Novel Pancreatic Developmentsprof. Peter Layer –  Gastro Update Europe 2019, Budapest
Nové poznatky o pankreatu

The steadily ris­­ing incidence over the previous decades of acute and chronic pancreatitis, presumably related to alcohol and tabacco consumption, obesity and cholelithiasis, was recently shown in a large American insurance data base to decline in adults, but not in children (Fig. 1and 2 –  available only on the web site www.cshg.info). If this decline is related to decreas­­ing nicotine consumption or increas­­ing endoscopic/ surgical obesity treatment remains speculative.

Eluxadoline, a mixed opioid receptor modulator, available in some European countries for diar­rhea-predominant ir­ritable bowel syndrome, was shown in a post-market­­ing surveil­lance, to be responsible for induc­­ing acute pancreatitis in over 16% of the adverse events compared to less than 1% for all other anti-diar­rheas (related to sphicter of Oddi dysfunction). This would demand a re-evaluation of eluxadoline’s benefit-hazard ratio (HR).

Ramadan, celebrated by Muslims, includes dawn-to-dusk fasting, fol­lowed by an opulent even­­ing meal which may lead to mas­sive gall bladder contractions, perhaps favor­­ing gall stone mobilization with risk of pancreatitis. Indeed, the risk of acute pancreatitis was shown to be 2.5× higher dur­­ing the Ramadan month. Fol­low­­ing prolonged fasting, mas­sive nutritive stimulation may lead to vigorous contraction of a distended gall bladder, to rapid increase in serum triglycerides and glucose and to mas­sive stimulation of pancreatic enzyme secretion. Ramadan fol­lowers should be advised to break the fast gradual­ly, especial­ly if cholelithiasis is present.

A simple cheap and particularly rapid prognostic marker in acute pancreatitis is the neutrophil-to-lymphocyte ratio in peripheral blood. The normal ratio is approx. 1.65. A value > 10 was shown to predict high severity of acute hypertriglyceridemia-induced pancreatitis, with prolonged hospital stay, enhanced risk for Systemic inflam­matory response syndrome and renal failure. These excit­­ing data war­rant further prospective evaluation in all forms of acute pancreatitis.

Acute pancreatitis is often as­sociated with nausea, vomiting, gastrointestinal hypomotility and subileus, conditions favor­­ing bacterial overgrowth, bacterial translocation and infectious complications. Bacterial overgrowth, studied by a (poorly sensitive) glucose breath test at day (d) 7 in over 200 pancreatitis patients, was demonstrable in over 25% of the patients with a severe cause and with organ complications. Early enteral feeding, whenever feasable, would presumably lead to early stimulation of gastrointestinal motility and reduction of intestinal stagnation and bacterial overgrowth.

Heal­­ing of acute pancreatitis may be as­sociated with ir­reversible structural and functional deficits. The prevalence of exocrine pancreatic insuf­ficiency was evaluated some 36 months (m) after the acute attack in a meta-analysis involv­­ing almost 1,500 patients. Exocrine insuf­ficiency was present in one quarter of the patients, particularly in patients with alcoholic pancreatitis or with a severe necrotiz­­ing course. Clinicians should be on the outlook for insuf­ficiency dur­­ing fol­low-up. Unfortunately, an easy simple (stool) test, also sensitive for minor degrees of insuf­ficiency, is still not available.

Over the last few years, a paradigm shift has occur­red with respect to the management of acute necrotis­­ing pancreatitis. Early emergency surgery (often open necrosectomy) is obsolete and initial management should be conservative. If surgical intervention should be neces­sary it should be selective, late elective and lead­­ing to minimal trauma. Minimal­ly invasive surgery led to a 20– 30% lower mortality compared to open necrosectomy. Also, endother­apy in high risk patients had a 60– 79% lower mortality compared to open necrosectomy. Optimal management of severe acute pancreatitis with infected necrosis requires an individual­ly adapted minimal­ly invasive strategy. If interventions are needed, endoscopic methods are less traumatic and produce over­all better results compared with minimal­ly invasive surgery. This was again confirmed in a recent study, show­­ing that endoscopic ther­apy when performed in experienced centers by experts is safe and cost-ef­fective. The main reasons for endoscopic superiority was a les­ser occur­rence of enteral or pancreatic-cutaneous fistulae and lower rate of systemic inflam­matory response syndrome.

