Fat malabsorption in pancreatic cancer: Pathophysiology and management.

Exocrine pancreatic insufficiency (EPI) is common in pancreatic ductal adenocarcinoma (PDAC) and may lead to significant nutrition compromise. In the setting of cancer cachexia and gastrointestinal toxicities of cancer treatments, untreated (or undertreated) EPI exacerbates weight loss, sarcopenia, micronutrient deficiencies, and malnutrition. Together, these complications contribute to poor tolerance of oncologic therapies and negatively impact survival. Treatment of EPI in PDAC involves the addition of pancreatic enzyme replacement therapy, with titration to improve gastrointestinal symptoms. Medical nutrition therapies may also be applicable and may include fat-soluble vitamin replacement, medium-chain triglycerides, and, in some cases, enteral nutrition. Optimizing nutrition status is an important adjunct treatment approach to improve quality of life and may also improve overall survival.

An Updated Review of Exocrine Pancreatic Insufficiency Prevalence finds EPI to be More Common in General Population than Rates of Co-Conditions.

Exocrine pancreatic insufficiency (EPI) is frequently described as underscreened, underdiagnosed, and undertreated. The treatment for EPI is pancreatic enzyme replacement therapy (PERT), which is costly, and provider confidence in prescribing may be one barrier to reducing undertreatment. The lack of interchangeability studies for prescription PERT and/or lack of efficacy studies of over-the-counter enzyme options may be another barrier. This paper reviewed the prevalence of EPI in the general population and in co-conditions. Prevalence of EPI in the general population is commonly estimated around 10-20%, and further research is needed to evaluate EPI across all age groups and to better understand in which age group EPI becomes more prevalent, as an age effect is often seen in EPI prevalence studies. EPI is perceived to be highly correlated with certain co-conditions, and the majority (~65%) of EPI literature is related to a co-condition such as cystic fibrosis, pancreatitis, post-surgery, cancer, or diabetes. It can be estimated that 85% of literature in identified co-conditions, or 56% of total EPI literature, is on rarer co-conditions which only represent <1% of EPI overall. In contrast, there is very little research and literature on EPI in the general population. The highest absolute rates of EPI with co-conditions are likely diabetes and possibly irritable bowel syndrome with diarrhea, yet they are among the least commonly researched in co-condition and EPI studies. A lack of research on EPI in the general population and in the more common co-conditions may be contributing to the rates of underdiagnosis and underscreening, as well as undertreatment for those with low fecal elastase-1 levels.

Diagnosis and management of pancreatic insufficiency in patients with gastrectomy due to cancer or gastric ulcers: a virtual roundtable expert discussion.

INTRODUCTION: Pancreatic exocrine insufficiency (PEI) is common after gastric resection for cancer or ulcers but is under-recognized and undertreated. Although pancreatic enzyme replacement therapy (PERT) is the mainstay of PEI management, robust evidence supporting its use after gastric surgery is limited. AREAS COVERED: In the absence of guideline recommendations specific for patients with pancreatic insufficiency after gastrectomy, a panel of experts from different geographical regions convened in a virtual meeting to discuss their approach to patient management. EXPERT OPINION: Pancreatic insufficiency after gastrointestinal surgery is not a simple post-surgical complication as several factors contribute to its development. Although the pancreas is unimpaired after gastrectomy, it cannot function normally in the altered environment. Pancreatic insufficiency can be challenging to diagnose in gastrectomy patients due to nonspecific symptoms and the absence of a simple diagnostic test. Fecal elastase appears to be the default test, although it is not sufficiently sensitive nor reliable for diagnosing or monitoring PEI. Patients with maldigestion symptoms after gastrectomy are treated pragmatically: those with clinical suspicion of pancreatic insufficiency receive a trial of PERT and are monitored for symptom improvement. There is a clear need for high-quality evidence from clinical trials to guide the management of this patient population.

Clinical features, epidemiology, and treatment of Shwachman-Diamond syndrome: a systematic review.

