Clinical assessment and management of severe acute pancreatitis: a multi-disciplinary approach in the XXI century.

Acute pancreatitis (AP) is the most common gastrointestinal disorder requiring hospitalization, with a high rate of morbidity and mortality. Severe AP is characterized by the presence of persistent organ failure involving single or multiple organs. Clinical evolution, laboratory and radiological assessment are necessary to evaluate the prognosis and inform the management of AP. The onset of severe AP may be classified in two principal phases. The early phase, during the first week, is characterized by the activation of the auto-inflammatory cascade, gut dysbiosis, bacterial translocation, and the down-regulation of immune responses. The late phase is characterized by the development of local and systemic complications. Several old paradigms have been amended in the management of AP patients, such as the indication of nutrition, the use of antibiotic therapy, pain control strategies, and even the use of surgery. Real world evidence has shown that in the majority of cases a step-up approach is most effective. In this review, we discuss the clinical assessment and improvements to the management of patients with severe AP in a high volume center where a multi-disciplinary approach is performed.

Gut Microbiota-Immune System Crosstalk and Pancreatic Disorders.

Gut microbiota is key to the development and modulation of the mucosal immune system. It plays a central role in several physiological functions, in the modulation of inflammatory signaling and in the protection against infections. In healthy states, there is a perfect balance between commensal and pathogens, and microbiota and the immune system interact to maintain gut homeostasis. The alteration of such balance, called dysbiosis, determines an intestinal bacterial overgrowth which leads to the disruption of the intestinal barrier with systemic translocation of pathogens. The pancreas does not possess its own microbiota, and it is believed that inflammatory and neoplastic processes affecting the gland may be linked to intestinal dysbiosis. Increasing research evidence testifies a correlation between intestinal dysbiosis and various pancreatic disorders, but it remains unclear whether dysbiosis is the cause or an effect. The analysis of specific alterations in the microbiome profile may permit to develop novel tools for the early detection of several pancreatic disorders, utilizing samples, such as blood, saliva, and stools. Future studies will have to elucidate the mechanisms by which gut microbiota is modulated and how it tunes the immune system, in order to be able to develop innovative treatment strategies for pancreatic disorders.

The association of pancreatic cystosis and IPMN in cystic fibrosis: case report and literature review.

Pancreatic cystosis is a rare presentation of cystic fibrosis involving pancreatic gland. To date, only very few cases of pancreatic cystosis have been described in literature. Pancreatic cystosis may begin during the second decade of life and is the rarest presentation of cystic fibrosis. This disease is characterized by the presence of multiloculated cysts without ductal system communication of different sizes in all the pancreatic tissue. Herein, we report a case of a young woman affected by cystic fibrosis that was admitted to our Pancreatic Centre to evaluate a picture of diffuse multiloculated pancreatic cysts. After magnetic resonance imaging (MRI) and endoscopic ultrasound (EUS) assessment, we perform the diagnosis of the concomitant presence of the rare condition of pancreatic cystosis with Branch Duct-Intraductal Papillary Mucinous Neoplasm (BD-IPMN). To our knowledge, this is the first reported case of a cystic fibrosis patient with the combination of pancreatic cystosis and IPMN.

Uptodate in the assessment and management of intraductal papillary mucinous neoplasms of the pancreas.

Intraductal Papillary Mucinous Neoplasms (IPMNs) are the most common cystic tumors of the pancreas and are considered premalignant lesions. IPMNs are characterized by the papillary growth of the ductal epithelium with rich mucin production, which is responsible for cystic segmental or diffuse dilatation of the main pancreatic duct (MPD) and/or its branches. According to the different involvement of pancreatic duct system, IPMNs are divided into main duct type (MD-IPMN), branch duct type (BD-IPMN), and mixed type (MT-IPMN). IPMNs may be incidentally discovered in asymptomatic patients, particularly in those with BD-IPMNs, when imaging studies are performed for unrelated indications. The increase in their frequency may reflect the combined effects of new diagnostic techniques, the improvement of radiologic exams and progress in the recognition of the pathology. MD-IPMNs present a higher risk of malignant progression than BD-IPMNs; as a consequence, all the guidelines strictly suggest the need of surgery for MD- and MT- IPMNs with MPD > 10 mm, while the management of BD-IPMNs is still controversial and depends on several cysts and patients features. The choice between non-operative and surgical management depends on the distinction between benign and invasive IPMN forms, assessment of malignancy risk, patient's wellness and its preferences. This manuscript revises the different guidelines for the management of IPMNs that have been published in different world countries: the international (Sendai 2006 and Fukuoka 2012), the 2013 European, the 2014 Italian, and finally the 2015 American guidelines. In summary, this review will integrate the recent insights in the combination of diagnostic techniques, such as Magnetic Resonance Imaging (MRI) and endoscopic ultrasound (EUS), pathology classification, and management of IPMNs.

