Clinical Profile of Idiopathic Chronic Pancreatitis in North India

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2009;7:594 599 Clinical Profile of Idiopathic Chronic Pancreatitis in North India DEEPAK K. BHASIN,* GURSEWAK SINGH,* SURINDER S. RANA,* SHOKET M. CHOWDRY,* NUSRAT SHAFIQ, SAMIR MALHOTRA, SAROJ K. SINHA,* and BIRINDER NAGI* *Department of Gastroenterology and Department of Clinical Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Background & Aims: Tropical pancreatitis, a form of idiopathic chronic pancreatitis (ICP) with unique features, has been described in South and North India. We investigated the clinical profile of ICP patients in North India. Methods: Detailed demographic data were recorded; hematological and biochemical analyses were performed on samples from 155 patients (mostly from North India) who had been diagnosed with chronic pancreatitis. Ultrasonography and computed tomography were performed on all patients. Magnetic resonance cholangiopancreatography, endoscopic retrograde cholangiopancreatography, glucose tolerance tests, and fecal fat studies were performed on some patients. Patients were divided into groups based on early- or late-onset ICP (before or after 35 years of age). Results: ICP was reported in 41.3% of patients and alcoholic chronic pancreatitis in 38.1%. The mean age of ICP patients was 33.0 13.0 years and the mean duration of symptoms at the time of presentation was 40.2 34.4 months. Pain was the dominant symptom in patients with early- (95.1%) and lateonset (100%) ICP; pseudocyst was the most common local complication. Diabetes was observed in 17.1% of patients with early-onset ICP and 34.8% with late-onset ICP. Pancreatic calcification was noted in 46.3% of patients with earlyonset and 47.8% with late-onset ICP. Pseudocyst and segmental portal hypertension occurred more frequently in non-calcific ICP, whereas diabetes mellitus and abnormal fecal fat excretion occurred more frequently in patients with calcific ICP. Conclusions: In North India, ICP differs from the classical tropical pancreatitis described in the literature. It is associated with a higher prevalence of pain and lower frequencies of diabetes, calcification, and intraductal calculi. Chronic pancreatitis is characterized by irreversible damage to the pancreas that eventually leads to pain and/or exocrine and endocrine insufficiency. 1 It is a major health problem worldwide and is associated with considerable morbidity. In spite of a large number of reports on chronic pancreatitis, it remains a fascinating process of uncertain pathogenesis, unpredictable clinical course, and unclear treatment. 2 Although alcohol is an important cause of chronic pancreatitis, in a large proportion of patients with chronic pancreatitis, no etiology can be identified, and they are labeled as having idiopathic chronic pancreatitis (ICP). 1 Many studies have described the profile and course of alcoholic chronic pancreatitis, 3 9 but there are limited studies on the profile of ICP, and the results are variable. 10 12 Layer et al 10 described a different clinical course in patients with ICP as compared with those having alcoholic pancreatitis. They found that patients with early-onset ICP (onset before 35 years of age) have a long course of severe pain but develop morphologic and functional pancreatic damage slowly, whereas patients with late-onset ICP (onset after 35 years of age) have a mild and often painless disease. In contrast, Lankisch et al 12 found that the clinical course is the same in alcohol and nonalcohol-induced chronic pancreatitis. Studies from South India and other tropical countries have described a distinctive form of idiopathic chronic calcific pancreatitis that is characterized by distinctive features of younger age at onset, presence of large intraductal calculi, and accelerated course leading to diabetes and/or steatorrhea. 13 20 Several names including tropical chronic pancreatitis, tropical calcific pancreatitis, juvenile pancreatitis syndrome, Afro-Asian pancreatitis, and fibrocalculous pancreatic diabetes have been proposed for this type of chronic pancreatitis. 19 Studies from North India have also studied idiopathic calcific chronic pancreatitis and have found features similar to tropical pancreatitis as described from South India. 