3 Diabetes secondary to tropical calcific pancreatitis

3 Diabetes secondary to tropical calcific pancreatitis C . S . YAJNIK

Diabetes secondary to calcific pancreatitis was reported in the tropics in the early twentieth century but assumed importance after its description by Zuidema (1959). Geevarghese (1968) highlighted its significant contribution to diabetes in the young from South India and succinctly described its natural history: 'abdominal pain in childhood, diabetes in youth and death at the prime of life'. Different aspects of 'tropical calcific pancreatitis' (TCP) have been extensively discussed in many of the classic reviews (Geevarghese, 1968, 1986; Viswanathan, 1980; Narendranathan, 1981; Pitchumoni, 1984; AbuBakare et al, 1986; Balakrishnan, 1987; Assan et al, 1988; Mohan V e t al, 1988c; Mohan and Alberti, 1990; Yajnik, 1990, 1992). Recent revival of interest in this condition can be ascribed to the report of a W H O Study Group (1985) who named diabetes secondary to TCP 'fibrocalculous pancreatic diabetes (FCPD)' and classified it as one of the two subgroups of the so-called malnutrition-related diabetes mellitus (MRDM), the other group being protein-deficient-pancreatic diabetes (PDPD or PDDM). The W H O study group also felt that it was justifiable to include M R D M as a major clinical subclass of diabetes 'in recognition of its clinical distinctiveness and severity, and its high prevalence in some tropical countries'. This has stimulated research and raised new controversies. The first international meeting on M R D M was held in London under the auspices of the W H O and the Wellcome Trust. The proceedings of this meeting are in press and contain a wealth of information. I have devoted this review mostly to the relatively 'new' aspects of TCP which are likely to occupy the thoughts of workers in this field for some time. DEFINITION AND THE SPECTRUM OF TCP

Until recently there were no uniform diagnostic criteria for TCP; nor have there been any studies of its prevalence in the community. The W H O terminology of FCPD is now used by most but a potential confusion is its classification as a subgroup of MRDM, implying that malnutrition is aetiologically and diagnostically important. As we will see later, the role of malnutrition in the aetiology of TCP is still not fully clear. Some patients Bailli~re's Clinical Endocrinology and Metabolism-777 Vol. 6, No. 4, October 1992 Copyright © 1992, by Bailli~re Tindall ISBN 0-7020-1621-7 All rights of reproduction in any form reserved

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Table 1. Diagnostic criteria for fibro-calculouspancreatic diabetes (FCPD) (Mohan et al, 1988b, 1988c). 1. Occurrence in a 'tropical' country. 2. Diabetes by WHO (1985) criteria. 3. Evidenceof chronic pancreatitis: pancreatic calculi on X-ray or at least three of the following: (a) abnormalpancreatic morphologyby sonography, CT-scan or ERCP; (b) chronicabdominal pain since childhood; (c) steatorrhoea; (d) abnormalpancreatic function test. 4. Absenceof other causes of chronic pancreatitis, i.e. alcoholism, hepatobiliary disease or primary hyperparathyroidism, etc. Features like clinicalmalnutrition, youngage at onset and absenceof ketosis are usefuladjuncts but not diagnosticallyessential. with TCP/FCPD do not show any evidence of malnutrition, and rarely FCPD may be associated with obesity (Mohan V et al, 1990a). We now know that the hallmark of this condition is a chronic calcific pancreatitis which occurs at a relatively young age where alcohol is not an aetiological factor. Mohan reviewed the literature and proposed a set of diagnostic criteria for FCPD which are the most comprehensive to date (Table 1). It should be noted that young age and low BMI ('malnutrition') are of relatively 'minor' significance and not 'absolute' criteria as many previous workers suggested them to be (Ahuja, 1985) and as the W H O classification of FCPD under M R D M assumes. To date there is no specific marker for TCP except pancreatic calculi, although we know that 'non-calcific' cases occur. In the absence of such a criterion, diagnosis remains geographic, partly historic, and 'exclusive'. Clinicians in rural areas have to depend principally on clinical-historical criteria and at the most could have an X-ray of the abdomen. Sonography and pancreatic enzyme measurements (the more sensitive indices) are not available in the remote areas where the disease could be more prevalent. No reliable data on the prevalence of this condition are therefore available. Most of the data are from referral clinics and perhaps biased in favour of more advanced cases. In the South Indian state of Kerala where the largest number of cases have been described so far, hospital statistics suggests that TCP/FCPD is on the decline (Geevarghese, 1986). However in the neighbouring state of Tamil Nadu, Mohan has collected the largest 'active' series of TCP/FCPD patients. A high index of suspicion is important because the classic clinical manifestations of malnutrition are seen infrequently. The true diagnosis is perhaps missed in many patients. A study of pancreatic enzyme concentrations in diabetic patients attending a hospital clinic suggested that exocrine pancreatic involvement is much more common in a tropical country than clinically apparent (Yajnik et al, 1990b), The classic description of patients with large pancreatic calculi may represent only an extreme end of the spectrum ('end stage' pancreatitis) (Yajnik, 1990). One point of interest is the relationship between 'tropical' calcific pancreatitis and non-alcoholic pancreatitis seen in the Western countries. Diabetes in the latter is not called 'FCPD' and is classified as 'secondary

