Tropical chronic pancreatitis

Tropical chronic pancreatitis, also known as fibrocalculous pancreatic diabetes (FCPD), is a unique form of chronic pancreatitis seen only in developing countries. It has clinical, radiological and pathological features that distinguish it from alcoholic and other forms of chronic pancreatitis. It affects young adults, who present with abdominal pain due to pancreatic calculi, and progressive exocrine pancreatic failure resulting in malabsorption and diabetes. Alcohol abuse is not a feature. The aetiology of the condition is unknown, although it commonly develops against a background of poverty and malnutrition. Micronutrient deficiency and/or toxins are possible causal factors. Typical microvascular complications of diabetes may develop, although macrovascular complications are rare, and the condition also carries a high risk of carcinoma of the pancreas. Diabetes develops up to a decade after the first symptoms of tropical chronic pancreatitis appear, typically in the 20–40-year age group. Patients may present with very high blood glucose levels, but diabetic ketoacidosis is rare. Most patients will require insulin for glucose control, and the long-term prognosis is good relative to other causes of chronic pancreatitis.

Background

Tropical chronic pancreatitis, is the precursor to fibrocalculous pancreatic diabetes (FCPD) is a distinctive syndrome encountered only in developing countries. It is characterised by non-alcoholic pancreatitis affecting young adults, presenting with progressive exocrine pancreatic deficiency, and (typically, but not invariably) with abdominal pain. Diabetes is a late manifestation, and it has been proposed that the term tropical chronic pancreatitis should be reserved for the prediabetic phase of the syndrome and FCPD for the later stages in which diabetes becomes manifest.[1] The terms are, however, often used interchangeably.

The condition was first described in association with protein–energy malnutrition, and accordingly classified as malnutrition-related diabetes. The role of protein–energy malnutrition in its pathogenesis is, however, contentious: it has been reclassified as tropical chronic pancreatitis by WHO, although the condition may be found in immigrants to the temperate zones.

Tropical chronic pancreatitis was first described in Indonesia[2] in 1959, but it really came to notice via a series of reports from Kerala in South India, where it has its greatest incidence, and from other parts of India.

Epidemiology

Tropical chronic pancreatitis has been reported from many parts of Africa, South America and South-East Asia. Its highest prevalence is in Southern India.

There are no reliable population-based estimates of the prevalence of FCPD, but experience at one large centre in Chennai indicates that it affected 1.6% of new cases of diabetes in 1991–1995, compared with 0.2% in 2006–2010, whereas the prevalence of alcoholic chronic pancreatitis remained stable at about 0.1% over the same period.[3] Both the body mass index (BMI) and the age of new patients with FCPD increased over the same period, suggesting that improved nutrition was a factor in the decline of FCPD.

FCPD is common in several parts of the world in which cassava is consumed. Cassava is a root crop originating from South America that grows well in poor soils, but it contains thiocyanates, which are incompletely removed by crude extraction procedures. Cassava was accordingly proposed as a possible cause of FCPD, but this has not been substantiated by animal studies, the epidemiologal association is inconsistent, and the hypothesis has fallen out of favour.

Genetics

Associations between FCPD and the HLA system have been reported, notably increased transmission of HLA-DQB1*0302 and decreased transmission of HLA-DQ*0202. Both alleles are positively associated with type 1 diabetes in the Indian subcontinent.[4]

An association has also been reported for the trypsin inhibitor gene SPINK1, whose function is to inhibit premature activation of trypsinogen within the pancreas. SPINK1 is associated with other forms of chronic pancreatitis. The N34S variant of this gene was found in 33% of those with FCPD compared with 4% of controls.

Clinical features

Early clinical descriptions emphasised extreme emaciation, parotid enlargement and a distended abdomen. More recent accounts imply a better state of nutrition, even though the patients are typically lean with a BMI of about 20 kg/m2. Some are well nourished or even overweight at presentation.

Abdominal pain is the presenting feature of tropical chronic pancreatitis in up to 90% of cases. The pain is intermittent, severe, upper abdominal radiating to the back, and is relieved by leaning forward. The pain often diminishes in parallel with clinical progression of other features of FCPD.