20 23 But recently it has been suggested that ICP of North India is probably different from tropical pancreatitis. 20 The data supporting this observation are sparse, and also, to the best of our literature search, there is no published study from North India that has specifically dealt with ICP, especially the noncalcific variety. The present study was conducted to investigate the clinical profile including the epidemiologic features and initial presenting symptoms of patients with ICP at a tertiary care center in North India. Materials and Methods All patients with chronic pancreatitis seen in our unit in the Department of Gastroenterology at Post Graduate Institute of Medical Education and Research, Chandigarh, India from June 1999 to June 2004 were studied. The patients attending the endocrinology clinic for diabetes mellitus and on evaluation found to have chronic pancreatitis were referred to us and were also included in the study. The diagnosis of chronic pancreatitis was made on the basis of clinical, biochemical, and radiologic investigations. 1 A thorough diagnostic evaluation was done of patients with chronic abdominal pain, and diagnosis of chronic pancreatitis was established if there was evidence of pancreatic calcification on abdominal x-ray and/or ultrasonography and/or abdominal computed tomography, and/or there were Abbreviations used in this paper: ERCP, endoscopic retrograde cholangiopancreatography; ICP, idiopathic chronic pancreatitis; MRCP, magnetic resonance cholangiopancreatography. 2009 by the AGA Institute 1542-3565/09/$36.00 doi:10.1016/j.cgh.2009.01.009

May 2009 ICP IN NORTH INDIA 595 characteristic ductal changes on magnetic resonance cholangiopancreatography (MRCP) and/or endoscopic retrograde cholangiopancreatography (ERCP). A detailed history specifically assessing the family history, alcohol consumption, and presence and severity of abdominal pain was recorded. The absence of alcohol consumption was confirmed by repeated interviews of the patient as well as of the family members. All the patients were subjected to a thorough clinical examination, routine hematologic and biochemical investigations, abdominal x-ray ultrasonography, and computed tomography. Additional investigations such as MRCP, ERCP, glucose tolerance test, and fecal fat studies were performed when indicated. ERCP was performed in patients who were treated with pancreatic endotherapy. Glucose tolerance test was performed in patients with impaired fasting blood glucose levels. Fecal fat studies were performed in patients who had history of chronic diarrhea or steatorrhea. Diagnosis of alcohol-induced chronic pancreatitis was made in patients with features of chronic pancreatitis who had consumed more than 50g/day of alcohol for at least 5 years. 14 ICP was diagnosed if preexisting disorders likely to cause chronic pancreatitis (hypertriglyceridemia, primary hyperparathyroidism, abdominal trauma, and pancreatic duct stenosis caused by operation), hereditary pancreatitis (as determined by family history), and excessive alcohol consumption were absolutely ruled out. 24 The patients with ICP were divided into early-onset and late-onset ICP depending on the age of onset of symptoms (before or after age of 35 years). Statistical Analysis All results were expressed as mean standard deviation, median, or range as appropriate. The information thus collected was coded and transferred to a personal computer. Discrete variables comparison between different groups was done with 2 test. Continuous variables in different groups were compared with Student t test (for 2 groups) or with one-way analysis of variance (for 2 groups). Results Epidemiology A total of 155 patients with chronic pancreatitis were studied during the study period. The majority of the patients belonged to the North Indian states of Punjab, Haryana, Himachal Pradesh, and Jammu and Kashmir. ICP was the most common etiology (n 64, 41.3%) followed by alcoholic chronic pancreatitis (n 59, 38.1%), pancreas divisum alone (n 23, 14.8%), pancreas divisum along with excessive alcohol consumption (n 4, 2.6%), and hyperparathyroidism (n 5, 3.2%). The age of patients with chronic pancreatitis ranged from 7 69 years (mean, 36.2 12.4 years), and 121 of 155 (78%) patients of chronic