Pancreas and Diabetes Mellitus: The Relationship between the Organ and the Disease.

Diabetes mellitus has been a fascinating disease from the dawn of medical history. The first breakthrough in its treatment came in 1922, with the discovery of insulin which was extracted from the pancreas of a dog. Even earlier, a relationship between pancreas and diabetes mellitus had been suspected by medical scientists. However, the study of diabetes mellitus is much more than its relationship with the pancreas. On the other hand the pancreas has been known to be a very reclusive organ that is hidden away from physicians and surgeons for centuries. In recent times, it has become more accessible and has yielded some of its secrets. The relationship between the pancreas and diabetes mellitus is a story full of complexities and surprises. This article attempts to reveal some of the important events and persons in the story and the controversies surrounding them.

Time trends in the etiology of chronic pancreatitis in South India.

BACKGROUND: Recent reports indicate a decline in prevalence of classical tropical chronic pancreatitis (TCP). We studied the etiologies and risk factors over a 14-year period at a tertiary care university hospital. METHODS: We compared the etiology in chronic pancreatitis (CP) patients presenting and followed-up in our Pancreas Clinic over two time periods (2000-06 and 2007-13). RESULTS: Idiopathic chronic pancreatitis (ICP) was the predominant etiology seen over the two time periods. However an increase in prevalence of alcoholic chronic pancreatitis (ACP) during the latter time period suggests that it may be emerging as a dominant etiology over recent years. Hypertriglyceridemia and hyperparathyroidism were uncommon causes of non-alcoholic CP. Autoimmune pancreatitis was noted only during 2007-13, but remains a rare cause of CP. There are multiple risk factors for CP in our population. CONCLUSIONS: The high prevalence of ICP indicates need closer examination of risk factors and ICP pathogenesis. ACP appears to be emerging as a dominant cause of CP which suggests a need to reorient preventive strategies.

Clinical profile of early-onset and late-onset idiopathic chronic pancreatitis in South India.

BACKGROUND AND AIM: Idiopathic chronic pancreatitis (ICP) is the most common form of chronic pancreatitis reported in India. There is paucity of literature on the prevalence and profiles of early- and late-onset forms of ICP in India. MATERIAL AND METHODS: We compared the profile of early- and late-onset ICP in a patient population attending a tertiary care hospital in South India. RESULTS: Pain was the characteristic feature as more than 90 % with both early-onset and late-onset ICP had pain as the most significant symptom. Onset of pain was at age 14.9 ± 7.7 years in early-onset and at 38.1 ± 9.9 in late-onset ICP (p < 0.001). There was considerable delay between onset of pain in early onset as compared to late-onset ICP. Diabetes was seen in 41.4 % in early-onset as compared to 69.1 % in late-onset ICP (p < 0.001). Pancreatic exocrine insufficiency was seen in 34.4 % in early-onset as compared to 53.2 % in late-onset ICP (p < 0.001). Increased prevalence of exocrine insufficiency and diabetes was observed in late-onset as compared to early-onset ICP. Univariate analysis showed that alcohol use, smoking, age, and family history of diabetes were significantly associated with diabetes. Multivariate analysis showed strong associations for diabetes with smoking (odds ratio (OR) = 4.2), calcification (OR = 7.7), as well as family history and age >40 years. CONCLUSIONS: There were differences between early-onset and late-onset ICP in southern Indian patients. Diabetes was strongly associated with smoking and pancreatic calcification.

Diet, nutrient deficiency and chronic pancreatitis.

The aetiopathogenesis of chronic pancreatitis (CP) appears to be multifactorial with interplay of genetic and environmental factors such as alcohol, smoking and diet. Dietary factors in the form of a fat- and protein-rich diet are important cofactors in the aetiopathogenesis of alcoholic pancreatitis. Malnutrition used to be a hallmark in tropical pancreatitis. Presently, it appears that malnutrition is an effect rather than a causative factor for tropical pancreatitis; however, micronutrient deficiency could possibly be implicated in the aetiopathogenesis. The role of dietary toxins such as cassava is no longer considered an important risk factor; however, these patients are at a higher risk for defective detoxification of cyanogens. Decrease in levels of sulphur amino acids (SAAs), folate and zinc have been reported. Oxidative stress and antioxidant depletion are key pathogenetic mechanisms. The role of antioxidants in pain relief is an area of interest. Supplementation of fat-soluble vitamins and micronutrients is a cornerstone in medical management. Folate and zinc supplementation may be beneficial and is a focus of ongoing research. In the future, prophylaxis for CP by a daily micronutrient tablet among high-risk groups in endemic areas could prove to be a potentially important public health measure. However, further studies are required.

