Gallbladder and Pancreatic Disease and Dysfunction an Overview

Dr Carrie Decker ND discusses the role of the pancreas and gall bladder in human digestion and health and explores some common problems, signs and symptoms and makes some recommendations for treatment and functional interventions.

Normal pancreatic and gallbladder function:

Digestive secretions of the gallbladder and pancreas are necessary for appropriate digestion of food substances. The digestion of foodstuff begins in the oral cavity with the process of chewing mixing foods with saliva, and salivary amylase initiates digestion by beginning to breakdown carbohydrates into smaller molecules. Subsequent to this, the food particles continue to be broken down by mechanical action and the acidic pH of the stomach. The partially digested substances, mixed into a semi-fluid mass called chyme, leave the stomach and enter the duodenum where bile from the gallbladder and pancreatic enzymes are both added via the ductal system of the biliary tree.

The central nervous system also plays an important role in the digestive process. Normal function of the pancreas and gallbladder requires input from the central nervous system in response to food intake. Postprandial release of cholecystokinin (CCK) plays a central role in the activation of intestinal feedback control of gastrointestinal function, and is stimulated by parasympathetic nerve fibres of the vagus nerve. Actions of CCK include stimulation of the exocrine pancreas and postprandial gallbladder emptying as well as inhibition of gastric emptying and acid secretion.[1],[2] CCK also acts via vagal afferent pathways to inhibit food intake.

Gallbladder dysfunction:

Biliary dysfunction can include multiple issues, which if not resolved can lead to pathology such as gallstones. Bile that is supersaturated with excess amounts of cholesterol or bilirubin leads to a sludge of precipitates.[3] Bile salts are an important part of the bile as they act as detergents to solubilise lipids. They also aid in the absorption of dietary lipids in the intestine. When there is excess cholesterol or bilirubin relative to bile salts, it will precipitate and can lead to the formation of stones. Gallbladder hypomotility or bile stasis also is a factor that leads to stone formation. Gallbladder stones can lead to obstruction of the biliary tree via which gallbladder and pancreas enzymes are secreted into the duodenum, causing emergency events such as acute cholecystitis or acute pancreatitis.

Gallbladder hypomotility or poor bile ejection can be associated with certain disease conditions, or may be a functional issue. Gallbladder tone is regulated by smooth muscle activity, hormones, and neurotransmitters released from intrinsic neurons and extrinsic sympathetic nerves.^[4] Gallbladder hypomotility has been shown to be associated with polyneuropathy of diabetes mellitus, as well as other conditions such as spinal cord injuries which affect nervous system function.^[5],^[6] Animal studies have shown that the lack of CCK induces gallbladder hypomotility, prolonging the time that excess cholesterol resides in the gallbladder. ^[7] Biliary dyskinesia is a motility disorder that also may affect gallbladder function or the sphincter of Oddi, which connects the biliary tree to the duodenum. This also may lead to symptoms similar to gallstones as well as pancreatitis.^[8]

Risk factors for gallstone formation include being of the female sex, obesity, rapid weight loss, pregnancy, oestrogen therapies, diabetes mellitus, and a family history of gallbladder disease.[9] Individuals with Crohn’s disease or haemolytic disorders such as sickle cell disease or hereditary spherocytosis also have an increased risk for forming gallstones.[10] Native Americans are an ethnic group with a higher risk for gallstones, while African Americans have been observed to have the lowest risk.[11] Historically, haemolytic disease was primary risk factor in children, while now gallstone disease in children is more often associated with obesity.[12]

Symptoms of gallbladder dysfunction and gallstones may include right upper quadrant pain, nausea, changes in stool colour or fat malabsorption, and acutely with obstruction there may be vomiting. Symptoms commonly occur after a meal or snack with increased fat content. More often than not the presence of gallstones will be asymptomatic and they are an incidental finding on abdominal imaging. Laboratory studies are usually normal in individuals with uncomplicated gallstone disease. With acute cholangitis (obstruction and infection of biliary tract) there may be elevations in the white blood cell count, serum alkaline phosphatase, gamma-glutamyl transpeptidase, bilirubin, and possibly aminotransferases. Patients with acute cholecystitis (gallbladder inflammation) typically have elevated white blood cell counts, possibly with mild elevations in serum aminotransferases and bilirubin. “Murphy’s sign,” a sensation of discomfort with deep inspiration when pressure is applied along the right lower rib margin at the mid-clavicular line, is usually is positive with acute cholecystitis.[13]