BACKGROUND: Shwachman-Diamond syndrome (SDS) is an autosomal recessive disease which results in inherited bone marrow failure (IBMF) and is characterized by exocrine pancreatic dysfunction and diverse clinical phenotypes. In the present study, we reviewed the internationally published reports on SDS patients, in order to summarize the clinical features, epidemiology, and treatment of SDS. METHODS: We searched the WangFang and China National Knowledge Infrastructure databases with the keywords "Shwachman-Diamond syndrome," "SDS," "SBDS gene" and "inherited bone marrow failure" for relevant articles published from January 2002 to October 2022. In addition, studies published from January 2002 to October 2022 were searched from the Web of Science, PubMed, and MEDLINE databases, using "Shwachman-diamond syndrome" as the keyword. Finally, one child with SDS treated in Tongji Hospital was also included. RESULTS: The clinical features of 156 patients with SDS were summarized. The three major clinical features of SDS were found to be peripheral blood cytopenia (96.8%), exocrine pancreatic dysfunction (83.3%), and failure to thrive (83.3%). The detection rate of SDS mutations was 94.6% (125/132). Mutations in SBDS, DNAJC21, SRP54, ELF6, and ELF1 have been reported. The male-to-female ratio was approximately 1.3/1. The median age of onset was 0.16 years, but the diagnostic age lagged by a median age of 1.3 years. CONCLUSIONS: Pancreatic exocrine insufficiency and growth failure were common initial symptoms. SDS onset occurred early in childhood, and individual differences were obvious. Comprehensive collection and analysis of case-related data can help clinicians understand the clinical characteristics of SDS, which may improve early diagnosis and promote effective clinical intervention.

Functional sequelae after pancreatic resection for cancer.

The morbidity and mortality of pancreatic cancer surgery has seen substantial improvement due to the standardization of surgical techniques, the optimization of perioperative multidisciplinary management and the organization of specialized care systems. The identification and treatment of postoperative functional and nutritional sequelae have thereby become major issues in patients who undergo pancreatic surgery. This review addresses the functional sequelae of pancreatic resection for cancerous and pre-cancerous lesions (excluding chronic pancreatitis). Its aim is to specify the prevalence and severity of sequelae according to the type of pancreatic resection and to document, where appropriate, the therapeutic management. Exocrine pancreatic insufficiency (ExPI) is observed in nearly one out of three patients at one year after surgery, and endocrine pancreatic insufficiency (EnPI) is present in one out of five patients after pancreatoduodenectomy (PD) and one out of three patients after distal pancreatectomy (DP). In addition, digestive functional disorders may appear, such as delayed gastric emptying (DGE), which affects 10 to 45% of patients after PD and nearly 8% after DP. Beyond these functional sequelae, pancreatic surgery can also induce nutritional and vitamin deficiencies secondary to a lack of uptake for certain vitamins or to the loss of absorption site in the duodenum. In addition to the treatment of ExPI with oral pancreatic enzymes, nutritional management is based on a high-calorie, high-protein diet with normal lipid intake in frequent small feedings, combined with vitamin supplementation adapted to monitored deficiencies. Better knowledge of the functional consequences of pancreatic cancer surgery can improve the overall management of patients.

[Diagnosis and treatment of Shwachman-Diamond syndrome in Chinese children: An evidence-based study].

OBJECTIVE: To explore the characteristics of Shwachman-Diamond syndrome (SDS) in Chinese children in order to provide a reference for early diagnosis. METHODS: With Shwachman-Diamond syndrome, SDS, SBDS gene and inherited bone marrow failure as the keywords, the search period was set from January 2002 to October 2022. Relevant literature was retrieved from the Wanfang Database and China National Knowledge Infrastructure (CNKI) database. In addition, by using Shwachman-diamond syndrome as a keyword, the search period was also retrieved from the Web of Science, PubMed, and MEDLINE databases from January 2002 to October 2022. A child with SDS treated at the Tongji Hospital was also included. A total of 44 cases with complete clinical data were analyzed with reference to the International Standard for SDS Diagnosis. Chi-square test and t test were used for statistical analysis. Evidence-based research was carried out in the form of systematic review. The epidemiology, clinical characteristics and key points of early diagnosis of the Chinese SDS children were summarized and compared with the international data. RESULTS: The main characteristics of SDS in Chinese children were summarized as follows: The ratio of males to females was about 1.3 : 1, the median age of onset was 3 months, and the median age of diagnosis was 14 months. The first symptoms were often exocrine pancreatic insufficiency (31.8%) and granulocytopenia with infection (31.8%). According to the international consensus, the incidence rates of the three major diseases of SDS were hemocytopenia (95.4%), pancreatic disease (72.7%), and bone abnormality (40.9%). The common factors underlying SDS disease were variants of the SBDS gene (c.258+2T>C and c.183_184TA>CT), albeit there was no significant correlation between genotype and phenotype (P > 0.05). Compared with international reports, the clinical manifestations and genotypes of Chinese SDS children are different (P < 0.05). CONCLUSION: The SDS children have an early age of onset and significant individual difference. It is necessary to analyze the case-related data to facilitate early recognition, diagnosis and clinical intervention.