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diabetes'. Both Braganza (1993) and Pitchumoni et al (1993) have proposed unifying hypotheses for the pathogenesis of chronic pancreatitis in these two different situations. Similarly, the relationship of TCP to PDPD (if any) is not known. AETIOLOGY AND PATHOGENESIS We know very little about the aetiology of TCP. There are many hypotheses and many likely candidates. Probably the aetiology is multifactorial. Geographical distribution (by definition) in the tropical belt, mostly in the developing countries, suggests a significant role for environmental factor(s). Two prime suspects are 'malnutrition' and cyanogenic alkaloids (cassava or other food items). Childhood infections, diarrhoeas and attendant changes in pancreatic secretion have also been suggested as significant factors. Recently, 'oxidant stress' damage has been proposed as an important mechanism in pancreatic damage. It is not agreed whether diabetes in TCP is secondary to pancreatitis or a disease entity in its own right. It is well known, however, that pancreatitis precedes diabetes by many years. Recent reports suggest that [~-cell reserve in TCP parallels the exocrine pancreatic reserve, implying that hyperglycaemia is 'secondary' to exocrine pancreatic damage. It could also suggest independent damage to both pancreatic components by a common (or related) aetiological agent(s). Additional susceptibility factors could operate in the evolution of hyperglycaemia. Another vexing problem is the possible role of ductal stones in the pathogenesis of TCP. Many authorities ascribe a primary aetiological role to calculous obstruction in the pathogenesis of 'pancreatitis'. However, a non-calculous 'variety' certainly exists and as a rule calculi seem to develop after 'pancreatitis' is well established. Whether stones contribute to further pancreatic damage by ductal obstruction, or are an inconsequential epiphenomenon is not known. Malnutrition

Severe malnutrition at presentation in many of these patients suggested to many workers a causative role for nutritional deficiencies (Zuidema, 1959; Shaper, 1964; Ahuja, 1985). Pros and cons of a nutritional aetiology for TCP/FCPD have been extensively discussed (Pitchumoni, 1984; Balakrishnan, 1987; Balakrishnan et al, 1993; Bajaj and Subba Rao, 1988; Mohan Vet al, 1988c, 1988d; Yajnik, 1990). Clinical histories in these patients rarely show any evidence of kwashiorkor in childhood or unusually low intake of protein. Malnutrition at presentation could be secondary to severe exocrine and endocrine pancreatic deficiency; a case for pancreatitis-related and diabetes-related malnutrition rather than malnutrition-related diabetes. On the other hand, protein malnutrition has long been known to affect pancreatic function and cause pancreatic fibrosis (Pitchumoni, 1973; Durie et al, 1989). Children with kwashiorkor and adults from famine areas show pancreatic acinar atrophy, reduced enzyme output, and fibrosis of the gland.

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Endocrine pancreatic function (insulin secretion) is also known to be diminished in malnutrition (Baig and Edozien, 1965; Becket et al, 1971; Smith et al, 1975). There is usually a complete recovery of these functions after refeeding, though some studies have shown a long-term defect (Cook, 1967; James and Coore, 1970). Recent animal work has suggested that even mild to moderate protein malnutrition in utero (Snoeck et al, 1990), or in early childhood (Swenne et al, 1987, 1988; Crace et al, 1989) or even later (Khardori et al, 1980) can lead to [3-cell dysfunction and hyperglycaemia in later life. Similar long-term studies are not available in humans. It is possible that a pancreas 'weakened' by 'early life' malnutrition could be more susceptible to many 'toxic' influences to which it might be exposed in later life. Interesting reports from the UK have shown an association of low birth weight (an indicator of intrauterine growth retardation) with 'Type 2' diabetes, hypertension and coronary heart disease in adult life (Barker, 1990); no information is yet available on exocrine pancreatic function. Prospective studies of malnourished children in the developing countries are urgently needed. Our classical thinking on 'malnutrition' is usually restricted to deficiency of calories and proteins. However, micronutrient deficiencies (selenium, vitamins, etc.) could set in motion a series of pathological processes in the pancreas which could culminate in the final picture of TCP. Relative deficiency of certain elements or excess of others might produce deleterious effects. These avenues have not been explored in relation to TCP. An international comparative study of dietary factors suggested that high protein intake was associated with alcoholic pancreatitis and low fat intake with tropical pancreatitis (Durbec and Sarles, 1978). This observation was confirmed recently in Kerala (South India) and Marseille (France) (Balakrishnan et al, 1988b). The biochemical significance of this observation is not clear. Nwokolo and Oli suggested that recurrent infections and a highcarbohydrate, low-protein diet (mostly from cassava) in children in the tropics lead to pancreatic stasis, lamination of secretions and inspissation of mucus, ultimately leading to calcification in the pancreatic duct and chronic pancreatitis (Nwokolo and Oli, 1980). In summary, nutritional factors are probably important in the aetiotogy of this condition but the actual food components and mechanisms of damage are not clear. We also need to know more about the interactions of nutritional factors with other possible aetiological agents (Rao, 1988).

