Pancreas and Biliary Tract

Acute pancreatitis can be associated with multiorgan system failure, including respiratory failure, which has a high mortality rate. Acute respiratory distress syndrome (ARDS) is a known complication of severe, acute pancreatitis, and is fatal in up to 40% of cases. Mortality rates exceed 80% in patients with PaO₂/FiO₂ < 100 mm Hg.² Although ARDS is typically associated with bilateral pulmonary infiltrates, severe hypoxemia in pancreatitis may not be visible in radiography in up to 50% of cases.¹

Hypertriglyceridemia is the third-most common cause of acute pancreatitis, with an incidence of 2% to 10% among patients diagnosed with acute pancreatitis.^3.4 Elevated serum triglycerides have been proposed to trigger acute pancreatitis by increasing plasma viscosity, which leads to ischemia and inflammation of the pancreas.⁴ In severe cases of hypertriglyceridemia-induced acute pancreatitis, plasmapheresis is used to rapidly reduce serum chylomicron and triglyceride levels.³    

This case report discusses a patient with acute pancreatitis whose hypoxemia coincided with the severity of hypertriglyceridemia, but without radiographic evidence of pulmonary infiltrates or other known pulmonary causes.

Case Presentation

A 60-year-old male presented to the emergency department with several hours of diffuse abdominal pain, nausea, and vomiting. The patient reported that his symptoms began after eating fried chicken. He reported no dyspnea, fever, chills, or other symptoms. His medical history included type 2 diabetes (hemoglobin A_1c, 11.1%), Hashimoto hypothyroidism, severe obstructive sleep apnea not on continuous positive airway pressure (apnea-hypoxia index, 59/h), and obesity (body mass index, 52). Initial vital signs were afebrile, heart rate of 90 beats/min, and oxygen saturation (SpO₂) of 85% on 6L oxygen via nasal cannula. He was admitted to the intensive care unit and quickly maximized on high flow nasal cannula, ultimately requiring endotracheal intubation and mechanical ventilation.

Initial laboratory studies were remarkable for serum sodium of 120 mmol/L (reference range, 136-146 mmol/L), creatinine of 1.65 mg/dL (reference range, 0.52-1.28 mg/dL), anion gap of 18 mEq/L (reference range, 3-11 mEq/L), lipase level of 1115 U/L (reference range, 11-82 U/L), glucose level of 334 mg/dL (reference range, 70-110 mg/dL), white blood count of 13.1 K/uL (reference range, 4.5-11.0 K/uL), lactate level of 3.8 mmol/L (reference range, 0.5-2.2 mmol/L), triglyceride level of 1605 mg/dL (reference range, 40-160 mg/dL), cholesterol level of 565 mg/dL (reference range, < 200 mg/dL), aminotransferase of 21 U/L (reference range, 13-36 U/L), alanine aminotransferase of < 3 U/L (reference range, 7-45 U/L), and total bilirubin level of 1.6 mg/dL (reference range, 0.2-1 mg/dL).     

The patient had an initial arterial blood gas pH of 7.26, partial pressure of CO₂ and O₂ of 64.1 mm Hg and 74.1 mm Hg, respectively, on volume control with a tidal volume of 500 mL, positive end-expiratory pressure of 10 cm H₂O, respiratory rate of 26 breaths/min, and FiO₂ was 100%, which yielded a PaO₂/FiO₂ of 74 mm Hg. The patient was maintained in steep reverse-Trendelenburg position with moderate improvement in his SpO₂.    

Chest X-ray and computed tomography angiogram did not reveal pleural effusions, pulmonary infiltrates, or pulmonary embolism (Figure 1). Computed tomography of the abdomen and pelvis demonstrated severe acute interstitial edematous pancreatitis with no evidence of pancreatic necrosis or evidence of gallstones (Figure 2). A transthoracic echocardiogram with bubble was negative for intracardiac right to left shunting.    

The leading diagnosis was ARDS secondary to acute pancreatitis with hypoxemia exacerbated by morbid obesity and untreated obstructive sleep apnea leading to hypoventilation.

Treatment

The patient was intubated and restricted to nothing by mouth and provided fluid resuscitation with crystalloids. On hospital day 1, he remained intubated and on mechanical ventilation, started on plasmapheresis and continued insulin infusion for severe hypertriglyceridemia. The patient’s PaO₂/FiO₂ ratio remained persistently < 100 mm Hg despite maximal ventilatory support. After 3 sessions of plasmapheresis, the serum triglyceride levels and oxygen requirements improved (Figure 3).

Due to prolonged intubation, the patient ultimately required a tracheostomy. By hospital day 48, the patient was successfully weaned off mechanical ventilation. His tracheostomy was decannulated uneventfully on hospital day 55 and the stoma was closed. The patient was discharged to a skilled nursing home for rehabilitation and received intensive physical therapy for deconditioning from prolonged hospitalization.

Discussion

Respiratory insufficiency is a common and potentially lethal complication observed in one-third of patients with acute pancreatitis.¹ Radiographic evidence of pleural effusions, atelectasis and pulmonary infiltrates are often present. Acute lung injury (ALI) and ARDS are the most severe pulmonary complications of acute pancreatitis.⁵ It has been proposed that ALI and ARDS are driven by a hyperinflammatory state, which has multiple downstream effects. Pulmonary parenchymal and vascular damage has been associated with activated proinflammatory cytokines, trypsin, phospholipase A, and free fatty acids (Figure 4).¹

Hypoxemia secondary to acute pancreatitis may occur without initial radiographic findings and has been observed in up to half of patients.¹ Hypoxemia in ARDS occurs due to ventilation-perfusion defects causing gas exchange impairments which may be worsened further by high distending volumes and pressures on mechanical ventilation, dyssynchronous breathing, and/or lung derecruitment.⁶ Patients who require intubation for pancreatitis-associated ALI or ARDS eventually exhibit imaging findings consistent with their disease.¹ The patient in this case exhibited severe hypoxemia for several days despite persistently negative radiographic studies. His history of obstructive sleep apnea and a body mass index of 52 may have contributed to respiratory failure; however, assessment of other contributors to the acute and profound hypoxemia yielded largely unremarkable results. The patient did not have a history or evidence of heart failure and his hypoxemia did not improve with diuresis. He tested positive for COVID-19 on admission and was briefly treated with remdesivir and dexamethasone, but it was determined that the test was likely a false positive due to negative subsequent tests and elevated cycle thresholds (> 40). A concomitant COVID-19 infection likely did not contribute to his symptoms.    

Ventilation-perfusion mismatch is a well-recognized complication of pancreatitis, which results in right-to-left shunting.⁵ While we considered whether an intracardiac shunt may have contributed to the patient’s hypoxemia, a transthoracic echocardiogram with bubble contrast was negative.    

The patient had a peak serum triglyceride of > 6000 mg/dl, which meets the criteria for very severe hypertriglyceridemia.⁷ As observed in prior reports, the extent of the hypertriglyceridemia in this patient resulted in pronounced lipemic blood, which was appreciable by the eye and necessitated several rounds of centrifugation to analyze the laboratory studies.⁸ In this case, plasmapheresis was used to rapidly treat the hypertriglyceridemia, thereby reducing inflammation and further damage to the pancreas.⁹    

It is possible the patient’s hypertriglyceridemia may have been associated with his hypoxemia. His hypoxemia was most pronounced approximately 24 hours postadmission, which coincided with the peak of the hypertriglyceridemia. It remains unclear whether the severity of triglyceride elevation could accurately predict the severity of respiratory insufficiency. Hypoxemia is thought to modulate triglyceride metabolism through stimulation of intracellular lipolysis, upregulation of very low-density lipoproteins production in the liver, and inhibition of triglyceride-rich lipoprotein metabolism.¹⁰ Evidence from rodent studies supports the idea that acute hypoxemia increases triglycerides, and the degree of hypoxemia correlates with the elevated triglyceride levels.¹¹ However, this has not been consistently observed in humans and may vary by prandial state.^12,13 Thus, dysfunction of lipid metabolism may be a relevant clinical indicator of hypoxemia; further work is needed to elucidate this association.

Patient Perspective

The patient continues to undergo extensive rehabilitation following his prolonged illness and hospitalization. He expressed gratitude for the care received. However, he has limited and distorted recollection of the events during his hospitalization and stated that it felt “like an extraterrestrial state.”

Conclusions

This report describes a case of marked hypoxemia in the setting of acute pancreatitis. Pulmonary insufficiency in acute pancreatitis is commonly associated with imaging findings such as atelectasis, pleural effusions, and pulmonary infiltrates; however, up to half of cases initially lack any radiographic findings. Plasmapheresis is an effective treatment for hypertriglyceridemia-induced pancreatitis to both directly reduce circulating triglycerides and inflammation. Plasmapheresis also represents a promising therapy for the prevention of further episodes of pancreatitis in patients with recurrent pancreatitis. We propose a feedback mechanism through which pancreatitis induces severe hypoxemia, which may modulate lipid metabolism and severe hypertriglyceridemia correlates with respiratory failure.

Acute pancreatitis can be associated with multiorgan system failure, including respiratory failure, which has a high mortality rate. Acute respiratory distress syndrome (ARDS) is a known complication of severe, acute pancreatitis, and is fatal in up to 40% of cases. Mortality rates exceed 80% in patients with PaO₂/FiO₂ < 100 mm Hg.² Although ARDS is typically associated with bilateral pulmonary infiltrates, severe hypoxemia in pancreatitis may not be visible in radiography in up to 50% of cases.¹

Hypertriglyceridemia is the third-most common cause of acute pancreatitis, with an incidence of 2% to 10% among patients diagnosed with acute pancreatitis.^3.4 Elevated serum triglycerides have been proposed to trigger acute pancreatitis by increasing plasma viscosity, which leads to ischemia and inflammation of the pancreas.⁴ In severe cases of hypertriglyceridemia-induced acute pancreatitis, plasmapheresis is used to rapidly reduce serum chylomicron and triglyceride levels.³    

This case report discusses a patient with acute pancreatitis whose hypoxemia coincided with the severity of hypertriglyceridemia, but without radiographic evidence of pulmonary infiltrates or other known pulmonary causes.

Case Presentation

A 60-year-old male presented to the emergency department with several hours of diffuse abdominal pain, nausea, and vomiting. The patient reported that his symptoms began after eating fried chicken. He reported no dyspnea, fever, chills, or other symptoms. His medical history included type 2 diabetes (hemoglobin A_1c, 11.1%), Hashimoto hypothyroidism, severe obstructive sleep apnea not on continuous positive airway pressure (apnea-hypoxia index, 59/h), and obesity (body mass index, 52). Initial vital signs were afebrile, heart rate of 90 beats/min, and oxygen saturation (SpO₂) of 85% on 6L oxygen via nasal cannula. He was admitted to the intensive care unit and quickly maximized on high flow nasal cannula, ultimately requiring endotracheal intubation and mechanical ventilation.

Initial laboratory studies were remarkable for serum sodium of 120 mmol/L (reference range, 136-146 mmol/L), creatinine of 1.65 mg/dL (reference range, 0.52-1.28 mg/dL), anion gap of 18 mEq/L (reference range, 3-11 mEq/L), lipase level of 1115 U/L (reference range, 11-82 U/L), glucose level of 334 mg/dL (reference range, 70-110 mg/dL), white blood count of 13.1 K/uL (reference range, 4.5-11.0 K/uL), lactate level of 3.8 mmol/L (reference range, 0.5-2.2 mmol/L), triglyceride level of 1605 mg/dL (reference range, 40-160 mg/dL), cholesterol level of 565 mg/dL (reference range, < 200 mg/dL), aminotransferase of 21 U/L (reference range, 13-36 U/L), alanine aminotransferase of < 3 U/L (reference range, 7-45 U/L), and total bilirubin level of 1.6 mg/dL (reference range, 0.2-1 mg/dL).     

The patient had an initial arterial blood gas pH of 7.26, partial pressure of CO₂ and O₂ of 64.1 mm Hg and 74.1 mm Hg, respectively, on volume control with a tidal volume of 500 mL, positive end-expiratory pressure of 10 cm H₂O, respiratory rate of 26 breaths/min, and FiO₂ was 100%, which yielded a PaO₂/FiO₂ of 74 mm Hg. The patient was maintained in steep reverse-Trendelenburg position with moderate improvement in his SpO₂.    

Chest X-ray and computed tomography angiogram did not reveal pleural effusions, pulmonary infiltrates, or pulmonary embolism (Figure 1). Computed tomography of the abdomen and pelvis demonstrated severe acute interstitial edematous pancreatitis with no evidence of pancreatic necrosis or evidence of gallstones (Figure 2). A transthoracic echocardiogram with bubble was negative for intracardiac right to left shunting.    

The leading diagnosis was ARDS secondary to acute pancreatitis with hypoxemia exacerbated by morbid obesity and untreated obstructive sleep apnea leading to hypoventilation.

Treatment

The patient was intubated and restricted to nothing by mouth and provided fluid resuscitation with crystalloids. On hospital day 1, he remained intubated and on mechanical ventilation, started on plasmapheresis and continued insulin infusion for severe hypertriglyceridemia. The patient’s PaO₂/FiO₂ ratio remained persistently < 100 mm Hg despite maximal ventilatory support. After 3 sessions of plasmapheresis, the serum triglyceride levels and oxygen requirements improved (Figure 3).

Due to prolonged intubation, the patient ultimately required a tracheostomy. By hospital day 48, the patient was successfully weaned off mechanical ventilation. His tracheostomy was decannulated uneventfully on hospital day 55 and the stoma was closed. The patient was discharged to a skilled nursing home for rehabilitation and received intensive physical therapy for deconditioning from prolonged hospitalization.