Nutritional support in acute pancreatitis: from physiopathology to practice. An evidence-based approach.

Acute Pancreatitis (AP) is a potentially fatal syndrome, associated with a hyper-catabolic state as well as early and late complications that may lead to multi-organ failure and death. Clinical researches produced in recent years suggest that acute pancreatitis may benefit from early oral or enteral nutrition. Nevertheless, many clinicians still believe erroneously that fasting - particularly in the early phase - may reduce AP complications and mortality. The goal of our review is to demonstrate that such false belief may harm the patients and that the whole management paradigm must change, adopting a more rational, evidence-based approach. First, we will describe AP physiopathology and the clinical assessment of its severity. Then we will discuss evidence-based data supporting early oral or enteral nutrition in AP. Finally, we will offer some practice recommendations as regards nutritional support.

Prevalence of the K469E polymorphism of intercellular adhesion molecule 1 gene in Italian patients with inflammatory bowel disease.

BACKGROUND: Intercellular adhesion molecule 1 plays an important role in the recruitment of leucocytes at sites of inflammation and is up-regulated in intestinal mucosa of inflammatory bowel disease. Intercellular adhesion molecule 1 gene lies on chromosome 19p13, implicated in determining susceptibility to inflammatory bowel disease. Recently, the polymorphism K469E of intercellular adhesion molecule 1 gene has been identified. AIM: To assess the potential association of this polymorphism with inflammatory bowel disease. PATIENTS: A total of 165 inflammatory bowel disease patients, 75 with Crohn's disease and 90 with ulcerative colitis, and 187 controls were studied. METHODS: The K469E polymorphism was detected by polymerase chain reaction and restriction enzyme analysis. Statistical analysis was performed by chi2-test. RESULTS: In inflammatory bowel disease, the distribution of intercellular adhesion molecule 1 genotypes was 24.9% E/E, 44.2% E/K and 30.9% K/K. In controls, 11.8% showed E/E genotype, 55.6% E/K and 32.6% K/K. The frequency of the E/E genotype was significantly higher in inflammatory bowel disease (Crohn's disease and ulcerative colitis) patients than in controls. Subgroup analysis showed that the frequency of the E469 allele was significantly increased only in Crohn's disease patients with ileocolonic location of disease and penetrating behaviour compared with controls. CONCLUSIONS: We found an association of inflammatory bowel disease with the E/E genotype of intercellular adhesion molecule 1 gene, while allele E469 was associated with a subgroup of Crohn's disease patients with more extensive location of disease and penetrating behaviour. However, further studies are needed to confirm our findings.

The -174 G/C polymorphism of the interleukin-6 gene promoter is associated with peripheral artery occlusive disease.

OBJECTIVE AND DESIGN: high plasma levels of Interleukin-6 (IL-6) are found in patients with atherosclerotic disorders. Recently, a common polymorphism of the IL-6 gene promoter, influencing the transcription rate of the gene, has been described and associated with atherosclerosis of carotid and coronary arteries. The objective of this study was to test whether IL-6 gene promoter polymorphism is associated with peripheral artery occlusive disease (PAOD) in a case-control study. METHODS: IL-6 gene promoter polymorphism was evaluated by polymerase chain reaction followed by restriction enzyme analysis in 84 patients affected by PAOD and 183 controls. RESULTS: the distribution of IL-6 genotypes was: patients with PAOD: 44 GG, 30 GC, 10 CC; control subjects: 53 GG, 80 GC, 50 CC. The GG genotype was significantly more common in the PAOD group (p<0.0001), while the CC genotype was significantly more common in control patients (p=0.005). CONCLUSIONS: this study indicates a strong association between IL-6 gene polymorphism and PAOD and support the hypothesis that IL-6 and IL-6 gene polymorphism are important in the pathophysiology and evolution of ischaemic diseases of the lower limbs.

