Other causes of pancreatic exocrine insufficiency

Written by Miroslav Vujasinovic and Djuna Cahen

Pancreatic exocrine insufficiency is traditionally associated with primary pancreatic diseases such as chronic pancreatitis, cystic fibrosis, and pancreatic cancer.¹ However, emerging evidence suggests that pancreatic exocrine insufficiency can also occur secondary to various extrapancreatic conditions.¹ This phenomenon, referred to as secondary pancreatic exocrine insufficiency, highlights the complex interplay between the pancreas and other systemic diseases. Despite the growing recognition of secondary pancreatic exocrine insufficiency, the pathophysiology and prevalence in these conditions remain inadequately understood, and the level of evidence is low, necessitating further research and clinical awareness.¹

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Aging

Aging is associated with changes in pancreatic volume, structure, and perfusion, which can lead to pancreatic exocrine insufficiency.¹,² The prevalence of pancreatic exocrine insufficiency in aging varies, with low faecal elastase-1 levels reported in 21.7% of individuals over 60 years and 11.5% of those aged 50-75 years.³,⁴ Although studies do not unanimously support old age as a risk factor for pancreatic exocrine insufficiency, some reports indicate lower enzyme and bicarbonate output in the elderly.¹ The largest study on pancreatic function in elderly individuals showed low fecal elastase-1 levels in 11.5% of participants aged 50-75 years.⁴ Although the real prevalence and clinical relevance of pancreatic exocrine insufficiency in aging is unknown, older individuals with proven pancreatic exocrine insufficiency should not be treated differently from other patients with this condition.¹

Diabetes mellitus

The prevalence of pancreas exocrine insufficiency in patients with diabetes mellitus is greater than in controls. Unfortunately, the fecal elastase-1 test is less reliable in this patient group. In addition, the clinical relevance of pancreas exocrine insufficiency is debatable, as most individuals are asymptomatic. However, symptomatic patients with diabetes mellitus should be screened for pancreas exocrine insufficiency and treated to relief gastrointestinal symptoms and prevent complications.

fatty pancreas

Low fecal elastase-1 levels have been reported in 9.5-35.5% of patients with non-alcoholic fatty pancreas disease.⁵ Studies show varying prevalence rates, with some indicating a significant inverse relationship between pancreatic fat accumulation and fecal elastase-1 levels.¹ However, despite low fecal elastase-1 levels, some patients do not show clinical symptoms of pancreatic exocrine insufficiency, suggesting that the clinical relevance of fatty pancreas in causing pancreatic exocrine insufficiency is still uncertain.⁵

chronic liver and biliary diseases

There is limited evidence for pancreatic exocrine insufficiency in chronic hepatobiliary diseases, except for alcohol-related conditions.¹ Studies show varying results, with some indicating a significant prevalence of pancreatic exocrine insufficiency in patients with alcoholic liver disease. More research is needed to establish a clear connection between chronic liver diseases and pancreatic exocrine insufficiency.¹

Diseases of the luminal digestive tract

Low fecal elastase-1 values have been reported in 0-41% of inflammatory bowel disease patients.⁹ pancreatic exocrine insufficiency is more common in patients with autoimmune pancreatitis and inflammatory bowel disease, with prevalence rates of 19-31%.¹

There is a symptomatic crossover between diarrhea-predominant irritable bowel syndrome (D-IBS) and pancreatic exocrine insufficiency. Low fecal elastase-1 levels are reported in 4-13% of D-IBS patients.¹,¹⁰ The clinical relevance of this association is still unclear. Studies show that some patients with D-IBS have low fecal elastase-1 levels, suggesting a possible overlap with pancreatic exocrine insufficiency.¹ Treatment with pancreatic enzyme replacement therapy has shown symptom improvement in some patients in small studies, but more research is needed to establish the clinical significance of this association.¹,¹⁰