Discussion

Respiratory insufficiency is a common and potentially lethal complication observed in one-third of patients with acute pancreatitis.¹ Radiographic evidence of pleural effusions, atelectasis and pulmonary infiltrates are often present. Acute lung injury (ALI) and ARDS are the most severe pulmonary complications of acute pancreatitis.⁵ It has been proposed that ALI and ARDS are driven by a hyperinflammatory state, which has multiple downstream effects. Pulmonary parenchymal and vascular damage has been associated with activated proinflammatory cytokines, trypsin, phospholipase A, and free fatty acids (Figure 4).¹

Hypoxemia secondary to acute pancreatitis may occur without initial radiographic findings and has been observed in up to half of patients.¹ Hypoxemia in ARDS occurs due to ventilation-perfusion defects causing gas exchange impairments which may be worsened further by high distending volumes and pressures on mechanical ventilation, dyssynchronous breathing, and/or lung derecruitment.⁶ Patients who require intubation for pancreatitis-associated ALI or ARDS eventually exhibit imaging findings consistent with their disease.¹ The patient in this case exhibited severe hypoxemia for several days despite persistently negative radiographic studies. His history of obstructive sleep apnea and a body mass index of 52 may have contributed to respiratory failure; however, assessment of other contributors to the acute and profound hypoxemia yielded largely unremarkable results. The patient did not have a history or evidence of heart failure and his hypoxemia did not improve with diuresis. He tested positive for COVID-19 on admission and was briefly treated with remdesivir and dexamethasone, but it was determined that the test was likely a false positive due to negative subsequent tests and elevated cycle thresholds (> 40). A concomitant COVID-19 infection likely did not contribute to his symptoms.    

Ventilation-perfusion mismatch is a well-recognized complication of pancreatitis, which results in right-to-left shunting.⁵ While we considered whether an intracardiac shunt may have contributed to the patient’s hypoxemia, a transthoracic echocardiogram with bubble contrast was negative.    

The patient had a peak serum triglyceride of > 6000 mg/dl, which meets the criteria for very severe hypertriglyceridemia.⁷ As observed in prior reports, the extent of the hypertriglyceridemia in this patient resulted in pronounced lipemic blood, which was appreciable by the eye and necessitated several rounds of centrifugation to analyze the laboratory studies.⁸ In this case, plasmapheresis was used to rapidly treat the hypertriglyceridemia, thereby reducing inflammation and further damage to the pancreas.⁹    

It is possible the patient’s hypertriglyceridemia may have been associated with his hypoxemia. His hypoxemia was most pronounced approximately 24 hours postadmission, which coincided with the peak of the hypertriglyceridemia. It remains unclear whether the severity of triglyceride elevation could accurately predict the severity of respiratory insufficiency. Hypoxemia is thought to modulate triglyceride metabolism through stimulation of intracellular lipolysis, upregulation of very low-density lipoproteins production in the liver, and inhibition of triglyceride-rich lipoprotein metabolism.¹⁰ Evidence from rodent studies supports the idea that acute hypoxemia increases triglycerides, and the degree of hypoxemia correlates with the elevated triglyceride levels.¹¹ However, this has not been consistently observed in humans and may vary by prandial state.^12,13 Thus, dysfunction of lipid metabolism may be a relevant clinical indicator of hypoxemia; further work is needed to elucidate this association.

Patient Perspective

The patient continues to undergo extensive rehabilitation following his prolonged illness and hospitalization. He expressed gratitude for the care received. However, he has limited and distorted recollection of the events during his hospitalization and stated that it felt “like an extraterrestrial state.”

Conclusions

This report describes a case of marked hypoxemia in the setting of acute pancreatitis. Pulmonary insufficiency in acute pancreatitis is commonly associated with imaging findings such as atelectasis, pleural effusions, and pulmonary infiltrates; however, up to half of cases initially lack any radiographic findings. Plasmapheresis is an effective treatment for hypertriglyceridemia-induced pancreatitis to both directly reduce circulating triglycerides and inflammation. Plasmapheresis also represents a promising therapy for the prevention of further episodes of pancreatitis in patients with recurrent pancreatitis. We propose a feedback mechanism through which pancreatitis induces severe hypoxemia, which may modulate lipid metabolism and severe hypertriglyceridemia correlates with respiratory failure.

Acute pancreatitis can be associated with multiorgan system failure, including respiratory failure, which has a high mortality rate. Acute respiratory distress syndrome (ARDS) is a known complication of severe, acute pancreatitis, and is fatal in up to 40% of cases. Mortality rates exceed 80% in patients with PaO₂/FiO₂ < 100 mm Hg.² Although ARDS is typically associated with bilateral pulmonary infiltrates, severe hypoxemia in pancreatitis may not be visible in radiography in up to 50% of cases.¹

Hypertriglyceridemia is the third-most common cause of acute pancreatitis, with an incidence of 2% to 10% among patients diagnosed with acute pancreatitis.^3.4 Elevated serum triglycerides have been proposed to trigger acute pancreatitis by increasing plasma viscosity, which leads to ischemia and inflammation of the pancreas.⁴ In severe cases of hypertriglyceridemia-induced acute pancreatitis, plasmapheresis is used to rapidly reduce serum chylomicron and triglyceride levels.³    

This case report discusses a patient with acute pancreatitis whose hypoxemia coincided with the severity of hypertriglyceridemia, but without radiographic evidence of pulmonary infiltrates or other known pulmonary causes.

Case Presentation

A 60-year-old male presented to the emergency department with several hours of diffuse abdominal pain, nausea, and vomiting. The patient reported that his symptoms began after eating fried chicken. He reported no dyspnea, fever, chills, or other symptoms. His medical history included type 2 diabetes (hemoglobin A_1c, 11.1%), Hashimoto hypothyroidism, severe obstructive sleep apnea not on continuous positive airway pressure (apnea-hypoxia index, 59/h), and obesity (body mass index, 52). Initial vital signs were afebrile, heart rate of 90 beats/min, and oxygen saturation (SpO₂) of 85% on 6L oxygen via nasal cannula. He was admitted to the intensive care unit and quickly maximized on high flow nasal cannula, ultimately requiring endotracheal intubation and mechanical ventilation.

Initial laboratory studies were remarkable for serum sodium of 120 mmol/L (reference range, 136-146 mmol/L), creatinine of 1.65 mg/dL (reference range, 0.52-1.28 mg/dL), anion gap of 18 mEq/L (reference range, 3-11 mEq/L), lipase level of 1115 U/L (reference range, 11-82 U/L), glucose level of 334 mg/dL (reference range, 70-110 mg/dL), white blood count of 13.1 K/uL (reference range, 4.5-11.0 K/uL), lactate level of 3.8 mmol/L (reference range, 0.5-2.2 mmol/L), triglyceride level of 1605 mg/dL (reference range, 40-160 mg/dL), cholesterol level of 565 mg/dL (reference range, < 200 mg/dL), aminotransferase of 21 U/L (reference range, 13-36 U/L), alanine aminotransferase of < 3 U/L (reference range, 7-45 U/L), and total bilirubin level of 1.6 mg/dL (reference range, 0.2-1 mg/dL).     

The patient had an initial arterial blood gas pH of 7.26, partial pressure of CO₂ and O₂ of 64.1 mm Hg and 74.1 mm Hg, respectively, on volume control with a tidal volume of 500 mL, positive end-expiratory pressure of 10 cm H₂O, respiratory rate of 26 breaths/min, and FiO₂ was 100%, which yielded a PaO₂/FiO₂ of 74 mm Hg. The patient was maintained in steep reverse-Trendelenburg position with moderate improvement in his SpO₂.    

Chest X-ray and computed tomography angiogram did not reveal pleural effusions, pulmonary infiltrates, or pulmonary embolism (Figure 1). Computed tomography of the abdomen and pelvis demonstrated severe acute interstitial edematous pancreatitis with no evidence of pancreatic necrosis or evidence of gallstones (Figure 2). A transthoracic echocardiogram with bubble was negative for intracardiac right to left shunting.    

The leading diagnosis was ARDS secondary to acute pancreatitis with hypoxemia exacerbated by morbid obesity and untreated obstructive sleep apnea leading to hypoventilation.

Treatment

The patient was intubated and restricted to nothing by mouth and provided fluid resuscitation with crystalloids. On hospital day 1, he remained intubated and on mechanical ventilation, started on plasmapheresis and continued insulin infusion for severe hypertriglyceridemia. The patient’s PaO₂/FiO₂ ratio remained persistently < 100 mm Hg despite maximal ventilatory support. After 3 sessions of plasmapheresis, the serum triglyceride levels and oxygen requirements improved (Figure 3).

Due to prolonged intubation, the patient ultimately required a tracheostomy. By hospital day 48, the patient was successfully weaned off mechanical ventilation. His tracheostomy was decannulated uneventfully on hospital day 55 and the stoma was closed. The patient was discharged to a skilled nursing home for rehabilitation and received intensive physical therapy for deconditioning from prolonged hospitalization.

Discussion

Respiratory insufficiency is a common and potentially lethal complication observed in one-third of patients with acute pancreatitis.¹ Radiographic evidence of pleural effusions, atelectasis and pulmonary infiltrates are often present. Acute lung injury (ALI) and ARDS are the most severe pulmonary complications of acute pancreatitis.⁵ It has been proposed that ALI and ARDS are driven by a hyperinflammatory state, which has multiple downstream effects. Pulmonary parenchymal and vascular damage has been associated with activated proinflammatory cytokines, trypsin, phospholipase A, and free fatty acids (Figure 4).¹

Hypoxemia secondary to acute pancreatitis may occur without initial radiographic findings and has been observed in up to half of patients.¹ Hypoxemia in ARDS occurs due to ventilation-perfusion defects causing gas exchange impairments which may be worsened further by high distending volumes and pressures on mechanical ventilation, dyssynchronous breathing, and/or lung derecruitment.⁶ Patients who require intubation for pancreatitis-associated ALI or ARDS eventually exhibit imaging findings consistent with their disease.¹ The patient in this case exhibited severe hypoxemia for several days despite persistently negative radiographic studies. His history of obstructive sleep apnea and a body mass index of 52 may have contributed to respiratory failure; however, assessment of other contributors to the acute and profound hypoxemia yielded largely unremarkable results. The patient did not have a history or evidence of heart failure and his hypoxemia did not improve with diuresis. He tested positive for COVID-19 on admission and was briefly treated with remdesivir and dexamethasone, but it was determined that the test was likely a false positive due to negative subsequent tests and elevated cycle thresholds (> 40). A concomitant COVID-19 infection likely did not contribute to his symptoms.    

Ventilation-perfusion mismatch is a well-recognized complication of pancreatitis, which results in right-to-left shunting.⁵ While we considered whether an intracardiac shunt may have contributed to the patient’s hypoxemia, a transthoracic echocardiogram with bubble contrast was negative.    

The patient had a peak serum triglyceride of > 6000 mg/dl, which meets the criteria for very severe hypertriglyceridemia.⁷ As observed in prior reports, the extent of the hypertriglyceridemia in this patient resulted in pronounced lipemic blood, which was appreciable by the eye and necessitated several rounds of centrifugation to analyze the laboratory studies.⁸ In this case, plasmapheresis was used to rapidly treat the hypertriglyceridemia, thereby reducing inflammation and further damage to the pancreas.⁹    

It is possible the patient’s hypertriglyceridemia may have been associated with his hypoxemia. His hypoxemia was most pronounced approximately 24 hours postadmission, which coincided with the peak of the hypertriglyceridemia. It remains unclear whether the severity of triglyceride elevation could accurately predict the severity of respiratory insufficiency. Hypoxemia is thought to modulate triglyceride metabolism through stimulation of intracellular lipolysis, upregulation of very low-density lipoproteins production in the liver, and inhibition of triglyceride-rich lipoprotein metabolism.¹⁰ Evidence from rodent studies supports the idea that acute hypoxemia increases triglycerides, and the degree of hypoxemia correlates with the elevated triglyceride levels.¹¹ However, this has not been consistently observed in humans and may vary by prandial state.^12,13 Thus, dysfunction of lipid metabolism may be a relevant clinical indicator of hypoxemia; further work is needed to elucidate this association.

Patient Perspective

The patient continues to undergo extensive rehabilitation following his prolonged illness and hospitalization. He expressed gratitude for the care received. However, he has limited and distorted recollection of the events during his hospitalization and stated that it felt “like an extraterrestrial state.”

Conclusions

This report describes a case of marked hypoxemia in the setting of acute pancreatitis. Pulmonary insufficiency in acute pancreatitis is commonly associated with imaging findings such as atelectasis, pleural effusions, and pulmonary infiltrates; however, up to half of cases initially lack any radiographic findings. Plasmapheresis is an effective treatment for hypertriglyceridemia-induced pancreatitis to both directly reduce circulating triglycerides and inflammation. Plasmapheresis also represents a promising therapy for the prevention of further episodes of pancreatitis in patients with recurrent pancreatitis. We propose a feedback mechanism through which pancreatitis induces severe hypoxemia, which may modulate lipid metabolism and severe hypertriglyceridemia correlates with respiratory failure.

Exocrine pancreatic insufficiency (EPI) is a recognized condition in patients with underlying pancreatic disease. However, it is a disease state that requires a meticulous approach to diagnose, as misdiagnosis can lead to inappropriate testing and unnecessary treatment.

EPI has been defined as “a near total decline in the quantity and/or activity of endogenous pancreatic enzymes to a level that is inadequate to maintain normal digestive capacity leading to steatorrhea.”¹ It can lead to complications including malnutrition, micronutrient deficiencies, metabolic bone disease and have significant impact on quality of life. In this article, we will review the approach to diagnosis of EPI, differential diagnosis considerations, the approach to treatment of EPI, and screening for complications.
 