The K469E polymorphism of the ICAM-1 gene is a risk factor for peripheral arterial occlusive disease.

Intercellular adhesion molecule-1 (ICAM-1) plays a crucial role in lymphocyte migration and activation, and is considered important in the pathogenesis of atherosclerosis. K469E is a common polymorphism of the ICAM-1 gene with potential functional significance. The aim of the present case-control study was to evaluate the association between this polymorphism and peripheral arterial occlusive disease (PAOD). ICAM-1 gene polymorphism was examined by polymerase chain reaction and restriction enzyme analysis in 75 Italian subjects affected by PAOD and 227 controls. The distribution of ICAM-1 genotypes in patients affected by PAOD was 32.1% EE, 50.6% EK, and 17.3% KK. The distribution of ICAM-1 genotypes in control subjects was 17.2% EE, 55.1% EK, and 27.7% KK. The EE genotype was significantly more common in patients than controls (P = 0.006). Logistic regression analysis indicated that the presence of the EE genotype significantly increases the risk of PAOD (odds ratio, 3.5; 95% confidence interval, 1.5-8.4; P = 0.004). This is the first study documenting a role of the ICAM-1 gene polymorphism in the pathogenesis of a cardiovascular disease, such as PAOD. Our data support the hypothesis that inflammatory mechanisms are important in the pathophysiology of vascular diseases with an atherosclerotic basis.

Abdominal aortic aneurysm in normotensive patients: association with angiotensin-converting enzyme gene polymorphism.

OBJECTIVE AND DESIGN: to assess if deletion of the angiotensin-converting enzyme (ACE) gene is a risk factor for abdominal aortic aneurysms (AAAs) in normotensive patients. MATERIALS AND METHODS: ACE gene polymorphism was examined by polymerase chain reaction in 124 subjects with AAA and in 112 control subjects. AAA normotensive patients (group A, n=56) were compared to normotensive control subjects (group B, n =112) and to AAA hypertensive patients (group C, n =68). All subjects enrolled in this study were Caucasian and from central and southern Italy. RESULTS: the distribution of ACE genotypes was: normotensive patients with AAAs (group A): 3 II, 14 ID, 39 DD; normotensive control subjects (group B): 36 II, 48 ID, 28 DD; hypertensive patients with AAAs (group C): 14 II, 32 ID, 22 DD. The DD genotype was more common in group A than in control groups (A vs B p<0.001; A vs C p <0.001). The ID genotype was more common in group A as well (A vs B p <0.05; A vs C p <0.005). CONCLUSIONS: our data suggest a role for ACE I/D gene polymorphism in the pathogenesis of AAA in normotensive patients.

Association between Helicobacter pylori cytotoxic type I CagA-positive strains and migraine with aura.

Recent studies have suggested an association between Helicobacter pylori infection and migraine. However, various strains of the bacterium are present, some endowed with greater pathogenicity. In particular, H. pylori type I CagA-positive strains induce a higher release of proinflammatory substances by the gastric mucosa that could trigger systemic vasospasms. The aim of the present study was to assess the prevalence of H. pylori CagA-positive strains in subjects with migraine. One hundred and seventy-five patients affected by migraine (49 with aura, 126 without aura) were consecutively enrolled and matched for sex, age, social background and geographical origin with 152 controls. Helicobacter pylori infection was assessed through 13C-urea breath test. Specific serological IgG against CagA were detected through ELISA. The prevalence of H. pylori infection was similar in migraine patients and in controls (40% vs. 39%, respectively). Among migraine patients, prevalence of infection was not related to presence or absence of aura (45% vs. 37%, respectively). However, among infected subjects, a significantly higher prevalence of CagA-positive strains was observed in patients affected by migraine with aura when compared with those affected by migraine without aura (41% vs. 19%, P < 0.01) and with controls (41% vs. 17%, P < 0.01). CagA-positive H. pylori strains were found to be strongly associated with migraine with aura. A higher inflammatory response of the gastric mucosa to more virulent strains could release substances that may act as triggers of vasospasm in peculiar cerebral arterial districts, probably implicated in the 'aura' phenomenon.

