Clinical consequences of pancreatic exocrine insufficiency

Sammanfattning: Background: Chronic pancreatitis (CP) is characterized by a chronic inflammation with fibrosis and irreversible morphological changes that can result in permanent structural changes with a loss of exocrine and endocrine pancreas function. Exocrine dysfunction leads to reduced production of pancreatic digestive enzymes which is the reason of maldigestion and malabsorption of ingested nutrients like fats, microelements, vitamins and proteins which can lead to osteopathy. Aims: To determine the prevalence of fat-soluble vitamin deficiency in CP patients by a meta-analysis. To evaluate the prevalence of osteopenia and osteoporosis in patients with CP and investigate the correlation between bone mineral density (BMD) and CP features, and vitamin D and pancreatic exocrine insufficiency (PEI). To evaluate the prevalence of PEI in patients with Crohn`s disease (CD). To evaluate the prevalence of PEI and gastrointestinal symptoms in patients with Sjögren´s syndrome (SS). Methods: In paper I we performed a systematic review and meta-analysis. MEDLINE was searched up to January 2016 for case series and case-control studies reporting of fat-soluble vitamin deficiency in CP patients. In paper II, a multicenter cross-sectional study was performed in CP patients. Key clinical and biochemical variables were recorded. PEI was assessed by fecal elastase (FE-1) and standardized osteodensitometry was performed by DEXA. In paper III, patients with CD were recruited at Karolinska University Hospital and demographic, clinical and laboratory data were analyzed. PEI was assessed by FE-1. In paper IV, a cross-sectional monocenter study including 57 patients with well-characterized primary SS. Patients were recruited from the Department for Rheumatology at Karolinska University Hospital in Stockholm, Sweden, between June and December 2019. Key clinical characteristics were recorded. Pancreatic exocrine insufficiency (PEI) was assessed by fecal elastase FE-1 and 13C-mixed triglyceride breath test (13C-MTG-BT). PEI was defined as FE1 <200 μg/g and a cumulative 13C-exhalation <20.9%, respectively. The presence and severity of gastrointestinal symptoms were assessed by a well-established and validated survey on the basis of seven-point Likert scale (SSRS/GSRS-IBS). Results of the questionnaire were compared with sex and age-matched controls. Results: In paper I, twelve studies with 548 patients were included. With a random-effect model, the pooled prevalence rate of vitamin A, D and E deficiency were 16.8%, 57.6% and 29.2% respectively, with considerable heterogeneity (I2 . 75%, 87.1% and 92%). Only one study evaluated vitamin K deficiency. The pooled OR for vitamin D deficiency in CP cases compared with controls was 1.17 (95% CI 0.77-1.78). Sensitivity analyses showed lower prevalence of vitamin A and E, and higher prevalence of vitamin D deficiency in high-quality studies. The rate of pancreatic exocrine insufficiency did not seem affect the deficiency rates, while the use of different cut-offs influences results and heterogeneity for vitamin E, but not A. In paper II, 188 consecutive CP patients were enrolled at 6 centres (67% M; mean age 60 years). Osteopenia was diagnosed in 42% and osteoporosis in 22% of cases. The underlying etiology was alcohol in 43% of cases, and 18% had severe CP. Fifty-three % of patients had PEI. The mean value of vitamin D was 21 ng/ml and 56% of cases had vitamin D insufficiency. There was no correlation between vitamin D levels and fecal elastase-1 levels or the t-score (spine or femur). Alcoholic etiology was associated with higher risk of having low levels of fecal elastase-1 (p=0.02) and with lower level of vitamin D (p=0.001) but not with osteopenia or osteoporosis. BMI was lower in patients with osteoporosis (p=0.001). In paper III, 20 patients were included comprising 13 (65%) males and 7 (35%) females with a mean age of 48.3+-1.4 years. The mean duration of CD was 15.7+- years (range 1-40 years). There were 11 (55%) patients without history of bowel surgery and 9 (45%) patients after ileocecal resection. FE-1 test was normal in all patients. In paper IV, fifty-seven patients with primary SS were included in the study, comprising 92% females with a median age of 63 years. In total, (87%) 50/57 of SS patients were tested for FE-1 and all had normal results. All patients who underwent a 13C-MTG-BT (21/57; 37%) had a normal cumulative 13C-exhalation (>20.9%). Compared to the control group, significantly more patients suffered from GI symptoms (p<0.01 in all 11 items). The same number of patients noted moderate to severe loose bowel movements (38%) and constipation (38%). Eleven GI symptom parameters were compared to controls, the highest odd ratios were noted for the following moderate to severe symptoms: bloating (OR: 27.9, 95% CI: 9.81-91.9), feeling of incomplete emptied bowel after defecation (OR 21.4, 95%: 6.95-75.8), and abdominal pain relieved by bowel action (OR 17.8, 95% CI: 6.04-62.2). Conclusions: In our meta-analysis, fat-soluble vitamins deficiency is frequent in CP patients, but there is considerable heterogeneity between different studies. With regards to vitamin D, there are few case-control studies and no apparent increased deficiency risk in CP vs controls.