EPI Diagnosis

EPI results from ineffective or insufficient pancreatic digestive enzyme secretion. In 2021, a group of experts from the American Gastroenterological Association (AGA) and PancreasFest met and proposed a new mechanistic definition of EPI. This suggests that EPI is the failure of sufficient pancreatic enzymes to effectively reach the intestine in order to allow for optimal digestion of ingested nutrients, leading to downstream macronutrient and micronutrient deficiencies with symptoms of maldigestion including post-prandial abdominal pain, bloating, steatorrhea, loose stools, or weight loss.²

A more pragmatic definition by Khan, et al in 2022 utilized a staging system to distinguish exocrine pancreatic dysfunction (EDP) from EPI. As such EPD occurs when there is a decline in pancreatic function without impaired digestive capacity, while EPI requires digestive capacity impairment leading to objective steatorrhea (coefficient of fat absorption <93 %).³Differential Diagnosis: There are many factors that can impact normal digestion. In approaching EPI, symptoms are often the most common reason to test for disease state in the appropriate clinical context. There can be pancreatic causes of EPI and non-pancreatic (secondary) causes of EPI (see Figure 1), though the latter can be challenging to detect.

The most common parenchymal etiologies for EPI include chronic pancreatitis, recurrent acute pancreatitis, cystic fibrosis, pancreatic cancer or prior pancreatic resections. Non-pancreatic conditions that impact synchronous mixing of endogenous pancreatic enzymes with meals (i.e., Roux-en-Y gastric bypass, short bowel syndrome, delayed gastric emptying), mucosal barriers causing decrease endogenous pancreatic stimulation despite intact parenchyma, such as celiac disease, foregut Crohn’s disease, intraluminal inactivation of pancreatic enzymes (Zollinger-Ellison syndrome), and bile salts de-conjugation with small intestinal bacterial overgrowth (SIBO) can predispose to EPI.^4-6 The true prevalence of EPI is difficult to ascertain due to a variety of factors including challenges in diagnosis and misdiagnosis.

Some of the major challenges in the diagnosis and treatment of EPI is that the symptoms of EPI overlap with many other GI conditions including celiac disease, diabetes mellitus, SIBO, irritable bowel syndrome (IBS), bile acid diarrhea, and other functional GI syndromes. These non-pancreatic conditions can also be associated with falsely low FE-1. Hence, ordering FE-1 should be employed with caution when the pretest probability is low. Patients with EPI will generally have a significant response to pancreatic enzyme replacement therapy (PERT) if it is adequately dosed and a lack of response should prompt consideration of an alternative diagnosis. A framework to factors which contribute to EPI is outlined in Figure 2.

Symptoms Screening and Signs: Pancreatic enzymes output estimation is the most reliable indicator for pancreatic digestive capacity. However, EPI diagnosis requires a combination of symptoms screening, stool-based (indirect pancreatic function) testing or direct pancreatic function testing (PFT).

Although symptoms might not correlate with objective disease state, in screening for symptoms of steatorrhea or maldigestion, it is important to ask specific questions regarding bloating, abdominal pain, stool frequency, consistency, and quality. Screening questions should be specific and include question such as, “Is there oil in the toilet bowl or is the stool greasy/shiny?”, “Is the stool sticky and difficult to flush or wipe?”, “Is there malodorous flatus?” If patients screen positive for EPI symptoms and there is a high pre-test probability of EPI such as the presence of severe chronic pancreatitis or significant pancreatic resection (> 90% loss of pancreatic parenchyma), then cautious trial of PERT and assessment for treatment response can be considered without additional stool-based testing. However, this practice end points are unclear and mainly based on subjective response.

Patients with EPI are at increased risk for malnutrition and micronutrient deficiencies. While not required for the diagnosis, low levels of fat-soluble vitamins (vitamin AEDK) or other minerals (zinc, selenium, magnesium, phosphorus) can suggest issues with malabsorption. Once the diagnosis of EPI is made, micronutrient screening should occur annually.

Stool Based Testing: The gold standard clinical test for steatorrhea is measuring coefficient of fat absorption (CFA). With a normal range of 93% fat absorption, the test is performed on a 72-hours fecal fat collection kit. To ensure accurate results, a patient must adhere to a diet with a minimum of 100 grams of fat per day in the three days leading up to the test and during the duration of the test. Patients must also abstain from taking PERT during the duration of the test. This can be incredibly challenging for someone with underlying steatorrhea but can reliably distinguish between EPD and EPI.

A more commonly used stool test is fecal elastase (FE-1). While easier to perform, the test often results in many false positives and false negatives. FE-1 is an ELISA based test, which measures the concentration of the specific isoform CELA3 (chymotrypsin-like elastase family) in the stool sample. The test must be run on a solid stool sample as soft or liquid stool will dilute down elastase concentration falsely. One test advantage is that a patient can continue PERT if needed. FE-1 test measures the concentration of patients’ elastase and PERT is porcine derived. As such, there is no interaction between porcine lipase and human elastase in stool. FE-1 sensitivity and specificity are high for severe disease (<100 mcg/g) if the test is performed properly on patients with a high pretest probability. However, the sensitivity and specificity are poor in mild to moderate pancreatic disease and in the absence of known pancreatic disease.⁷

Our suggested approach to utilizing FE-1 test is to reserve it for patients with known severe chronic pancreatitis or prior pancreatic surgery in patients with symptoms. In patients without pancreatic disease who are at low risk of EPI, a positive FE-1 can lead to misdiagnosis, further diagnostic testing, and unnecessary treatment. Currently, there is no stool-based test that is accurate, reproducible, and reliable.

Direct Pancreatic Function testing: Secretin stimulated PFT is highly reliable in measuring ductal function with bicarbonate concentration. However, it cannot reliably estimate acinar function as both do not decline at the same rate, unless in severe pancreatic disease. A much more robust test should include cholecystokinin analog to measure pancreatic enzymes concentration. This test involves endoscopy, administration of secretin, and/or a cholecystokinin analog, and subsequent measurement of bicarbonate and digestive enzymes in the pancreatic juice. This test is not routinely offered as it is invasive, cumbersome, and difficult to repeat for reassessment of pancreatic function over time.⁸

Treatment

The primary goal of treatment is to improve symptoms and nutritional status of the patient. EPI treatment consists of PERT and nutritional counseling. In the United States, there are multiple FDA approved PERT preparations, which include Creon, Zenpep, Pancreaze, Pertzye, Viokase, and Relizorb. While dosing is dependent on lipase concentration, all PERT (aside from Relizorb) preparations have a combination of lipase, proteases, and amylase. All but Viokace and Relizorb are enteric-coated formulations.⁹

In patients with an inadequate response to enteric coated PERT, non-enteric coated PERT can be added as it may provide a more immediate effect than enteric coated formulations, specially if concern about rapid gut transit with inadequate mixing is raised. If a non-enteric formations is used, acid suppression should be added to prevent inactivation of the PERT. Relizorb is a cartridge system which delivers lipase directly to tube feeds. This cartridge is only utilized in patients receiving enteral nutrition and allows for treatment of EPI even when patients are unable to tolerate oral feeding.

PERT dosing is intended to at least compensate for 10% of the physiologically secreted amount of endogenous lipase after a normal meal (approximately 30,000 IU). Hence, dosing is primarily weight-based. In symptomatic adults, PERT dose of 500-1000 units/kg/meal and half of the amount with snacks is appropriate. Although higher doses of 1500-2000 units/kg/meal may be needed when there is significant steatorrhea, weight loss, or micronutrient deficiencies, PERT doses exceeding 2500 units/kg/meal are not recommended and warrant further investigation.¹⁰

Proper counseling is important to ensure compliance with pancreatin preparations. PERT will generally be effective in improving steatorrhea, weight loss, bowel movement frequency, and reversal of nutritional deficiencies, but it does not reliably help symptoms of bloating or abdominal pain. If a patient’s steatorrhea does not respond to PERT, then alternative diagnoses such as SIBO, or diarrhea-predominant IBS should be considered.

PERT must be taken with meals. There are studies that support split dosing as a more effective way of absorbing fat.¹¹ If PERT is ineffective or minimally effective, review of appropriate dosing and timing of PERT to a meal is recommended. Addition of acid suppression may be required to improve treatment efficacy, especially in patients with abnormal intestinal motility or prior pancreatic surgery as PERT is effective at a pH of 4.5. Cost, pill burden, and persistence of certain symptoms may impact adherence to PERT and thus pre-treatment counseling and close follow-up after initiation is important. This aids in assessment of patients’ response to therapy, ensure appropriate PERT administration, and identifying any barriers to therapy adherence.

Nutritional management of EPI consists of an assessment of nutritional status, diet, and lifestyle. An important component of nutritional management is the assessment of micronutrient deficiencies. Patients with a confirmed diagnosis of EPI should be screened for the following micronutrients annually: Vitamins (A, E, D, K, B12), folate, zinc, selenium, magnesium, and iron. Patients with chronic pancreatitis and EPI should also be screened for metabolic bone disease once every two years and for diabetes mellitus annually.^{4, 12}

Conclusion

EPI is a challenging diagnosis as many symptoms overlap with other GI conditions. Pancreas exocrine function is rich with significant reserve to allow for proper digestive capacity, yet EPI occurs when an individual’s pancreatic digestive enzymes are insufficient to meet their nutritional needs. In patients with high likelihood of having EPI, such as those with pre-existing pancreatic disease, diagnosing EPI combines clinical evidence based on subjective symptoms and stool-based testing to support a disease state.

Appropriate dosing and timing of PERT is critical to improve nutritional outcomes and improve certain symptoms of EPI. Failure of PERT requires evaluating for proper dosing/timing, and consideration of additional or alternative diagnosis. EPI morbidity can lead to significant impact on patients’ quality of life, but with counseling, proper PERT use, nutritional consequences can be mediated, and quality of life can improve.

Dr. Hernandez-Barco is based in the Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts. Dr. Ashkar is based in the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Dr. Hernandez-Barco disclosed consulting for AMGEN and served as a scientific advisor for Nestle Health Science. She had project-related funding support or conflicts of interest to disclose. Dr. Ashkar disclosed consulting for AMGEN. He had no project-related funding support or conflicts of interest to disclose.

References

1. Othman MO, et al. Introduction and practical approach to exocrine pancreatic insufficiency for the practicing clinician. Int J Clin Pract. 2018 Feb. doi: 10.1111/ijcp.13066.

2. Whitcomb DC, et al. AGA-PancreasFest Joint Symposium on Exocrine Pancreatitic Insufficiency. Gastro Hep Adv. 2022 Nov. doi: 10.1016/j.gastha.2022.11.008.

3. Khan A, et al. Staging Exocrine Pancreatic Dysfunction. Pancreatology. 2022 Jan. doi: 10.1016/j.pan.2021.11.005.

4. Whitcomb DC, et al. AGA Clinical Practice Update on the Epidemiology, Evaluation, and Management of Exocrine Pancreatitis insufficiency: Expert Review. Gastroenterology. 2023 Nov. doi: 10.1053/j.gastro.2023.07.007.

5. Kunovský L, et al. Causes of Exocrine Pancreatic Insufficiency Other than Chronic Pancreatitis. J Clin Med. 2021 Dec. doi: 10.3390/jcm10245779.

6. Singh VK, et al. Less common etiologies of exocrine pancreatic insufficiency. World J Gastroenterol. 2017 Oct. doi: 10.3748/wjg.v23.i39.7059.

7. Lankisch PG, et al. Faecal elastase 1: not helpful in diagnosing chronic pancreatitis associated with mid to moderate exocrine pancreatic insufficiency. Gut. 1998 Apr. doi: 10.1136/gut.42.4.551.

8. Gardner TB, et al. ACG Clinical Guideline: Chronic Pancreatitis. Am J Gastroenterol. 2020 Mar. doi: 10.14309/ajg.0000000000000535.

9. Lewis DM, et al. Exocrine Pancreatic Insufficiency Dosing Guidelines for Pancreatic Enzyme Replacement Therapy Vary Widely Across Disease Types. Dig Dis Sci. 2024 Feb. doi: 10.1007/s10620-023-08184-w.

10. Borowitz DS, et al. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. Consensus Committee. J Pediatr. 1995 Nov. doi: 10.1016/s0022-3476(95)70153-2.

11. Domínguez-Muñoz JE, et al. Effect of the Administration Schedule on the therapeutic efficacy of oral pancreatic enzyme supplements in patients with exocrine pancreatic insufficiency: a randomized, three-way crossover study. Aliment Pharmacol Ther. 2005 Apr. doi: 10.1111/j.1365-2036.2005.02390.x.

12. Hart PA and Conwell DL. Chronic Pancreatitis: Managing a Difficult Disease. Am J Gastroenterol. 2020 Jan. doi: 10.14309/ajg.0000000000000421.

Exocrine pancreatic insufficiency (EPI) is a recognized condition in patients with underlying pancreatic disease. However, it is a disease state that requires a meticulous approach to diagnose, as misdiagnosis can lead to inappropriate testing and unnecessary treatment.

EPI has been defined as “a near total decline in the quantity and/or activity of endogenous pancreatic enzymes to a level that is inadequate to maintain normal digestive capacity leading to steatorrhea.”¹ It can lead to complications including malnutrition, micronutrient deficiencies, metabolic bone disease and have significant impact on quality of life. In this article, we will review the approach to diagnosis of EPI, differential diagnosis considerations, the approach to treatment of EPI, and screening for complications.
 

