Quantitative study of digestive enzyme secretion and gastrointestinal lipolysis in chronic pancreatitis.

BACKGROUND & AIMS: The contribution of human gastric lipase (HGL) to the overall lipolysis process in chronic pancreatitis (CP), as well as the relative pancreatic enzyme levels, rarely are addressed. This study was designed to quantify pancreatic and extrapancreatic enzyme output, activity, and stability in CP patients vs. healthy volunteers. METHODS: Healthy volunteers (n = 6), mild CP patients (n = 5), and severe (n = 7) CP patients were intubated with gastric and duodenal tubes before the administration of a test meal. HGL, human pancreatic lipase (HPL), chymotrypsin, and amylase concentrations were assessed in gastric and duodenal samples by measuring the respective enzymatic activities. Intragastric and overall lipolysis levels at the angle of Treitz were estimated based on quantitative analysis of lipolysis products. Similar analyses were performed on duodenal contents incubated ex vivo for studying enzyme stability and evolution of lipolysis. RESULTS: Although HPL, chymotrypsin, and amylase outputs all were extremely low, HGL outputs in patients with severe CP (46.8 +/- 31.0 mg) were 3-4-fold higher than in healthy controls (13.3 +/- 13.8 mg). Intragastric lipolysis did not increase, however, in patients with severe CP, probably because of the rapid decrease in the pH level of the gastric contents caused by a higher gastric acid secretion. HGL remains active and highly stable in the acidic duodenal contents of CP patients, and, overall, can achieve a significant lipolysis of the dietary triglycerides (30% of the control values) in the absence of HPL. CONCLUSIONS: Although all pancreatic enzyme secretions are simultaneously reduced in severe CP, gastric lipase can compensate partly for the loss of pancreatic lipase but not normalize overall lipolytic activity.     

A 6-month, open-label clinical trial of pancrelipase delayed-release capsules (Creon) in patients with exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatic surgery

Aliment Pharmacol Ther 2011; 33: 1152–1161

Summary

Background Pancreatic enzyme replacement therapy (PERT) is necessary to prevent severe maldigestion and unwanted weight loss associated with exocrine pancreatic insufficiency (EPI) due to chronic pancreatitis (CP) or pancreatic surgery (PS). Aim To assess the long‐term safety and efficacy of pancrelipase (pancreatin) delayed‐release capsules (Creon) in this population. Methods This was a 6‐month, open‐label extension of a 7‐day, double‐blind, placebo‐controlled study enrolling patients ≥18 years old with confirmed EPI due to CP or PS who were previously receiving PERT. Patients received individualised pancrelipase doses as directed by investigators (administered as Creon 24 000‐lipase unit capsules). Results Overall, 48 of 51 patients completed the open‐label phase; one withdrew due to the unrelated treatment‐emergent adverse event (TEAE) of cutaneous burns and two were lost to follow‐up. The mean age was 50.9 years, 70.6% of patients were male, 76.5% had CP and 23.5% had undergone PS. The mean ± s.d. pancrelipase dose was 186 960 ± 74 640 lipase units/day. TEAEs were reported by 22 patients (43.1%) overall. Only four patients (7.8%) had TEAEs that were considered treatment related. From double‐blind phase baseline to end of the open‐label period, subjects achieved a mean ± s.d. body weight increase of 2.7 ± 3.4 kg (P < 0.0001) and change in daily stool frequency of ?1.0 ± 1.3 (P < 0.001). Improvements in abdominal pain, flatulence and stool consistency were observed. Conclusions Pancrelipase was well tolerated over 6 months and resulted in statistically significant weight gain and reduced stool frequency in patients with EPI due to CP or PS previously managed with standard PERT.

     

Early treatment efficacy of S-adenosylmethionine in patients with intrahepatic cholestasis: A systematic review

BACKGROUND S-adenosylmethionine(Ado Met) is a metabolically pleiotropic molecule used to treat intrahepatic cholestasis(IHC) and chronic liver diseases. While the efficacy of Ado Met has been demonstrated previously, it has not been systematically investigated within the early weeks of treatment.AIM To systematically review the early treatment efficacy of Ado Met in adult patients with IHC.METHODS Studies reporting the efficacy of intravenous, intramuscular, or oral forms of Ado Met within 8 wk of treatment initiation were considered; three randomized and six non-randomized studies were eligible for inclusion(PROSPERO registration number CRD42018090936). Of the three randomized studies, two were double-blind and placebo-controlled, and one was comparator-controlled with unclear blinding and a relatively high risk of bias. Mean serum levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), alkaline phosphatase(ALP), and gamma-glutamyl transferase(_γGT) following Ado Met treatment vs placebo, comparator, or baseline were summarized to determine differences in liver enzymes. Changes in patient-reported clinical symptoms of cholestasis were also summarized.RESULTS Both placebo-controlled randomized studies reported significant reductions in serum ALT levels with Ado Met vs placebo within 2 wk. One of these also reported significant ALP reductions, and the other reported significant AST and _γGT reductions within 2 wk. The comparator-controlled randomized study,which had a number of notable limitations, reported significant reductions in serum ALT and AST levels with Ado Met vs potassium magnesium aspartate within 4 wk, but not within2 wk. All of the non-randomized studies(4/4) that investigated ALT, AST, ALP and/or _γGT reported significant reductions in at least two of these parameters within 2 wk. Of the five studies that evaluated fatigue, reductions were observed within 2 wk in one randomized and two nonrandomized studies. The remaining two non-randomized studies reported improvements in fatigue within 6 and 8 wk. Of the four studies reporting symptoms of depression, two non-randomized studies observed improvements within 2 wk and the other two observed improvements within 17 d and 8 wk.CONCLUSION Data from both randomized and non-randomized studies suggest that Ado Met improves some biochemical liver parameters and symptoms of cholestasis within2 wk, with further improvements observed in some studies after 4 and 8 wk of treatment.     

Does the pancreas really produce much more lipase than required for fat digestion?

Thirty years ago, it was reported that a linear relationship does not exist between the amounts of human pancreatic lipase secreted in chronic pancreatitis and the degree of steatorrhea, which was considered to appear only after more than 90% of the pancreatic secretory capacity had been lost. From these observations, it was generally thought that the lipolytic potential of the pancreas is much higher than required. In recent years, however, it has been noted that: 1) the level of inhibition of digestive lipases and gastrointestinal lipolysis by the lipase inhibitor orlistat were almost linearly correlated with the amount of excreted fat; 2) in minipigs with experimentally-induced pancreatic exocrine insufficiency, the amounts of enteric-coated pancreatic extracts needed for restoring fat digestion to normal levels were estimated to be much higher than those usually administered; 3) human pancreatic lipase specific activity on meal triglycerides is 3 orders of magnitude lower than the very high specific activity usually measured under experimental in vitro conditions which are far from physiological conditions; 4) in patients with reduced human pancreatic lipase secretion, gastric lipase plays a significant role in fat digestion. This last observation might explain the absence of a linear relationship between human pancreatic lipase secretion in chronic pancreatitis and steatorrhea. From the low specific activity displayed by human pancreatic lipase on meal triglycerides, one can better understand why more lipase than expected is needed, why fat digestion lasts for more than a few minutes and, finally, why there is not such an excess secretory capacity for lipase as had been previously thought.