Cyanogenic alkaloids The geographical distribution of TCP in areas where cassava is grown and consumed as a staple food suggest a causative role for cassava in the aetiology of this condition (McMillan and Geevarghese, 1979; McMillan, 1993). A further observation that cassava causes goitres in iodine-deficient areas (elevated concentrations of thiocyanate from cassava in blood inhibit iodine uptake by the thyroid gland) but that goitre and FCPD almost never co-exist suggested to McMillan that a failure of detoxification of cyanide could be responsible. Deficiency of dietary sulfur amino acids (methionine,

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cystine) could hamper detoxification of cyanide to thiocyanate and lead to high levels of 'free cyanide' which might be toxic to [3-cells. Acute cyanide poisoning is known to be associated with hyperglycaemia and McMillan produced hyperglycaemia in rats by feeding cyanide (McMillan and Geevarghese, 1979). The relevance of these animal experiments to the clinical situation is still unclear, especially the role of cyanide in causing exocrine pancreatic damage. Recently Pitchumoni (1988) has suggested a universal role for 'cyanide toxicity' in the pathogenesis of pancreatitis; he proposes that 'alcoholic' pancreatitis in Western countries results from concomitant exposure to cyanide in cigarette smoke while tropical pancreatitis results from cyanogenic alkaloids in the diet, especially from cassava. Braganza (1993) has proposed that the toxicity of cyanogenic alkaloids might operate through increased oxidant stress. However, recent studies in Africa failed to find TCP or FCPD in areas where cassava is eaten as a staple food (Teuscher et al, 1987). These reports cast doubt over the aetiological role of cassava in TCP, but the absence of a 'susceptibility factor' in these populations could also explain the results. Occurrence of TCP in areas where cassava is not eaten is also cited as evidence against an aetiological role for cyanide. However, other cyanidecontaining foodstuffs (ragi, sorghum etc.) could be responsible (McMillan and Geevarghese, 1979; Nagalotimath, 1980; Kakrani et al, 1985; Patole et al, 1988). If cyanogenic alkaloids are indeed responsible, processing of foods to reduce cyanide content or development of low-cyanide varieties will be a simple preventive measure for this condition. The verdict on the role of cassava or other cyanogenic foodstuffs in the aetiology of TCP and FCPD must remain 'open'. Genetic, familial and immunological factors Although the geographical distribution of TCP is highly suggestive of an environmental aetiology, familial clustering has also been reported from South India. Families with more than one TCP patient, sometimes in successive generations, have been described (Pitchumoni, 1970; Geevarghese, 1986; Balakrishnan, 1987). A systematic study from South India looked at oral glucose tolerance, abdominal X-ray, ultrasound of the pancreas, and stool chymotrypsin concentrations in families of 38 FCPD patients (Mohan V et al, 1989a). Twelve percent of parents and 21% of siblings showed some evidence of exocrine pancreatic involvement, and 21% of parents and 11% of siblings revealed previously undiagnosed 'Type 2' diabetes. Unless a specific marker is available it is difficult to decide whether these results reflect genetic transmission or a strong environmental influence. However, consanguinity was common in families with TCP in successive generations, and this might indicate a genetic connection. Genetic markers for Type 1 and Type 2 diabetes (HLA-DQ gene and the 'insulin gene' polymorphism respectively) have been studied in the same population (Kambo et al, 1989). Approximately 40% of FCPD patients showed presence of an HLA-DQ-B marker (p <0.05 compared to controls), 40%