EPI Diagnosis

EPI results from ineffective or insufficient pancreatic digestive enzyme secretion. In 2021, a group of experts from the American Gastroenterological Association (AGA) and PancreasFest met and proposed a new mechanistic definition of EPI. This suggests that EPI is the failure of sufficient pancreatic enzymes to effectively reach the intestine in order to allow for optimal digestion of ingested nutrients, leading to downstream macronutrient and micronutrient deficiencies with symptoms of maldigestion including post-prandial abdominal pain, bloating, steatorrhea, loose stools, or weight loss.²

A more pragmatic definition by Khan, et al in 2022 utilized a staging system to distinguish exocrine pancreatic dysfunction (EDP) from EPI. As such EPD occurs when there is a decline in pancreatic function without impaired digestive capacity, while EPI requires digestive capacity impairment leading to objective steatorrhea (coefficient of fat absorption <93 %).³Differential Diagnosis: There are many factors that can impact normal digestion. In approaching EPI, symptoms are often the most common reason to test for disease state in the appropriate clinical context. There can be pancreatic causes of EPI and non-pancreatic (secondary) causes of EPI (see Figure 1), though the latter can be challenging to detect.

The most common parenchymal etiologies for EPI include chronic pancreatitis, recurrent acute pancreatitis, cystic fibrosis, pancreatic cancer or prior pancreatic resections. Non-pancreatic conditions that impact synchronous mixing of endogenous pancreatic enzymes with meals (i.e., Roux-en-Y gastric bypass, short bowel syndrome, delayed gastric emptying), mucosal barriers causing decrease endogenous pancreatic stimulation despite intact parenchyma, such as celiac disease, foregut Crohn’s disease, intraluminal inactivation of pancreatic enzymes (Zollinger-Ellison syndrome), and bile salts de-conjugation with small intestinal bacterial overgrowth (SIBO) can predispose to EPI.^4-6 The true prevalence of EPI is difficult to ascertain due to a variety of factors including challenges in diagnosis and misdiagnosis.

Some of the major challenges in the diagnosis and treatment of EPI is that the symptoms of EPI overlap with many other GI conditions including celiac disease, diabetes mellitus, SIBO, irritable bowel syndrome (IBS), bile acid diarrhea, and other functional GI syndromes. These non-pancreatic conditions can also be associated with falsely low FE-1. Hence, ordering FE-1 should be employed with caution when the pretest probability is low. Patients with EPI will generally have a significant response to pancreatic enzyme replacement therapy (PERT) if it is adequately dosed and a lack of response should prompt consideration of an alternative diagnosis. A framework to factors which contribute to EPI is outlined in Figure 2.

Symptoms Screening and Signs: Pancreatic enzymes output estimation is the most reliable indicator for pancreatic digestive capacity. However, EPI diagnosis requires a combination of symptoms screening, stool-based (indirect pancreatic function) testing or direct pancreatic function testing (PFT).

Although symptoms might not correlate with objective disease state, in screening for symptoms of steatorrhea or maldigestion, it is important to ask specific questions regarding bloating, abdominal pain, stool frequency, consistency, and quality. Screening questions should be specific and include question such as, “Is there oil in the toilet bowl or is the stool greasy/shiny?”, “Is the stool sticky and difficult to flush or wipe?”, “Is there malodorous flatus?” If patients screen positive for EPI symptoms and there is a high pre-test probability of EPI such as the presence of severe chronic pancreatitis or significant pancreatic resection (> 90% loss of pancreatic parenchyma), then cautious trial of PERT and assessment for treatment response can be considered without additional stool-based testing. However, this practice end points are unclear and mainly based on subjective response.

Patients with EPI are at increased risk for malnutrition and micronutrient deficiencies. While not required for the diagnosis, low levels of fat-soluble vitamins (vitamin AEDK) or other minerals (zinc, selenium, magnesium, phosphorus) can suggest issues with malabsorption. Once the diagnosis of EPI is made, micronutrient screening should occur annually.

Stool Based Testing: The gold standard clinical test for steatorrhea is measuring coefficient of fat absorption (CFA). With a normal range of 93% fat absorption, the test is performed on a 72-hours fecal fat collection kit. To ensure accurate results, a patient must adhere to a diet with a minimum of 100 grams of fat per day in the three days leading up to the test and during the duration of the test. Patients must also abstain from taking PERT during the duration of the test. This can be incredibly challenging for someone with underlying steatorrhea but can reliably distinguish between EPD and EPI.

A more commonly used stool test is fecal elastase (FE-1). While easier to perform, the test often results in many false positives and false negatives. FE-1 is an ELISA based test, which measures the concentration of the specific isoform CELA3 (chymotrypsin-like elastase family) in the stool sample. The test must be run on a solid stool sample as soft or liquid stool will dilute down elastase concentration falsely. One test advantage is that a patient can continue PERT if needed. FE-1 test measures the concentration of patients’ elastase and PERT is porcine derived. As such, there is no interaction between porcine lipase and human elastase in stool. FE-1 sensitivity and specificity are high for severe disease (<100 mcg/g) if the test is performed properly on patients with a high pretest probability. However, the sensitivity and specificity are poor in mild to moderate pancreatic disease and in the absence of known pancreatic disease.⁷

Our suggested approach to utilizing FE-1 test is to reserve it for patients with known severe chronic pancreatitis or prior pancreatic surgery in patients with symptoms. In patients without pancreatic disease who are at low risk of EPI, a positive FE-1 can lead to misdiagnosis, further diagnostic testing, and unnecessary treatment. Currently, there is no stool-based test that is accurate, reproducible, and reliable.

Direct Pancreatic Function testing: Secretin stimulated PFT is highly reliable in measuring ductal function with bicarbonate concentration. However, it cannot reliably estimate acinar function as both do not decline at the same rate, unless in severe pancreatic disease. A much more robust test should include cholecystokinin analog to measure pancreatic enzymes concentration. This test involves endoscopy, administration of secretin, and/or a cholecystokinin analog, and subsequent measurement of bicarbonate and digestive enzymes in the pancreatic juice. This test is not routinely offered as it is invasive, cumbersome, and difficult to repeat for reassessment of pancreatic function over time.⁸

Treatment

The primary goal of treatment is to improve symptoms and nutritional status of the patient. EPI treatment consists of PERT and nutritional counseling. In the United States, there are multiple FDA approved PERT preparations, which include Creon, Zenpep, Pancreaze, Pertzye, Viokase, and Relizorb. While dosing is dependent on lipase concentration, all PERT (aside from Relizorb) preparations have a combination of lipase, proteases, and amylase. All but Viokace and Relizorb are enteric-coated formulations.⁹

In patients with an inadequate response to enteric coated PERT, non-enteric coated PERT can be added as it may provide a more immediate effect than enteric coated formulations, specially if concern about rapid gut transit with inadequate mixing is raised. If a non-enteric formations is used, acid suppression should be added to prevent inactivation of the PERT. Relizorb is a cartridge system which delivers lipase directly to tube feeds. This cartridge is only utilized in patients receiving enteral nutrition and allows for treatment of EPI even when patients are unable to tolerate oral feeding.

PERT dosing is intended to at least compensate for 10% of the physiologically secreted amount of endogenous lipase after a normal meal (approximately 30,000 IU). Hence, dosing is primarily weight-based. In symptomatic adults, PERT dose of 500-1000 units/kg/meal and half of the amount with snacks is appropriate. Although higher doses of 1500-2000 units/kg/meal may be needed when there is significant steatorrhea, weight loss, or micronutrient deficiencies, PERT doses exceeding 2500 units/kg/meal are not recommended and warrant further investigation.¹⁰

Proper counseling is important to ensure compliance with pancreatin preparations. PERT will generally be effective in improving steatorrhea, weight loss, bowel movement frequency, and reversal of nutritional deficiencies, but it does not reliably help symptoms of bloating or abdominal pain. If a patient’s steatorrhea does not respond to PERT, then alternative diagnoses such as SIBO, or diarrhea-predominant IBS should be considered.

PERT must be taken with meals. There are studies that support split dosing as a more effective way of absorbing fat.¹¹ If PERT is ineffective or minimally effective, review of appropriate dosing and timing of PERT to a meal is recommended. Addition of acid suppression may be required to improve treatment efficacy, especially in patients with abnormal intestinal motility or prior pancreatic surgery as PERT is effective at a pH of 4.5. Cost, pill burden, and persistence of certain symptoms may impact adherence to PERT and thus pre-treatment counseling and close follow-up after initiation is important. This aids in assessment of patients’ response to therapy, ensure appropriate PERT administration, and identifying any barriers to therapy adherence.

Nutritional management of EPI consists of an assessment of nutritional status, diet, and lifestyle. An important component of nutritional management is the assessment of micronutrient deficiencies. Patients with a confirmed diagnosis of EPI should be screened for the following micronutrients annually: Vitamins (A, E, D, K, B12), folate, zinc, selenium, magnesium, and iron. Patients with chronic pancreatitis and EPI should also be screened for metabolic bone disease once every two years and for diabetes mellitus annually.^{4, 12}

Conclusion

EPI is a challenging diagnosis as many symptoms overlap with other GI conditions. Pancreas exocrine function is rich with significant reserve to allow for proper digestive capacity, yet EPI occurs when an individual’s pancreatic digestive enzymes are insufficient to meet their nutritional needs. In patients with high likelihood of having EPI, such as those with pre-existing pancreatic disease, diagnosing EPI combines clinical evidence based on subjective symptoms and stool-based testing to support a disease state.

Appropriate dosing and timing of PERT is critical to improve nutritional outcomes and improve certain symptoms of EPI. Failure of PERT requires evaluating for proper dosing/timing, and consideration of additional or alternative diagnosis. EPI morbidity can lead to significant impact on patients’ quality of life, but with counseling, proper PERT use, nutritional consequences can be mediated, and quality of life can improve.

Dr. Hernandez-Barco is based in the Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts. Dr. Ashkar is based in the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Dr. Hernandez-Barco disclosed consulting for AMGEN and served as a scientific advisor for Nestle Health Science. She had project-related funding support or conflicts of interest to disclose. Dr. Ashkar disclosed consulting for AMGEN. He had no project-related funding support or conflicts of interest to disclose.

References

1. Othman MO, et al. Introduction and practical approach to exocrine pancreatic insufficiency for the practicing clinician. Int J Clin Pract. 2018 Feb. doi: 10.1111/ijcp.13066.

2. Whitcomb DC, et al. AGA-PancreasFest Joint Symposium on Exocrine Pancreatitic Insufficiency. Gastro Hep Adv. 2022 Nov. doi: 10.1016/j.gastha.2022.11.008.

3. Khan A, et al. Staging Exocrine Pancreatic Dysfunction. Pancreatology. 2022 Jan. doi: 10.1016/j.pan.2021.11.005.

4. Whitcomb DC, et al. AGA Clinical Practice Update on the Epidemiology, Evaluation, and Management of Exocrine Pancreatitis insufficiency: Expert Review. Gastroenterology. 2023 Nov. doi: 10.1053/j.gastro.2023.07.007.

5. Kunovský L, et al. Causes of Exocrine Pancreatic Insufficiency Other than Chronic Pancreatitis. J Clin Med. 2021 Dec. doi: 10.3390/jcm10245779.

6. Singh VK, et al. Less common etiologies of exocrine pancreatic insufficiency. World J Gastroenterol. 2017 Oct. doi: 10.3748/wjg.v23.i39.7059.

7. Lankisch PG, et al. Faecal elastase 1: not helpful in diagnosing chronic pancreatitis associated with mid to moderate exocrine pancreatic insufficiency. Gut. 1998 Apr. doi: 10.1136/gut.42.4.551.

8. Gardner TB, et al. ACG Clinical Guideline: Chronic Pancreatitis. Am J Gastroenterol. 2020 Mar. doi: 10.14309/ajg.0000000000000535.

9. Lewis DM, et al. Exocrine Pancreatic Insufficiency Dosing Guidelines for Pancreatic Enzyme Replacement Therapy Vary Widely Across Disease Types. Dig Dis Sci. 2024 Feb. doi: 10.1007/s10620-023-08184-w.

10. Borowitz DS, et al. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. Consensus Committee. J Pediatr. 1995 Nov. doi: 10.1016/s0022-3476(95)70153-2.

11. Domínguez-Muñoz JE, et al. Effect of the Administration Schedule on the therapeutic efficacy of oral pancreatic enzyme supplements in patients with exocrine pancreatic insufficiency: a randomized, three-way crossover study. Aliment Pharmacol Ther. 2005 Apr. doi: 10.1111/j.1365-2036.2005.02390.x.

12. Hart PA and Conwell DL. Chronic Pancreatitis: Managing a Difficult Disease. Am J Gastroenterol. 2020 Jan. doi: 10.14309/ajg.0000000000000421.

Exocrine pancreatic insufficiency (EPI) is a recognized condition in patients with underlying pancreatic disease. However, it is a disease state that requires a meticulous approach to diagnose, as misdiagnosis can lead to inappropriate testing and unnecessary treatment.

EPI has been defined as “a near total decline in the quantity and/or activity of endogenous pancreatic enzymes to a level that is inadequate to maintain normal digestive capacity leading to steatorrhea.”¹ It can lead to complications including malnutrition, micronutrient deficiencies, metabolic bone disease and have significant impact on quality of life. In this article, we will review the approach to diagnosis of EPI, differential diagnosis considerations, the approach to treatment of EPI, and screening for complications.
 