Resolution of syndrome X after eradication of virulent CagA-positive Helicobacter pylori.

A 42-year-old man with chest pain was found to have ST depression in leads V1 through V4. The coronary arteries appeared normal on angiography. Positive results of ventricular pacing and acetylcholine test led to a diagnosis of syndrome X. Other studies revealed gastritis due to CagA-positive Helicobacter pylori. Classic therapy for angina did not resolve chest pain, but eradication of H. pylori led to disappearance of symptoms and negative test results.

Hemodynamic and functional consequences of radial artery removal for coronary artery bypass grafting.

Five years after surgery the echo-Doppler characteristics of the forearm circulation and the transcutaneous oxygen and carbon dioxide pressures of the operated and control arm were determined at rest and under conditions of hand exercise in 34 patients who received a radial artery graft for myocardial revascularization. Doppler measurements showed the ulnar compensation to radial artery removal, and transcutaneous measurements demonstrated a moderate degree of exercise-induced hand ischemia on the operated site.

Effects of propionyl-L-carnitine on peripheral arterial obliterative disease of the lower limbs: a double-blind clinical trial.

The authors evaluated the efficacy of propionyl-l-carnitine, a drug able to reduce peripheral resistance and protect the cells against oxidative stress damage, in patients affected by peripheral arterial obliterative disease at class II of Fontaine. The study was performed on 22 patients according to a double-blind, randomized design in parallel with placebo. The drug was administered at a dosage of 1 g three times a day orally for 90 days. At recruitment and at the end of the study all patients underwent physical examination, treadmill test, doppler C.W. of the lower limbs, ankle/brachial index, dosage of tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), hematocrit, hematic filtration, and viscosity. In the group treated with propionyl-l-carnitine a statistically significant increase of claudication distance, blood flow velocity, PAI-1 activity and red blood cell deformity was observed. These data suggest the usefulness of propionyl-l-carnitine in the treatment of patients affected by peripheral arterial obliterative disease.

Do internal mammary artery side-branches have the potential for haemodynamically significant flow steal?

OBJECTIVE: To evaluate the potential for flow steal of the internal mammary artery (IMA) side-branches at rest and in case of dilatation of their vascular bed (as probably occurs during physical exercise). METHODS: Transthoracic echo-Doppler evaluation of IMA flow was performed preoperatively in 40 patients undergoing myocardial revascularization. IMA flow was measured at rest and in condition of peripheral vasodilatation (obtained using forced ventilation for 2 min, dypiridamole 0.84 mg/kg endovenous (e.v.), xantinole nicotinate 500 mg e.v., nifedipine 20 mg sublingual (s.l.)). RESULTS: IMA mean peak systolic velocity increased 23% after forced ventilation (from 67 to 83 cm/s), 6% after dypiridamole (from 75 to 80 cm/s), 30% after xantinole infusion (from 62 to 81 cm/s) and 23% after nifedipine administration (from 60 to 74 cm/s). IMA flow increased 17.7% after forced ventilation (from 39.5 to 46.5 ml/min), 4.8% after dypiridamole (from 39.2 to 41.1 ml/min), 20.2% after xantinole infusion (from 41.4 to 49.8 ml/min) and 16.5% after nifedipine administration (from 41.6 to 48.5 ml/min). CONCLUSIONS: The limited functional flow reserve of the in situ IMA, even after pure muscular vasodilatation, seems to minimize the possibility of significant flow steal from patent IMA graft collaterals.

[The radial artery in coronary surgery: the midterm clinical and angiographic results and the variation in vasoreactivity over time]. / L'arteria radiale in chirurgia coronarica: risultati clinici ed angiografici a medio termine e variazione della vasoreattività nel tempo.