Spectrum of pancreatitis in children and adolescents.

BACKGROUND: Very little is known about the early stages of tropical chronic pancreatitis except that many patients give history of childhood abdominal pain. AIM: To examine whether tropical chronic pancreatitis may initially present clinically as recurrent acute pancreatitis. METHODS: Children and adolescents with acute, recurrent acute and chronic pancreatitis were prospectively followed up from 2003 to 2010. Seventy-three consecutive patients were analyzed for progression from acute to recurrent and recurrent acute to chronic pancreatitis. RESULTS: Of the 36 acute, 28 were recurrent acute pancreatitis patients. Similarly of the 37 chronic pancreatitis patients 27 were de novo and 10 had progressed to chronicity from recurrent acute. The mean age of patients was not significantly different between the different groups. Majority of patients in all groups were of idiopathic etiology. The progression of recurrent acute to chronic took 1 to 5 years. Minimum number of episodes of acute pancreatitis before progression to chronicity was 2 and minimum period was 1 year. In 11 of the 27 de novo chronic pancreatitis patients, the age of first pain and diagnosis were identical, in the remaining 16, there were varying intervals between the first pain and diagnosis (1-12 years). DISCUSSION: There was a continuum of acute pancreatitis to recurrent acute pancreatitis, some of the recurrent acute pancreatitis patients further progressed to chronic. CONCLUSION: In some instances tropical chronic pancreatitis may initially present clinically as recurrent acute pancreatitis.

Alcoholic chronic pancreatitis and alcoholic liver cirrhosis: differences in alcohol use habits and patterns in Indian subjects.

OBJECTIVES: Alcohol abuse is a risk factor for both liver cirrhosis and chronic pancreatitis. However, less than 15% of heavy drinkers develop these complications. Coexistence of cirrhosis and pancreatitis in the same patient is considered uncommon. We compared drinking patterns and related patient factors in patients with alcoholic liver cirrhosis and alcoholic chronic pancreatitis. METHODS: A prospective evaluation of 307 patients (all men: 188 with alcoholic liver cirrhosis and 119 with alcoholic chronic pancreatitis) was conducted over a 7-year period using a detailed alcohol assessment proforma. Assessment of demographic features, diet, and other habits like tobacco smoking were recorded. RESULTS: Patients with alcoholic liver cirrhosis were older. The mean ± SD age in alcoholic liver cirrhosis was 52.4 ± 9.16 years and 47.1 ± 9.78 years (P < 0.001) in alcoholic chronic pancreatitis. The mean ± SD age when they started drinking was similar in both groups (22.8 ± 5.32 years and 24.3 ± 6.94; P > 0.05). The mean ± SD duration of drinking was higher in the cirrhosis group (29.5 ± 10.25 years) than in the pancreatitis group (21.5 ± 9.61 years) (P < 0.001). Fifty-nine percent of cirrhosis and 75% of pancreatitis were heavy tobacco smokers (P = 0.004). CONCLUSIONS: There are distinct differences in drinking patterns and related patient factors between alcoholic liver cirrhosis and alcoholic chronic pancreatitis, suggesting the need to orient different interventional strategies.

Pancreatitis in the setting of the metabolic syndrome.

There is paucity of literature on the relation of obesity with recurrent and chronic pancreatitis. We recorded the clinical details and the outcome of five patients with recurrent pancreatitis who had components of the metabolic syndrome. Their age ranged from 8 to 20 years. All five patients had acanthosis nigricans. Body mass index (BMI) could not be evaluated as these patients lost weight following episodes of pancreatitis. Three patients had two or more first-degree relatives who had diabetes mellitus. Only one patient had severe necrotizing pancreatitis. Coexisting liver disease was seen in two patients. Elevated serum cholesterol levels and moderately elevated serum triglycerides along with elevated serum amylase levels observed in these patients suggest possibility of a different mechanism from that of hypertriglyceridemia-related pancreatitis. Evaluation of pancreatic steatosis should be considered in patients with pancreatitis in the setting of metabolic syndrome.

Assessment of cassava toxicity in patients with tropical chronic pancreatitis.