EPI Diagnosis

EPI results from ineffective or insufficient pancreatic digestive enzyme secretion. In 2021, a group of experts from the American Gastroenterological Association (AGA) and PancreasFest met and proposed a new mechanistic definition of EPI. This suggests that EPI is the failure of sufficient pancreatic enzymes to effectively reach the intestine in order to allow for optimal digestion of ingested nutrients, leading to downstream macronutrient and micronutrient deficiencies with symptoms of maldigestion including post-prandial abdominal pain, bloating, steatorrhea, loose stools, or weight loss.²

A more pragmatic definition by Khan, et al in 2022 utilized a staging system to distinguish exocrine pancreatic dysfunction (EDP) from EPI. As such EPD occurs when there is a decline in pancreatic function without impaired digestive capacity, while EPI requires digestive capacity impairment leading to objective steatorrhea (coefficient of fat absorption <93 %).³Differential Diagnosis: There are many factors that can impact normal digestion. In approaching EPI, symptoms are often the most common reason to test for disease state in the appropriate clinical context. There can be pancreatic causes of EPI and non-pancreatic (secondary) causes of EPI (see Figure 1), though the latter can be challenging to detect.

The most common parenchymal etiologies for EPI include chronic pancreatitis, recurrent acute pancreatitis, cystic fibrosis, pancreatic cancer or prior pancreatic resections. Non-pancreatic conditions that impact synchronous mixing of endogenous pancreatic enzymes with meals (i.e., Roux-en-Y gastric bypass, short bowel syndrome, delayed gastric emptying), mucosal barriers causing decrease endogenous pancreatic stimulation despite intact parenchyma, such as celiac disease, foregut Crohn’s disease, intraluminal inactivation of pancreatic enzymes (Zollinger-Ellison syndrome), and bile salts de-conjugation with small intestinal bacterial overgrowth (SIBO) can predispose to EPI.^4-6 The true prevalence of EPI is difficult to ascertain due to a variety of factors including challenges in diagnosis and misdiagnosis.

Some of the major challenges in the diagnosis and treatment of EPI is that the symptoms of EPI overlap with many other GI conditions including celiac disease, diabetes mellitus, SIBO, irritable bowel syndrome (IBS), bile acid diarrhea, and other functional GI syndromes. These non-pancreatic conditions can also be associated with falsely low FE-1. Hence, ordering FE-1 should be employed with caution when the pretest probability is low. Patients with EPI will generally have a significant response to pancreatic enzyme replacement therapy (PERT) if it is adequately dosed and a lack of response should prompt consideration of an alternative diagnosis. A framework to factors which contribute to EPI is outlined in Figure 2.

Symptoms Screening and Signs: Pancreatic enzymes output estimation is the most reliable indicator for pancreatic digestive capacity. However, EPI diagnosis requires a combination of symptoms screening, stool-based (indirect pancreatic function) testing or direct pancreatic function testing (PFT).

Although symptoms might not correlate with objective disease state, in screening for symptoms of steatorrhea or maldigestion, it is important to ask specific questions regarding bloating, abdominal pain, stool frequency, consistency, and quality. Screening questions should be specific and include question such as, “Is there oil in the toilet bowl or is the stool greasy/shiny?”, “Is the stool sticky and difficult to flush or wipe?”, “Is there malodorous flatus?” If patients screen positive for EPI symptoms and there is a high pre-test probability of EPI such as the presence of severe chronic pancreatitis or significant pancreatic resection (> 90% loss of pancreatic parenchyma), then cautious trial of PERT and assessment for treatment response can be considered without additional stool-based testing. However, this practice end points are unclear and mainly based on subjective response.

Patients with EPI are at increased risk for malnutrition and micronutrient deficiencies. While not required for the diagnosis, low levels of fat-soluble vitamins (vitamin AEDK) or other minerals (zinc, selenium, magnesium, phosphorus) can suggest issues with malabsorption. Once the diagnosis of EPI is made, micronutrient screening should occur annually.

Stool Based Testing: The gold standard clinical test for steatorrhea is measuring coefficient of fat absorption (CFA). With a normal range of 93% fat absorption, the test is performed on a 72-hours fecal fat collection kit. To ensure accurate results, a patient must adhere to a diet with a minimum of 100 grams of fat per day in the three days leading up to the test and during the duration of the test. Patients must also abstain from taking PERT during the duration of the test. This can be incredibly challenging for someone with underlying steatorrhea but can reliably distinguish between EPD and EPI.

A more commonly used stool test is fecal elastase (FE-1). While easier to perform, the test often results in many false positives and false negatives. FE-1 is an ELISA based test, which measures the concentration of the specific isoform CELA3 (chymotrypsin-like elastase family) in the stool sample. The test must be run on a solid stool sample as soft or liquid stool will dilute down elastase concentration falsely. One test advantage is that a patient can continue PERT if needed. FE-1 test measures the concentration of patients’ elastase and PERT is porcine derived. As such, there is no interaction between porcine lipase and human elastase in stool. FE-1 sensitivity and specificity are high for severe disease (<100 mcg/g) if the test is performed properly on patients with a high pretest probability. However, the sensitivity and specificity are poor in mild to moderate pancreatic disease and in the absence of known pancreatic disease.⁷

Our suggested approach to utilizing FE-1 test is to reserve it for patients with known severe chronic pancreatitis or prior pancreatic surgery in patients with symptoms. In patients without pancreatic disease who are at low risk of EPI, a positive FE-1 can lead to misdiagnosis, further diagnostic testing, and unnecessary treatment. Currently, there is no stool-based test that is accurate, reproducible, and reliable.

Direct Pancreatic Function testing: Secretin stimulated PFT is highly reliable in measuring ductal function with bicarbonate concentration. However, it cannot reliably estimate acinar function as both do not decline at the same rate, unless in severe pancreatic disease. A much more robust test should include cholecystokinin analog to measure pancreatic enzymes concentration. This test involves endoscopy, administration of secretin, and/or a cholecystokinin analog, and subsequent measurement of bicarbonate and digestive enzymes in the pancreatic juice. This test is not routinely offered as it is invasive, cumbersome, and difficult to repeat for reassessment of pancreatic function over time.⁸

Treatment

The primary goal of treatment is to improve symptoms and nutritional status of the patient. EPI treatment consists of PERT and nutritional counseling. In the United States, there are multiple FDA approved PERT preparations, which include Creon, Zenpep, Pancreaze, Pertzye, Viokase, and Relizorb. While dosing is dependent on lipase concentration, all PERT (aside from Relizorb) preparations have a combination of lipase, proteases, and amylase. All but Viokace and Relizorb are enteric-coated formulations.⁹

In patients with an inadequate response to enteric coated PERT, non-enteric coated PERT can be added as it may provide a more immediate effect than enteric coated formulations, specially if concern about rapid gut transit with inadequate mixing is raised. If a non-enteric formations is used, acid suppression should be added to prevent inactivation of the PERT. Relizorb is a cartridge system which delivers lipase directly to tube feeds. This cartridge is only utilized in patients receiving enteral nutrition and allows for treatment of EPI even when patients are unable to tolerate oral feeding.

PERT dosing is intended to at least compensate for 10% of the physiologically secreted amount of endogenous lipase after a normal meal (approximately 30,000 IU). Hence, dosing is primarily weight-based. In symptomatic adults, PERT dose of 500-1000 units/kg/meal and half of the amount with snacks is appropriate. Although higher doses of 1500-2000 units/kg/meal may be needed when there is significant steatorrhea, weight loss, or micronutrient deficiencies, PERT doses exceeding 2500 units/kg/meal are not recommended and warrant further investigation.¹⁰

Proper counseling is important to ensure compliance with pancreatin preparations. PERT will generally be effective in improving steatorrhea, weight loss, bowel movement frequency, and reversal of nutritional deficiencies, but it does not reliably help symptoms of bloating or abdominal pain. If a patient’s steatorrhea does not respond to PERT, then alternative diagnoses such as SIBO, or diarrhea-predominant IBS should be considered.

PERT must be taken with meals. There are studies that support split dosing as a more effective way of absorbing fat.¹¹ If PERT is ineffective or minimally effective, review of appropriate dosing and timing of PERT to a meal is recommended. Addition of acid suppression may be required to improve treatment efficacy, especially in patients with abnormal intestinal motility or prior pancreatic surgery as PERT is effective at a pH of 4.5. Cost, pill burden, and persistence of certain symptoms may impact adherence to PERT and thus pre-treatment counseling and close follow-up after initiation is important. This aids in assessment of patients’ response to therapy, ensure appropriate PERT administration, and identifying any barriers to therapy adherence.

Nutritional management of EPI consists of an assessment of nutritional status, diet, and lifestyle. An important component of nutritional management is the assessment of micronutrient deficiencies. Patients with a confirmed diagnosis of EPI should be screened for the following micronutrients annually: Vitamins (A, E, D, K, B12), folate, zinc, selenium, magnesium, and iron. Patients with chronic pancreatitis and EPI should also be screened for metabolic bone disease once every two years and for diabetes mellitus annually.^{4, 12}

Conclusion

EPI is a challenging diagnosis as many symptoms overlap with other GI conditions. Pancreas exocrine function is rich with significant reserve to allow for proper digestive capacity, yet EPI occurs when an individual’s pancreatic digestive enzymes are insufficient to meet their nutritional needs. In patients with high likelihood of having EPI, such as those with pre-existing pancreatic disease, diagnosing EPI combines clinical evidence based on subjective symptoms and stool-based testing to support a disease state.

Appropriate dosing and timing of PERT is critical to improve nutritional outcomes and improve certain symptoms of EPI. Failure of PERT requires evaluating for proper dosing/timing, and consideration of additional or alternative diagnosis. EPI morbidity can lead to significant impact on patients’ quality of life, but with counseling, proper PERT use, nutritional consequences can be mediated, and quality of life can improve.

Dr. Hernandez-Barco is based in the Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts. Dr. Ashkar is based in the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Dr. Hernandez-Barco disclosed consulting for AMGEN and served as a scientific advisor for Nestle Health Science. She had project-related funding support or conflicts of interest to disclose. Dr. Ashkar disclosed consulting for AMGEN. He had no project-related funding support or conflicts of interest to disclose.

References

1. Othman MO, et al. Introduction and practical approach to exocrine pancreatic insufficiency for the practicing clinician. Int J Clin Pract. 2018 Feb. doi: 10.1111/ijcp.13066.

2. Whitcomb DC, et al. AGA-PancreasFest Joint Symposium on Exocrine Pancreatitic Insufficiency. Gastro Hep Adv. 2022 Nov. doi: 10.1016/j.gastha.2022.11.008.

3. Khan A, et al. Staging Exocrine Pancreatic Dysfunction. Pancreatology. 2022 Jan. doi: 10.1016/j.pan.2021.11.005.

4. Whitcomb DC, et al. AGA Clinical Practice Update on the Epidemiology, Evaluation, and Management of Exocrine Pancreatitis insufficiency: Expert Review. Gastroenterology. 2023 Nov. doi: 10.1053/j.gastro.2023.07.007.

5. Kunovský L, et al. Causes of Exocrine Pancreatic Insufficiency Other than Chronic Pancreatitis. J Clin Med. 2021 Dec. doi: 10.3390/jcm10245779.

6. Singh VK, et al. Less common etiologies of exocrine pancreatic insufficiency. World J Gastroenterol. 2017 Oct. doi: 10.3748/wjg.v23.i39.7059.

7. Lankisch PG, et al. Faecal elastase 1: not helpful in diagnosing chronic pancreatitis associated with mid to moderate exocrine pancreatic insufficiency. Gut. 1998 Apr. doi: 10.1136/gut.42.4.551.

8. Gardner TB, et al. ACG Clinical Guideline: Chronic Pancreatitis. Am J Gastroenterol. 2020 Mar. doi: 10.14309/ajg.0000000000000535.

9. Lewis DM, et al. Exocrine Pancreatic Insufficiency Dosing Guidelines for Pancreatic Enzyme Replacement Therapy Vary Widely Across Disease Types. Dig Dis Sci. 2024 Feb. doi: 10.1007/s10620-023-08184-w.

10. Borowitz DS, et al. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. Consensus Committee. J Pediatr. 1995 Nov. doi: 10.1016/s0022-3476(95)70153-2.

11. Domínguez-Muñoz JE, et al. Effect of the Administration Schedule on the therapeutic efficacy of oral pancreatic enzyme supplements in patients with exocrine pancreatic insufficiency: a randomized, three-way crossover study. Aliment Pharmacol Ther. 2005 Apr. doi: 10.1111/j.1365-2036.2005.02390.x.

12. Hart PA and Conwell DL. Chronic Pancreatitis: Managing a Difficult Disease. Am J Gastroenterol. 2020 Jan. doi: 10.14309/ajg.0000000000000421.

Below are some selections from what I am reading in the AGA journals, highlighting clinically applicable and possibly practice-changing expert reviews and studies.

Esophagus/Motility

Carlson DA, et al. A Standardized Approach to Performing and Interpreting Functional Lumen Imaging Probe Panometry for Esophageal Motility Disorders: The Dallas Consensus. Gastroenterology. 2025 Feb. doi: 10.1053/j.gastro.2025.01.234.

Parkman HP, et al; NIDDK Gastroparesis Clinical Research Consortium. Characterization of Patients with Symptoms of Gastroparesis Having Frequent Emergency Department Visits and Hospitalizations. Clin Gastroenterol Hepatol. 2025 Apr. doi: 10.1016/j.cgh.2025.01.033.

Dellon ES, et al. Long-term Safety and Efficacy of Budesonide Oral Suspension for Eosinophilic Esophagitis: A 4-Year, Phase 3, Open-Label Study. Clin Gastroenterol Hepatol. 2025 Feb. doi: 10.1016/j.cgh.2024.12.024.

Small Bowel

Hård Af Segerstad EM, et al; TEDDY Study Group. Early Dietary Fiber Intake Reduces Celiac Disease Risk in Genetically Prone Children: Insights From the TEDDY Study. Gastroenterology. 2025 Feb. doi: 10.1053/j.gastro.2025.01.241.

