present study is adding an additional parameter, possibly with a high diagnostic reliability, namely the age of onset of chronic pancreatitis. If confirmed by other studies, this parameter might be a valuable criterion to separate patients before proceeding towards more invasive and cost-intensive diagnostic evaluations. However, the results of the present study need to be interpreted with caution. The incidence of auto-immune pancreatitis might be far too high because of the patient selection bias in this specialized tertiary referral center. The most important criticism has to be directed at the inconsistent diagnostic methods by which the patients were studied. Hard diagnostic criteria like pancreatic biopsy or rapid response to corticoids have been applied only to a minority of patients, so that in several cases the diagnosis of
228
Pancreatology 2004;4:223–228
auto-immune pancreatitis is based on weak arguments. Even chronic pancreatitis was diagnosed sometimes only by a single diagnostic method and not by combining morphologic and function tests. Further work has to be encouraged to describe autoimmune pancreatitis in more detail, especially to allow valid diagnostic and therapeutic recommendations. Longterm follow-up should document the unique course of the disease and the proposed excellent responsiveness to immunosuppressive therapy. In analogy to hereditary pancreatitis, a broadened knowledge should lead to a common awareness of this interesting new entity. References 1 Ammann RW, Akovbiantz A, Largiadèr F, Schueler G: Course and outcome of chronic pancreatitis: Longitudinal study of a mixed medical-surgical series of 245 patients. Gastroenterology 1984;86(5 Pt 1):820–828. 2 Kamisawa T, Yoshiike M, Egawa N, Nakajima H, Tsuruta K, Okamoto A, Nakamura T: Chronic pancreatitis in the elderly in Japan. Pancreatology 2004;4:223–228. 3 Okazaki K, Chiba T: Autoimmune related pancreatitis. Gut 2002;51:1–4.
Kamisawa/Yoshiike/Egawa/Nakajima/ Tsuruta/Okamoto/Nakamura
Received: July 11, 2003 Accepted after revision: January 18, 2004 Published online: May 12, 2004
Chronic Pancreatitis in the Elderly in Japan Terumi Kamisawa a Masami Yoshiike a Naoto Egawa a Hitoshi Nakajima a Kouji Tsuruta b Atsutake Okamoto b Teruo Nakamura c Departments of a Internal Medicine and b Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo, and of Health Science, Hirosaki University School of Medicine, Aomori, Japan
c Department
Key Words Chronic pancreatitis, elderly Japanese W Elderly Japanese, chronic pancreatitis W Autoimmune pancreatitis, elderly Japanese
Abstract Background/Aim: Although the elderly comprise an increasingly large segment of the population, little has been written about chronic pancreatitis in this age group in Japan. In this study, we analyzed the clinical features of elderly Japanese patients with chronic pancreatitis and compared them with those of late-onset chronic pancreatitis patients in Western countries. Methods: Subjects were 182 patients (162 males and 20 females) with chronic pancreatitis. They were divided into two groups: early-onset group (onset !65 years of age, n = 119) and late-onset group (onset 665 years of age, n = 63). Clinical findings and follow-up data were examined for each group. Results: Alcohol abuse was the most common etiological factor in early-onset pancreatitis patients. In the late-onset group, the frequencies of idiopathic and autoimmune pancreatitis increased. Furthermore, the age at onset of autoimmune pancreatitis was 160 years in 94% of the cases. The late-onset group was more likely to have painless disease, and calcifica-
ABC
© 2004 S. Karger AG, Basel and IAP 1424–3903/04/0044–0223$21.00/0
Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com
Accessible online at: www.karger.com/pan
tion of the pancreas and steatorrhea were rare in this group. Major causes of death were malignancy and malnutrition in each group. Conclusions: Early- and lateonset chronic pancreatitis showed different clinical features. Clinicians should consider autoimmune pancreatitis in the differential diagnosis in elderly patients with obstructive jaundice. Copyright © 2004 S. Karger AG, Basel and IAP
Introduction
Chronic pancreatitis is morphologically defined as an irreversible, irregular sclerosis of the gland with destruction of the exocrine parenchyma and ductal distortion. Chronic pancreatitis, usually related to alcohol abuse, is generally a disease of the young rather than the elderly, perhaps because many patients with alcoholic pancreatitis die earlier in life. Clinically, it is associated with recurrent or persistent abdominal pain, often accompanied by signs of pancreatic exocrine insufficiency. Due to a steadily increasing life span and a diminishing birth rate, the elderly comprise an increasingly large segment of the population. As a result, physicians are being faced more often with the need to treat chronic pancreatitis in patients in this age group. In the West, the incidence
Dr. Terumi Kamisawa Department of Internal Medicine, Tokyo Metropolitan Komagome Hospital 3-18-22 Honkomagome, Bunkyo-ku Tokyo 113-8677 (Japan) Tel. +81 3 3823 2101, Fax +81 3 3824 1552, E-Mail [email protected]
of chronic pancreatitis is 5–10 cases/100,000 in the population as a whole, and many studies on chronic pancreatitis in the elderly have been published [1–4]. In Japan, although the incidence is 5.0–5.9/100,000 [5], there has been relatively little published about chronic pancreatitis in the elderly. We examined the clinical features of elderly Japanese patients with chronic pancreatitis and compared them with those in elderly Western populations.
