Tropical Chronic Pancreatitis - A unique clinico-radiological entitiy. Why is it important to know this?

Tropical Chronic Pancreatitis - A unique clinico-radiological entitiy. Why is it important to know this? Poster No.: C-1571 Congress: ECR 2015 Type: Educational Exhibit Authors: C. B. Kulkarni, S. Moorthy, S. Karumathil Pullara, N. K. Prabhu, R. Kannan; Kochi/IN Keywords: Pancreas, CT, MR, Stents, Tropical diseases DOI: 10.1594/ecr2015/C-1571 Any information contained in this pdf file is automatically generated from digital material submitted to EPOS by third parties in the form of scientific presentations. References to any names, marks, products, or services of third parties or hypertext links to thirdparty sites or information are provided solely as a convenience to you and do not in any way constitute or imply ECR's endorsement, sponsorship or recommendation of the third party, information, product or service. ECR is not responsible for the content of these pages and does not make any representations regarding the content or accuracy of material in this file. As per copyright regulations, any unauthorised use of the material or parts thereof as well as commercial reproduction or multiple distribution by any traditional or electronically based reproduction/publication method ist strictly prohibited. You agree to defend, indemnify, and hold ECR harmless from and against any and all claims, damages, costs, and expenses, including attorneys' fees, arising from or related to your use of these pages. Please note: Links to movies, ppt slideshows and any other multimedia files are not available in the pdf version of presentations. www.myesr.org Page 1 of 25

Learning objectives To understand aetio-pathogenesis, unique imaging features and complications associated with Tropical Chronic Pancreatitis (TCP). To understand the role of radiologist in management of Tropical Chronic Pancreatitis (TCP). Background Topical chronic pancreatitis (TCP) represents a juvenile nonalcoholic form of chronic pancreatitis more prevalent in many tropical developing [1,2] countries. Tropical chronic pancreatitis differs from temperate zone pancreatitis in its younger age of onset, more accelerated course, higher prevalence of pancreatic calculi and diabetes, and greater propensity to pancreatic [1,2] malignancy. The diabetic stage of the disease is referred to as fibrocalculous pancreatic diabetes. The diabetes is severe and insulin requiring although [1,2] ketosis resistant. TCP is unique as compared to other forms of chronic pancreatits in its aetiology, imaging features and prognosis. Page 2 of 25

Fig. 1: Overview of Tropical Chronic pancreatitis References: Dr.Chinmay Kulkarni Findings and procedure details Aetio-Pathogenesis: There is lack of clear understanding of etiopathogenesis of TCP. Various hypotheses are proposed. Page 3 of 25

Fig. 2: Aetiology of Tropical Chronic pancreatitis References: Dr.chinmay Kulkarni Malnutrition: [3,4,5] Initially based on the observation that TCP mainly affects poor, malnutrition was suspected to be an etiologic factor The present understanding is that malnutrition appears to be effect rather than cause. Undernutrion and micronutrient deficiency has definite complimentary role in pathogenesis of TCP. Concept of subclinical pancreatopathy According to this concept the pancreatic juice of healthy subjects in developing countries has low enzyme levels and high calcium and lactoferrin levels which favour stone formation. Page 4 of 25

High carbohydrate, low fat and low protein diet might be contributing factor for such pancreatopathy. This makes pancreas vulnerable to various insults and might contribute to delevopement of chronic calcific pancreatitis. [6] Dietary toxins (Cassava hypothesis): Cassava is the root of tropical plant belonging to genus manihot and family Enphorbiaceae.The sap contains hydrocyanic acid in the form of cyanogenic glycosides as linamarin and lotaustralin. Normally cyanide is detoxified in the body by conversion into thiocyanate. This step requires sulfur which is derived from sulfur containing amino acids (metionine and cystine). These aminoacids are deficient in malnourished state and thus aggravating the action of cyanides. TCP was thought to be secondary to toxic injury of these cyanides in malnourished patients. In kerala, the state with highest prevalence of TCP, geographical distributuion of TCP co-incides with areas of consumption of cassava. Infection: [7,8] Studies have shown that patients with TCP had antibodies to mumps virus, cytomegalovirus and coxsackie B virus (B1 to B6 types). This might prompt the hypothesis that viral infections might have a role in triggering initial episode of pancreatitis and act as co-factor for further later recurrent attacks. Familial and genetic factors: [9] Familial clustering of TCP among parents,children and siblings raises the possibility of genetic factors in eitiology of TCP. Mutations in genes that prevent premature activation of trypsinogen to trypsin lead to pancreatitis. The most important mutations are those involving serene protease inhibitor (SPINK 1), cationic trypsinoge gene (PRSS 1), and cystic fibrosis transmembrane conductance reulator (CFTR) gene. In recent study from India showed high association of Tropical pancreatitis with SPINK 1 N34S mutation. Page 5 of 25