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showed class 3 insulin gene marker (p <0.001 compared to controls); 20% of FCPD patients but only 1% of controls showed both markers (p <0.001). The relevance of these markers in the pathogenesis of FCPD is debatable, especially if diabetes is 'secondary' to pancreatitis. On the other hand, a genetic 'diabetic predisposition' in subjects with chronic pancreatitis might cause a more severe diabetes or bring it on at an earlier age. Markers of autoimmune islet damage (pancreatic islet cell antibodies) are, however, absent in TCP/FCPD and histology does not show 'insulitis'. It will be interesting to look at phenotypic, metabolic and endocrine differences between FCPD patients with H L A and insulin gene associations. Familial clustering of TCP and FCPD appears uncommon outside South India. In our North Indian Aryan population we have not yet seen families with more than one TCP patient. On systematic screening, we discovered 'Type 2' diabetes in - 2 5 % of the parents of FCPD patients. However, serum immunoreactive trypsin concentrations and sonography of pancreas did not reveal significant abnormalities in family members of TCP probands (Yajnik et al, unpublished). We noticed adult polycystic kidney disease in two families of our FCPD patients. Similar association has been reported from South India. The significance of this finding is not known. Looking for islet cell antibodies we were surprised by the frequent occurrence of antibodies to exocrine pancreatic acini in our population (Yajnik and Chapel, unpublished). These were seen not only in FCPD but also in 'primary' varieties of diabetes and even in non-diabetic controls. It implies that pancreatic damage (? environmental) may be common in tropical countries.

Oxidant stress and anti-oxidant deficiency Braganza suggested that non-alcoholic pancreatitis in the UK is a result of (i) heightened but unmitigated oxidative detoxification reactions in pancreas and liver, coupled with (ii) exposure to xenobiotics biotransformed by cytochrome P-450 and (iii) a relative deficiency of antioxidants (Braganza, 1986). She has now extended the hypothesis to include TCP (Braganza, 1993). In preliminary studies she found evidence of increased exposure to xenobiotics, especially polycyclic aromatic hydrocarbons (cigarette and firewood smoke and vehicular fumes) in patients of FCPD compared to controls (Chaloner et al, 1990). This was associated with elevated theophylline clearance (a marker for heightened cytochrome P-450 activity), but the detoxifying mechanisms (measured as urinary D-glucaric acid) were not activated. These interesting observations need to be substantiated and extended before we attribute an aetiological role to these factors. PATHOLOGY

Histopathology The pathology of TCP has been reported from surgical observations, biopsies obtained at surgery and autopsies. Little information is available in

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the early stages. Detailed reviews of pathology are available (Nagalotimath, 1980; Pitchumoni, 1993). Ultrasonography, CT scan and ERCP have now allowed visualization of pancreatic morphology during life. Initial studies on patients with very advanced disease stressed the 'absence' of inflammatory changes in the pancreas (Nagalotimath et al, 1979), and some suggested that the term 'pancreatitis' was a misnomer (Nair and Latha, 1986; Nair, pers. comm.). Subsequent studies in 'early' stages, however, have described inflammatory changes in the exocrine pancreas (Nagalotimath, 1980, 1987). These consist of infiltration by lymphocytes, plasma cells and eosinophilic cells. Nagalotimath described lymphocytic aggregations with germinal centres and compared the condition to woody thyroiditis (Nagalotimath, 1980, 1987). As the disease progresses, widespread destruction and acinar loss are seen. Nair insists that TCP is a non-inflammatory, degenerative condition and that inflammation might be observed only in advanced cases in the periductal areas, in relation to the stones. Fibrosis starts early and classically leads to 'cirrhosis of the pancreas'. In some cases, extensive fat infiltration without much fibrosis is seen (Joshi, 1982; Nair and Latha, 1987). Ducts and ductules show degenerative changes, and the lining epithelium may show goblet or squamous cell metaplasia. Ductules crowd together due to loss of intervening acinar tissue and also show true proliferation. Nesidioblastosis has been described. Nagalotimath (1987) described two autopsies with pathological changes restricted to the tail of the pancreas. He called them 'localized and arrested'. The head and the body of the pancreas were reportedly normal. The visible islets of Langerhans appear intact and 'untouched'. There is no 'insulitis'. Hypertrophy as well as atrophy are seen. Nesidioblastosis is a well described feature (Nair and Latha, 1987). Immunoperoxidase staining has shown normal insulin and glucagon content in the cells (Nair and Latha, 1987; Clark and Yajnik, unpublished). The islets are probably destroyed due to surrounding fibrosis ('strangulation'), and possibly also by disruption of vasculature. The latter could affect transport of hormones into the circulation, and also derange fuel-mediated modulation of islet function. There are no studies of islet number in TCP but extensive loss of pancreatic mass suggests that the total number must be severely diminished with progression of the disease. One of the diagnostic features of TCP (by definition) is ductal calculi. Their characteristics have been described in detail (Geevarghese, 1986) including scanning electron microscope appearance and X-ray diffraction patterns (Schultz et al, 1983; Shenoy et al, 1985). The ultrastructure of stones in TCP is no different from that observed in alcoholic pancreatitis, suggesting there is nothing peculiar about stone formation in TCP. It is usually stressed that the intraductal calcification in TCP is characteristically different from 'parenchymal' calcification in alcoholic pancreatitis. The myth of 'parenchymal' calcification was destroyed by Sarles and other workers who demonstrated that the apparently diffuse parenchymal calcification in fact represents amorphous calculi in smaller radicles of the pancreatic ducts and that the lining epithelium of these ducts had perished

