This condition is characterized by progressive and irreversible destruction of the exocrine pancreatic tissue, leading to exocrine pancreatic insufficiency and varying degrees of glucose intolerance, which often require insulin. The causes of chronic pancreatitis vary according to the geographical location (Table 1).
Table1. Causes of chronic pancreatitis.
Alcohol misuse accounts for most of the cases (>85%) in European and North American populations. Alcohol alters the composition of pancreatic secretions, leading to the formation of proteinaceous plugs that block the ducts and act as foci for calculi formation. Tropical chronic pancreatitis is a distinct form of the disease that is not associated with excessive alcohol intake and is prevalent in low- and middle- income countries.
Hereditary chronic relapsing pancreatitis is a rare entity, inherited in an autosomal dominant fashion. Mutations in a number of genes have been implicated, including PRSS1 (encoding cationic trypsinogen), SPINK1 (serine protease inhibitor, Kazal type 1), and CFTR (cystic fibrosis transmembrane conductance regulator).
Obstructive chronic pancreatitis is a rare condition that follows occlusion of pancreatic ducts by tumours, scarring, pseudocysts, or congenital anomalies. Stones are not seen. Surgery or endoscopic dilatation may occasionally be curative.
Idiopathic pancreatitis, which accounts for 10–20% of all cases, affects two distinct age groups, one with onset at 15–25 years and the other at 55–65 years. Cigarette smoking is a risk factor and mutations in specific genes have also been postulated.
Epidemiology
Chronic pancreatitis is prevalent worldwide. The incidence varies between 7 and 14 cases per 100 000 population per year, with significant differences between populations and countries. The incidence appears to have increased over time in many parts of the world. Tropical chronic pancreatitis is confined to tropical and subtropical regions of the world, with the highest prevalence rates reported in southern India.
Pathological features
The term chronic calcific pancreatitis accurately describes the pathological changes in over 95% of cases of chronic pancreatitis in European and North American countries. The ductal and acinar lumina are filled with proteinaceous plugs that later calcify, forming small stones composed chiefly of calcium carbonate or calcite. Huge stones can occur, but are more characteristic of tropical pancreatitis. The stones are found diffusely throughout the affected organ. Microscopically, there is atrophy of the ductal epithelium and stenosis of the ducts, associated with patchy fibrosis. There may also be foci of necrosis, with infiltration by lymphocytes, plasma cells, and histiocytes. Ultimately, the pancreas shrivels and develops an opaque capsule that may adhere to surrounding organs.
As fibrosis progresses, the acini atrophy and eventually disappear, leaving clusters of islets surrounded by sclerosed parenchyma. Neoformation of islet cells from ductal tissue can occur (nesidioblastosis) (Figure 1). Immunohistochemistry studies reveal a generalized decrease in the number of islets, accompanied by overall reduction in β- cell density and insulin immunoreactivity, which correspond to dis ease duration and C- peptide levels (Figure 2; Table 2).
Fig1. Nesidioblastosis, from a case of fibrocalculous pancreatic diabetes, showing islet tissue arising from ductal remnants. Stain aminoethylcarbazole; magnification ×40.
Fig2. Histological features of chronic pancreatitis, from cases of fibrocalculous pancreatic diabetes. (a) Exocrine tissue is entirely replaced by dense fibrosis that spares the islets. Haematoxylin and eosin stain; magnification ×40. (b) A hyperplastic islet. Section immunostained for insulin; magnification ×40.
Table2. Islet cell changes in chronic pancreatitis.
Clinical features and diagnosis
Abdominal pain is the predominant symptom and the usual reason for seeking medical care. The pain is usually steady, boring, and agonizing, and located in the epigastrium or left hypochondrium with radiation to the dorsal spine or the left shoulder. Bending forward or assuming the knee–chest position relieves the pain. The cause of the pain is unknown, but may relate to increased intrapancreatic or intraductal pressure, or to ischaemia of the pancreas. It tends to remit and relapse and follows an unpredictable course. The development of end- stage pancreatic dis ease is associated with disappearance of the pain in many cases.
Exocrine pancreatic insufficiency may manifest with steatorrhoea and features of fat- soluble vitamin deficiency, although steatorrhoea may not be apparent on a low- fat diet. The combination of oily and greasy stools with diabetes should raise the suspicion of chronic pancreatitis.