Pancreatic dysfunction:

Pancreatic exocrine insufficiency (PEI), although often not discussed in the medical realm outside of the context of cystic fibrosis or acute and chronic pancreatitis, may exist in many individuals who do not have these conditions. Although it is possible to detect mild changes in pancreatic exocrine function with early pancreatic disease, overt maldigestion of fat and protein does not occur until approximately 90 percent of pancreas glandular function has been lost.[14] Symptoms of mild PEI can include bloating, cramping, increased flatulence, and diarrhea. As mentioned, malabsorption also may occur depending on severity. As the early symptoms are common complaints associated with irritable bowel syndrome (IBS), it often may be diagnosed as such without further workup to determine the aetiology of these symptoms.

Risk factors for PEI in addition to cystic fibrosis and acute or chronic pancreatitis include age, smoking, small intestine infection, diabetes mellitus, coeliac disease, inflammatory bowel disease, and excess alcohol intake. [15],[16],[17],[18],[19],[20] Lower levels of pancreatic elastase also have been shown in some individuals with IBS.[21] Increased rates of chronic pancreatitis have been found in association with autoimmune disease, with increased autoantibodies to pancreatic antigen being found in individuals with Sjögren’s syndrome and idiopathic chronic pancreatitis.[22] As an increased frequency of autoimmune related pancreatitis has been observed over the last 10 years, it has been suggested that chronic pancreatitis due to autoimmune disease will continue to rise.[23] Sphincter of Oddi dysfunction also can lead to pancreatic insufficiency and chronic pancreatitis.[24] As vagal stimulation of CCK also stimulates pancreatic exocrine function, poor vagal tone also can contribute to pancreatic insufficiency.

There are a variety of techniques utilised to assess pancreatic exocrine function. Measurement of pancreatic exocrine function by faecal chymotrypsin or elastase-1 are commonly available, non-invasive diagnosis techniques that have been well studied for the diagnosis of pancreatic exocrine insufficiency. A direct correlation of pancreatic elastase-1 concentrations have been shown between pancreatic exocrine fluid and stool, and this marker has been shown to be highly sensitive for the diagnosis of moderate to severe pancreatic exocrine insufficiency.[25],[26] Although faecal chymotrypsin and elastase-1 are both relatively stable through intestinal transit, elastase-1 has been shown to be a more sensitive marker of pancreatic exocrine insufficiency and levels are not affected by the use of digestive enzymes.[27]

Supporting gallbladder and pancreatic health and function:

A deficiency of ascorbic acid (vitamin C) is associated with the development of gallstones, and supplementation may exert a protective effect.[28],[29] Increased consumption of fruits, vegetables, nuts, polyunsaturated and monounsaturated fats, and coffee has also been shown to reduce the risk of gallstone formation in different populations.[30],[31],[32],[33] Increased physical activity has also been shown to reduce the incidence of symptomatic gallstones independent of obesity and recent weight loss, while individuals with a sedentary lifestyle are at increased risk of having a cholecystectomy.[34]

Taurine deficiency has been shown in animal studies to lead to increased cholesterol gallstone formation, while supplementation with taurine reduced the incidence of gallstones, likely due to enhanced cholesterol degradation and the excretion of bile acid.[35],[36],[37] Ox bile, taken as a supplement, supports the production and flow of bile, which may lead to a reduction in stone formation as well as improving symptoms of fat malabsorption. Dietary fat and stomach acid secretion promotes gallbladder emptying, which may improve symptoms on a long term basis if they are related to stasis and poor ejection.^[38]

The presence of larger asymptomatic gallstones may be treated by cholecystectomy as it is associated with increased risk of gallbladder cancer. Because of the high incidence of gallstones in populations with haemolytic disorders and after gastric bypass, gallbladder removal is recommended in these populations.^[39] However, overall, only about 30% of patients with asymptomatic cholelithiasis have been observed to require surgery during their lifetime.^[40]