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(a)

(b)

(c) Figure 1. (a) and (b) CT scans of a non-diabetic TCP patient showing a solitary calculus in the head region (a) and a relatively normal looking pancreas except for mildly dilated duct (b); (c) CT scan from another non-diabetic TCP patient showing multiple calculi in the head of pancreas and swollen parenchyma; (d) CT scan of a diabetic TCP (FCPD) patient showing multiple calculi and heterogeneous, oedematous pancreas; (e) CT scan of a diabetic TCP patient with atrophic ('fibrotic') pancreas, stones were seen in other sections; (f) CT scan of a severely malnourished FCPD patient showing severe atrophy of the pancreas with fat infiltration and 'bag of stones' appearance.

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due to degenerative changes (Wellmann and Volk, 1977). Some of the elaborate hypotheses of the pathogenesis of TCP and the assumption that TCP is pathologically unique (Bajaj, 1993) must, therefore be viewed in this perspective. 'TCP without calculi' (non-calcific TCP) has been described. Balakrishnan compared characteristics of patients with and without calculi (B alakrishnan et al, 1985; Balakrishnan, 1987; Punnose et al, 1987). In general, patients without calculi have a less severe exocrine problem. It is possible that the rates of calcification are different in different patients. Some might never calcify because the physico-chemical requirements for calcification are not fulfilled; whether these aetiologically and pathogenetically form a distinct entity is not known. The role of pancreatic stone protein (PSP) is yet to be investigated in TCP. Ultrasonography and CT scan

Mohan and his colleagues reported the findings on sonography of the pancreas in FCPD (Mohan V e t al, 1985a; Suresh et al, 1989). The pancreas appears hyperechoic with irregular margins, and the duct is irregularly dilated and shows stones in the lumen. Sonography is perhaps more sensitive in detecting calcification than X-ray but is observer-dependent. It also has the advantage of being 'non-invasive' and could diagnose 'non-calcific' TCP; as such sonography would be the ideal method for community studies. It also allows simultaneous visualization of the hepatobiliary system which is helpful in planning surgical treatment. CT scanning has allowed a closer look at pancreatic morphology during life. We have studied CT scan appearances in TCP patients with different degrees of exocrine-endocrine dysfunction (unpublished). Pancreatic mass is preserved in the 'early' stages (serum immunoreactive trypsin normal or elevated, glucose tolerance normal) and swelling of parenchyma is evident (Figure la-d). In more advanced disease (serum immunoreactive trypsin diminished and progressive glucose intolerance) the pancreas shows varying degrees of atrophy; in extreme cases little pancreatic parenchyma is visible, its place being taken by a 'bag of stones' (Figure le,f). In some cases, fat infiltration is prominent, which can be easily demonstrated by CT scan because of the characteristic density. Duct appears irregularly dilated with stones in the lumen. Balakrishnan reported ERCP findings in TCP which reflect the ductal pathology described above (Balakrishnan et al, 1985). EXOCRINE PANCREATIC FUNCTION The paucity of data on exocrine pancreatic function in TCP is mainly due to the unpleasantness and inconvenience of the 'older' pancreatic function tests (stool fat and tube tests). Recently, measurements of specific pancreatic enzymes (serum immunoreactive trypsin, pancreatic isoamylase, lipase and stool chymotrypsin) have led to a better understanding of exocrine pancreatic damage in TCP. Serum immunoreactive trypsin measurements showed a

787

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Figure 2. (a) Peak plasma C-peptide concentrations during oral glucose tolerance tests in different groups of TCP patients. (b) Serum immunoreactive trypsin in non-diabetic, impairedglucose-tolerant (IGT) and diabetic (FCPD) TCP patients. Median (5th-95th centile) values are shown, a and b indicating significant (p<0.05) differences from non-diabetic and IGT groups, respectively.