pancreatitis were male. Age Most of the patients with ICP were young, with a mean age of 33.0 13.0 years. In contrast, the patients with alcoholinduced chronic pancreatitis were significantly older than patients with ICP; the mean age of patients with alcohol-induced chronic pancreatitis was 41.5 9.9 years (P.0001) (Table 1). When patients with ICP were divided into 2 groups according to the onset of symptoms before and after 35 years of age, the Table 1. Comparison of Alcoholic and Idiopathic Chronic Pancreatitis Patients Alcoholic (N 59) Idiopathic (N 64) P value Age (y) 41.5 9.9 33.0 13.0.0001 Symptom duration (mo) 27.6 20.6 40.2 34.4.05 Body mass index (kg/m 2 ) 20.7 3.6 20.2 3.5 NS Clinical features Male 59 42.0001 Calcification 21 30 NS Pain 54 62 NS Jaundice 6 7 NS Diarrhea 4 3 NS Lump 7 4 NS Vomiting 5 5 NS Gastrointestinal bleed 2 2 NS mean age of the patients at presentation with early-onset (n 41) and late-onset (n 23) ICP was 25.2 6.75 years and 48.24 7.84 years, respectively. Sex Distribution Of 64 patients with ICP, there were 42 (65.6%) male patients, with male to female ratio of 1.9:1. In contrast, all of the 59 patients with alcohol-induced chronic pancreatitis were male (P.0001) (Table 1). On comparing the sex distribution between early- and late-onset ICP, there was a significantly higher frequency of male patients in early-onset ICP (75% [31/ 41] vs 47.28% [11/23], respectively; P.02). Clinical Features The mean duration of symptoms at the time of presentation in patients with ICP was 40.2 34.4 months, whereas patients with alcoholic pancreatitis had significantly shorter duration of symptoms at the time of presentation (27.6 20.6 months, P.05). Pain was the dominant symptom in patients with alcohol-induced chronic pancreatitis as well as those with ICP (54/59, 91.5% and 62/64, 96.8% patients, respectively). In patients with early-onset ICP, pain was the dominant symptom; it was present in 95.1% (39/41) of patients. Even in patients with late-onset ICP, pain was the most common symptom; it was present in 100% (23/23) of patients. There was no significant difference in the body mass index between patients with alcoholic chronic pancreatitis and those with ICP (20.7 3.6 kg/m 2 vs 20.2 3.5 kg/m 2, respectively). Of 5 patients with painless alcohol-related chronic pancreatitis, 2 presented with gastrointestinal bleed, and 1 each presented with obstructive jaundice, dyspnea because of pleural effusion, and chronic fatty diarrhea. Of 2 patients with painless ICP, 1 each presented with symptoms of hyperglycemia and hematemesis. Complications Pseudocyst was the most common complication; it was noted in 58 of 155 (37.4%) patients. In 7 patients who had history of gastrointestinal bleed, 4 had gastric varices, and 3 had pseudoaneurysm (splenic artery, 2; gastroduodenal artery, 1). In patients with ICP, pseudocyst was also the most common complication; it was present in 22 of 64 (34.3%) patients. Similarly, pseudocyst was the most common complication recorded

596 BHASIN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 5 Table 2. Comparison of Frequency of Complications Between Alcoholic and Idiopathic Chronic Pancreatitis Complication Alcoholic (N 59) Idiopathic (N 64) P value Pseudocyst 28 (47.4%) 22 (34.3%) NS Diabetes mellitus 13 (22%) 15 (23.4%) NS Portal hypertension 12 (20.3%) 11 (17.1%) NS Ascites and/or pleural 11 (18.6%) 5 (7.8%) NS effusion Fecal fat 7 g/d 7/25 (28%) 3/25 (12%) NS Gastric outlet obstruction 1 (1.6%) 1 (1.5%) NS in patients with alcohol-induced chronic pancreatitis (28/59, 47.4%). There was no significant difference in the frequency of various local and systemic complications between ICP and alcoholic chronic pancreatitis (Table 2). Diabetes Mellitus Diabetes on presentation was seen in 15 of 64 (23.4%) patients with ICP and in 13 of 59 (22%) patients with alcoholrelated chronic pancreatitis, and this difference was not statistically significant (Table 2). Three of 15 patients with ICP and 4 of 13 patients with alcohol-related chronic pancreatitis had impaired fasting blood glucose level and had an abnormal glucose tolerance test result. Diabetes on presentation was seen in more patients with late-onset ICP in comparison to earlyonset ICP, but this difference did not reach statistical significance (7/41, 