BACKGROUND AND AIM: There have been conflicting reports on the role of cassava ingestion in tropical pancreatitis (TCP). In this study we aimed to estimate cyanogens detoxifying enzyme rhodanese, thiocyanate and sulfur containing amino acids in cassava consumer as well as cassava non-consumer TCP patients and healthy controls and compare the same. METHODS: Eighty-six TCP patients and 90 healthy controls were recruited. Serum rhodanese, thiocyanate, plasma amino acids, urinary inorganic sulfate/creatinine were measured. RESULTS: There was significant reduction in serum rhodanese activity in both cassava consumer- and non-consumer TCP patients as compared to controls but no significant difference between cassava consumer- and non-consumer TCP patients was observed. Serum thiocyanate was significantly lower in cassava consumer TCP patients as compared to cassava consumer controls but not significantly different from cassava non-consumer TCP patients. Plasma methionine, cysteine and urinary inorganic sulfate / creatinine ratio was significantly lower in both cassava consumer and non-consumer TCP patients as compared to controls but were comparable among cassava consumers and non-consumers. CONCLUSIONS: Significant reduction in rhodanese activity with concomitant decrease in sulfur containing amino acids and antioxidants such as glutathione suggests that TCP patients are at higher risk of defective detoxification of cyanogens. However there was no difference between cassava consumers and non-consumers. Low levels of sulfur amino acids may contribute to the development of pancreatitis.

Assessment of oxidative status in chronic pancreatitis and its relation with zinc status.

BACKGROUND: Oxidative stress-induced free radicals have been implicated in the pathology of chronic pancreatitis (CP). AIM: We aimed to estimate oxidative stress and antioxidant status in tropical chronic pancreatitis (TCP) and alcoholic chronic pancreatitis (ACP) and correlate with zinc status. METHODS: One hundred and seventy-five CP patients (91 TCP, 84 ACP) and 113 healthy subjects were prospectively studied. Disease characteristics and imaging features were recorded. Erythrocyte reduced glutathione, glutathione peroxidase (GPx), superoxide dismutase (SOD), plasma vitamin C, and erythrocyte thiobarbituric acid reactive substance (TBARS) were estimated by spectrophotometry. Erythrocyte zinc was estimated by flame atomic absorption spectrophotometry. RESULTS: Enhanced lipid peroxidation with concomitant decrease in antioxidant status was observed in both TCP and ACP patients (p < 0.05). The findings were comparable in both diabetic and non-diabetic CP patients. Significantly, lower plasma vitamin C and elevated levels of erythrocyte TBARS was noted in TCP as compared to ACP patients. The erythrocyte zinc significantly correlated with SOD activity (r = 0.450, p < 0.001). CONCLUSIONS: Our study corroborates the role of oxidative stress in CP and suggests some differences in oxidative status in TCP and ACP patients. Zinc deficiency appears to affect oxidative status in CP patients.

Clinical characteristics of 327 Asian patients with autoimmune pancreatitis based on Asian diagnostic criteria.

OBJECTIVES: To clarify the clinical and pathophysiological characteristics of autoimmune pancreatitis (AIP) in Asia. METHODS: A retrospective, actual situation survey of AIP diagnosed by Asian criteria was conducted in 10 centers of Japan, Korea, Taiwan, China, and India. RESULTS: A total of 327 AIP cases (258 male and 69 female subjects; average age, 60.0 years) were enrolled. Obstructive jaundice was the most frequent initial symptom (46%-74%), followed by weight loss (4%-51%) and abdominal pain (19%-44%). Diffuse swelling of the pancreas was frequent in Japan (64%) and Korea (81%), but segmental swelling of the pancreas was more frequent in Taiwan (70%) and China (72%) (P < 0.01). Serum immunoglobulin G4 levels were elevated in 58%-100% of cases in Japan, Korea, and Taiwan. Pathologically, almost all AIPs in Asia were lymphoplasmacytic sclerosing pancreatitis. Sclerosing cholangitis was the most frequent extrapancreatic lesion (60%-81%). Steroid therapy was a major and effective therapeutic strategy in Japan, Korea, and Taiwan. However, the rate of resection or bypass operation was higher in Taiwan (40%) and China (72%) (P < 0.01). CONCLUSIONS: Features of AIP are fundamentally similar in Japan, Korea, Taiwan, and China. Knowledge of emerging AIP should be more widespread in Asia to avoid unnecessary operation.

Alterations in plasma amino acid levels in chronic pancreatitis.