Abstinence from alcohol and tobacco, as well as treatment of hyperglycemia and small intestine bacterial overgrowth if present also will impact pancreatic exocrine function and related symptoms.[41],[42] Antioxidant therapies have been shown to reduce the pain and oxidative stress associated with chronic pancreatitis.^[43] Support for an acidic stomach pH also may play a role in normalising pancreatic exocrine function of a functional nature, while supplementation of pancreatic enzymes including lipase, proteases, and amylase with meals is recommended to improve absorption of nutrients as well as digestive symptoms.[44],[45]

For individuals with documented PEI, the initial dose of enzyme supplementation has been recommended to be is 25,000 units of lipase per meal possibly increasing to 90,000 units of lipase per meal.^35,[46]  Supplementation of papain (papaya) and bromelain (pineapple) also may be used to support the digestion of protein.[47] Pancreatin, a mixture of digestive enzymes secreted by the pancreas, also has been shown to be effective, but preparations have been shown to vary.[48],[49] Even in absence of testing that indicates PEI, a trial of supplementation with enzymes may be found to improve symptoms and if so may indicate insufficiency. If symptoms are exaggerated, discontinue supplementation until further investigations have been completed, as some patients with PEI will describe an increase in gastric distress with exogenous pancreatic enzymes.

Supporting parasympathetic balance may improve a variety of digestive complaints as the vagus nerve plays a significant role in digestion including gallbladder ejection and pancreas exocrine function.[50],[51] Poor vagal tone has also been documented in individuals with functional dyspepsia.[52]

Consumption of fat may play a role in digestive function via the parasympathetic nervous system as well. Increased enteral fat has been shown to reduce release of inflammatory mediators by acting as a stimulant of parasympathetic outflow via the vagus nerve, mediated by CCK release.[53],[54] Other interventions which support parasympathetic balance and improved digestion include making time for meals, chewing food thoroughly, engaging in a meditative or mindfulness practice including at meal times, eating meals in less stressful settings (away from the laptop or work environment), as well as other stress management techniques.

References

[1] Raybould HE. Mechanisms of CCK signaling from gut to brain. Curr Opin Pharmacol. 2007 Dec;7(6):570-4. View Full Paper

[2] Schjoldager BT. Role of CCK in gallbladder function. Ann N Y Acad Sci. 1994 Mar 23;713:207-18. View Abstract

[3] Donovan JM. Physical and metabolic factors in gallstone pathogenesis. Gastroenterol Clin North Am. 1999 Mar;28(1):75-97. View Abstract

[4] Portincasa P, et al. Smooth muscle function and dysfunction in gallbladder disease. Curr Gastroenterol Rep. 2004 Apr;6(2):151-62. View Abstract

[5] Várkonyi TT, et al. Gallbladder hypomotility in diabetic polyneuropathy. Clin Auton Res. 2001 Dec;11(6):377-81. View Abstract

[6] Baltas CS, et al. Gallstones and biliary sludge in Greek patients with complete high spinal cord injury: an ultrasonographical evaluation. Singapore Med J. 2009 Sep;50(9):889-93. View Abstract

[7] Wang HH, et al. Effect of gallbladder hypomotility on cholesterol crystallization and growth in CCK-deficient mice. Biochim Biophys Acta. 2010 Feb;1801(2):138-46. View Full Paper

[8] Toouli J, et al. Biliary Dyskinesia. Curr Treat Options Gastroenterol. 2002 Aug;5(4):285-291. View Abstract

[9] Lambou-Gianoukos S, et al. Lithogenesis and bile metabolism. Surg Clin North Am. 2008 Dec;88(6):1175-94. View Abstract

[10] Lapidus A, et al. The prevalence of gallstone disease in a defined cohort of patients with Crohn’s disease. Am J Gastroenterol. 1999 May;94(5):1261-6. View Abstract

[11] Shaffer EA. Epidemiology and risk factors for gallstone disease: has the paradigm changed in the 21st century? Curr Gastroenterol Rep. 2005 May;7(2):132-40. View Abstract

[12] Mehta S, et al. Clinical characteristics and risk factors for symptomatic pediatric gallbladder disease. Pediatrics. 2012 Jan;129(1):e82-8. View Abstract