Colon

Shaukat A, et al. AGA Clinical Practice Update on Current Role of Blood Tests for Colorectal Cancer Screening: Commentary. Clin Gastroenterol Hepatol. 2025 Apr. doi: 10.1016/j.cgh.2025.04.003.

Bergman D, et al. Cholecystectomy is a Risk Factor for Microscopic Colitis: A Nationwide Population-based Matched Case Control Study. Clin Gastroenterol Hepatol. 2025 Mar. doi: 10.1016/j.cgh.2024.12.032.

Inflammatory Bowel Disease

Ben-Horin S, et al; Israeli IBD Research Nucleus (IIRN). Capsule Endoscopy-Guided Proactive Treat-to-Target Versus Continued Standard Care in Patients With Quiescent Crohn’s Disease: A Randomized Controlled Trial. Gastroenterology. 2025 Mar. doi: 10.1053/j.gastro.2025.02.031.

Pancreas

Guilabert L, et al; ERICA Consortium. Impact of Fluid Therapy in the Emergency Department in Acute Pancreatitis: a posthoc analysis of the WATERFALL Trial. Clin Gastroenterol Hepatol. 2025 Apr. doi: 10.1016/j.cgh.2025.01.038.

Hepatology

Rhee H, et al. Noncontrast Magnetic Resonance Imaging vs Ultrasonography for Hepatocellular Carcinoma Surveillance: A Randomized, Single-Center Trial. Gastroenterology. 2025 Jan. doi: 10.1053/j.gastro.2024.12.035.

Kronsten VT, et al. Hepatic Encephalopathy: When Lactulose and Rifaximin Are Not Working. Gastroenterology. 2025 Jan. doi: 10.1053/j.gastro.2025.01.010.

Edelson JC, et al. Accuracy and Safety of Endoscopic Ultrasound–Guided Liver Biopsy in Patients with Metabolic Dysfunction–Associated Liver Disease. Tech Innov Gastrointest Endosc. 2025 Apr. doi: 10.1016/j.tige.2025.250918.

Miscellaneous

Martin J, et al. Practical and Impactful Tips for Private Industry Collaborations with Gastroenterology Practices. Clin Gastroenterol Hepatol. 2025 Mar. doi: 10.1016/j.cgh.2025.01.021.

Tejada, Natalia et al. Glucagon-like Peptide-1 Receptor Agonists Are Not Associated With Increased Incidence of Pneumonia After Endoscopic Procedures. Tech Innov Gastrointest Endosc. 2025 Apr. doi: 10.1016/j.tige.2025.250925.

Lazaridis KN, et al. Microplastics and Nanoplastics and the Digestive System. Gastro Hep Adv. 2025 May. doi: 10.1016/j.gastha.2025.100694.

Dr. Trieu is assistant professor of medicine, interventional endoscopy, in the Division of Gastroenterology at Washington University in St. Louis School of Medicine, Missouri.

Below are some selections from what I am reading in the AGA journals, highlighting clinically applicable and possibly practice-changing expert reviews and studies.

Esophagus/Motility

Carlson DA, et al. A Standardized Approach to Performing and Interpreting Functional Lumen Imaging Probe Panometry for Esophageal Motility Disorders: The Dallas Consensus. Gastroenterology. 2025 Feb. doi: 10.1053/j.gastro.2025.01.234.

Parkman HP, et al; NIDDK Gastroparesis Clinical Research Consortium. Characterization of Patients with Symptoms of Gastroparesis Having Frequent Emergency Department Visits and Hospitalizations. Clin Gastroenterol Hepatol. 2025 Apr. doi: 10.1016/j.cgh.2025.01.033.

Dellon ES, et al. Long-term Safety and Efficacy of Budesonide Oral Suspension for Eosinophilic Esophagitis: A 4-Year, Phase 3, Open-Label Study. Clin Gastroenterol Hepatol. 2025 Feb. doi: 10.1016/j.cgh.2024.12.024.

Small Bowel

Hård Af Segerstad EM, et al; TEDDY Study Group. Early Dietary Fiber Intake Reduces Celiac Disease Risk in Genetically Prone Children: Insights From the TEDDY Study. Gastroenterology. 2025 Feb. doi: 10.1053/j.gastro.2025.01.241.

Colon

Shaukat A, et al. AGA Clinical Practice Update on Current Role of Blood Tests for Colorectal Cancer Screening: Commentary. Clin Gastroenterol Hepatol. 2025 Apr. doi: 10.1016/j.cgh.2025.04.003.

Bergman D, et al. Cholecystectomy is a Risk Factor for Microscopic Colitis: A Nationwide Population-based Matched Case Control Study. Clin Gastroenterol Hepatol. 2025 Mar. doi: 10.1016/j.cgh.2024.12.032.

Inflammatory Bowel Disease

Ben-Horin S, et al; Israeli IBD Research Nucleus (IIRN). Capsule Endoscopy-Guided Proactive Treat-to-Target Versus Continued Standard Care in Patients With Quiescent Crohn’s Disease: A Randomized Controlled Trial. Gastroenterology. 2025 Mar. doi: 10.1053/j.gastro.2025.02.031.

Pancreas

Guilabert L, et al; ERICA Consortium. Impact of Fluid Therapy in the Emergency Department in Acute Pancreatitis: a posthoc analysis of the WATERFALL Trial. Clin Gastroenterol Hepatol. 2025 Apr. doi: 10.1016/j.cgh.2025.01.038.

Hepatology

Rhee H, et al. Noncontrast Magnetic Resonance Imaging vs Ultrasonography for Hepatocellular Carcinoma Surveillance: A Randomized, Single-Center Trial. Gastroenterology. 2025 Jan. doi: 10.1053/j.gastro.2024.12.035.

Kronsten VT, et al. Hepatic Encephalopathy: When Lactulose and Rifaximin Are Not Working. Gastroenterology. 2025 Jan. doi: 10.1053/j.gastro.2025.01.010.

Edelson JC, et al. Accuracy and Safety of Endoscopic Ultrasound–Guided Liver Biopsy in Patients with Metabolic Dysfunction–Associated Liver Disease. Tech Innov Gastrointest Endosc. 2025 Apr. doi: 10.1016/j.tige.2025.250918.

Miscellaneous

Martin J, et al. Practical and Impactful Tips for Private Industry Collaborations with Gastroenterology Practices. Clin Gastroenterol Hepatol. 2025 Mar. doi: 10.1016/j.cgh.2025.01.021.

Tejada, Natalia et al. Glucagon-like Peptide-1 Receptor Agonists Are Not Associated With Increased Incidence of Pneumonia After Endoscopic Procedures. Tech Innov Gastrointest Endosc. 2025 Apr. doi: 10.1016/j.tige.2025.250925.

Lazaridis KN, et al. Microplastics and Nanoplastics and the Digestive System. Gastro Hep Adv. 2025 May. doi: 10.1016/j.gastha.2025.100694.

Dr. Trieu is assistant professor of medicine, interventional endoscopy, in the Division of Gastroenterology at Washington University in St. Louis School of Medicine, Missouri.

Below are some selections from what I am reading in the AGA journals, highlighting clinically applicable and possibly practice-changing expert reviews and studies.

Esophagus/Motility

Carlson DA, et al. A Standardized Approach to Performing and Interpreting Functional Lumen Imaging Probe Panometry for Esophageal Motility Disorders: The Dallas Consensus. Gastroenterology. 2025 Feb. doi: 10.1053/j.gastro.2025.01.234.

Parkman HP, et al; NIDDK Gastroparesis Clinical Research Consortium. Characterization of Patients with Symptoms of Gastroparesis Having Frequent Emergency Department Visits and Hospitalizations. Clin Gastroenterol Hepatol. 2025 Apr. doi: 10.1016/j.cgh.2025.01.033.

Dellon ES, et al. Long-term Safety and Efficacy of Budesonide Oral Suspension for Eosinophilic Esophagitis: A 4-Year, Phase 3, Open-Label Study. Clin Gastroenterol Hepatol. 2025 Feb. doi: 10.1016/j.cgh.2024.12.024.

Small Bowel

Hård Af Segerstad EM, et al; TEDDY Study Group. Early Dietary Fiber Intake Reduces Celiac Disease Risk in Genetically Prone Children: Insights From the TEDDY Study. Gastroenterology. 2025 Feb. doi: 10.1053/j.gastro.2025.01.241.

Colon

Shaukat A, et al. AGA Clinical Practice Update on Current Role of Blood Tests for Colorectal Cancer Screening: Commentary. Clin Gastroenterol Hepatol. 2025 Apr. doi: 10.1016/j.cgh.2025.04.003.

Bergman D, et al. Cholecystectomy is a Risk Factor for Microscopic Colitis: A Nationwide Population-based Matched Case Control Study. Clin Gastroenterol Hepatol. 2025 Mar. doi: 10.1016/j.cgh.2024.12.032.

Inflammatory Bowel Disease

Ben-Horin S, et al; Israeli IBD Research Nucleus (IIRN). Capsule Endoscopy-Guided Proactive Treat-to-Target Versus Continued Standard Care in Patients With Quiescent Crohn’s Disease: A Randomized Controlled Trial. Gastroenterology. 2025 Mar. doi: 10.1053/j.gastro.2025.02.031.

Pancreas

Guilabert L, et al; ERICA Consortium. Impact of Fluid Therapy in the Emergency Department in Acute Pancreatitis: a posthoc analysis of the WATERFALL Trial. Clin Gastroenterol Hepatol. 2025 Apr. doi: 10.1016/j.cgh.2025.01.038.

Hepatology

Rhee H, et al. Noncontrast Magnetic Resonance Imaging vs Ultrasonography for Hepatocellular Carcinoma Surveillance: A Randomized, Single-Center Trial. Gastroenterology. 2025 Jan. doi: 10.1053/j.gastro.2024.12.035.

Kronsten VT, et al. Hepatic Encephalopathy: When Lactulose and Rifaximin Are Not Working. Gastroenterology. 2025 Jan. doi: 10.1053/j.gastro.2025.01.010.

Edelson JC, et al. Accuracy and Safety of Endoscopic Ultrasound–Guided Liver Biopsy in Patients with Metabolic Dysfunction–Associated Liver Disease. Tech Innov Gastrointest Endosc. 2025 Apr. doi: 10.1016/j.tige.2025.250918.

Miscellaneous

Martin J, et al. Practical and Impactful Tips for Private Industry Collaborations with Gastroenterology Practices. Clin Gastroenterol Hepatol. 2025 Mar. doi: 10.1016/j.cgh.2025.01.021.

Tejada, Natalia et al. Glucagon-like Peptide-1 Receptor Agonists Are Not Associated With Increased Incidence of Pneumonia After Endoscopic Procedures. Tech Innov Gastrointest Endosc. 2025 Apr. doi: 10.1016/j.tige.2025.250925.

Lazaridis KN, et al. Microplastics and Nanoplastics and the Digestive System. Gastro Hep Adv. 2025 May. doi: 10.1016/j.gastha.2025.100694.

Dr. Trieu is assistant professor of medicine, interventional endoscopy, in the Division of Gastroenterology at Washington University in St. Louis School of Medicine, Missouri.

“Defined about 30 years ago, autoimmune pancreatitis [AIP] remains a diagnostic challenge,” said Vinciane Rebours, MD, PhD, professor and head of the Pancreatology and Digestive Oncology Department, Beaujon Hospital in Clichy, France. She spoke at the Francophone Days of Hepatology, Gastroenterology, and Digestive Oncology 2025, held in Paris. The challenge lies in the fact that AIP includes two distinct clinical entities, neither of which is truly autoimmune. However, much remains unknown, including its natural history, cancer risk, and optimal treatment strategies. However, some aspects are now better understood.

Autoimmune Pancreatitis

AIP has two forms of involvement: Type 1 AIP, linked to immunoglobulin G4–related disease (IgG4-RD), and type 2 AIP, primarily associated with inflammatory bowel disease (IBD). These forms differ in their histological characteristics. Type 1 exhibits lymphoplasmacytic infiltration, extensive fibrosis, and IgG4-positive plasma cells. Type 2 presents with granulocytic lesions similar to those in Crohn’s disease.

Type 1 AIP typically affects men aged 50 years or older and is often associated with jaundice, pseudotumor formation, diabetes, and exocrine pancreatic insufficiency. “It is a systemic disease where lymphoplasmacytic infiltration can affect multiple organs, with the pancreas and lymph nodes most commonly involved,” said Rebours.

A definitive diagnosis of type 1 AIP requires three criteria: Organ involvement, serum IgG4 levels more than twice the normal level, and histological abnormalities on biopsy. If one of these criteria is missing, the diagnosis is considered probable or possible.

Diagnosing type 1 AIP is challenging because it can affect multiple organs, often with few symptoms, leading to significant clinical variability. Type 2 AIP, in contrast, generally affects younger individuals, with no gender preference. It is pathophysiologically distinct and is linked to IBD in 87% of cases. Diagnosis relies on clinical criteria, imaging abnormalities (parenchymal or ductal changes identifiable on scans), response to corticosteroids in symptomatic patients, and the presence of IBD. The absence of IgG4 can also aid in the diagnosis. However, gathering all these elements can be difficult.

 

Evolving Treatment

Symptomatic patients and those at risk for organ failure, particularly lung and kidney failure, are eligible for induction treatment. This involves the administration of full-dose corticosteroids for 4 weeks, followed by a tapering regimen. Remission was achieved in 99% of type 1 and 92% of type 2 cases. Corticosteroids can also be used as a “trial treatment” to assess corticosteroid sensitivity in patients with type 2 AIP.