CONTEXT: Dietary proteins and amino acids can modulate pancreatic function. OBJECTIVE: Our aim was to estimate the levels of plasma amino acids in chronic pancreatitis patients and study their relationship with disease characteristics as well as exocrine and endocrine insufficiency. PATIENTS: One hundred and seventy-five consecutive adult patients with chronic pancreatitis: 84 patients with alcoholic chronic pancreatitis and 91 patients with tropical chronic pancreatitis. One hundred and thirteen healthy controls were also studied. DESIGN: Prospective study. MAIN OUTCOME MEASURES: Disease characteristics and imaging features were recorded. Plasma-free amino acid levels were estimated using reverse-phase high-performance liquid chromatography. Polyclonal antibody ELISA was used to assess pancreatic fecal elastase-1. RESULTS: The majority of the plasma free amino acid levels decreased in chronic pancreatitis patients whereas glutamate, glycine, proline and lysine were elevated as compared to the controls. Multivariate logistic regression analysis revealed that the decrease in branched chain amino acid concentration was significantly associated with the presence of diabetes and low fecal elastase-1. In addition, a significant positive correlation was observed between branched chain amino acids and pancreatic elastase-1 (rs=0.724, P<0.001). CONCLUSION: Reductions of plasma amino acid levels are seen in chronic pancreatitis, particularly sulphur containing amino acids and branched chain amino acids. Selective amino acid deficiencies seem to correlate with exocrine and endocrine insufficiency.

Chronic pancreatitis is associated with hyperhomocysteinemia and derangements in transsulfuration and transmethylation pathways.

OBJECTIVES: Homocysteine has been implicated in vascular dysfunction and thrombosis, as well as inflammatory conditions. This study was aimed to find out whether chronic pancreatitis (CP) is associated with hyperhomocysteinemia and derangements of transmethylation and transsulfuration pathways. METHODS: We estimated homocysteine and its metabolites in 45 alcoholic CP patients, 45 tropical CP patients, and 48 healthy controls. RESULTS: Significant increases in plasma total homocysteine and decreases in red blood cell folate, reduced glutathione, plasma methionine, cysteine, and urinary inorganic sulfate/creatinine ratio were observed in both alcoholic and tropical CP patients in comparison with healthy controls. Red blood cell glutathione and plasma cysteine levels were significantly lower in alcoholic than in tropical CP patients. However, plasma vitamin B12 levels were comparable between CP patients and controls. No significant differences in these parameters were observed between diabetic patients and nondiabetic patients. Multivariate regression analysis showed a significant negative correlation between homocysteine and folate (r = -0.415, P = 0.001) and a positive correlation between glutathione and cysteine levels (r = 0.37, P = 0.003). CONCLUSIONS: Chronic pancreatitis is associated with hyperhomocysteinemia and derangements in transmethylation and transsulfuration pathways. Low folate levels observed in these patients seem to have a key role in this derangement.

Anthropometric, biochemical, clinical and dietary assessment for malnutrition in south Indian patients with chronic pancreatitis.

BACKGROUND AND AIM: Recent surveys suggest a change in nutritional status of population in Kerala along with a steep rise in alcoholism. We aimed to conduct a comprehensive assessment of anthropometric, biochemical, clinical and dietary parameters and study the association of nutritional status with dietary intake. METHODS: We compared the nutrient intake of a cohort of patients with chronic pancreatitis with a recent population survey. We also sought to compare the prevalent nutritional status of patients with previous series. RESULTS: Chronic pancreatitis patients had poor intake of most nutrients. However, severe malnutrition is present only in a small minority (4%) as compared to previous series. Fat intake in patients with tropical chronic pancreatitis was significantly lower in alcoholic chronic pancreatitis patients (27.5 g/d vs. 43 g/d). CONCLUSIONS: Malnutrition remains an important problem in chronic pancreatitis; however severe malnutrition is rare as compared to previous series. Energy (calorie) deprivation and micronutrient deficiency are major nutritional issues. Use of additional anthropometric parameters, especially triceps skin fold thickness, in conjunction with body mass index, is helpful. Subjective global assessment is a useful method for assessment for nutritional status in chronic pancreatitis patients.

Zinc status in chronic pancreatitis and its relationship with exocrine and endocrine insufficiency.

CONTEXT: A major role of the pancreas in zinc homeostasis has been suggested. OBJECTIVE: To assess erythrocyte zinc status in chronic pancreatitis and to correlate it with pancreatic exocrine and endocrine insufficiency. PATIENTS: One hundred and one patients with chronic pancreatitis (34 alcoholic chronic pancreatitis, 67 tropical chronic pancreatitis) were prospectively studied. MAIN OUTCOME MEASURE: Disease characteristics and imaging features were recorded. Erythrocyte zinc was estimated by flame atomic absorption spectrophotometry. Exocrine insufficiency was assessed using polyclonal antibody ELISA for pancreatic stool elastase1. Endocrine insufficiency was assessed by serum glucose levels and insulin requirement. RESULTS: Erythrocyte zinc was significantly lower in chronic pancreatitis patients than in the controls (26.5+/-9.5 microg/g Hb vs. 38.0+/-6.6 microg/g Hb; P<0.001), and in tropical chronic pancreatitis than in alcoholic chronic pancreatitis (25.0+/-10.4 microg/g Hb vs. 29.6+/-6.5 microg/g Hb, P=0.001). In chronic pancreatitis patients who had exocrine insufficiency, erythrocyte zinc positively correlated with stool elastase1 (r=0.587, P<0.001). Erythrocyte zinc levels were significantly lower in diabetic patients as compared to non-diabetics (P=0.036). CONCLUSIONS: This study demonstrates zinc deficiency in chronic pancreatitis patients, and that zinc deficiency correlates with exocrine and endocrine insufficiency. Further studies may clarify the possible benefits of zinc supplementation in chronic pancreatitis.