Evaluation and management of exocrine pancreatic insufficiency: pearls and pitfalls.

PURPOSE OF REVIEW: The diagnosis and management of exocrine pancreatic dysfunction (EPD) can be challenging. EPD classically results from conditions that cause loss of pancreatic acinar cell function and decreased digestive enzyme production. However, several conditions may contribute to signs or symptoms of EPD with otherwise normal pancreatic exocrine function. A thoughtful approach to considering these conditions, along with their specific therapies, can guide a tailored management approach. RECENT FINDINGS: An EPD severity classification schema has been proposed, which emphasizes a shift towards a more restrictive prescription of pancreas enzyme replacement therapy (PERT) for patients with milder EPD. In contrast, PERT use has been associated with a measurable survival benefit among individuals with EPD and pancreatic cancer, so the prescription of PERT may be more liberal in this population. Recent publications in the cystic fibrosis population offer pearls guiding the titration and optimization of PERT. SUMMARY: Among individuals with severe EPD, PERT is an effective therapy. Among individuals with milder EPD, although PERT is effective, there may be opportunities to provide additional and potentially more effective therapies.

[Other specific types of diabetes and exocrine pancreatic insufficiency (update 2023)]. / Andere spezifische Diabetesformen und exokrine Pankreasinsuffizienz (Update 2023).

The heterogenous category "specific types of diabetes due to other causes" encompasses disturbances in glucose metabolism due to other endocrine disorders such as acromegaly or hypercortisolism, drug-induced diabetes (e.g. antipsychotic medications, glucocorticoids, immunosuppressive agents, highly active antiretroviral therapy (HAART), checkpoint inhibitors), genetic forms of diabetes (e.g. Maturity Onset Diabetes of the Young (MODY), neonatal diabetes, Down­, Klinefelter- and Turner Syndrome), pancreatogenic diabetes (e.g. postoperatively, pancreatitis, pancreatic cancer, haemochromatosis, cystic fibrosis), and some rare autoimmune or infectious forms of diabetes. Diagnosis of specific diabetes types might influence therapeutic considerations. Exocrine pancreatic insufficiency is not only found in patients with pancreatogenic diabetes but is also frequently seen in type 1 and long-standing type 2 diabetes.

Predisposition to myeloid malignancies in Shwachman-Diamond syndrome: biological insights and clinical advances.

Shwachman-Diamond syndrome (SDS) is an inherited multisystem ribosomopathy characterized by exocrine pancreatic deficiency, bone marrow failure, and predisposition to myeloid malignancies. The pathobiology of SDS results from impaired ribosomal maturation due to the deficiency of SBDS and the inability to evict the antiassociation factor eIF6 from the 60S ribosomal subunit. Clinical outcomes for patients with SDS who develop myeloid malignancies are extremely poor because of high treatment-related toxicities and a high rate of refractory disease/relapse even after allogeneic hematopoietic stem cell transplant (HSCT). Registry data indicate that outcomes are improved for patients with SDS who undergo routine bone marrow surveillance and receive an HSCT before developing an overt malignancy. However, the optimal approach to hematologic surveillance and the timing of HSCT for patients with SDS is not clearly established. Recent studies have elucidated distinct patterns of somatic blood mutations in patients with SDS that either alleviate the ribosome defect via somatic rescue (heterozygous EIF6 inactivation) or disrupt cellular checkpoints, resulting in increased leukemogenic potential (heterozygous TP53 inactivation). Genomic analysis revealed that most myeloid malignancies in patients with SDS have biallelic loss-of-function TP53 mutations. Single-cell DNA sequencing of SDS bone marrow samples can detect premalignant biallelic TP53-mutated clones before clinical diagnosis, suggesting that molecular surveillance may enhance the detection of incipient myeloid malignancies when HSCT may be most effective. Here, we review the clinical, genetic, and biologic features of SDS. In addition, we present evidence supporting the hematologic surveillance for patients with SDS that incorporates clinical, pathologic, and molecular data to risk stratify patients and prioritize transplant evaluation for patients with SDS with high-risk features.