Patients and Methods We identified 182 patients (162 males and 20 females, average age at the time of diagnosis 57.7 B 8.2 years) who had the diagnosis of chronic pancreatitis at the Tokyo Metropolitan Komagome Hospital between 1976 and 2003. The medical records of these patients were analyzed retrospectively. The diagnosis of chronic pancreatitis was made when at least one of the following criteria was positive: pancreatic calcification on computed tomography or ultrasound (n = 82), typical histological changes (n = 47; 37 at surgery and 10 at autopsy), irregular dilation or irregularly narrowing of the pancreatic duct on endoscopic retrograde pancreatography (n = 160), and an abnormally low bicarbonate concentration combined with either decreased enzyme output or decreased secretory volume based on secretin test results (n = 38) [6–8]. Forty-four cases were confirmed only by endoscopic retrograde pancreatography findings. Alcoholic chronic pancreatitis was diagnosed on the basis of typical clinical features in the presence of a history of excessive alcohol intake (usually 1 80 g/day for more than 7 years). Idiopathic chronic pancreatitis was diagnosed in cases having chronic pancreatitis without alcohol abuse, family history, biliary tract disease, hyperparathyroidism, hyperlipidemia, autoimmune etiology, and trauma. Autoimmune pancreatitis was diagnosed in the presence of the following: swelling of the pancreas (n = 15), diffuse narrowing of the main pancreatic duct (n = 16), hypergammaglobulinemia (n = 10), autoimmune antibodies (n = 9), lymphoplasmacytic infiltration with fibrosis on histological examination (n = 8), and effectiveness of steroid treatment (n = 7). Patients with obstructive pancreatitis secondary to pancreatic duct obstruction due to invasion into the pancreas of extrapancreatic tumor or without adequate data were excluded. The patients were divided into two groups by the age at which chronic pancreatitis was diagnosed during the first hospitalization: early onset (! 65 years) and late onset (665 years). Clinical findings and follow-up data were reviewed for each group. In particular, we assessed alcohol consumption with or without smoking (1 20 cigarettes/day) and the presence of abdominal pain (requiring analgesics), diabetes mellitus (requiring insulin or hypoglycemic agent), manifest steatorrhea (fecal fat excretion 1 5 g/day by the Van de Kamer method and/or appearance of fatty stools by naked eyes) [9, 10], and malnutrition (presence of more than two of the following factors: ideal body weight index ! 0.8, serum albumin concentration ! 3.0 g/dl, and serum total cholesterol level ! 120 mg/dl). Statistical analyses were done using Fisher’s exact probability test. The duration of survival was estimated by means of the KaplanMeier method, and the survival curves were established using the generalized Wilcoxon test. p ! 0.05 was considered statistically significant. Values are expressed as mean B SD.