Investigations
Demonstration of pancreatic calculi on a plain X- ray of the abdomen is diagnostic (Figure 3). In cases where obvious calculi cannot be found, ultrasonography, CT scanning, or endoscopic retrograde cholangiopancreatography (ERCP) will help to confirm the diagnosis (Figure 4). ERCP is considered the gold standard and usually reveals irregular dilatation of the pancreatic ducts with filling defects caused by stones (Figure 4a). CT scanning shows patchy increases in parenchymal density and, ultimately, atrophy of the gland.
Fig3. Pancreatic calculi, showing characteristic patterns in (a) alcoholic chronic pancreatitis and (b) fibrocalculous pancreatic diabetes.
Fig4. Investigations in chronic pancreatitis. (a) Endoscopic retrograde cholangiopancreatogram, showing dilatation and irregularity of the pancreatic ductal system in a person with alcoholic chronic pancreatitis. Source: Courtesy of Professor Jonathan Rhodes, Liverpool, UK. (b) Ultrasound scan of the pancreas from a person with fibrocalculous pancreatic diabetes, demonstrating highly echogenic parenchyma and duct walls (fibrosis), grossly dilated ducts, and calculi. The lower drawing shows the salient features of the ultrasound scan. Source: Courtesy of Dr S. Suresh, Chennai, India.
Exocrine pancreatic function can be assessed by measuring the urinary excretion of compounds that are liberated in the gut by pancreatic enzyme action on orally ingested precursors such as N- benzoyl- L- tyrosyl- p- aminobenzoic acid (NBT- PABA) or fluorescein dilaurate (pancreolauryl). Screening tests of pancreatic enzymes (faecal chymotrypsin, faecal elastase) are also used, as they are simpler to perform but are less specific. Measurement of pancreatic output (via a tube placed in the duodenum) following ingestion of the Lundh test meal may also be helpful. Serum amylase is usually normal, except during acute attacks.
Diabetes in chronic pancreatitis
Abnormal glucose tolerance and diabetes complicate around 40–50% of cases of chronic pancreatitis. Unlike acute pancreatitis, the cause here is damage to the β cells, owing to loss of trophic signals from the exocrine tissue, although some authors have postulated a role for reduced insulin sensitivity as well. The diabetes is of insidious onset and usually occurs several years after the onset of pain. The prevalence has been assessed at 60% after 20 years. Half or more of patients require insulin for optimal glycaemic management, but ketoacidosis is rare, even if insulin is withdrawn. Possible explanations include better preservation of β- cell function (compared with type 1 diabetes), reduced glucagon secretion, and lower body stores of triglyceride, the major substrate for ketogenesis. On account of the lower glucagon reserve, these people are also prone to severe and prolonged hypoglycaemia, and often diabetes is difficult to manage with wide fluctuations of blood glucose levels.
Chronic diabetic complications
It was originally thought that people with pancreatic diabetes were not at increased risk of microvascular complications; however, retinopathy and nephropathy occur at frequencies similar to those with type 2 diabetes, while the prevalence of neuropathy might be higher. The risks of macrovascular complications, nevertheless, are relatively low. This may partly be explained by the favourable blood lipid profile that often accompanies the malnutrition commonly seen in these people.
Management of diabetes in chronic pancreatitis
Removal of obvious causes, such as alcohol and hypertriglyceridaemia, will help to prevent progression of the damage to the gland. Pain can be very difficult to manage. Measures include total abstinence from alcohol, dietary modification (small frequent meals with low fat content), analgesics, and the somatostatin analogue octreotide, which suppresses pancreatic exocrine secretion. In a subgroup of individuals, massive doses of non- enteric- coated preparations of pancreatic enzymes may reduce pain. Surgical interventions include sphincterotomy, internal drainage of pancreatic cysts, endoscopic removal of calculi (via ERCP), insertion of duct stents, and denervation procedures. Total resection of the pancreas followed by whole pancreas or islet cell transplantation is an option for intractable cases. Malabsorption can be effectively treated with a low- fat diet with pancreatic enzyme supplements (along with histamine H2 blocker or proton pump inhibitor to block gastric acid secretion) taken at meal times.