Pancreatitis crónica: análisis de factores de progresión de la enfermedad / Chronic pancreatitis: analysis of disease progression factors

BACKGROUND: Alcohol and tobacco are important risk factors for chronic pancreatitis (CP). AIM: To analyze the effect of etiological factors such as tobacco and alcohol and pancreatic enzyme replacement therapy (PERT) in the progression of CP. MATERIAL AND METHODS: Patients with a diagnosis of CP were recruited and grouped according to variables such as tobacco, alcohol and PERT. They were followed for 18 months. Subsequently, different variables and analytical parameters involved in the progression of the disease were analyzed. RESULTS: A total of 50 patients diagnosed with CP were included. Of these, 28 patients underwent PERT, 39 were smokers and 33 were alcohol users. Compared with patients without PERT, those with PERT had a higher proportion of diabetes (64 and 32%, respectively), had a higher need for endoscopic treatment (25 and 0%, respectively) and a normal body mass index (71 and 27.3%, respectively. The smokers had higher calcium levels and increased lymphocytosis and leukocytosis. The alcohol consumption group had a higher mean age (p = 0.04) CONCLUSIONS: PERT may improve the nutritional status but does not reduce the need for endoscopic or surgical treatment. Smoking and alcohol consumption favored the progression of CP. Also, smoking induced a pro-inflammatory state.

Improvements in anthropometric measures and gastrointestinal tolerance in patients with cystic fibrosis by using a digestive enzyme cartridge with overnight enteral nutrition.

BACKGROUND: Patients with cystic fibrosis (CF) and pancreatic insufficiency are at risk for suboptimal fat absorption, inability to maintain weight, poor growth, and increased gastrointestinal (GI) symptoms due to malabsorption. Enteral nutrition (EN) is used to supplement caloric intake and requires pancreatic enzyme replacement for effective digestion. We evaluated the relationship between long-term use of an in-line digestive enzyme cartridge with EN and changes in anthropometric measures and GI symptoms in patients with CF. METHODS: This is a single-center, retrospective case review of patients with CF using a digestive enzyme cartridge with EN. Data were collected from the patient medical records and included weight, height, body mass index, EN regimen, and reported GI symptoms. RESULTS: Thirteen pediatric and five adult patients with a mean age of 12.6 years used a digestive enzyme cartridge with EN for a period of 3-27 months. Most patients (n = 14) had been using oral digestive enzymes with EN before using the digestive enzyme cartridge, whereas four started from the onset of EN. The indications to convert from oral enzymes to the digestive enzyme cartridge included poor growth (72.2%) and poor tolerance of EN (69.2%). There was a reduction in reported GI symptoms after initiating use of the digestive enzyme cartridge. After 12 months of digestive cartridge use, there were improvements in anthropometrics. CONCLUSIONS: This real-world experience with prolonged use of a digestive enzyme cartridge with EN demonstrated improved clinical outcomes and a reduction in GI symptoms in patients with CF.

Expert opinion on management of pancreatic exocrine insufficiency in pancreatic cancer.

Pancreatic exocrine insufficiency (PEI) is a common condition in patients with pancreatic cancer (PC). PEI can be due to the tumor, which, if located in the head, causes obstruction of the pancreatic duct with subsequent atrophy of the pancreatic parenchyma, or it can be the consequence of pancreatic surgical resection. The standard treatment of PEI is pancreatic enzyme replacement therapy (PERT). Clinical data to support the use of PERT in PC are however limited. There are very few randomized clinical trials that evaluated PERT in PC. Most data come from observational studies. Despite this limited clinical evidence, PERT treatment for PEI is an essential part of supportive therapy to ensure optimal nutritional status in PC patients who will receive surgery, neoadjuvant/adjuvant or palliative treatment. The objective of this review is to increase the awareness about PEI in PC patients and to provide expert recommendations on the use of PERT in resected, borderline resectable and unresectable patients, based on clinical experience and literature review.