224
Pancreatology 2004;4:223–228
Results
The numbers of the patients in the early- and late-onset pancreatitis groups were 119 and 63, respectively. Males were affected much more frequently than females; however, the male/female ratio gradually decreased with age. Long-standing alcohol abuse was the most common etiological factor in patients with onset before the age of 65 years. Most patients with alcoholic chronic pancreatitis were smokers. In chronic pancreatitis manifesting for the first time in the elderly, the frequency of idiopathic and autoimmune pancreatitis increased and that of alcoholic pancreatitis decreased. 15 of 16 cases (13 males and 3 females) having autoimmune pancreatitis were 160 years old at the time of diagnosis. Five late-onset patients were diagnosed as having biliary chronic pancreatitis, because of the presence of long-term cholecystolithiasis/choledocholithiasis (n = 2) or papillary stenosis with biliary dilation (n = 3). Hereditary chronic pancreatitis was not observed (table 1). Although no significant differences in the incidence of associated diabetes were apparent, the late-onset group was more likely to experience painless disease (p ! 0.01). However, calcification of the pancreas (p ! 0.05) and steatorrhea (p ! 0.01) were rare in the late-onset pancreatitis group. Significantly more early-onset patients underwent pancreatic surgery than late-onset patients (p ! 0.01). Intractable pain or a pseudocyst was the main indication for pancreatic surgery in early-onset patients, but 4 lateonset patients underwent pancreatic surgery for suspicion of pancreatic carcinomas (table 2).
Table 1. Clinical findings in each group of patients having chronic
pancreatitis Early onset
Late onset
n Male/female ratio Age at the time of diagnosis, years Follow-up period, years
119 1/0.06 49.5B8.5 6.5B6.1
63 1/0.26 71.9B6.4 3.5B3.4
Etiology Alcoholic With smoking Without smoking Idiopathic Autoimmune Biliary Trauma Radiation
108 (91%) 69 8 6 (5%) 3 (2%) 0 1 (1%) 1 (1%)
26 (41%) 17 3 19 (30%) 13 (21%) 5 (8%) 0 0
Kamisawa/Yoshiike/Egawa/Nakajima/ Tsuruta/Okamoto/Nakamura
Late-onset patients survived significantly longer than early-onset patients (p ! 0.01; fig. 1). During the follow-up period, 24 patients of the early-onset group and 19 patients of the late-onset group died. Age and period between onset of disease and death were 58.8 B 10.4 and 6.8 B 4.6 years and 74.3 B 16.9 and 3.1 B 2.2 years, respectively. Major causes of death were malignancy and malnutrition in each group. Fifteen patients died of malignancy (pulmonary carcinoma 6 patients, pancreatic carcinoma 3, gastric carcinoma 3, esophageal carcinoma 2, biliary carcinoma 1, urinary bladder carcinoma 1, and leukemia 1 patient). Pancreatic carcinomas occurred in 2 early-onset patients and in 1 late-onset patient (table 3). Fig. 1. Overall survival for patients with early- and late-onset
chronic pancreatitis.
Discussion
Table 2. Complications and surgical intervention in each group of
patients having chronic pancreatitis
Pain Calcification Diabetes Steatorrhea Pancreatic surgery
Early onset (n = 119)
Late onset (n = 63)
n
%
n
%
72 60 62 33 34
61** 50* 52 28** 29**
17 22 28 6 5
27 35 44 10 8
* p ! 0.05; ** p ! 0.01.
In Western countries, the clinical onset of chronic pancreatitis tends to be between 30 and 40 years of age, with onset after 60 years of age being rare [1, 11]. Alcohol abuse is the leading cause of chronic pancreatitis, responsible for about 70% of the cases [2]. Alcoholic chronic pancreatitis, however, is not a common problem among older patients, because the mean age of onset is 37 B 10 years, and it rarely develops after age 60 years. Alcoholic chronic pancreatitis usually burns out after a mean duration of 10 years, and the majority of patients do not live beyond age 70 years [1]. During the early phase of most cases of alcoholic chronic pancreatitis, recurrent attacks of upper abdominal pain occur with increasing frequency, but later this pancreatitis is characterized by absence of pain and the appearance of symp-
Table 3. Age and cause of death in each group of patients having chronic pancreatitis
Number of deaths Age at the time of death, years Period between pancreatitis onset and death, years Pancreatic surgery Cause of death (n; %)
Chronic Pancreatitis in the Elderly
Early onset (n = 119)
Late onset (n = 63)
24 58.8B10.4 6.8B4.6 34 (29%) malignancy (8; 33%) malnutrition (7; 29%) portal hypertension (3; 13%) pneumonia (2; 8%) unexplained (2; 8%) hypoglycemia (1; 4%) surgery (1; 4%)
19 74.3B16.9 3.1B2.2 5 (8%) malignancy (7; 37%) malnutrition (3; 16%) cerebral infarction (3; 16%) pneumonia (1; 5%) hypoglycemia (1; 5%) acute myocardial infarction (1; 5%) renal failure (1; 5%) hepatic failure (1; 5%) senility (1; 5%)
Pancreatology 2004;4:223–228
225