The risk for recurrence (in case of nonresponse or recurrence before 12 months posttreatment) is higher in type 1 (one third of cases) than in type 2 (15%). In such cases, immunomodulators, primarily rituximab, are recommended for type 1 AIP. Rituximab can also be used as an induction treatment, either alone or in combination, or as maintenance therapy. Alternatives include mycophenolate mofetil or inebilizumab, which showed an 87% reduction in relapse risk according to data published in 2024.

Maintenance treatment for type 2 AIP is not yet fully standardized. The disease is often managed in a manner similar to that of IBD treatment. Rebours cautioned, “Management cannot stop at the pancreas; it is essential to detect all other paucisymptomatic manifestations through comprehensive annual imaging and biannual biological and functional screenings.”

 

Monitoring IgG4

Monitoring IgG4 levels is important for therapeutic follow-up but is not the “holy grail” for diagnosis, Rebours acknowledged. For instance, 20% of IgG4-RD cases have normal IgG4 levels, 20% of pancreatic cancers show elevated IgG4 levels, and some patients achieve clinical remission despite persistently abnormal IgG4 levels. Without strong suspicion of type 1 AIP, measuring IgG4 levels is “zero cost-effective.”

This disease, which is associated with the risk for underlying cancer, requires extensive imaging (CT, MRI, and endoscopic ultrasound) to differentiate between AIP and cancer. This step is essential to avoid unnecessary surgery on organs affected by IgG4-RD or for treating cancer with corticosteroids.

A version of this article appeared on Medscape.com.

“Defined about 30 years ago, autoimmune pancreatitis [AIP] remains a diagnostic challenge,” said Vinciane Rebours, MD, PhD, professor and head of the Pancreatology and Digestive Oncology Department, Beaujon Hospital in Clichy, France. She spoke at the Francophone Days of Hepatology, Gastroenterology, and Digestive Oncology 2025, held in Paris. The challenge lies in the fact that AIP includes two distinct clinical entities, neither of which is truly autoimmune. However, much remains unknown, including its natural history, cancer risk, and optimal treatment strategies. However, some aspects are now better understood.

Autoimmune Pancreatitis

AIP has two forms of involvement: Type 1 AIP, linked to immunoglobulin G4–related disease (IgG4-RD), and type 2 AIP, primarily associated with inflammatory bowel disease (IBD). These forms differ in their histological characteristics. Type 1 exhibits lymphoplasmacytic infiltration, extensive fibrosis, and IgG4-positive plasma cells. Type 2 presents with granulocytic lesions similar to those in Crohn’s disease.

Type 1 AIP typically affects men aged 50 years or older and is often associated with jaundice, pseudotumor formation, diabetes, and exocrine pancreatic insufficiency. “It is a systemic disease where lymphoplasmacytic infiltration can affect multiple organs, with the pancreas and lymph nodes most commonly involved,” said Rebours.

A definitive diagnosis of type 1 AIP requires three criteria: Organ involvement, serum IgG4 levels more than twice the normal level, and histological abnormalities on biopsy. If one of these criteria is missing, the diagnosis is considered probable or possible.

Diagnosing type 1 AIP is challenging because it can affect multiple organs, often with few symptoms, leading to significant clinical variability. Type 2 AIP, in contrast, generally affects younger individuals, with no gender preference. It is pathophysiologically distinct and is linked to IBD in 87% of cases. Diagnosis relies on clinical criteria, imaging abnormalities (parenchymal or ductal changes identifiable on scans), response to corticosteroids in symptomatic patients, and the presence of IBD. The absence of IgG4 can also aid in the diagnosis. However, gathering all these elements can be difficult.

 

Evolving Treatment

Symptomatic patients and those at risk for organ failure, particularly lung and kidney failure, are eligible for induction treatment. This involves the administration of full-dose corticosteroids for 4 weeks, followed by a tapering regimen. Remission was achieved in 99% of type 1 and 92% of type 2 cases. Corticosteroids can also be used as a “trial treatment” to assess corticosteroid sensitivity in patients with type 2 AIP.

The risk for recurrence (in case of nonresponse or recurrence before 12 months posttreatment) is higher in type 1 (one third of cases) than in type 2 (15%). In such cases, immunomodulators, primarily rituximab, are recommended for type 1 AIP. Rituximab can also be used as an induction treatment, either alone or in combination, or as maintenance therapy. Alternatives include mycophenolate mofetil or inebilizumab, which showed an 87% reduction in relapse risk according to data published in 2024.

Maintenance treatment for type 2 AIP is not yet fully standardized. The disease is often managed in a manner similar to that of IBD treatment. Rebours cautioned, “Management cannot stop at the pancreas; it is essential to detect all other paucisymptomatic manifestations through comprehensive annual imaging and biannual biological and functional screenings.”

 

Monitoring IgG4

Monitoring IgG4 levels is important for therapeutic follow-up but is not the “holy grail” for diagnosis, Rebours acknowledged. For instance, 20% of IgG4-RD cases have normal IgG4 levels, 20% of pancreatic cancers show elevated IgG4 levels, and some patients achieve clinical remission despite persistently abnormal IgG4 levels. Without strong suspicion of type 1 AIP, measuring IgG4 levels is “zero cost-effective.”

This disease, which is associated with the risk for underlying cancer, requires extensive imaging (CT, MRI, and endoscopic ultrasound) to differentiate between AIP and cancer. This step is essential to avoid unnecessary surgery on organs affected by IgG4-RD or for treating cancer with corticosteroids.

A version of this article appeared on Medscape.com.

“Defined about 30 years ago, autoimmune pancreatitis [AIP] remains a diagnostic challenge,” said Vinciane Rebours, MD, PhD, professor and head of the Pancreatology and Digestive Oncology Department, Beaujon Hospital in Clichy, France. She spoke at the Francophone Days of Hepatology, Gastroenterology, and Digestive Oncology 2025, held in Paris. The challenge lies in the fact that AIP includes two distinct clinical entities, neither of which is truly autoimmune. However, much remains unknown, including its natural history, cancer risk, and optimal treatment strategies. However, some aspects are now better understood.

Autoimmune Pancreatitis

AIP has two forms of involvement: Type 1 AIP, linked to immunoglobulin G4–related disease (IgG4-RD), and type 2 AIP, primarily associated with inflammatory bowel disease (IBD). These forms differ in their histological characteristics. Type 1 exhibits lymphoplasmacytic infiltration, extensive fibrosis, and IgG4-positive plasma cells. Type 2 presents with granulocytic lesions similar to those in Crohn’s disease.

Type 1 AIP typically affects men aged 50 years or older and is often associated with jaundice, pseudotumor formation, diabetes, and exocrine pancreatic insufficiency. “It is a systemic disease where lymphoplasmacytic infiltration can affect multiple organs, with the pancreas and lymph nodes most commonly involved,” said Rebours.

A definitive diagnosis of type 1 AIP requires three criteria: Organ involvement, serum IgG4 levels more than twice the normal level, and histological abnormalities on biopsy. If one of these criteria is missing, the diagnosis is considered probable or possible.

Diagnosing type 1 AIP is challenging because it can affect multiple organs, often with few symptoms, leading to significant clinical variability. Type 2 AIP, in contrast, generally affects younger individuals, with no gender preference. It is pathophysiologically distinct and is linked to IBD in 87% of cases. Diagnosis relies on clinical criteria, imaging abnormalities (parenchymal or ductal changes identifiable on scans), response to corticosteroids in symptomatic patients, and the presence of IBD. The absence of IgG4 can also aid in the diagnosis. However, gathering all these elements can be difficult.

 

Evolving Treatment

Symptomatic patients and those at risk for organ failure, particularly lung and kidney failure, are eligible for induction treatment. This involves the administration of full-dose corticosteroids for 4 weeks, followed by a tapering regimen. Remission was achieved in 99% of type 1 and 92% of type 2 cases. Corticosteroids can also be used as a “trial treatment” to assess corticosteroid sensitivity in patients with type 2 AIP.

The risk for recurrence (in case of nonresponse or recurrence before 12 months posttreatment) is higher in type 1 (one third of cases) than in type 2 (15%). In such cases, immunomodulators, primarily rituximab, are recommended for type 1 AIP. Rituximab can also be used as an induction treatment, either alone or in combination, or as maintenance therapy. Alternatives include mycophenolate mofetil or inebilizumab, which showed an 87% reduction in relapse risk according to data published in 2024.

Maintenance treatment for type 2 AIP is not yet fully standardized. The disease is often managed in a manner similar to that of IBD treatment. Rebours cautioned, “Management cannot stop at the pancreas; it is essential to detect all other paucisymptomatic manifestations through comprehensive annual imaging and biannual biological and functional screenings.”

 

Monitoring IgG4

Monitoring IgG4 levels is important for therapeutic follow-up but is not the “holy grail” for diagnosis, Rebours acknowledged. For instance, 20% of IgG4-RD cases have normal IgG4 levels, 20% of pancreatic cancers show elevated IgG4 levels, and some patients achieve clinical remission despite persistently abnormal IgG4 levels. Without strong suspicion of type 1 AIP, measuring IgG4 levels is “zero cost-effective.”

This disease, which is associated with the risk for underlying cancer, requires extensive imaging (CT, MRI, and endoscopic ultrasound) to differentiate between AIP and cancer. This step is essential to avoid unnecessary surgery on organs affected by IgG4-RD or for treating cancer with corticosteroids.

A version of this article appeared on Medscape.com.

Pancreatic cancer remains one of the most challenging cancers to diagnose early, with almost half of patients presenting with metastatic disease. Now, a growing body of evidence indicates that this deadly cancer has been steadily on the rise, particularly in younger individuals who may not even realize they are at risk.

A recent survey, for instance, found that 33% of 1000 respondents younger than 50 years believe that only older adults are at risk for pancreatic cancer, and more than half said they wouldn’t even recognize the early signs and symptoms, which include unexplained weight loss, fatigue, jaundice, abdominal pain that radiates to the back, nausea, and vomiting.

These survey findings allude to a bigger challenge: Identifying the disease remains elusive against a backdrop of these increasing rates and nonspecific risks and symptoms.

Currently, only about 15% of pancreatic cancers are caught at a localized, resectable stage, when 5-year survival rates are highest at 44%. But most are found later, after symptoms arise, and at this point, the 5-year survival odds plummet —16% for regional disease, 3% for distant, and 1% for stage IV.

 

“This disease is too often a silent killer, with no symptoms until it has progressed to less treatable stages,” said survey coauthor Zobeida Cruz-Monserrate, PhD, in the division of gastroenterology, hepatology and nutrition at Ohio State University Medical Center, Columbus.

 

Rising Rates

Since 2001, rates of pancreatic cancer have steadily increased by about 1% annually, and this increase appears greater among younger individuals, especially women.

A recent study in Gastroenterology, for instance, found that, while overall rates of pancreatic cancer among people aged 15-34 years remained low (0.3% in women and 0.2% in men) between 2001 and 2018, the average annual percent change in this age group was considerably higher than that for older individuals — 6.45% for women and 2.97% for men compared with 1.11% for women aged 55 years and 1.17% for men aged 55 years. Another recent analysis, published in Annals of Internal Medicine, reported similar increased rates in men and women aged 15-39 years between 2011 and 2019.

Although more than 90% of cases do occur in those 55 years or older, “we’re now seeing this disease in people who are in their 40s much more regularly,” Cruz-Monserrate said. “This is a concerning trend — and more research is needed to learn why.”

But it’s early days. Studies so far indicate that early onset pancreatic cancer tends to be even more aggressive, but the “underlying reason is not yet clear,” researcher wrote in a 2025 review.

Some evidence indicates younger individuals may have distinct molecular characteristics, whereas other research shows younger and older patients have similar genetic profiles. Younger patients may also be more likely to smoke, drink more, and delay seeking medical attention as well as experience delays in being diagnosed by physicians, the authors explained.

 

Catching It Early

Given the rising rates, early detection is especially important.

There are some known genetic and medical risk factors for pancreatic cancer. About 10% of these cancers are linked to heredity risk or genetic markers, including BRCA1 and BRCA2 or Lynch syndrome. People with chronic pancreatitis, type 2 diabetes, obesity, or with a family history of pancreatic cancer face an elevated risk.

Lifestyle factors can play a role as well. Alcohol consumption, a poor diet that includes red or processed meat, and smoking increase people’s risk for pancreatic cancer. In fact, smoking leads to a twofold higher risk, compared with not smoking.

 

However, uncovering pancreatic cancer from these factors alone can be like “finding a needle in a haystack,” said Srinivas Gaddam, MD, head of the pancreatic cancer screening and early detection program at Cedars-Sinai Medical Center in Los Angeles.

One strategy to help detect the disease earlier would be to screen more.

The latest guidance from the American Cancer Society suggests that people with a genetic predisposition or a family history of pancreatic cancer could benefit from annual surveillance with endoscopic ultrasound or MRI.

But the US Preventive Services Task Force currently recommends against routine screening of average-risk asymptomatic adults (JAMA. 2019;322[5]:438-444). The task force found no evidence that screening for pancreatic cancer improves disease-specific morbidity or mortality or all-cause mortality.

“The absolute incidence in younger people is far too small to make screening beneficial,” explained The Lancet Gastroenterology & Hepatology editors in a 2023 editorial.

In fact, more screening could lead to overdiagnosis, a concern reinforced by the recent study in Annals of Internal Medicine. That analysis found that much of the observed increase in early-onset pancreatic cancer stemmed from the detection of more small, early-stage endocrine cancer, rather than pancreatic adenocarcinoma, whereas mortality from the disease remained stable over the study period.