Diabetes should be managed along conventional lines, with a few caveats. High carbohydrate and protein intakes are encouraged along with fat restriction in order to prevent steatorrhoea while preventing weight loss. Over 80% of these individuals require insulin; however, the required doses are typically low, around 30–40 units/day. Despite this, frequent and severe hypo glycaemia may occur as a result of reduced glucagon secretion.
Individuals with type 2 diabetes exhibit evidence of reduced exocrine pancreatic function, albeit not to the degree found in ‘pancreatic’ diabetes. In a study from India, the prevalence of exocrine pancreatic insufficiency (measured by the faecal chymotrypsin assay) was 4.5% in type 2 diabetes, as compared to 88% and 24% in fibrocalculous pancreatic diabetes and type 1 diabetes, respectively. Pancreatic insufficiency has been postulated to occur due to loss of the trophic action of insulin on the exocrine tissue; however, autonomic neuropathy affecting the enteropancreatic reflexes may play a role in the pathogenesis. Routine screening of persons with type 2 diabetes for exocrine pancreatic insufficiency in the absence of symptoms is not recommended.
Tropical chronic pancreatitis
This is a distinct variety of chronic pancreatitis seen predominantly in low- and middle- income countries in the tropical and subtropical regions of the world [45, 46]. This entity was first reported in 1959 by Zuidema in people from Indonesia, but the disease was subsequently reported in several countries in Africa and Asia. The highest prevalence appears to be in southern India, particularly in the states of Kerala and Tamil Nadu; however, the prevalence seems to be declining even in these areas.
The disease usually starts in childhood with recurrent abdominal pain and during adolescence progresses to large pancreatic calculi and ductal dilatation (Figures 3 and 5). By adulthood, frank diabetes is found in more than 90% of these individuals. Nevertheless, it remains a rare cause of diabetes, constituting less than 1% of all cases of diabetes (and a slightly higher proportion of all young- onset diabetes) even in regions where it is most prevalent. A recent population- based study in urban southern India reported a prevalence of 0.36% among people with self- reported diabetes and 0.019% among the general population.
Fig5. Calcite stones of various sizes removed from the pancreas of a person with fibrocalculous pancreatic diabetes.
The term tropical chronic pancreatitis is used to denote the pre- diabetes stage of the disease, whereas the term fibrocalculous pancreatic diabetes is used to describe the clinical picture once diabetes has supervened (Figure 6).
Fig6. Natural history of tropical calcific pancreatitis (TCP) and fibrocalculous pancreatic diabetes (FCPD). IGT, impaired glucose tolerance.
The aetiology of the condition remains unknown. Poor nutrition has been implicated as a possible factor; however, this may be a consequence rather than a cause of the pancreatopathy. The condition may also affect well- nourished individuals. In the past, attention was focused on the role of dietary toxins such as cyanogens (found in cassava), but this link has not been substantiated. Cases tend to cluster in families, which may suggest a genetic aetiology for the disease. Several studies have reported an association of tropical chronic pancreatitis with the SPINK1 gene, as also with the cathepsin B (CTSB) gene. A role has been suggested for oxidant stress and free radical– mediated injury, but this has not been proven conclusively.
Salient differences between alcoholic chronic pancreatitis and tropical chronic pancreatitis are summarized in Table 3. The classic clinical triad of tropical chronic pancreatitis comprises abdominal pain, steatorrhoea, and eventually diabetes. The dis ease often progresses steadily from euglycaemia through impaired glucose tolerance to frank diabetes. Most people require insulin but are generally not prone to ketosis; some can be managed with oral anti- diabetes agents (Figure 7). The risk of developing pancreatic carcinoma in tropical chronic pancreatitis is 100- fold greater than in those without the disease and is much higher than in other forms of chronic pancreatitis. Pancreatic malignancy should be suspected in individuals with tropical chronic pancreatitis if they complain of intractable pain or significant weight loss even after attaining optimal glycaemic levels. Management of tropical chronic pancreatitis and fibrocalculous pancreatic diabetes is similar to that outlined for chronic pancreatitis.
Table3. Differences between tropical chronic pancreatitis and alcoholic chronic pancreatitis.
Fig7. The spectrum of diabetes in fibrocalculous pancreatic diabetes. Source: Data from Mohan et al. 1989.