A systematic review and meta-analysis found a pooled prevalence of pancreatic exocrine insufficiency in new celiac disease patients to be 26.2%, with a lower prevalence in those treated with a gluten-free diet.⁷ The mechanism for pancreatic exocrine insufficiency in newly diagnosed celiac disease is likely due to villous atrophy causing reduced cholecystokinin and secretin release.¹ Patients with celiac disease were at a 5.34-fold increased risk of receiving supplementation with pancreatic enzyme products after celiac disease diagnosis.⁸ Although pancreatic function tests are not routinely recommended in newly diagnosed celiac disease patients, testing with fecal elastase-1 and pancreatic enzyme replacement therapy could be considered in celiac patients if significant malnutrition is present at diagnosis or if symptoms persist despite a gluten-free diet.¹

hemochromatosis

The prevalence and clinical relevance of pancreatic exocrine insufficiency in hemochromatosis are not well-documented.¹ Data from studies on other iron overload disorders, such as beta-thalassemia major, indicate that pancreatic exocrine insufficiency may be present, but the results are difficult to interpret due to heterogeneity in study methods.¹,⁶

Congestive heart failure

Low fecal elastase-1 values are reported in 6.9-56.7% of congestive heart failure patients.¹⁷ pancreatic exocrine insufficiency may occur due to decreased splanchnic circulation, and pancreatic enzyme replacement therapy can improve symptoms in some cases.¹ Studies indicate that chronic heart failure is associated with a significant prevalence of pancreatic exocrine insufficiency and treatment with pancreatic enzyme replacement therapy has shown improvement in appetite and nutritional status in affected patients.¹⁸

chronic renal failure and chronic uremia

The prevalence of pancreatic exocrine insufficiency in patients with chronic kidney disease is reported to be up to 72%, but the quality of evidence is low.¹,¹⁴ Studies show that patients with chronic kidney disease may have reduced pancreatic enzyme secretion, but more research is needed to confirm these findings.¹

infectious diseases

Low fecal elastase-1 values are reported in 20-50% of patients with human immunodeficiency viruses (HIV).^12,¹³ Pancreatic exocrine insufficiency in other infectious diseases is possible but not well-documented. The impact of COVID-19 on pancreatic function is still being studied, with some evidence suggesting pancreatic involvement in severe cases.¹

Sjogren’s syndrome

The prevalence of pancreatic exocrine insufficiency in Sjogren’s syndrome varies between 0-63%, depending on diagnostic methods.¹ Studies show that some patients with Sjogren’s syndrome may have disturbed pancreatic function, but the clinical significance is still unclear.¹⁹

Rare and inherited diseases

Pancreatic exocrine insufficiency is associated with several rare inherited diseases, including Shwachman-Bodian-Diamond syndrome, Johanson-Blizzard syndrome, Pearson syndrome, and others.¹ The prevalence varies, and treatment typically involves pancreatic enzyme replacement therapy. These conditions often present with a combination of symptoms, including pancreatic insufficiency, and require specialized management.¹

Drug-related pancreatic exocrine insufficiency

Low fecal elastase-1 values are reported in 1-10% of patients treated with immune-checkpoint inhibitors and tyrosine kinase inhibitors.¹¹ Pancreatic atrophy and pancreatic exocrine insufficiency can occur, but symptoms often resolve with pancreatic enzyme replacement therapy.^1,11 Studies have shown that patients treated with these drugs may develop pancreatic exocrine insufficiency, but the prevalence varies.¹

Pancreatic exocrine insufficiency prevalence varies from 8-24% in patients treated with somatostatin analogues.¹⁵,¹⁶ These drugs significantly inhibit pancreatic enzyme secretion, leading to pancreatic exocrine insufficiency in some cases. Studies show that patients treated with somatostatin analogues for neuroendocrine tumors may develop pancreatic exocrine insufficiency, and treatment with pancreatic enzyme replacement therapy can be effective in managing symptoms.¹