OBJECTIVE: To evaluate the mid-term angiographic results of radial artery grafts used for myocardial revascularization. METHODS: The first 68 consecutive surviving patients who received a radial artery graft proximally anastomosed to the aorta at our institution were restudied in a five-year follow-up (mean 59 +/- 6.5 months); 48 of these patients had already undergone an early angiographic examination. The response of the radial artery to the endovascular infusion of serotonin was evaluated one and five years after surgery and the mid-term status of the radial artery grafts was correlated with the degree of stenosis of the target vessel and with the Ca(++)-channel-blocker therapy. RESULTS: The patency and perfect patency rates of the radial artery five years after the operation were 91.9 and 87.0% respectively. All radial artery grafts that were patent early after surgery remained patent at mid-term follow-up and in seven patients early parietal irregularities disappeared after five years. The early propensity to graft spasm after serotonin challenge decreased markedly at mid-term follow-up. The continued use of Ca(++)-antagonists after the first postoperative year did not affect the status of the radial artery graft, whereas the severity of target-vessel stenosis markedly influenced the angiographic results. CONCLUSIONS: The mid-term angiographic results of RA grafts used for myocardial revascularization are excellent. A correct surgical indication is essential, whereas continued therapy with Ca(++)-antagonists after the first year does not influence the mid-term angiographic results.

Raynaud's Phenomenon and Helicobacter Pylori Infection.

Raynaud's phenomenon is an intermittent vasospasm of the arterioles of the distal limbs which occurs mostly following exposure to cold or emotional stimuli. Helicobacter pylori infection, the most relevant cause of gastritis, has been associated with some vascular diseases. The aim of this study was to assess the prevalence of H. pylori infection and effects of eradication on Raynaud attacks. Twenty-five patients affected by primary Raynaud's phenomenon were evaluated. H. pylori infection was assessed by the 13C urea breath test and 20 subjects were found to be infected by the bacterium. Triple therapy consisting of amoxicillin, clarithromycin, and lansoprazole was given to the patients for 7 days at the time of diagnosis. Duration and frequency of clinical attacks of Raynaud's phenomenon per week were assessed for 12 weeks after eradication. In 80 percent of the patients Raynaud's was eradicated after therapy. Clinical attacks of Raynaud's phenomenon completely disappeared in 18% of the eradicated patients. Duration and frequency of attacks were significantly reduced in 68% of the remaining patients. The preliminary findings from this study show that H. pylori eradication significantly ameliorates primary Raynaud's disease.

Primary Headache and Helicobacter Pylori.

H. pylori infection has recently been associated with various vascular disorders. The aim of this study was to investigate its role in primary headache, a pathology strictly associated with vascular alterations. A total of 200 subjects affected by primary headache were evaluated. H. pylori infection was diagnosed by the 13C urea breath test. Headache was classified in tension-type headache, cluster headache, and migraine with or without aura. Prevalence of H. pylori infection and gastrointestinal (GI) symptoms were evaluated. H. pylori infection was found in 40% of the patients; prevalence of migraine without aura was found to be significantly greater in infected patients. The positive group showed no significant differences in the prevalence of the GI symptoms evaluated. In 30 infected patients, it was assessed whether the eradication of the bacterium was able to reduce frequency, intensity, and duration of clinical attacks of headache. After eradication, clinical attacks of headache completely disappeared in 17% of patients. Moreover, intensity, duration, and frequency of headache attacks were reduced in 69% of the remaining subjects. In conclusion, H. pylori infection is common in primary headache; bacterium eradication appears to be related to a significant reduction in clinical attacks of the disease.

Helicobacter pylori eradication ameliorates primary Raynaud's phenomenon.