Recent findings do “suggest the potential for overdiagnosis and overtreatment, particularly in cases of indolent pancreatic neuroendocrine tumors,” Gaddam said.

Gaddam has observed an increase in both adenocarcinoma and neuroendocrine tumors in the clinic and in his research, especially in women younger than 50 years, but he noted these early onset diagnoses do remain rare.

 

Staying Vigilant

As the understanding of pancreatic cancer risks and symptoms evolves, ensuring that patients, especially younger individuals, recognize the warning signs, without causing alarm, remains a challenge.

The disease “presents more advanced in younger patients, but symptoms are so nonspecific,” said Randall Brand, MD, AGAF, director of the gastrointestinal malignancy early detection, diagnosis, and prevention program at the University of Pittsburgh Medical Center, Pennsylvania. Given that, “I am not sure how to best highlight a communication approach that would not cause undue stress to the patient and our healthcare resources.”

Gaddam agreed that it’s tough to pinpoint or communicate straightforward risks or symptoms to the general public without potentially leading to unnecessary screening.

At a minimum, however, clinicians can share more general risk-mitigating strategies with their patients.

Communicating such strategies may be especially important for younger patients, given that the recent survey found almost 40% of younger adults believe there’s nothing they can do to change their risk for pancreatic cancer.

However, Cruz-Monserrate explained, adults of all ages can lower their risks through regular exercise, limited alcohol and tobacco use, and a healthy diet with less red meat or processed meat.

Ultimately, for clinicians, given how difficult it is now to identify pancreatic cancer early, we have to “follow their good clinical judgment when alarming features, such as weight loss or nuances of pancreatic pain arise, and then get good imaging,” Gaddam said.

Cruz-Monserrate, Brand, and Gaddam reported no relevant disclosures.

A version of this article appeared on Medscape.com.

Pancreatic cancer remains one of the most challenging cancers to diagnose early, with almost half of patients presenting with metastatic disease. Now, a growing body of evidence indicates that this deadly cancer has been steadily on the rise, particularly in younger individuals who may not even realize they are at risk.

A recent survey, for instance, found that 33% of 1000 respondents younger than 50 years believe that only older adults are at risk for pancreatic cancer, and more than half said they wouldn’t even recognize the early signs and symptoms, which include unexplained weight loss, fatigue, jaundice, abdominal pain that radiates to the back, nausea, and vomiting.

These survey findings allude to a bigger challenge: Identifying the disease remains elusive against a backdrop of these increasing rates and nonspecific risks and symptoms.

Currently, only about 15% of pancreatic cancers are caught at a localized, resectable stage, when 5-year survival rates are highest at 44%. But most are found later, after symptoms arise, and at this point, the 5-year survival odds plummet —16% for regional disease, 3% for distant, and 1% for stage IV.

 

“This disease is too often a silent killer, with no symptoms until it has progressed to less treatable stages,” said survey coauthor Zobeida Cruz-Monserrate, PhD, in the division of gastroenterology, hepatology and nutrition at Ohio State University Medical Center, Columbus.

 

Rising Rates

Since 2001, rates of pancreatic cancer have steadily increased by about 1% annually, and this increase appears greater among younger individuals, especially women.

A recent study in Gastroenterology, for instance, found that, while overall rates of pancreatic cancer among people aged 15-34 years remained low (0.3% in women and 0.2% in men) between 2001 and 2018, the average annual percent change in this age group was considerably higher than that for older individuals — 6.45% for women and 2.97% for men compared with 1.11% for women aged 55 years and 1.17% for men aged 55 years. Another recent analysis, published in Annals of Internal Medicine, reported similar increased rates in men and women aged 15-39 years between 2011 and 2019.

Although more than 90% of cases do occur in those 55 years or older, “we’re now seeing this disease in people who are in their 40s much more regularly,” Cruz-Monserrate said. “This is a concerning trend — and more research is needed to learn why.”

But it’s early days. Studies so far indicate that early onset pancreatic cancer tends to be even more aggressive, but the “underlying reason is not yet clear,” researcher wrote in a 2025 review.

Some evidence indicates younger individuals may have distinct molecular characteristics, whereas other research shows younger and older patients have similar genetic profiles. Younger patients may also be more likely to smoke, drink more, and delay seeking medical attention as well as experience delays in being diagnosed by physicians, the authors explained.

 

Catching It Early

Given the rising rates, early detection is especially important.

There are some known genetic and medical risk factors for pancreatic cancer. About 10% of these cancers are linked to heredity risk or genetic markers, including BRCA1 and BRCA2 or Lynch syndrome. People with chronic pancreatitis, type 2 diabetes, obesity, or with a family history of pancreatic cancer face an elevated risk.

Lifestyle factors can play a role as well. Alcohol consumption, a poor diet that includes red or processed meat, and smoking increase people’s risk for pancreatic cancer. In fact, smoking leads to a twofold higher risk, compared with not smoking.

 

However, uncovering pancreatic cancer from these factors alone can be like “finding a needle in a haystack,” said Srinivas Gaddam, MD, head of the pancreatic cancer screening and early detection program at Cedars-Sinai Medical Center in Los Angeles.

One strategy to help detect the disease earlier would be to screen more.

The latest guidance from the American Cancer Society suggests that people with a genetic predisposition or a family history of pancreatic cancer could benefit from annual surveillance with endoscopic ultrasound or MRI.

But the US Preventive Services Task Force currently recommends against routine screening of average-risk asymptomatic adults (JAMA. 2019;322[5]:438-444). The task force found no evidence that screening for pancreatic cancer improves disease-specific morbidity or mortality or all-cause mortality.

“The absolute incidence in younger people is far too small to make screening beneficial,” explained The Lancet Gastroenterology & Hepatology editors in a 2023 editorial.

In fact, more screening could lead to overdiagnosis, a concern reinforced by the recent study in Annals of Internal Medicine. That analysis found that much of the observed increase in early-onset pancreatic cancer stemmed from the detection of more small, early-stage endocrine cancer, rather than pancreatic adenocarcinoma, whereas mortality from the disease remained stable over the study period.

Recent findings do “suggest the potential for overdiagnosis and overtreatment, particularly in cases of indolent pancreatic neuroendocrine tumors,” Gaddam said.

Gaddam has observed an increase in both adenocarcinoma and neuroendocrine tumors in the clinic and in his research, especially in women younger than 50 years, but he noted these early onset diagnoses do remain rare.

 

Staying Vigilant

As the understanding of pancreatic cancer risks and symptoms evolves, ensuring that patients, especially younger individuals, recognize the warning signs, without causing alarm, remains a challenge.

The disease “presents more advanced in younger patients, but symptoms are so nonspecific,” said Randall Brand, MD, AGAF, director of the gastrointestinal malignancy early detection, diagnosis, and prevention program at the University of Pittsburgh Medical Center, Pennsylvania. Given that, “I am not sure how to best highlight a communication approach that would not cause undue stress to the patient and our healthcare resources.”

Gaddam agreed that it’s tough to pinpoint or communicate straightforward risks or symptoms to the general public without potentially leading to unnecessary screening.

At a minimum, however, clinicians can share more general risk-mitigating strategies with their patients.

Communicating such strategies may be especially important for younger patients, given that the recent survey found almost 40% of younger adults believe there’s nothing they can do to change their risk for pancreatic cancer.

However, Cruz-Monserrate explained, adults of all ages can lower their risks through regular exercise, limited alcohol and tobacco use, and a healthy diet with less red meat or processed meat.

Ultimately, for clinicians, given how difficult it is now to identify pancreatic cancer early, we have to “follow their good clinical judgment when alarming features, such as weight loss or nuances of pancreatic pain arise, and then get good imaging,” Gaddam said.

Cruz-Monserrate, Brand, and Gaddam reported no relevant disclosures.

A version of this article appeared on Medscape.com.

Pancreatic cancer remains one of the most challenging cancers to diagnose early, with almost half of patients presenting with metastatic disease. Now, a growing body of evidence indicates that this deadly cancer has been steadily on the rise, particularly in younger individuals who may not even realize they are at risk.

A recent survey, for instance, found that 33% of 1000 respondents younger than 50 years believe that only older adults are at risk for pancreatic cancer, and more than half said they wouldn’t even recognize the early signs and symptoms, which include unexplained weight loss, fatigue, jaundice, abdominal pain that radiates to the back, nausea, and vomiting.

These survey findings allude to a bigger challenge: Identifying the disease remains elusive against a backdrop of these increasing rates and nonspecific risks and symptoms.

Currently, only about 15% of pancreatic cancers are caught at a localized, resectable stage, when 5-year survival rates are highest at 44%. But most are found later, after symptoms arise, and at this point, the 5-year survival odds plummet —16% for regional disease, 3% for distant, and 1% for stage IV.

 

“This disease is too often a silent killer, with no symptoms until it has progressed to less treatable stages,” said survey coauthor Zobeida Cruz-Monserrate, PhD, in the division of gastroenterology, hepatology and nutrition at Ohio State University Medical Center, Columbus.

 

Rising Rates

Since 2001, rates of pancreatic cancer have steadily increased by about 1% annually, and this increase appears greater among younger individuals, especially women.

A recent study in Gastroenterology, for instance, found that, while overall rates of pancreatic cancer among people aged 15-34 years remained low (0.3% in women and 0.2% in men) between 2001 and 2018, the average annual percent change in this age group was considerably higher than that for older individuals — 6.45% for women and 2.97% for men compared with 1.11% for women aged 55 years and 1.17% for men aged 55 years. Another recent analysis, published in Annals of Internal Medicine, reported similar increased rates in men and women aged 15-39 years between 2011 and 2019.

Although more than 90% of cases do occur in those 55 years or older, “we’re now seeing this disease in people who are in their 40s much more regularly,” Cruz-Monserrate said. “This is a concerning trend — and more research is needed to learn why.”

But it’s early days. Studies so far indicate that early onset pancreatic cancer tends to be even more aggressive, but the “underlying reason is not yet clear,” researcher wrote in a 2025 review.

Some evidence indicates younger individuals may have distinct molecular characteristics, whereas other research shows younger and older patients have similar genetic profiles. Younger patients may also be more likely to smoke, drink more, and delay seeking medical attention as well as experience delays in being diagnosed by physicians, the authors explained.

 

Catching It Early

Given the rising rates, early detection is especially important.

There are some known genetic and medical risk factors for pancreatic cancer. About 10% of these cancers are linked to heredity risk or genetic markers, including BRCA1 and BRCA2 or Lynch syndrome. People with chronic pancreatitis, type 2 diabetes, obesity, or with a family history of pancreatic cancer face an elevated risk.

Lifestyle factors can play a role as well. Alcohol consumption, a poor diet that includes red or processed meat, and smoking increase people’s risk for pancreatic cancer. In fact, smoking leads to a twofold higher risk, compared with not smoking.

 

However, uncovering pancreatic cancer from these factors alone can be like “finding a needle in a haystack,” said Srinivas Gaddam, MD, head of the pancreatic cancer screening and early detection program at Cedars-Sinai Medical Center in Los Angeles.

One strategy to help detect the disease earlier would be to screen more.

The latest guidance from the American Cancer Society suggests that people with a genetic predisposition or a family history of pancreatic cancer could benefit from annual surveillance with endoscopic ultrasound or MRI.

But the US Preventive Services Task Force currently recommends against routine screening of average-risk asymptomatic adults (JAMA. 2019;322[5]:438-444). The task force found no evidence that screening for pancreatic cancer improves disease-specific morbidity or mortality or all-cause mortality.

“The absolute incidence in younger people is far too small to make screening beneficial,” explained The Lancet Gastroenterology & Hepatology editors in a 2023 editorial.

In fact, more screening could lead to overdiagnosis, a concern reinforced by the recent study in Annals of Internal Medicine. That analysis found that much of the observed increase in early-onset pancreatic cancer stemmed from the detection of more small, early-stage endocrine cancer, rather than pancreatic adenocarcinoma, whereas mortality from the disease remained stable over the study period.

Recent findings do “suggest the potential for overdiagnosis and overtreatment, particularly in cases of indolent pancreatic neuroendocrine tumors,” Gaddam said.

Gaddam has observed an increase in both adenocarcinoma and neuroendocrine tumors in the clinic and in his research, especially in women younger than 50 years, but he noted these early onset diagnoses do remain rare.

 

Staying Vigilant

As the understanding of pancreatic cancer risks and symptoms evolves, ensuring that patients, especially younger individuals, recognize the warning signs, without causing alarm, remains a challenge.

The disease “presents more advanced in younger patients, but symptoms are so nonspecific,” said Randall Brand, MD, AGAF, director of the gastrointestinal malignancy early detection, diagnosis, and prevention program at the University of Pittsburgh Medical Center, Pennsylvania. Given that, “I am not sure how to best highlight a communication approach that would not cause undue stress to the patient and our healthcare resources.”

Gaddam agreed that it’s tough to pinpoint or communicate straightforward risks or symptoms to the general public without potentially leading to unnecessary screening.

At a minimum, however, clinicians can share more general risk-mitigating strategies with their patients.

Communicating such strategies may be especially important for younger patients, given that the recent survey found almost 40% of younger adults believe there’s nothing they can do to change their risk for pancreatic cancer.

However, Cruz-Monserrate explained, adults of all ages can lower their risks through regular exercise, limited alcohol and tobacco use, and a healthy diet with less red meat or processed meat.

Ultimately, for clinicians, given how difficult it is now to identify pancreatic cancer early, we have to “follow their good clinical judgment when alarming features, such as weight loss or nuances of pancreatic pain arise, and then get good imaging,” Gaddam said.

Cruz-Monserrate, Brand, and Gaddam reported no relevant disclosures.

A version of this article appeared on Medscape.com.