Fig. 3: Aetio-Pathogenesis of Tropical Chronic Pancreatitis References: Dr.Chinmay Kulkarni Imaging: [10,11,12] Imaging and diagnosis of TCP is never made in early stages as symptoms of pain abdomen is usually attributed to non-specific causes. The imaging feature depends on the stage of the disease. In early stages the small calculi can be detected only on CT or ultrasound and can be easily missed on plain radiographs. Ultrasound is useful tool to regularly follow-up these patients and detect complications. CT is modality of choice as it allows complete visualization of gland, sensitive for detecting calcifications and identify the complications associated with TCP. Page 6 of 25

Pancreatic parenchyma: The size is inversely proportional to duration. As the disease progresses the pancreas become atropic and in advanced stage in few patients is completely replaced by adipose tissue. The important pitfall of imaging the pancreas in these patients with ultrasound at this stage is that the fat might look homogenously hyperechoic mimicking normal pancreas. However CT will solve the problem showing fat attenuation in pancreatic region. Ductal Changes: Dilatation and stenosis predominantly involve the main duct and also the branch ducts. The amount of dilatation increases as the disease progresses. Diffuse ductal dilatation is the commnest pattern, however focal dilatation involving either head, body or tail region is also observed. Pancreatic calculi: Identifying the characteristics and pattern of distribution of calculi is crucial factor in establishing the diagnosis of TCP. The main factor determining the size of calculi is the distensibility of the ducts. Usually the stones in head region are larger and denser where as size and density progressively decreases towards tail region. The shape of calculi depends on location, may be smooth elongated, rounded or staghorn like (when extending into accessory duct or duct of uncinate process). Page 7 of 25

Fig. 4: Mechanism of stone formation in Tropical Chronic Pancreatitis References: Dr.Chinmay Kulkarni Patterns of calcification in TCP: [11,12] Page 8 of 25

Fig. 5: Patterns of calcifications in Tropical Chronic pancreatitis References: Dr.Chinmay Kulkarni Numerous tiny calculi diffusely scatterd throughout the gland. Mimics alcoholic and hereditary calcific pancreatitis. Calculi in alcoholic pancreatitis are fine, speckled and have hazy margins while those in TCP are dense and discrete. Hereditary pancreatits, a rare autosomal dominant disease occurring in children. The calculi in hereditary pancreatitis are similar to alcoholic pancreatits and ductal dilatation, parenchymal atrophy is less as compare to TCP. Page 9 of 25

Fig. 6: A 14-year male patient with TCP. Axial images of Computed tomography (CT) shows uniform sized small calculi distributed throughout the pancreas [arrow]. References: Radiology, Amrita institute of medical sciences and research center., Amrita institute of medical sciences and research center. - Kochi/IN Fig. 7: Tropical Chronic Pancreatitis Vs Alcoholic Pancreatitis References: Dr.chinmay Kulkarni Page 10 of 25

Large calculi distributed predominantly in the the head region of pancreas. Fig. 8: A 25-year male patient with TCP. Axial images of Computed tomography (CT) shows artophic pancreas [C, small arrow] and large calculi in head region of pancreas [arrow]. Note absence of calculi in body and tail region. References: Radiology, Amrita institute of medical sciences and research center., Amrita institute of medical sciences and research center. - Kochi/IN Most common and characteristic pattern is diffusely scattered large calculi through head, body and tail region. Page 11 of 25

Fig. 9: A 15-year male patient with TCP. Axial images of Computed tomography (CT) shows artophic pancreas and uniform sized calculi distributed throughout the pancreas [arrow]. References: Radiology, Amrita institute of medical sciences and research center., Amrita institute of medical sciences and research center. - Kochi/IN Page 12 of 25

Fig. 10: A 20-year male patient with TCP. Axial images of Computed tomography (CT) shows artophic pancreas and uniform sized calculi distributed throughout the pancreas [arrow]. References: Radiology, Amrita institute of medical sciences and research center., Amrita institute of medical sciences and research center. - Kochi/IN Complications: Acute on chronic pancreatitis: Page 13 of 25