Raynaud's phenomenon is defined by an intermittent vasospasm of the arterioles of the distal limbs. Helicobacter pylori infection has been recently associated with Raynaud's phenomenon. The aim of this study was to assess the effects of H. pylori eradication on Raynaud's attacks. Forty-six patients affected by primary Raynaud's phenomenon were evaluated. H. pylori infection was assessed by [13C]urea breath test. Eradication therapy was given to infected patients for seven days. Discomfort and the duration and frequency of attacks of Raynaud's phenomenon per week were assessed. Thirty-six subjects were infected with H. pylori; the bacterium was eradicated in 83% of these after therapy. Attacks of Raynaud's phenomenon completely disappeared in 17% of the patients with H. pylori eradication. Discomfort and the duration and frequency of attacks of Raynaud's phenomenon were significantly reduced in 72% of the remaining patients. Conversely, attacks of Raynaud's disease did not change significantly during the 12-week follow-up period either in the H. pylori-negative patients or in the infected subjects in whom the bacterium was not eradicated by therapy. The study shows that H. pylori eradication causes a significant decrease in clinical attacks of Raynaud's disease. The reduction of vasoactive substances determined by the eradication of the bacterium may be the pathogenetic mechanism underlying the phenomenon.

Non-invasive evaluation of mammary artery flow reserve and adequacy to increased myocardial oxygen demand.

OBJECTIVE: To evaluate the flow reserve and adequacy to meet myocardial requests in stress conditions of mammary artery-left anterior descending (IMA-LAD) grafts using a non-invasive method. METHODS: Patients (20) with angiographic evidence of normofunctioning left IMA-LAD grafts were submitted to dypiridamole Tl201 myocardial scintigraphy and concomitant transthoracic echo-doppler evaluation of the IMA flow at a mean interval of 32.5 months after surgery. RESULTS: Under basal conditions, the mean peak and end flow velocities in systole were 0.39 and 0.06 m/s, respectively. In diastole, the mean peak and end flow velocities were 0.27 and 0.02 m/s and mean tele-diastolic flow velocity was 0.14 m/s, with a mean systolic/diastolic ratio of 1.51. After dypiridamole infusion, mean systolic velocities were 0.47 (peak) and 0.23 (end) m/s, respectively + 20 and + 283%, whereas mean diastolic velocities were 0.56 (peak) and 0.06 (end) m/s, +107 and +200%, respectively. Mean tele-diastolic flow velocity increased to 0.32 m/s (+128%) and the systolic-diastolic index changed to 0.85. In all cases no significant scintigraphic evidence of induced ischemia was demonstrated in the LAD region. CONCLUSIONS: Transthoracic echo-doppler evaluation combined with Tl201 myocardial scintigraphy is a useful tool for the assessment of IMA flow reserve and adequacy to stress conditions. In the late postoperative period, the IMA shows the possibility of increasing the flow velocity, almost 2-fold; the increase in flow is prevalently diastolic and leads to a complete reversal of the physiological systolic/diastolic flow ratio. The flow reserve of IMA is always able to meet the augmented myocardial oxygen demand after dypiridamole infusion.

Steal phenomenon from mammary side branches: when does it occur?

BACKGROUND: The hemodynamic significance of patent mammary graft side branches is still controversial. This study was designed to evaluate the potential for flow steal of patent mammary side branches in different hemodynamic conditions. METHODS: Echo-Doppler measurement of mammary graft flow was performed at rest and after dipyridamole-induced coronary vasodilatation in 10 patients with angiographic demonstration of evident mammary graft side branches (study group) and in 10 matched control patients (control group). Concomitant thallium-201 myocardial scintigraphy was performed to assess the adequacy of mammary flow to the myocardial oxygen demand. Patients of the study group were also submitted to flow evaluation in condition of selective muscular or combined systemic and coronary relaxation. RESULTS: No difference in mammary flow and adequacy to myocardial oxygen demand was detected between patients of the study and control groups both at rest and after dipyridamole infusion. In patients with patent side branches the systolic-to-diastolic flow ratio was maintained in case of combined coronary and peripheral vasodilatation, whereas selective muscular relaxation led to an increase in the systolic and a reduction in the diastolic flow. CONCLUSIONS: Flow steal from patent mammary graft side branches is possible only in case of selective muscular vasodilatation. As this situation is unlikely to occur in the clinical setting, the potential for flow steal of mammary side branches in cardiac surgery patients seems to be minimal.