Nutrition management in adults with cystic fibrosis.

Cystic fibrosis (CF) is a lethal, monogenic, autosomal recessive disease with manifestations in multiple organ systems, including the lungs and gastrointestinal tract, that impact adequate nutrition. This review discusses important aspects of nutrition in adults with CF with a focus on exocrine pancreatic insufficiency, CF-related diabetes, and gastrointestinal motility, as well as how advanced lung disease, CF transmembrane conductance regulator modulators, and aging impact nutrition in CF.

[Chronic pancreatitis: analysis of disease progression factors]. / Pancreatitis crónica: análisis de factores de progresión de la enfermedad.

BACKGROUND: Alcohol and tobacco are important risk factors for chronic pancreatitis (CP). AIM: To analyze the effect of etiological factors such as tobacco and alcohol and pancreatic enzyme replacement therapy (PERT) in the progression of CP. MATERIAL AND METHODS: Patients with a diagnosis of CP were recruited and grouped according to variables such as tobacco, alcohol and PERT. They were followed for 18 months. Subsequently, different variables and analytical parameters involved in the progression of the disease were analyzed. RESULTS: A total of 50 patients diagnosed with CP were included. Of these, 28 patients underwent PERT, 39 were smokers and 33 were alcohol users. Compared with patients without PERT, those with PERT had a higher proportion of diabetes (64 and 32%, respectively), had a higher need for endoscopic treatment (25 and 0%, respectively) and a normal body mass index (71 and 27.3%, respectively. The smokers had higher calcium levels and increased lymphocytosis and leukocytosis. The alcohol consumption group had a higher mean age (p = 0.04) Conclusions: PERT may improve the nutritional status but does not reduce the need for endoscopic or surgical treatment. Smoking and alcohol consumption favored the progression of CP. Also, smoking induced a pro-inflammatory state.

Clinical Implications of Malnutrition in the Management of Patients with Pancreatic Cancer: Introducing the Concept of the Nutritional Oncology Board.

Pancreatic cancer represents a very challenging disease, with an increasing incidence and an extremely poor prognosis. Peculiar features of this tumor entity are represented by pancreatic exocrine insufficiency and an early and intense nutritional imbalance, leading to the highly prevalent and multifactorial syndrome known as cancer cachexia. Recently, also the concept of sarcopenic obesity has emerged, making the concept of pancreatic cancer malnutrition even more multifaceted and complex. Overall, these nutritional derangements play a pivotal role in contributing to the dismal course of this malignancy. However, their relevance is often underrated and their assessment is rarely applied in clinical daily practice with relevant negative impact for patients' outcome in neoadjuvant, surgical, and metastatic settings. The proper detection and management of pancreatic cancer-related malnutrition syndromes are of primary importance and deserve a specific and multidisciplinary (clinical nutrition, oncology, etc.) approach to improve survival, but also the quality of life. In this context, the introduction of a "Nutritional Oncology Board" in routine daily practice, aimed at assessing an early systematic screening of patients and at implementing nutritional support from the time of disease diagnosis onward seems to be the right path to take.

Secondary oxalate nephropathy in a patient with exocrine pancreatic insufficiency successfully treated, with complete kidney recovery.

INTRODUCTION: Oxalate nephropathy is a relatively rare and under-recognized condition that commonly presents as acute kidney injury (AKI) and often leads to end-stage renal disease. Complete recovery of kidney function is extremely rare even when treatment is instituted early on. CASE PRESENTATION: We present the case of a 68-year-old man with known type 2 diabetes mellitus and an asymptomatic unrecognized exocrine pancreatic insufficiency, who was admitted due to dialysis-dependent AKI. Kidney biopsy revealed oxalate nephropathy. A wide diagnostic assessment and a multi-factorial treatment plan that included a change of diet, therapy for exocrine pancreatic insufficiency and fat malabsorption, sodium bicarbonate and potassium citrate, calcium supplements with meals, and methylprednisolone, resulted in complete recovery of kidney function. CONCLUSION: It is important for physicians to be aware of oxalate nephropathy in cases of prolonged AKI. After confirmation of diagnosis, a wide diagnostic approach is imperative to identify all the causes that have led to oxalosis. A multi-factorial therapeutic approach can lead to complete kidney recovery.