17.1% vs 8/23, 34.8%, respectively; P.05). Of 13 patients with diabetes and alcohol-related chronic pancreatitis, blood glucose was controlled by diet in 4 (30.7%), by oral hypoglycemic agent in 1 (7.6%), and by insulin in 8 (61.5%) patients. Of 15 patients with diabetes and ICP, blood glucose was controlled by diet in 4 (26.6%), by oral hypoglycemic agent in 3 (20%), and by insulin in 8 (53.3%) patients. Of 7 patients with diabetes and early-onset ICP, 3 (42.8%) were treated with insulin, and 2 patients each (28.6%) had their blood glucose controlled by diet and oral hypoglycemic agent. Of 8 patients with diabetes and late-onset ICP, 5 (62.5%) were treated with insulin, 1 (12.5%) was treated with oral hypoglycemic agent, and in 2 patients (25%) blood glucose was controlled by diet. None of the patients with diabetes had microvascular or macrovascular complications of diabetes on presentation. Pancreatic Calcification Twenty-one of 59 (35.5%) patients with alcoholic pancreatitis and 30 of 64 (46.8%) patients with ICP had pancreatic calcification, and this difference was not statistically significant. Pancreatic calcification on presentation was noted in 46.3% (19/41) of patients with early-onset ICP and 47.8% (11/23) of patients with late-onset ICP, and this difference was also not statistically significant (P.05). The pattern of pancreatic calcification was also similar in both groups, and in the majority of these patients, it was a small, speckled calcification. When calcific and noncalcific ICP was compared, there was no significant difference in age, sex ratio, duration of symptoms, and frequency of various symptoms including abdominal pain (Table 3). However, pseudocyst and segmental portal hypertension occurred more frequently in noncalcific ICP, whereas diabetes mellitus and abnormal fecal fat excretion occurred more frequently in patients with calcific ICP (P.05, Table 3). Endoscopic Retrograde Cholangiopancreatography ERCP was performed in 46 of 59 (77.9%) patients with alcohol-related chronic pancreatitis and in 58 of 64 (90.6%) patients with ICP. Mild, moderate, and marked changes of chronic pancreatitis as per Cambridge criteria 25 were seen in 1 (2.1%), 5 (10.8%), and 40 (86.9%) patients with alcohol-related chronic pancreatitis, respectively. Ductal strictures were observed in 5 (10.8%) patients, and 2 of these 5 patients (40%) had multiple strictures. In patients with ICP, mild, moderate, and marked changes of chronic pancreatitis as per Cambridge criteria were seen in 3 (5.1%), 11 (18.9%), and 44 (75.8%) patients, respectively. Ductal strictures were observed in 4 of 58 patients (6.8%), and all these patients had single stricture. Intraductal calculi were observed in 9 patients with ICP, and only 3 of these had 1 cm size ductal calculi. In patients with early-onset ICP (n 38), mild, moderate, and marked changes of chronic pancreatitis were seen in 2 (5.2%), 7 (18.4%), and 29 (76.3%) patients, respectively. In patients with late-onset ICP (n 20), mild, moderate, and marked changes of chronic pancreatitis were seen in 1 (5%), 4 (20%), and 15 (75%) patients, respectively. Discussion Chronic pancreatitis has varied etiology, and alcohol consumption accounts for the majority of the cases of chronic Table 3. Comparison of Idiopathic Calcific Versus Idiopathic Noncalcific Chronic Pancreatitis Idiopathic calcific (N 30) Idiopathic noncalcific (N 34) P value Age (y) 33.9 13.5 32.2 12.8 NS Symptom duration 39.5 26.5 40.8 40.5 NS (mo) Body mass index 18.8 3.4 21.0 3.4 NS (kg/m 2 ) Clinical features Male 20 22 NS Pain 28 34 NS Jaundice 4 3 NS Diarrhea 1 2 NS Lump 1 3 NS Vomiting 3 2 NS Gastrointestinal 1 1 NS bleed Complications Ascites and/or 1 4 NS pleural effusion Portal 1 10.05 hypertension Pseudocyst 5 17.05 Gastric outlet 1 0 NS obstruction Diabetes 11 4.05 mellitus Fecal fat 7 g/d 3/11 0/14.05