[13] Trowbridge RL, et al. Does this patient have acute cholecystitis? JAMA. 2003 Jan 1;289(1):80-6. View Full Paper

[14] DiMagno EP, et al. Relations between pancreatic enzyme ouputs and malabsorption in severe pancreatic insufficiency. N Engl J Med. 1973 Apr 19;288(16):813-5. View Abstract

[15] Rothenbacher D, et al. Prevalence and determinants of exocrine pancreatic insufficiency among older adults: results of a population-based study. Scand J Gastroenterol. 2005 Jun;40(6):697-704. View Abstract

[16] Salvatore S, et al. Low faecal elastase: potentially related to transient small bowel damage resulting from enteric pathogens. J Pediatr Gastroenterol Nutr. 2003 Mar;36(3):392-6. View Abstract

[17] Hardt PD, et al. High prevalence of exocrine pancreatic insufficiency in diabetes mellitus. A multicenter study screening faecal elastase 1 concentrations in 1,021 diabetic patients. Pancreatology. 2003;3(5):395-402. Epub 2003 Sep 24. View Abstract

[18] Leeds JS, et al. Is exocrine pancreatic insufficiency in adult coeliac disease a cause of persisting symptoms? Aliment Pharmacol Ther. 2007 Feb 1;25(3):265-71. View Full Paper

[19] Ramos LR, et al. Inflammatory Bowel Disease and Pancreatitis: A Review. J Crohns Colitis. 2015 Sep 7. pii: jjv153 View Abstract

[20] Ammann RW, et al. Differences in the natural history of idiopathic (nonalcoholic) and alcoholic chronic pancreatitis. A comparative long-term study of 287 patients. Pancreas. 1987;2(4):368-77. View Abstract

[21] Goepp J, et al. Frequency of abnormal faecal biomarkers in irritable bowel syndrome. Glob Adv Health Med. 2014 May;3(3):9-15. View Full Paper

[22] Nishimori I, et al. Identification of autoantibodies to a pancreatic antigen in patients with idiopathic chronic pancreatitis and Sjögren’s syndrome. Pancreas. 1994 May;9(3):374-81. View Abstract

[23] Pezzilli R. Aetiology of chronic pancreatitis: has it changed in the last decade? World J Gastroenterol. 2009 Oct 14;15(38):4737-40. View Full Paper

[24] Tarnasky PR, et al. Sphincter of Oddi dysfunction is associated with chronic pancreatitis. Am J Gastroenterol. 1997 Jul;92(7):1125-9. View Abstract

[25] Stein J, et al. Immunoreactive elastase I: clinical evaluation of a new noninvasive test of pancreatic function. Clin Chem. 1996 Feb;42(2):222-6. View Full Paper

[26] Löser C, et al. Faecal elastase 1: a novel, highly sensitive, and specific tubeless pancreatic function test. Gut. 1996 Oct;39(4):580-6. View Full Paper

[27] Dominici R, et al. Faecal elastase-1 as a test for pancreatic function: a review. Clin Chem Lab Med. 2002 Apr;40(4):325-32. View Abstract

[28] Simon JA, et al. Serum ascorbic acid and gallbladder disease prevalence among US adults: the Third National Health and Nutrition Examination Survey (NHANES III). Arch Intern Med. 2000 Apr 10;160(7):931-6. View Full Paper

[29] Walcher T, et al. Vitamin C supplement use may protect against gallstones: an observational study on a randomly selected population. BMC Gastroenterol. 2009 Oct 8;9:74. View Full Paper

[30] Tsai CJ, et al. Fruit and vegetable consumption and risk of cholecystectomy in women. Am J Med. 2006 Sep;119(9):760-7. View Abstract

[31] Tsai CJ, et al. A prospective cohort study of nut consumption and the risk of gallstone disease in men. Am J Epidemiol. 2004 Nov 15;160(10):961-8. View Abstract

[32] Tsai CJ, et al. he effect of long-term intake of cis unsaturated fats on the risk for gallstone disease in men: a prospective cohort study. Ann Intern Med. 2004 Oct 5;141(7):514-22. View Abstract

[33] Zhang YP, et al. Systematic review with meta-analysis: coffee consumption and the risk of gallstone disease. Aliment Pharmacol Ther. 2015 Sep;42(6):637-48. View Abstract