Fig. 11: A 30-year male patient with TCP presented with acute pain abdomen. Axial images of Computed tomography (CT) shows features of acute pancreatitis in background of TCP. References: Radiology, Amrita institute of medical sciences and research center., Amrita institute of medical sciences and research center. - Kochi/IN Pseudocyst: Page 14 of 25

Fig. 12: A 32-year male patient with TCP with recurrent episode of acute pancreatitis. MRI and MRCP images shows artophic pancreas, irregular dilated main pancreatic duct [A,C arrow] and pseudocyst in tail region [B, arrowhead]communicating with the main pancreatic duct. References: Radiology, Amrita institute of medical sciences and research center., Amrita institute of medical sciences and research center. - Kochi/IN Page 15 of 25

Fig. 13: A 35-year male patient with TCP with recurrent episode of acute pancreatitis. Axial CT images shows artophic pancreas, large calculi in dilated main pancreatic duct [A,B arrow] and pseudocyst in tail region [C, arrowhead]. References: Radiology, Amrita institute of medical sciences and research center., Amrita institute of medical sciences and research center. - Kochi/IN Vascular complications: The occurrence of vascular complications in the form of pseudoaneurysm of visceral arteries is reported to range from 1.2%-14% with greater incidence in chronic pancreatitis [7-10%] than in acute pancreatitis [1-6%]. [13,14] Page 16 of 25

Thrombosis of portal vein, superior mesenteric vessels. It is important to know this because usually vascular involvement is considered as sign of malignancy, which may not be true in all cases with TCP. Fig. 14: A 32-year male patient with TCP with haemetemesis. CT and DSA images shows calcifications in head region [A, large arrow] and pseudoaneurysm from gastroduodenal artery [A,B arrow]. Isolation of pseudoaneurysm achieved by coil embolization [coil trapping technique.[c,arrow] References: Radiology, Amrita institute of medical sciences and research center., Amrita institute of medical sciences and research center. - Kochi/IN Inflammatory mass: Focal inflammatory process may mimic carcinoma and it is a diagnostic challenge to differentiate two. Both pseudomasses and carcinomas histologically consist of abundant fibrosis and show hypoenhancement in contrast CT or MRI images. Secondary signs which can point towards malignancy are metastases (Liver, Lymphnodes), abrupt cutoff of CBD, vascular invasion. Page 17 of 25

Fig. 15: A 40-year male patient with TCP with recurrent episode of acute pancreatitis. CT images shows, irregular dilated main pancreatic duct [A, arrow] and calcifications in head region [C,arrow]. A hypodense mass seen in head region [A, B arrow] causing smooth narrowing of distal CBD [E, large arrow].eus guided biopsy from head mass taken and histopathology report was nonmalignant inflammatory mass. References: Radiology, Amrita institute of medical sciences and research center., Amrita institute of medical sciences and research center. - Kochi/IN Page 18 of 25

Fig. 16: A 40-year male patient with TCP with obstructive jaundice. pancreatitis. Initial CT images shows features of TCP with pancreatic head mass causing distal CBD obstruction and mild IHBRD. Follow-up CT after 2 years shows stable head mass wtih smooth narrowing of distal CBD and stable IHBRD. EUS guided biopsy from head mass taken and histopathology report was non-malignant inflammatory mass. References: Radiology, Amrita institute of medical sciences and research center., Amrita institute of medical sciences and research center. - Kochi/IN Malignant mass: 7-10% of patients with TCP develop pancreatic carcinoma. Malignancy complicating TCP occurs at much younger age and is more fatal as compared to de novo malignancy of pancreas. TCP has a hundread fold increased risk of developing pancreatic cancer than controls [15] Page 19 of 25

Fig. 17: A 42-year male patient with TCP. CT images shows hypodense mass in pancreatic head region with encasement and narrowing of hepatic artery [B,D]. Biopsy report was adenocarcinoma. References: Radiology, Amrita institute of medical sciences and research center., Amrita institute of medical sciences and research center. - Kochi/IN Page 20 of 25

Fig. 18: A 45-year male patient with TCP. CT images shows a hypodense mass in pancreatic body region with encasement and narrowing of celiac artery [C,arrow], SMA [F,arrow] and occlusion of main portal vein [E,arrow]. Biopsy report was adenocarcinoma. References: Radiology, Amrita institute of medical sciences and research center., Amrita institute of medical sciences and research center. - Kochi/IN [16] Changing trends in TCP: Page 21 of 25