May 2009 ICP IN NORTH INDIA 597 pancreatitis in Western countries. Other causative factors include genetic mutations, pancreatic duct obstruction by strictures, hypertriglyceridemia, hyperparathyroidism, and autoimmunity. 26 In a subset of patients with chronic pancreatitis, no obvious etiology can be found, and these heterogeneous groups of patients are labeled as ICP. ICP occurring in tropical regions like India is labeled as tropical pancreatitis. 19 Studies from South India have described tropical pancreatitis to be a juvenile form of chronic pancreatitis characterized by distinctive features of younger age at onset, presence of large intraductal calculi, and accelerated course leading to diabetes and/or steatorrhea. 13 20 There are limited studies that have looked into the profile of ICP of North India, and most of them have suggested it to be similar to the tropical pancreatitis of South India. 20 23 However, there are recent anecdotal observations that ICP of North India is probably different from the tropical pancreatitis of South India. 20 The current study has attempted to study the profile of ICP in North India. Comparison of ICP and alcohol-related chronic pancreatitis revealed that patients with ICP had significantly lower mean age of presentation (P.0001) and shorter duration of symptoms (P.05, Table 1). Also there was male preponderance in patients with alcohol-related chronic pancreatitis (P.0001). This could be related to the cultural habits of people of North India, where alcohol consumption is seen mostly in men. There was no significant difference in the frequency of pain as well as complications between alcohol-related chronic pancreatitis and ICP and lower frequency of ductal strictures in both alcoholrelated chronic pancreatitis and ICP. On comparing calcific ICP with noncalcific ICP, the frequency of endocrine and exocrine insufficiency was significantly higher in the calcific group. This could be due to the natural history of the disease, because it has been shown that with increasing disease duration there is an increase in pancreatic dysfunction as well as pancreatic calcification. 27 Another interesting finding in the current study is the trend toward higher incidence of portal hypertension and pseudocyst formation in the noncalcific ICP compared with calcific ICP. Further studies with a large sample size are required to confirm these differences as well as to study the possible pathologic mechanisms for these differences. On comparing the clinical profile of ICP of North India as derived from our results with the profile of tropical pancreatitis as revealed by published reports of tropical pancreatitis from various centers, various interesting differences can be noted (Table 4). In contrast to tropical pancreatitis where most of the patients are between 10 and 30 years of age when the diagnosis is made, the mean age at presentation in our series of ICP was 33 years. 13 19,23 Patients in our series had a normal mean body mass index, and 96.9% of the patients had abdominal pain as one of the presenting clinical features. In contrast to this, patients with tropical pancreatitis are usually malnourished and emaciated, and abdominal pain is seen in 30% 90% of the patients. 13 19 Patients with tropical pancreatitis have pancreatic calcification in more than 90% of the patients, and diabetes also occurs in more than 90% of patients, whereas in our patients with ICP, the frequency of pancreatic calcification and diabetes was 46.9% and 23.4%, respectively. Also the majority of patients with tropical pancreatitis have intraductal calculi, whereas they were noted in only 9 of 64 (14%) of our patients with ICP. 13 19,23 Of these 9 patients, only 3 (4.6%) were younger than 25 years. Also higher incidence of pancreatic malignancy has been reported in patients with tropical pancreatitis. 28 In contrast, in the current study none of the patients with ICP had pancreatic cancer. These findings lend support to the concept that ICP in North India might be a different entity that has higher prevalence of pain, lower frequency of diabetes and pancreatic calcification, as well as lower frequency of intraductal calculi. Recent studies from South India have suggested that the profile of ICP is changing. On comparing a cohort of 220 patients with ICP studied in 1984 with another cohort of 244 patients seen in 2004, Balakrishnan et al 29 found that the clinical profile and presentation of the disease have changed. They found that the ICP in the recent group occurred in older people, with the mean age at onset of disease being 30.6 years in contrast to 20.7 years in the 1984 cohort. The frequency of pain was found to be higher and the frequency of diabetes was found to be lower in the recent cohort (95.9% vs 81% and 59.7% vs 77%, respectively). They concluded that the presentation of ICP has become more heterogeneous, with 10% 15% of patients still presenting with the classic features of tropical pancreatitis. A recent prospective multicenter study from India involving 1086 subjects also reported that ICP is the most common form of chronic pancreatitis in India, and only 3.8% of the patients were diagnosed as having tropical pancreatitis. 