toms of diffuse glandular destruction and resultant severe insufficiency. As the proportion of the Japanese population aged 165 years was 17.5% [12], we separated two groups at the age of 65 years. In this study, the number of patients in the late-onset group was as large as 63, and alcoholic chronic pancreatitis manifesting for the first time after the age of 65 years was observed in 26 patients. In the early-onset group, 91% of the patients had alcoholic pancreatitis, and pain was observed in 61% of them, but most patients in the late-onset group had painless disease. On the other hand, the incidence of steatorrhea was less among Japanese patients than among those in Western countries. Healthy Japanese individuals consume fat ranging from 50 to 77 g/day [13, 14] which is almost half the European and American levels. Also, Japanese patients with chronic pancreatitis consume much smaller amounts of fat, ranging from 37 to 45 g/day [13, 14], about half that consumed by healthy Japanese individuals and one third of that consumed by European and American patients with chronic pancreatitis. The lower fecal fat excretion in Japanese patients with chronic pancreatitis is attributable to the lower fat consumption as compared with European and American patients. Many patients with late-onset disease fall into the idiopathic category. Ammann [15] proposed that ‘idiopathic senile chronic pancreatitis’ should be recognized as a distinct clinical entity. Generally, these patients are males, 65 years old or older, who present with some combination of steatorrhea, diabetes, weight loss, pancreatic calcification, and abdominal pain, with or without hyperamylasemia. In this study, 20 patients (12 males and 8 females) were diagnosed with late-onset idiopathic chronic pancreatitis, and associated calcification, diabetes, steatorrhea, and pain were observed in only 30, 20, 5, and 20% of them, respectively. Most cases of idiopathic chronic pancreatitis of late onset in Japan, therefore, appeared to differ from those having ‘idiopathic senile chronic pancreatitis’. On the other hand, in the experience of the Mayo Clinic [16], 66 patients with idiopathic chronic pancreatitis were divided into two groups: early onset (n = 25, !35 years old) and late onset (n = 41). In the early-onset idiopathic pancreatitis group, severe pain frequently occurred initially, whereas patients with late-onset pancreatitis had a mild and often a painless course. Although this study was performed in a specific health care center and could be subject to selection and/or referral bias, we experienced only 3 patients with chronic pancreatitis (alcoholic 2, autoimmune 1) whose ages at the time of diagnosis were !35 years.
226
Pancreatology 2004;4:223–228
One of the characteristics of late-onset chronic pancreatitis in Japan is the high incidence of autoimmune pancreatitis. Autoimmune pancreatitis is a recently described clinical entity, in which autoimmune mechanisms are involved in the pathogenesis. It is characterized clinically, histologically, and morphologically as follows: increased levels of serum gamma globulin or IgG and the presence of autoantibodies, fibrotic changes with lymphoplasmacytic infiltration, diffuse enlargement of the pancreas, diffusely irregular narrowing of the main pancreatic duct, sometimes association with other autoimmune diseases such as Sjögren’s syndrome, sclerosing cholangitis, and retroperitoneal fibrosis, and responsiveness to steroid therapy [17, 18]. Autoimmune pancreatitis frequently occurred in elderly men, being associated with obstructive jaundice due to stenosis of the bile duct and swelling of the pancreas. Consequently, pancreatic carcinoma is sometimes suspected, and pancreatectomy is performed in some cases. To avoid unnecessary pancreatic resections, autoimmune pancreatitis should be considered in the differential diagnosis in elderly patients with obstructive jaundice. The incidence of pancreatic carcinomas during the course of chronic pancreatitis is reported to range from 1.1% [19] to 1.9% [20] in Western countries. Ammann et al. [1] reported that of 86 patients who died with chronic pancreatitis, death resulted from malignancy in 16 (19%) of them. In this study, of 43 deaths among patients with chronic pancreatitis, 15 (35%) resulted from associated malignancies. The incidence of associated pancreatic carcinomas in the present study was 1.6%, similar to that observed in Western countries. Clinicians should thus be aware of the risk of associated malignancies, particularly in the treatment of elderly patients with chronic pancreatitis. The other common cause of death was malnutrition. To increase the quality of life in this condition, it is necessary to maintain adequate caloric intake with adequate supplementation of pancreatic enzymes [4]. In conclusion, early- and late-onset chronic pancreatitis showed different clinical features. In patients having late-onset chronic pancreatitis, the frequencies of idiopathic and autoimmune pancreatitis increased, and the frequency of alcoholic pancreatitis decreased. Clinicians should consider autoimmune pancreatitis in the differential diagnosis in elderly patients with obstructive jaundice. In the treatment of elderly patients with chronic pancreatitis, it is necessary to be aware of the possibility of associated malignancies.