References

Dominguez-Muñoz JE, Vujasinovic M, de la Iglesia D, et al. European guidelines for the diagnosis and treatment of pancreatic exocrine insufficiency: UEG, EPC, EDS, ESPEN, ESPGHAN, ESDO, and ESPCG evidence-based recommendations. United European Gastroenterol J 2024.
Löhr JM, Panic N, Vujasinovic M, Verbeke CS. The ageing pancreas: a systematic review of the evidence and analysis of the consequences. J Intern Med 2018; 283(5): 446-60.
Herzig KH, Purhonen AK, Räsänen KM, et al. Fecal pancreatic elastase-1 levels in older individuals without known gastrointestinal diseases or diabetes mellitus. BMC Geriatr 2011; 11: 4.
Rothenbacher D, Löw M, Hardt PD, Klör HU, Ziegler H, Brenner H. Prevalence and determinants of exocrine pancreatic insufficiency among older adults: results of a population-based study. Scand J Gastroenterol 2005; 40(6): 697-704.
Maetzel H, Rutkowski W, Panic N, et al. Non-alcoholic fatty pancreas disease and pancreatic exocrine insufficiency: pilot study and systematic review. Scand J Gastroenterol 2023; 58(9): 1030-7.
Gullo L, Corcioni E, Brancati C, Bria M, Pezzilli R, Sprovieri G. Morphologic and functional evaluation of the exocrine pancreas in beta-thalassemia major. Pancreas 1993; 8(2): 176-80.
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Sadr-Azodi O, Sanders DS, Murray JA, Ludvigsson JF. Patients with celiac disease have an increased risk for pancreatitis. Clin Gastroenterol Hepatol 2012; 10(10): 1136-42.e3.
Angelini G, Cavallini G, Bovo P, et al. Pancreatic function in chronic inflammatory bowel disease. Int J Pancreatol 1988; 3(2-3): 185-93.
Leeds JS, Hopper AD, Sidhu R, et al. Some patients with irritable bowel syndrome may have exocrine pancreatic insufficiency. Clin Gastroenterol Hepatol 2010; 8(5): 433-8.
Eshet Y, Baruch EN, Shapira-Frommer R, et al. Clinical Significance of Pancreatic Atrophy Induced by Immune-Checkpoint Inhibitors: A Case-Control Study. Cancer Immunol Res 2018; 6(12): 1453-8.
Carroccio A, Di Prima L, Di Grigoli C, et al. Exocrine pancreatic function and fat malabsorption in human immunodeficiency virus-infected patients. Scand J Gastroenterol 1999; 34(7): 729-34.
Price DA, Schmid ML, Ong EL, Adjukeiwicz KM, Peaston B, Snow MH. Pancreatic exocrine insufficiency in HIV-positive patients. HIV Med 2005; 6(1): 33-6.
Bartos V, Melichar J, Erben J. The function of the exocrine pancreas in chronic renal disease. Digestion 1970; 3(1): 33-40.
Faiss S, Pape UF, Böhmig M, et al. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors–the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol 2003; 21(14): 2689-96.
Lamarca A, McCallum L, Nuttall C, et al. Somatostatin analogue-induced pancreatic exocrine insufficiency in patients with neuroendocrine tumors: results of a prospective observational study. Expert Rev Gastroenterol Hepatol 2018; 12(7): 723-31.
Nikolic S, Dugic A, Steiner C, et al. Chronic pancreatitis and the heart disease: Still terra incognita? World J Gastroenterol 2019; 25(44): 6561-70.
Xia T, Chai X, Shen J. Pancreatic exocrine insufficiency in patients with chronic heart failure and its possible association with appetite loss. PLoS One 2017; 12(11): e0187804.
Hedström A, Kvarnström M, Lindberg G, et al. High prevalence of gastrointestinal symptoms in patients with primary Sjögren’s syndrome cannot be attributed to pancreatic exocrine insufficiency. Scand J Gastroenterol 2022; 57(10): 1250-6.

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