Fecal elastase1 and acid steatocrit estimation in chronic pancreatitis.

BACKGROUND: Measurement of pancreatic exocrine function and steatorrhea in chronic pancreatitis in the clinical setting has not received much attention. AIM: To assess pancreatic exocrine function and fecal fat excretion in a cohort of patients with chronic pancreatitis. METHODS: Stool elastase1 levels were measured in 101 patients using polyclonal ELISA and acid steatocrit was measured in 86 chronic pancreatitis patients. Associations with etiology, clinical and radiological features, and diabetic status were examined. RESULTS: Low pancreatic stool elastase1 (<200 microg/g stool) was observed in two-thirds of chronic pancreatitis patients and correlated with ductal dilatation, pancreatic atrophy and calcification (p<0.05). Diabetes was more prevalent in chronic pancreatitis patients with low elastase1 (p=0.045). There was no difference in mean acid steatocrit between diabetics and non-diabetics (p=0.069). Elastase1 levels had a negative correlation with acid steatocrit (r=-0.606, p<0.001), and a positive correlation (r=0.412) with body mass index (p=0.013). Fifty-three percent of chronic pancreatitis patients with normal BMI had low elastase1. CONCLUSIONS: Fecal elastase1 levels correlated with fecal fat excretion and BMI. Fecal elastase1 estimation may be helpful in early detection of malabsorption in chronic pancreatitis.

Muscle cell membrane damage by very low serum sodium.

A 63-year-old male was admitted with complaints of upper gastrointestinal symptoms with fatigue and myalgia. Investigations revealed severe hyponatremia with elevated creatine phosphokinase levels. Following further workup, it was diagnosed as a case of hyponatremia induced rhabdomyolysis. Because of prompt correction of hyponatremia, his renal function was preserved and myoglobinuria induced renal failure was avoided. The importance of early recognition of this potentially dangerous condition is emphasized.

Chronic pancreatitis. A prospective nationwide study of 1,086 subjects from India.

CONTEXT: Chronic pancreatitis is common in India. However, its risk factors are not clear. There is sparse data on the current prevalence of tropical pancreatitis in India. OBJECTIVE: To undertake a prospective nationwide study of the risk factors and clinical profile of chronic pancreatitis. SETTING: Thirty-two major centers from different regions of India contributed data on 1,086 patients to a common online website (www.ipans.org). MAIN OUTCOME MEASURES: Risk factors, clinical features complications and treatment of chronic pancreatitis. RESULTS: Of the 1,086 subjects, complete data on risk factors were available for 1,033 subjects. Idiopathic pancreatitis was the most common form of pancreatitis (n=622; 60.2%) and alcoholic chronic pancreatitis accounted for about a third of the cases (n=400; 38.7%); the rest (n=11; 1.1%) had rare risk factors. Smoking and cassava intake were documented in 292 (28.3%) and 189 (18.3%) subjects, respectively. Using well-defined criteria, only 39 (3.8%)cases could be labeled as 'tropical pancreatitis'. Pain occurred in 971 patients (94.0%). Four hundred and eighteen (40.5%) subjects had diabetes mellitus. Of alcohol consumers, alcoholism and female gender were independent risk factors for diabetes in subjects with chronic pancreatitis (OR=1.48, P=0.003; and OR=1.75, P<0.001, respectively). The most common complications were pseudocysts (15.8%) and biliary obstruction (8.2%). Pancreatic cancer occurred in 42 subjects (4.1%). Ultrasound detected calculi in 69.7%, ductal dilatation in 63.4% and atrophy in 27.3%. The majority of patients were on medical therapy (n=849; 82.2%); endotherapy and surgery accounted for the rest. About 50% percent of the patients with diabetes required insulin (198/418). CONCLUSIONS: In this first nationwide prospective survey of chronic pancreatitis in India, idiopathic pancreatitis was the most common form, followed by alcoholic pancreatitis. The classical form of tropical chronic pancreatitis is becoming less common.