Chronic pancreatitis is a dreadful condition. Alcohol and smok­­ing have a deleterious influence on the natural evolution as shown by an approx. 10 year (y) fol­low-up study compar­­ing alcoholics (75% smokers) to non-alcoholics (< 40% smokers). Chronic pain, pseudocysts, pancreatitis flares, exocrine insuf­ficiency, and number of hospitalisations were significantly higher in the alcoholic cohort. Stres­s­­ing the need to abstain from alcohol and to stop smok­­ing remains of high clinical relevance.

Intrigu­­ing is the impact of statins on the natural evolution of chronic pancreatitis, as shown in a population based cohort of close to 5,000 patients of whom 43% died and 2.4% developed pancreatic cancer. Over­all mortality, dis­ease progres­sion and pancreatic cancer risk were lower in statin users. Statin use may be as­sociated with protective (anti-fibrogenetic, anti-carcinogenetic) ef­fects in chronic inflam­matory dis­eases such as chronic pancreattis.

Intraductal papil­lary mucinous neoplasia (IPMN) may occasional­ly lead to cancer, particularly when involv­­ing the main pancreatic duct. Many use the Fukuoka criteria to estimate the cancer risk, look­­ing for wor­risome features (pancreatitis, cyst > 3 cm, thickened or enhanced cystic wal­l, main pancreatic duct > 5 m­m, non-enhanced cyst mural nodule, abrupt change in main pancreatic duct caliber with distal atrophy) and high-risk stigmata (HR) (obstructive jaundice, solid components with enhancement, main pancreatic duct > 10 m­m). European guidelines were recently published regard­­ing the dia­gnostic and therapeutic management of IPMN (Fig. 3).

Based on several new studies fol­low­­ing main recom­mendations conclusions can be drawn: IPMNs, even if initial­ly Fukuoka negative, are (and become) never „safe“. Therefore, long-term surveil­lance ( > 5 y) is war­ranted, as long as the patient is fit for surgery; initial cyst size alone is not a wor­risome feature per se but predicts later development of wor­risome features, as does also occur for rapidly enlarg­­ing cysts by > 2.5 m­m/ y.

For cysts of an indeterminate nature, measur­­ing glucose in the cyst fluid may of­fer a simple, quick, cheap and precise dia­gnostic marker for its neoplastic nature. This was shown in a study of over 150 resected cystic lesions of various subtypes. Cyst glucose was substantial­ly lower in the mucinous type cysts compared to non-mucinous cysts. Us­­ing a glucose cut-off value of 50 mg/ dl, the accuracy of the glucose test was 90% compared to 69% for Clinical use of carcinoembryonic antigen determination with a cut-off at 192 ng/ ml.

Cyst ablation may be attempted in high risk IPMN in patients unfit for pancreatic surgery by endoscopic ultrasound-guided instil­lation of cytostatic drugs (gemcitabine and paclitaxel) dis­solved in alcohol or saline respectively. Complete cyst ablation at 12 m was obtained in respectively 61 and 67, with severe 30 d adverse events in 6% vs. 0% and mild 30 d adverse events in 22 vs. 0%. These results need to be confirmed in other studies with long-term fol­low-up before this method becomes standard ther­apy.

Pancreatic cancer remains the number one dismal conundrum in gastroentero­logy. For many years, prevention has been suggested by drugs such as acetylsalicylic acid and vitamin D. Disappointingly, the large long term American nurses/ health profes­sionals study revealed that both drugs of­fered no relevant protection against pancreatic cancer. As bio­markers for early dis­ease are not yet available, we are left to be on the outlook for early symp­toms. Newly dia­gnosed diabetes may be the first symp­tom of an underly­­ing pancreatic malignancy. This was nicely shown in 219 cancer cases vs. 440 controls. As shown in the fig. 4 (available only on the web site www.cshg.info), hyperglycemia may be observed as early as 30– 36 m prior to cancer dia­gnosis. The degree of blood glucose elevation cor­related with both the tumour size and degree of undif­ferentiation.

Development of pancreatic cancer points to complex interactions with the metabolism of glucose, with chronic hyperglycemia favor­­ing neoplasia. Therefore, in all patients with new onset of diabetes, particularly when as­sociated with preced­­ing weight los­s, increased vigilance is mandatory and, as a rule, abdominal ultrasound is war­ranted.

The Gastro Update Europe 2020 will be held on September 4–5, 2020 in Bratislava, Slovakia. For more information visit www.gastro-update-europe.eu.

Prof. Guido Tytgat, MD, PhD

Department of Gastroenterology and

Hepatology

Academic Medical Center

Meibergdreef 9

1105 AZ Amsterdam

The Netherlands

 g.n.tytgat@amc.uva.nl