Difference in Performance of EPI Pigs Fed Either Lipase-Predigested or Creon®-Supplemented Semielemental Diet.

Pancreatic enzyme replacement therapy (PERT) and fat predigestion are key in ensuring the optimal growth of patients with cystic fibrosis. Our study attempted to highlight differences between fat predigestion and conventional PERT on body composition of young pigs with exocrine pancreatic insufficiency (EPI). EPI and healthy pigs were fed with high-fat diet for six weeks. During the last two weeks of the study, all pigs received additional nocturnal alimentation with Peptamen AF (PAF) and were divided into three groups: H-healthy pigs receiving PAF; P-EPI pigs receiving PAF+PERT; and L-EPI pigs receiving PAF predigested with an immobilized microbial lipase. Additional nocturnal alimentation increased the body weight gain of EPI pigs with better efficacy in P pigs. Humerus length and area in pigs in groups L and P were lower than that observed in pigs in group H (p value 0.005-0.088). However, bone mineral density and strength were significantly higher in P and L as compared to that of H pigs (p value 0.0026-0.0739). The gut structure was improved in P pigs. The levels of neurospecific proteins measured in the brain were mainly affected in P and less in L pigs as compared to H pigs. The beneficial effects of the nocturnal feeding with the semielemental diet in the prevention of EPI pigs' growth/development retardation are differently modified by PERT or fat predigestion in terms of growth, bone properties, neurospecific protein distribution, and gut structure.

Endoscopic Pancreatic Drainage Improves Exocrine Pancreatic Function in Patients With Unresectable Pancreatic Cancer: A Double-Blind, Prospective, Randomized, Single-Center, Interventional Study.

OBJECTIVES: Exocrine pancreatic insufficiency is a frequent and clinically relevant complication of pancreatic cancer probably secondary to pancreatic duct obstruction. We aimed at evaluating the impact of endoscopic pancreatic drainage on pancreatic function in patients with unresectable pancreatic cancer. METHODS: A double-blind, prospective, randomized, single-center, interventional study was designed. Patients undergoing endoscopic retrograde cholangiopancreatography for jaundice secondary to unresectable pancreatic cancer were randomized to biliary drainage (group A) or biliopancreatic drainage (group B). Pancreatic function was evaluated by 13C-mixed triglyceride breath test before and 2 weeks after endoscopic retrograde cholangiopancreatography. Breath test result is expressed as 13C-cumulative recovery rate. Abdominal symptoms and nutritional markers were evaluated as secondary outcomes. RESULTS: Twenty patients were included. Sixteen patients had exocrine pancreatic insufficiency, and 13 completed the study (7 in group A and 6 in group B). The median absolute improvement of 13C-cumulative recovery rate was of 23.75% (interquartile range, 9.62-31.74) after biliopancreatic drainage compared with -1.92% (interquartile range, -4.17 to 13.92) after biliary drainage (P = 0.015). Nutritional markers improved after biliopancreatic drainage, but not after biliary drainage. CONCLUSIONS: Biliopancreatic and not biliary endoscopic drainage is associated with a significant improvement of exocrine pancreatic function in patients with unresectable pancreatic cancer.

Understanding pancreatic exocrine insufficiency and replacement therapy in pancreatic cancer.

Pancreatic exocrine insufficiency (PEI) is highly prevalent in patients with pancreatic cancer, and has substantial implications for quality of life and survival. Post resection, PEI is associated with increased post-operative complications, longer hospital stays and higher costs. Treatment with pancreatic enzyme replacement therapy (PERT) improves quality of life and confers significant survival advantages. Despite this many patients with pancreatic cancer do not currently receive PERT. The nutritional consequences of PEI are extensive and even more relevant in the elderly owing to age related gastrointestinal tract and pancreatic changes that predispose to malnutrition.