Fig. 19: Changing trends in Tropical chronic pancreatitis References: Dr.chinmay Kulkarni Balakrishna et al have studied extensively the TCP over 30 years and have observed the changing trends in the TCP. [16] The disease now occurs in older individuals, have milder diabetes which can be controlled using oral hypoglycemic agents. Interestingly TCP has been reported in regions that fall outside the tropics and hence the term 'tropical pancreatitis' seems questionable. TCP is now a more heterogenous disease, sometimes presenting in classical form and often resembling idiopathic or alcoholic chronic pancreatitis. In a particular patient more than one etiological factor may be operating in tandem and there relative contributions determine the manifestations of TCP. Page 22 of 25

Conclusion Conclusion: Fig. 20 References: Dr.chinmay Kulkarni TCP is a unique form of chronic calcific pancreatitis which was seen exclusively in some tropical countries of the world but lately seen in nontropical countries also. The prognosis of TCP patients has improved in the last two to three decades because of the better understanding of the natural history of TCP but its aetio-pathogenesis continues to be elusive. Page 23 of 25

Imaging plays critical role in the diagnosis, detecting complications and management of TCP. Early diagnosis and newer therapeutic approaches could help to ensure better survival and prognosis of young patients with TCP. Future studies should explore the pathogenetic mechanisms that could pave the way for prevention of this condition. Personal information Dr.Chinmay Bhimaji Kulkarni Amrita Institute of Medical Sciences Kochi Kerala India E-mail- drchinmaykulkarni@gmail.com; chidoc@rediffmail.com References 1. Zuidema PJ. Cirrhosis and disseminated calcification of the pancreas in patients with malnutrition. Trop Geogr Med 1959; 11:70-4. 2. GeeVarghese PJ, Pillai VK, Joseph MP, Pitchumoni CS. The diagnosis of pancreatogenous diabetes mellitus. J Assoc Physicians India 1962; 10:173-78. 3. Balakrishnan V, Sauniere JF, Hariharan M, et al. Diet, pancreatic function and chronic pancreatitis in south India and France. Pancreas 1988;3:30-5. 4.Geevarghese PJ. Chronic Pancreatitis and Diabetes Mellitus in the Tropics. Bombay:Varghese Publishing House. 1992: 57-60. 5. Davies JNP. The essential pathology of kwashiorkor. Lancet 1948;i:317-20. 6. Mohan V, Premalatha G. Fibrocalculous pancreatic diabetes. Int J Diabetes 1995;3:71 82. Page 24 of 25

7.Shenoy KT, Shanmugam J, Balakrishnan V. Viral and Mycoplasma pneumoniae antibodies in chronic pancreatitis of tropics. Indian J Med Res 1986;84:22-6. 8. Shanmugam J, Balakrishnan V, George M, Shenoy KT. Study of coxsackie B viral infections in chronic pancreatitis patients from Kerala. J Postgrad Med 1997;33:29-31. 9.Swapna Mahurkar, D Nageshwar Reddy, G Venkat Rao, Giriraj Ratan Chandak. Genetic mechanisms underlying the pathogenesis of tropical calcific pancreatitis. World J Gastroenterol 2009 January 21; 15(3): 264-269. 10. Moorthy TR, Nalini N, Narendranathan M. Ultrasound imaging in tropical pancreatitis. J Clin Ultrasound 1992;20(6):389-393. 11. Balakrishnan V, Hariharan M, Rao VRK, Anand BS. Endoscopic pancreatography in chronic pancreatitis of the tropics. Digestion 1985;32:129-31. 12. Balakrishnan V. Tropical pancreatitis - epidemiology, pathogenesis and etiology. In: Balakrishnan V, Ed. Chronic Pancreatitis in India. Indian Society of Pancreatology, Trivandrum. 1987: 79-85. 13. Flati G, Andrén-Sandberg A, La Pinta M, Porowska B, Carboni M. Potentially fatal bleeding in acute pancreatitis: pathophysiology, prevention, and treatment.pancreas. 2003;26:8-14. 14.Sharma PK, Madan K, Garg PK. Hemorrhage in acute pancreatitis: should gastrointestinal bleeding be considered an organ failure? Pancreas. 2008;36:141-5. 15. Chari ST, Mohan V, Pitchumoni CS, Viswanathan M, Madanagopalan N, Lowenfels AB. Risk of pancreatic cancer in tropical calcifying pancreatitis: an epidemiologic study. Pancreas 1994;9(1):62-66. 16. V Balakrishnan, Prem Nair, Lakshmi Radhakrishnan, V A Narayanan.Tropical pancreatitis-a distinct entity, or merely a type of chronic pancreatitis? Indian J Gastroenterol 2006;25:74-81. Page 25 of 25