2.2 Phenotypic Perspectives
2.2.1 The Past
Kini in 1938 first presented a case of chronic pancreatitis with multiple pancreatic calculi from India（Kini 1938）.Zuidema，in 1950s described young diabetic patients who were often malnourished and also showed fibrosis and calcification of the pancreas（Zuidema 1955，1959）.Later，several similar observations from Southern India，Uganda，Nigeria and other parts of Africa，Brazil，Bangladesh，Sri Lanka and Thailand were reported（Shaper 1960；Kinnear 1963；Mngola 1982；Dani et al.1986；Azad Khan et al.1991；Illangovekara 1995；Vannasaeng et al.1998）.However，the largest series of studies conducted by Geevarghese describing young patients with malnutrition，pancreatic calculi and diabetes brought attention to this peculiar condition（Geevarghese 1968）.The close association of these reports with the tropical parts of the world led to the origin of term‘Tropical Calcific/Chronic Pancreatitis（TCP）’.It was identified as a juvenile form of chronic calcific，non-alcoholic pancreatitis with distinctive features like younger age of onset，presence of large intraductal calculi，accelerated course of the disease and high susceptibility to developing diabetes.Since then several terminologies such as juvenile pancreatitis，chronic calcific pancreatitis，fibrocalculous pancreatitis，tropical pancreatitis etc.，have been in use.In the simplest words，tropical pancreatitis was described by Geevarghese as a disease with“Pain in childhood，diabetes in puberty and death at the prime of life”（Geevarghese 1968）.
During 1970s，TCP patients particularly from Southern India were often malnourished children，adolescents or occasionally，young adults with a cyanotic hue of the lips，bilaterally enlarged parotid glands，a pot belly and sometimes pedal edema（Balakrishnan 1987；Balakrishnan et al.n.d.）.These features formed a‘classic picture’of diagnosing TCP.In the absence of sophisticated diagnostic methodologies，it was possible for gastroenterologists to make‘spot diagnosis’while walking around the hospital wards based on these striking features（Balakrishnan et al.n.d.）.They were such glaringly obvious that this clinical phenotype with plain abdomen X-ray showing pancreatic intraductal calculi would clinch the diagnosis.Notably，unlike alcoholic calcific/chronic pancreatitis（ACP）cases of the West，these patients did not have any history of alcohol abuse or smoking.Later imaging studies using endoscopic retrograde cholangiopancreatography（ERCP）and ultrasonography showed clear-cut distinction between TCP and ACP（Balakrishnan et al.1985）.Formation of large，discrete，intraductal dense calculi were observed in TCP whereas ACP had small speckled parenchymal calculi with irregular，indefinite margins.The extent of ductal dilation，pancreatic calculi，and pancreatic atrophy were also more in TCP compared with other forms of chronic pancreatitis（Moorthy et al.1992）.Moreover，majority of the patients invariably developed diabetes which was later termed as Fibrocalculous Pancreatic Diabetes（FCPD）（Mohan et al.1998）.The histopathology and immunochemistry of the pancreas in these subjects showed atrophy of the exocrine pancreatic tissue and reduced number of islets（Govindarajan et al.2001）.Collectively，insulin positivity in islets was reduced that directly correlated with serum C-peptide levels and inversely with the duration of diabetes（Yajnik et al.1990）.The series of patients reported by Geevarghese were indeed cases of FCPD（Geevarghese 1968）.
In brief，the following features distinguished TCP from other forms of chronic pancreatitis:（a）early age of onset；（b）malnourished patients；（c）presence in tropics；（d）non-alcoholism；（e）chronic abdominal pain；（f）manifestation of main pancreatic duct with ductal dilatation；（g）large pancreatic calculi primarily in the head region；（h）insulin-dependent but ketosis resistant diabetes；（i）absence of family history of pancreatitis；（j）no other discernible cause of CP.
2.2.2 The Present(https://www.daowen.com)
The‘classical picture’of TCP has undergone a significant change over the years.Compared with the patients of 1980s，the age of onset and presentation is almost a decade older now，but it is significantly earlier than ACP（Balakrishnan et al.2006，2008；Bhasin et al.2009；Rajesh et al.2014a）.Additionally，there is heterogeneity in macroscopic features observed in the pancreas of these patients.Reports from Southern India observe calcification in 90% of patients（Balakrishnan et al.n.d.；Rajesh et al.2014a）whereas those form Northern India suggest it to range from 40 to 80%（Bhasin et al.2009；Bhatia n.d.；Midha et al.2010）.Development of calculi（60-70%），dilated pancreatic duct（55-65%），and atrophy of the gland（30-40%）have been observed as the major imaging modalities（Balakrishnan et al.2008）.The proportion of FCPD cases has also reduced substantially from 1.6%of all diabetic patients during the early 1990s to 0.2%during the period 2006-2010，whereas the prevalence of diabetes secondary to ACP has remained unchanged（Papita et al.2012）.Moreover，during the above periods of study，while FCPD patients have shown a trend of delay in the age at diagnosis，diabetes secondary to ACP now develops at an earlier age（Papita et al.2012）.