Kamisawa/Yoshiike/Egawa/Nakajima/ Tsuruta/Okamoto/Nakamura
References 1 Ammann RW, Akovbiantz A, Largiadèr F, Schueler G: Course and outcome of chronic pancreatitis: Longitudinal study of a mixed medical-surgical series of 245 patients. Gastroenterology 1984;86(5 Pt 1):820–828. 2 Ammann RW: Chronic pancreatitis in the elderly. Gastroenterol Clin North Am 1990;19: 905–914. 3 Gullo L, Sipahi HM, Pezzilli R: Pancreatitis in the elderly. J Clin Gastroenterol 1994;19:64– 68. 4 Cohen SA: Pancreatic diseases in the elderly; in Gelb AM (ed): Clinical Gastroenterology in the Elderly. New York, Marcel Dekker, 1996, pp 213–226. 5 Lin Y, Tamakoshi A, Matsuno S, Takeda K, Hayakawa T, Kitagawa M, Naruse S, Kawamura T, Wakai K, Aoki R, Kojima M, Ohno Y: Nationwide epidemiological survey of chronic pancreatitis in Japan. J Gastroenterol 2000;35: 136–141. 6 Homma T, Harada H, Koizumi M: Diagnostic criteria for chronic pancreatitis by the Japan Pancreas Society. Pancreas 1997;15:14–15. 7 Lankish PG: Progression from acute to chronic pancreatitis: A physician’s view. Surg Clin North Am 1999;79:815–827. 8 Etemad B, Whitcomb DC: Chronic pancreatitis: Diagnosis, classification, and new genetic developments. Gastroenterology 2001;120: 682–707.
9 Nakamura T, Takebe K, Kudoh K, Ishii M, Imamura K, Kikuchi K, Kasai F, Tandoh Y, Yamada N, Arai Y, Terada A, Machida K: Steatorrhea in Japanese patients with chronic pancreatitis. J Gastroenterol 1995;30:79–83. 10 Nakamura T, Tando Y, Terada A, Watanabe T, Kaji A, Yamada N, Suda T: Can pancreatic steatorrhea be diagnosed without chemical analysis? Int J Pancreatol 1997;22:121–125. 11 Gullo L, Costa PL, Labo G: Chronic pancreatitis in Italy. Rendiconti Gastroenterol 1977;9: 97–104. 12 Bureau of Statistics, Ministry of Public Management, Home Affairs, Posts and Telecommunications: Population of Japan,1950–2000. Tokyo, Japan Statistical Association, 2003. 13 Nakamura T, Kikuchi H, Takebe K, Ishii M, Imamura K, Yamada N, Kudoh K, Terada A: Correlation between bile acid malabsorption and pancreatic exocrine dysfunction in patients with chronic pancreatitis. Pancreas 1994; 9:580–584. 14 Nakamura T, Takebe K, Yamada N, Arai Y, Tando Y, Terada A, Ishii M, Kikuchi H, Machida K, Imamura K: Bile acid malabsorption as a cause of hypocholesterolemia seen in patients with chronic pancreatitis. Int J Pancreatol 1994;16:165–169.
15 Ammann RW: Idiopathic senile chronic pancreatitis and pancreatic lithiasis in the aged. Gastroenterology 1984;87:253. 16 Layer PL, Yamamoto H, Kalthoff L, Clain JE, Bakken LJ, DiMagno EP: The different courses of early- and late-onset idiopathic and alcoholic chronic pancreatitis. Gastroenterology 1994; 107:1481–1487. 17 Okazaki K, Uchida K, Ohana M, Nakase H, Uose S, Inai M, Matsushima Y, Katamura K, Ohmori K, Chiba T: Autoimmune-related pancreatitis is associated with autoantibodies and Th1/Th2-type cellular immune response. Gastroenterology 2000;118:573–581. 18 Kamisawa T, Funata N, Hayashi Y, Tsuruta K, Okamoto A, Amemiya K, Egawa N, Nakajima H: Close relationship between autoimmune pancreatitis and multifocal fibrosclerosis. Gut 2003;52:683–687. 19 Malka D, Hammel P, Maire F, Rufat P, Madeira I, Pessione F, Levy P, Ruszniewski P: Risk of pancreatic adenocarcinoma in chronic pancreatitis. Gut 2002;51:849–852. 20 Talamini G, Falconi M, Bassi C, Sartori N, Salvia R, Caldiron E, Frulloni L, Francesco VD, Vaona B, Bovo P, Vantini I, Pederzoli P, Cavallini G: Incidence of cancer in the course of chronic pancreatitis. Am J Gastroenterol 1999; 94:1253–1260.