spectrum of exocrine pancreatic involvement (Yajnik et al, 1989, 1990b, 1990c). In early cases (normal glucose tolerance and IGT) serum immunoreactive trypsin was subnormal in only a few subjects, while in some it was markedly elevated suggesting active pancreatitis; the exocrine reserve appeared relatively well preserved (Figure 2). In advanced cases (FCPD) serum immunoreactive trypsin was subnormal in most cases and severely diminished in over two-thirds. Stool chymotrypsin measurements showed similar results (Mohan V et al, 1989c; Yajnik et al, 1990b), as did pancreatic isoamylase (Wiyono, 1988; Yajnik et al, 1990b), Secretin-pancreozymin test on a small number of patients showed that pancreatic enzyme output was severely diminished, trypsin being more affected than amylase (Tripathy et al, 1984; Tripathy and Samal, 1987; Punnose et al, 1987). Balakrishnan made the interesting observation that even some of the control subjects from South India showed evidence of early pancreatopathy (Balakrishnan et al, 1988b). We also observed elevated serum immunoreactive trypsin concentrations in our population in the absence of clinical or radiological evidence of TCP. It appears that a 'subclinical pancreatopathy' occurs in the tropics which may have an environmental aetiology and that the full-blown picture of TCP with calculi is the extreme end of the spectrum (Yajnik, 1990, 1991; Yajnik et al, 1990b, 1990c). The implications of such a 'pancreatopathy' in relation to endocrine pancreatic function and its possible interaction with 'primary' diabetes are not known. Population studies are needed to confirm these phenomena. An NBT-PABA test might help answer these questions but the cost is a major disadvantage. PANCREATIC ENDOCRINE FUNCTION IN TCP Systematic measurements of plasma insulin, C-peptide and pancreatic glucagon in TCP have been made only during the last decade. Kannan

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measured circulating 'free' insulin concentrations in patients with FCPD and showed that fasting plasma glucose concentrations reflected 13-cellfunction (Kannan, 1981). Subsequently many workers have measured plasma Cpeptide concentrations as a measure of ~-cell function (Mohan Vet al, 1983, 1985b; Ahuja and Sharma, 1985; Vannasaeng et al, 1986; Samal et al, 1987; Otim, 1988; Wiyono, 1988~ Yajnik et al, 1990c, 1992). Mohan correlated plasma C-peptide concentrations with the clinical behaviour of these patients including response to oral hypoglycaemic agents and proneness to ketosis. Subjects with good 13-cell function responded well to oral hypoglycaemic agents, and ketosis-prone subjects showed the lowest plasma C-peptide concentrations. As a group, FCPD patients showed better f3-cell function than Type 1 diabetic patients. We measured ~3-cell function in TCP patients with different degrees of glucose tolerance (Yajnik et al, 1990c). Plasma C-peptide concentrations were normal in those with normal glucose tolerance or IGT, whereas diabetic subjects as a group showed diminished concentrations (Figure 2). In the diabetic group (FCPD) plasma C-peptide concentrations were widely scattered; in ~ 75% they were severely diminished, indistinguishable from Type 1 diabetic patients. Interestingly, none of these FCPD patients had presented with ketosis, suggesting that mechanisms in addition to ~-cell function are involved in their 'ketosis-resistance'. There was an inverse correlation between peak plasma C-peptide concentrations during the glucose tolerance test and HbA1 concentrations (Figure 3a), suggesting that f3-cell function was an important determinant of regulation of blood glucose in TCP. Even more significantly, C-peptide and serum immunoreactive trypsin concentrations were directly correlated (Figure 3b). Thus, for the first time a direct relationship between exocrine and endocrine measurements in TCP has been described. Follow-up study showed that clinical improvement after anti-diabetic treatment was associated with improved [3-cell function (Yajnik et al, 1990a). In some, insulin treatment could be lID •

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stopped ('honeymoon phase'), at least for some time. The similarity of [3-cell behaviour in FCPD with that in Type 1 and Type 2 diabetes is obvious. Factors contributing to the improved [3-cell function are not known, but reduced 'glucotoxicity' (Unger and Grundy, 1985) and improved nutrition are possible candidates. Information on a-cell function in FCPD is sparse. The nature of islet destruction (secondary to exocrine pancreatitis and therefore involving the whole islet rather than specific cells) would suggest that insulinopenia be accompanied by glucagon deficiency. Proneness of these patients to hypoglycaemia and their resistance to ketosis have both been empirically ascribed to glucagon deficiency. Mohan V et al (1990b) reported plasma glucagon concentrations in FCPD patients with substantial residual [3-cell function. In this group, fasting plasma glucagon concentration was well preserved but the expected 'paradoxical' rise after oral glucose was absent. We observed normal plasma glucagon concentrations even in those with severe insulinopenia, and the 'paradoxical' rise after oral glucose was also present (Yajnik et al, 1992). It appears that a-cells are more resistant to damage than [3-cells or are able to compensate better; alternatively the islet damage in FCPD could be more selective for [3-cells than hitherto believed. Studies with specific oL-cell stimuli (arginine, for example) and careful histological quantitation of islet cells would be of interest.