[34] Leitzmann MF, et al. Recreational physical activity and the risk of cholecystectomy in women. N Engl J Med. 1999 Sep 9;341(11):777-84. View Full Paper

[35] Chen W, et al. The effect of taurine on cholesterol degradation in mice fed a high-cholesterol diet. Life Sci. 2004 Feb 27;74(15):1889-98. View Abstract

[36] Yamanaka Y, et al. Effect of dietary taurine on cholesterol gallstone formation and tissue cholesterol contents in mice. J Nutr Sci Vitaminol (Tokyo). 1985 Apr;31(2):225-32. View Abstract

[37] Chen W, et al. The effect of taurine on cholesterol metabolism. Mol Nutr Food Res. 2012 May;56(5):681-90. View Abstract

[38] Marciani L, et al. Effects of various food ingredients on gall bladder emptying. Eur J Clin Nutr. 2013 Nov;67(11):1182-7. View Full Paper

[39] Shiffman ML, et al. Gallstone formation after rapid weight loss: a prospective study in patients undergoing gastric bypass surgery for treatment of morbid obesity. Am J Gastroenterol. 1991 Aug;86(8):1000-5. View Abstract

[40] Schirmer BD, et al. Cholelithiasis and cholecystitis. J Long Term Eff Med Implants. 2005;15(3):329-38. View Abstract

[41] D’Haese JG, et al. Treatment options in painful chronic pancreatitis: a systematic review. HPB (Oxford). 2014 Jun;16(6):512-21. View Full Paper

[42] Pongprasobchai S. Maldigestion from pancreatic exocrine insufficiency. J Gastroenterol Hepatol. 2013 Dec;28 Suppl 4:99-102. View Abstract

[43] Bhardwaj P, et al. A randomized controlled trial of antioxidant supplementation for pain relief in patients with chronic pancreatitis. Gastroenterology. 2009 Jan;136(1):149-159.e2. View Abstract

[44] Domínguez-Muñoz JE. Pancreatic exocrine insufficiency: diagnosis and treatment. J Gastroenterol Hepatol. 2011 Mar;26 Suppl 2:12-6. View Abstract

[45] Toouli J, et al. Management of pancreatic exocrine insufficiency: Australasian Pancreatic Club recommendations. Med J Aust. 2010 Oct 18;193(8):461-7. View Abstract

[46] Rustemović N, et al. [Croatian guidelines for the management of pancreatic exocrine insufficiency]. Lijec Vjesn. 2012 May-Jun;134(5-6):141-7. View Abstract

[47] Roxas M. The role of enzyme supplementation in digestive disorders. Altern Med Rev. 2008 Dec;13(4):307-14. View Full Paper

[48] Ramesh H, et al. A 51-week, open-label clinical trial in India to assess the efficacy and safety of pancreatin 40000 enteric-coated minimicrospheres in patients with pancreatic exocrine insufficiency due to chronic pancreatitis. Pancreatology. 2013 Mar-Apr;13(2):133-9. View Abstract

[49] Löhr JM, et al. Properties of different pancreatin preparations used in pancreatic exocrine insufficiency. Eur J Gastroenterol Hepatol. 2009 Sep;21(9):1024-31. View Abstract

[50] Rogers RC, et al. Vagal control of digestion: modulation by central neural and peripheral endocrine factors. Neurosci Biobehav Rev. 1996;20(1):57-66. View Abstract

[51] Konturek SJ, et al. Neuroendocrinology of the pancreas; role of brain-gut axis in pancreatic secretion. Eur J Pharmacol. 2003 Nov 14;481(1):1-14. View Abstract

[52] Hausken T, et al. Low vagal tone and antral dysmotility in patients with functional dyspepsia. Psychosom Med. 1993 Jan-Feb;55(1):12-22. View Abstract

[53] Raybould HE. Mechanisms of CCK signaling from gut to brain. Curr Opin Pharmacol. 2007 Dec;7(6):570-4. View Full Paper

[54] Tracey KJ. Fat meets the cholinergic antiinflammatory pathway. J Exp Med. 2005 Oct 17;202(8):1017-21. View Full Paper