Editorial Comment Chronic Pancreatitis in Aged Patients – Not of Common Origin K. Kiehne, U.R. Fölsch Department of Internal Medicine, Universitätsklinikum Schleswig-Holstein, Kiel, Germany
Chronic pancreatitis commonly is envisaged as a sequel of alcohol abuse. Despite recent increasing knowledge of the various potential aetiologies, the majority of those with chronic pancreatitis consist of patients with former alcohol abuse. Their life expectancy is limited, and severe comorbidity exists. However, 20 years ago, distinct aetiologies especially for the aged patients have been postulated [1]. Only a few studies have been published on patients with late-onset chronic pancreatitis. Most of these patients have been diagnosed as having alcoholinduced chronic pancreatitis with a mild course or simply were identified late in their life because of minor symptoms. In the paper by Kamisawa et al. [2] in this issue of Pancreatology, 182 patients in a tertiary referral center in
Tokyo, Japan, are analyzed for symptoms, aetiology, and clinical course of their chronic pancreatitis. A major finding is the different aetiology found in relation to the age of onset of chronic pancreatitis. If a cutoff of 60 years at first presentation of symptoms is chosen, a high probability is given for this group of patients to have auto-immune chronic pancreatitis. The description of auto-immune pancreatitis has boosted clinical research similar to the identification of genes as causes of hereditary pancreatitis. Auto-immune pancreatitis should be suspected, if patients present with an enlarged pancreatic gland without calcifications, elevated immunoglobulin levels, especially of the IgG4 subfraction, a suggestive pancreatic duct picture on endoscopic retrograde pancreatography,
Chronic Pancreatitis in the Elderly
Pancreatology 2004;4:223–228
227
and, if performed, typical changes in the pancreatic biopsy specimen [3]. These patients should furthermore respond rapidly to treatment with glucocorticoids which might be a hallmark for a reliable diagnosis of autoimmune pancreatitis. The present study is adding an additional parameter, possibly with a high diagnostic reliability, namely the age of onset of chronic pancreatitis. If confirmed by other studies, this parameter might be a valuable criterion to separate patients before proceeding towards more invasive and cost-intensive diagnostic evaluations. However, the results of the present study need to be interpreted with caution. The incidence of auto-immune pancreatitis might be far too high because of the patient selection bias in this specialized tertiary referral center. The most important criticism has to be directed at the inconsistent diagnostic methods by which the patients were studied. Hard diagnostic criteria like pancreatic biopsy or rapid response to corticoids have been applied only to a minority of patients, so that in several cases the diagnosis of
228
Pancreatology 2004;4:223–228
auto-immune pancreatitis is based on weak arguments. Even chronic pancreatitis was diagnosed sometimes only by a single diagnostic method and not by combining morphologic and function tests. Further work has to be encouraged to describe autoimmune pancreatitis in more detail, especially to allow valid diagnostic and therapeutic recommendations. Longterm follow-up should document the unique course of the disease and the proposed excellent responsiveness to immunosuppressive therapy. In analogy to hereditary pancreatitis, a broadened knowledge should lead to a common awareness of this interesting new entity. References 1 Ammann RW, Akovbiantz A, Largiadèr F, Schueler G: Course and outcome of chronic pancreatitis: Longitudinal study of a mixed medical-surgical series of 245 patients. Gastroenterology 1984;86(5 Pt 1):820–828. 2 Kamisawa T, Yoshiike M, Egawa N, Nakajima H, Tsuruta K, Okamoto A, Nakamura T: Chronic pancreatitis in the elderly in Japan. Pancreatology 2004;4:223–228. 3 Okazaki K, Chiba T: Autoimmune related pancreatitis. Gut 2002;51:1–4.
Kamisawa/Yoshiike/Egawa/Nakajima/ Tsuruta/Okamoto/Nakamura