METABOLIC PECULIARITIES OF FCPD Ketosis resistance

FCPD patients (MRDM in general) show metabolic peculiarities which fall between those of Type 1 (insulin-dependent) and Type 2 (non-insulindependent) diabetic patients. Thus, hyperglycaemia may be severe but they are rarely ketotic. The majority do not become ketotic despite stopping insulin treatment for long periods even when requiring large doses for glycaemic control. Ketosis has been reported in <15% of patients in different series (Geevarghese, 1968; Mohan V et al, 1985b; Rai et al, 1988). In our experience of - 70 patients over the last 7 years we have not treated anyone for ketosis, though one girl died of 'coma' in a peripheral hospital. A number of our patients stopped insulin for months (for lack of money), became severely hyperglycaemic (plasma glucose _>40 mmol 1-1) but never ketotic, even when suffering severe systemic infections. It is possible that more severely ketotic patients from rural areas die without proper diagnosis (especially if previously undiagnosed) and would be excluded from clinicbased data. We also do not know whether 'ketosis resistance' is a phase in natural history or a pathognomonic feature of some FCPD patients. In the PDPD variety ketonuria appeared in some patients when patients' nutrition was improved (Abdulkadir et al, 1990). There are a number of hypotheses to explain this metabolic peculiarity of MRDM patients:

790 1. 2. 3. 4. 5.

c.S. YAJNIK Residual [3-cell function, adequate to prevent ketosis (Ahuja and Sharma, 1985; Mohan V e t al, 1985b, 1985c), Concomitant destruction of a-cells and thus loss of glucagon, a major ketogenic hormone (WHO, 1985), Subcutaneous fat loss and therefore, reduced supply of NEFA--the 'fuel' for ketogenesis, Resistance of subcutaneous adipose tissue lipolysis to adrenaline (Ahuja and Vishwanatham K, 1967; Hagroo et al, 1974; Krishna et al, 1984), Carnitine deficiency (Khan and Bamji, 1977) affecting transfer of NEFA across mitochondrial membrane.

In a recent study we did not find any significant difference in circulating concentrations of C-peptide, pancreatic glucagon, growth hormone and cortisol between Type 1 (ketosis-prone) diabetic and FCPD patients matched for age, BMI, triceps skinfold thickness and glycaemic status. However, FCPD patients showed significantly lower circulating concentrations of NEFA, glycerol and 3-hydroxybutyrate, suggesting that adipose tissue lipolysis in FCPD patients is more effectively suppressed than in Type 1 diabetic patients (Yajnik et al, 1992). Hepatic ketogenesis could also be less sensitive to glucagon stimulation ('glucagon resistance'). It is likely that 'ketosis resistance' in FCPD is multifactorial. Further studies are needed to understand this interesting phenomenon. Insulin resistance

'Insulin resistance' is said to be a feature of MRDM (Ahuja, 1985), though perhaps more so of PDPD. For FCPD patients most studies quote insulin doses of up to 1.5Ukg -1 day -1 for moderate glycaemic control. Recent studies have not found FCPD patients to be unusually insulin-resistant compared to other insulin-treated young diabetic patients. We recorded the insulin dosages in newly diagnosed FCPD patients admitted to the wards (Yajnik, 1993). During the first few days of treatment, when plasma glucose concentrations were very high and patients polyphagic, insulin requirements were as high as 10 U kg -1 day-i! Improvement in glycaemic control, weight gain and reduction of polyphagia were associated with reduced insulin requirements. Most of the patients were discharged on 1-2 U kg -1 day -1, the same dose as Type 1 diabetic patients are prescribed. In some there was a progressive fall in insulin requirements so that they could stop taking insulin for some time ('honeymoon phase') (Yajnik, 1993), though ultimately they needed to resume treatment. Improved [3-cell function (Yainik et al, 1990a) as well as improvement in insulin receptor function (Ramachandran et al, 1988) perhaps contribute to the fall in 'insulin resistance'. 'Insulin tolerance tests' showed that FCPD patients were no different from Type 2 diabetic patients (Mohan Vet al, 1988a). These results need to be interpreted with caution because FCPD patients were insulin-treated (with the conventional 'unpurified' variety) and therefore, presumably had high insulin antibody titres which would reduce 'free insulin' concentrations.