Steatorrhoea is present in about 20% of cases at diagnosis, but the proportion affected rises if the fat content of the diet is increased.

Diabetes is considered to be a relatively late feature, developing some 10 years after first presentation with abdominal pain. Marked hyperglycaemia may be present, and some 80% of patients require insulin. Diabetic ketoacidosis is, however, extremely rare, with only five cases reported in the literature. This has variously been attributed to residual insulin secretion, loss of pancreatic glucagon, or lack of subcutaneous fat resulting in inability to mobilise the non-esterified fatty acids (NEFA) needed as a substrate for ketogenesis.1

Pathology

The key features are progressive fibrosis resulting in shrinkage of the gland together with stone formation and dilatation of the pancreatic ducts. Histologically there is atrophy of the exocrine pancreas in association with intense fibrosis and loss of pancreatic islets, although some residual islets show hyperplasia and beta cell proliferation.[5]

Complications

Complications of the pancreatitis include a greatly increased risk of pancreatic carcinoma. Accurate estimates do not exist, but clinical series suggest that the rate is as high, or higher, than in other forms of chronic pancreatitis.

Large vessel complications of diabetes are rare, due to the youth of those affected and the absence of other risk factors for arterial disease. Typical microvascular complications develop, however, at a rate comparable to those with type 2 diabetes.

The median survival rate following a diagnosis of diabetes is about 25 years. Diabetic nephropathy was the cause of death in 40%, compared with 20% for pancreatic carcinoma.[6]

Diagnosis and investigation

The condition commonly presents in young adults before the age of 40 years. Men are affected two to three times more often than women. Diagnosis is based around the clinical triad of abdminal pain, malabsorption and diabetes. The hallmark of the condition is dilatation of the pancreatic ducts with formation of large stones. These show up well on abdominal x-ray, and are often best seen just to the right of the first lumbar vertebra. Dilatation of the ducts may be demonstrated on computerised tomography (CT), endoscopic cholangiopancreatography or endscopic ultrasound.

Tests of exocrine pancreatic function may support the diagnosis, but are rarely helpful in the earlier stages of the condition.

Differential diagnosis

The main diagnosis to consider is alcoholic pancreatitis, which is the leading cause of chronic pancreatitis in many parts of the world, but is rarely prevalent in areas in which FCPD is common. A history of alcohol abuse often provides the diagnosis, and those affected are older, typically male, may not have a background of socioeconomic deprivation, less commonly (50% vs 90%) have pancreatic stones, and the stones when present tend to be smaller with a speckled appearance.

Management

Pain is often self-limiting, but surgical procedures including drainage of the duct or pancreatic resection may sometimes be needed. Malabsorption can normally be controlled with pancreatic enzymes taken by mouth. Diabetes often requires insulin therapy for control, but about 20% of cases respond to dietary measures or oral agents. The prognosis is good relative to other causes of chronic pancreatitis.

References

  1. ^ Barman KK et al. Tropical chronic pancreatitis. Postgrad Med J 2003;79:606–15

  2. ^ Zuidema PJ. Cirrhosis and disseminated calcification of the pancreas in patients with malnutrition. Trop Geog Med 1959;11:70–4

  3. ^ Papita R et al. Secular trends of fibrocalculous pancreatic diabetes and diabetes secondary to alcoholic chronic pancreatitis at a tertiary care diabetes centre in South India. J Panrease 2012;13(2):205-9

  4. ^ Chowdhury ZM et al. Genetic susceptibility to fibrocalculous pancreatic diabetes in Bangladeshi subjects:a family study. Genes Immunity 2002;3:5–8

  5. ^ Govindarajan M et al. Histopathology and immunohistochemistry of pancreatic islets in fibrocalculous pancreatic diabetes. Diabetes Res Clin Pract 2001;51:29–38

  6. ^ Mohan V et al. Fibrocalculous pancreatic diabetes. Long term survival analysis. Diabetes Care 1996;19:1274–78

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