Recent reports have put forward the following diagnostic measures to define TCP:age at onset below 30 years，a body mass index（BMI）lower than 18.5 kg/m2，absence of any other causes of pancreatitis，and presence of diabetes（Balakrishnan et al.2008；Midha et al.2010）.Only 4-6%of patients fulfill the above criteria and can be classified as having TCP（Balakrishnan et al.2008；Midha et al.2010）.These reports have thus questioned the existence of TCP and emphasize on using the term idiopathic chronic pancreatitis（ICP）instead.However，several of these points have been debated（Paliwal et al.2011）.To begin with，using BMI as a diagnostic measure for classification of CP is questionable because a BMI＜18.5 kg/m2 indicates underweight status and not malnourishment.Moreover，prospective case-control studies to evaluate cause and effect relation of malnutrition with CP/TCP report that only 15-20%of cases are underweight/malnourished prior to the onset of the disease and majority of patients lost weight afterwards（Midha et al.2008；Sathiaraj et al.2010）.A study where Bonnet monkeys were fed with protein-poor carbohydrate-rich diet reported occurrence of ductal changes，with mucoid metaplasia and parenchymal atrophy（Sandhyamani et al.1999）.Further，the animals predominantly developed inflammatory and vascular changes in the pancreas and showed cardiac changes；pancreatic lesions were similar to those typically seen in FCPD.Nevertheless，pancreatic calculi were not seen.Putting all these together it is more likely that malnutrition is an aftereffect and not a cause.It is speculated that with the growing economy，there has been improvement in the nutritional status that is reflected in the phenotype，i.e.normal BMI and late presentation（Balakrishnan 2011）.
Over time，several other factors including cassava/cyanogens toxicity，oxidative stress and trace element deficiency have been proposed to be involved in the etiopathogenesis of TCP.Cassava（tapioca，Manihot esculenta）consumption is quite common in some parts of world including Kerala in Southern India，from where a large number of TCP cases have been reported.It has long been considered as one of the major causal factors for TCP.In theory，excessive consumption of cassava could cause TCP because cassava is 87.5%carbohydrate with negligible protein，vitamin or mineral content.It contains toxic harmful metabolites such as cyanogenic glycosides，detoxification of which requires sulphur containing amino acids methionine and cysteine amino acid reserve（Rosling 1987）.Later，hypothesis of cassava as the sole causal factor for TCP was rejected because，（1）all who consumed cassava did not develop TCP（Girish et al.2011 a），（2）TCP was also observed in places where cassava was not consumed（Balakrishnan et al.2008；Garg and Tandon 2004）；and，（3）rat model studies did not observe diabetes or pancreatitis on long-term cassava consumption（Mathangi et al.2000）.Though，now the community has rejected the causal role of cassava but the involvement of environmental toxins in disease pathophysiology cannot be denied as they could be playing a cofactor role rather than being involved in direct causation.
Micronutrient deficiencies are common in CP and might be participating in the pathogenesis via oxidative stress.An early study from Southern India（Braganza et al.1993）has shown that culinary practices that reduce the biological availability of ascorbic acid and beta-carotene may expose the pancreas to oxidative stress and thereby to the changes leading to development of TCP at an early age.Increased oxidative detoxification has been linked with chronic pancreatitis.This study also implicated the role of xenobiotic stress in the etiopathogenesis of TCP.Further studies from Southern India also report increased lipid peroxidation and reduced antioxidant status both in TCP and ACP（Girish et al.201 lb，2012）.This is an extension to the previous observation that wherein zinc deficiency was proposed to play a significant role in CP（Girish et al.2009）.Folate deficiency has also been reported in CP including TCP（Rajesh et al.2010）.
Studies have categorized ICP into early-onset（≤30 years）and late-onset（＞30 years）and there are reservations over the idea of considering those belonging to early-onset category to be similar to TCP（Bhasin et al.2009；Rajesh et al.2014a）.There are opinions that change in phenotype of TCP is due to modifications in diet and lifestyle that have occurred over a couple of decades（Balakrishnan 2011）.It is further argued that，“to deny retrospectively that there was no entity of TCP is historically incorrect”（Balakrishnan 2011）.Recent reports also suggest an increased tendency of alcohol consumption and smoking even in cases of TCP（Balakrishnan et al.2006；Rajesh et al.2014a）.Consequentially，TCP is now displaying phenotypic similarity to ICP and is also being edged out by ACP.Indeed，studies from Southern India（Balakrishnan et al.n.d.；Rajesh et al.2014b）report a sharp increase in proportion of ACP cases from a lowly 3%during the 1980s to approximately 33%over the last decade，whereas those from Northern India observe a parallel existence of ACP or slight predominance of TCP/ICP（Bhasin et al.2009；Midha et al.2010）.