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I have already alluded to the indirect evidence suggesting that adipose tissue lipolysis in FCPD patients is more sensitive to suppression by insulin. Further studies using specific techniques (such as the euglycaemic clamp) are needed before we draw any conclusions about insulin sensitivity of FCPD patients. CLINICAL FEATURES AND DIABETIC COMPLICATIONS This topic has been covered extensively in many previous reviews (Geevarghese, 1968; Pitchumoni, 1984; Geevarghese, 1986; Mohan V e t al, 1988c). Suffice it to say that many of the 'classic' features of severe malnutrition described in the 1960s might not be seen today due to improved nutrition and also to earlier referral by local doctors. Older reports of FCPD also stressed early death from metabolic and infectious complications. It was felt for some time that FCPD patients were 'immune' from vascular complications. With improved patient survival both microvascular (retinopathy, nephropathy, neuropathy) and macrovascular (coronary artery disease) problems have become evident (Mohan R et al, 1985; Mohan V e t al, 1985b, 1989b, 1989c, 1989d; Geevarghese, 1986; Ramachandran et al, 1986, 1987). MANAGEMENT

Management of many FCPD patients is influenced by their poor socioeconomic status and lack of education. Social beliefs often contradict medical principles and interfere with the treatment. This topic has been reviewed (Geevarghese, 1968, Balakrishnan, 1986; Yajnik, 1993). Treatment of diabetes mellitus

In TCP patients, diabetes commonly develops in the second or third decade of life, though our youngest diabetic patient was 9 years old when diagnosed. Hyperglycaemia is often moderate to severe and weight loss is a striking feature in many. Mean body weight in our first 30 patients was 36 kg (range 18--64 kg). General principles of dietary management are the same as for other types of diabetes except for some additional considerations. Extra caloric and protein intake are necessary for tissue building, and fats are restricted even more due to the exocrine pancreatic deficiency. Intake of food at regular intervals is stressed to avoid hypoglycaemia. Requirement and choice of anti-diabetic drugs are determined by residual [3-cell function. More than 80% require insulin for satisfactory control of hyperglycaemia and to ensure weight gain. Up to 20% of patients may respond to oral hypoglycaemic agents (usually sulfonylureas), sometimes for many years after diagnosis. Higher doses of insulin initially required in the more severely hyperglycaemic, usually settle down to --
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syringes without sterilization and insistence on self-injection have improved the compliance with insulin treatment in our patients, but many stop insulin injections because of poverty or the lure of a quick 'cure' by alternative medicine. The important role of a health educator cannot be overemphasized. Hypoglycaemia is not usually a frequent problem during the initial years of treatment, but can cause considerable morbidity due to delayed and inadequate treatment in remote places.

Treatment of the exocrine problem

In FCPD, pancreatitis precedes diabetes by many years (Geevarghese, 1968). Chronic abdominal pain is the hallmark of TCP. Its severity is usually diminished by the time diabetes is diagnosed because exocrine pancreatic damage is fairly advanced. Frank steatorrhoea is rarely reported, possibly due to low dietary fat intake. Oral pancreatic enzymes are useful in the treatment of steatorrhoea and also in those who fail to gain weight despite good control of blood glucose concentration and adequate dietary intake. The cost is the major restraint on their use. Surgery is performed for severe and 'intractable' pain. The Puestow procedure (Puestow and Gillesby, 1956) is the most popular but pancreatectomy may be needed (Joshi, 1982). Benefits of surgery include relief of pain and consequent improvement in quality of life. In some it is not long-lasting. Anecdotal claims of improved exocrine function and glycaemic control need to be substantiated in large controlled trials.

SUMMARY AND FUTURE PROSPECTS

Tropical calcific pancreatitis has attracted considerable attention of late. Recent studies have improved our understanding of the exocrine and endocrine involvement and their interaction in this condition, but little is known about the aetiopathogenesis. Clinical cases with multiple pancreatic calculi probably represent a very advanced stage. Attention should now be focused on the 'early' stages. Large-scale community studies are expected to provide useful information. Preliminary studies point towards a 'subclinical pancreatopathy' in the tropics, probably due to 'environmental' factors. Malnutrition and dietary cyanogenic alkaloids are implicated, but mechanisms of pancreatic damage are not known, although increased oxidant stress and free radical damage have been suggested.

Acknowledgements

I am gratefulto the WellcomeTrust, London, UK for financialsupport and to VaishaliJoshifor invaluable help with the manuscript and figures.

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