30 It is possible that in our study some of the patients with early-onset idiopathic chronic calcific pancreatitis might resemble tropical pancreatitis. But even these patients with early-onset ICP a lower frequency of diabetes as well as less dense calcification along with lower frequency of ductal calculi as compared with the classic form of tropical pancreatitis. Layer et al 10 had reported that in the United States there is a bimodal distribution of ages at the onset of symptomatic disease in patients with ICP, and they divided them into 2 Table 4. Comparison of Tropical Pancreatitis With Idiopathic Pancreatitis of North India (Present Study) Chari et al 14 Thomas et al 17 Balaji et al 13 Khan et al 18 Present study N 150 116 36 24 64 M:F 2.5:1 85:31 13:23 24:7 42:22 Age at onset (y) 22.9 12.6 23.9 12.0 30.6 13.01 Age at presentation (y) 32.6 11.9 31 (9 68) 32.8 12.6 33.0 13.0 Pain 82% 88 (76%) 11 (30.5%) 100% 96.9% Diabetes 78% 62 (53%) 19 (52.8%) 23.4% Calcification 84% 28 (77.8%) 46.9% Body mass index (kg/m 2 ) 18.9 3.0 17.53 2.94 20.23 2.11 Duration of symptoms 8.2 7.9 y 1 mo 5 y 40.2 34.4 mo

598 BHASIN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 5 Table 5. Comparison of Early- and Late-Onset ICP of United States and North India Present study (age 35 y) (N 41) Layer et al, 10 early-onset ICP (N 25) P value Present study (age 35 y) (N 23) Layer et al, 10 late-onset ICP (N 41) P value Male 75% 44%.01 48% 56% NS Median age at onset of 23 19.2 44 56.2 symptoms (y) Clinical features Pain 39 (95.1%) 25 (100%) NS 23 (100%) 31 (76%).01 Diabetes mellitus 7 (17.1%) 8 (32%) NS 8 (34.8%) 17 (41%) NS Calcification 19 (46.3%) 14 (56%) NS 11 (47.8%) 15 (37%) NS Exocrine insufficiency 3 (7.3%) 11 (44%).01 0 (0%) 19 (46%).0001 major forms of ICP, early-onset and late-onset ICP (onset before and after 35 years of age, respectively). Early-onset ICP was characterized by a long course of severe abdominal pain, but calcification and exocrine and endocrine insufficiency developed more slowly than in late-onset ICP. When we divided the ICP patients into early-onset and late-onset ICP (Table 5), it was noted that the median age at presentation in early-onset and late-onset ICP was found to be 23 and 44 years, respectively, whereas Layer et al found the median age to be 19.2 and 56.2 years, respectively. Early-onset ICP of North India in contrast to that of the West was also found to have significant male preponderance (P.05) and lower frequency of exocrine insufficiency (P.05). Also in contrast to absence of pain in a significant number of patients with late-onset ICP in the West, pain was observed in all of our patients with late-onset ICP (P.05). Exocrine insufficiency was seen in significantly more patients with late-onset ICP in the West in comparison to lateonset ICP in the current study (P.0001). This is an observational study of 155 patients with chronic pancreatitis who presented to a tertiary care center; therefore, the patients included in the current study are symptomatic patients, with the majority of them having pain and a large number of them having complications like pseudocyst, pancreatic ascites, pancreatic pleural effusion, and diabetes. It is possible that this might have caused referral bias in the results, and hence a large population-based study with a more heterogeneous population is required to confirm our initial results. ICP is a heterogeneous disease with varied clinical manifestations and course. As new genetic, environmental, and metabolic factors are identified, the number of patients in this category is diminishing. Genetic studies might show whether the ICP of North India is a different clinicopathologic entity from tropical pancreatitis or chronic pancreatitis of South India or from ICP of the West. 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