Malabsorption Syndromes Dublin PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn MALABSORPTION Department of Medicine LEARNING OUTCOMES 1. Define Malabsorption 2. List the causes of malabsorption 3. Describe how...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn MALABSORPTION Department of Medicine LEARNING OUTCOMES 1. Define Malabsorption 2. List the causes of malabsorption 3. Describe how each cause leads to development of malabsorption 4. Outline the common symptoms and signs in malabsorption 5. Develop a differential diagnosis for malabsorption 6. Discuss the assessment and investigative work-up 7. Describe the management LEARNING OUTCOME Define Malabsorption MALABSORPTION A broad clinical term which refers to the impaired absorption of nutrients (fats, carbohydrates, protein, vitamins, electrolytes, minerals and water) at any point where nutrient absorption takes place. Often presents as chronic diarrhoea. Three steps are required for normal nutrient absorption: 1. Luminal processing 2. Absorption into the intestinal mucosa 3. Transport into the circulation Malabsorption can result from defects in any of these three phases 1 2 CLASSIFICATION Malabsorption is a complication of many disease processes. Classification systems include: Global malabsorption – due to disease that affects the mucosa or causes reduced absorption area. This leads to nutrients not being adequately absorbed. Eg coeliac disease Partial malabsorption – localised disease that interferes with absorption of specific nutrients, eg B12 deficiency in pernicious anaemia Selective malabsorption – specific deficiency eg. Primary lactase deficiency. OR Primary, or congenital malabsorption – due to congenital defects in the membrane transport systems. Acquired, or secondary malabsorption – Malabsorption results from acquired defects (eg, Crohn disease, coeliac disease, or after extensive surgical resection or intestinal bypass operations) in the epithelial absorptive surface. LEARNING OUTCOMES List the causes of malabsorption Describe how each cause leads to development of malabsorption Develop a differential diagnosis for malabsorption FAT DIGESTION & ABSORPTION Bile Acid Metabolism Cycle  CAUSES OF FAT MALABSORPTION Small intestinal disease/resection: o Small bowel disease o Resection o Impairment of the enterohepatic circulation of bile salts Small intestinal bacterial overgrowth o Deconjugation of bile acids by bacteria Pancreatic exocrine insufficiency – o Impaired production of pancreatic enzymes o Due to chronic pancreatitis, or cystic fibrosis Disorders of bile acid metabolism o Inadequate synthesis (eg. cirrhosis) o Inadequate secretion of bile salts (eg. cholestasis) o Inadequate deliver of bile (eg. Biliary obstruction- tumour, stone) Other causes – o Abetalipoproteinemia: Rare inherited disorder, inadequate synthesis or defective structure of apoproteins necessary for the packaging of chylomicrons, impairs their secretion into the lymphatics o Abnormalities in lymphatic flow (eg, intestinal lymphangiectasia, TB tuberculous lymphadenitis, lymphoma) CARDINAL SYMPTOMS STEATORRHOEA: pale, greasy, foul smelling, frothy or foamy, bulky stools that are difficult to flush due to increased fat content PROTEIN Mechanism of protein digestion Causes of protein malabsorption ​ and absorption ​ Impaired pancreatic bicarbonate and Protein digestion begins in the stomach by protease secretion eg pancreatic the action of gastric pepsins.​ insufficiency due to cystic fibrosis or Amino acids released from chronic pancreatitis. gastric digestion results in the release Impaired activity of enzymes.​ of cholecystokinin (CCK) from Reduced intestinal absorptive surface. duodenal and jejunal endocrine epithelial cells. This stimulates the release of pancreatic enzymes responsible for the digestion of all three macronutrients.​ In the duodenum, several proteases act together to digest proteins into amino acids, or dipeptides and tripeptides.​ Amino acids, dipeptides, and tripeptides can be absorbed at the brush border membrane. Different classes of amino acid transporters exist on the brush Brush Border border. CARBOHYDRATE Mechanism of carbohydrate digestion Causes of carbohydrate and absorption ​ malabsorption Dietary starch and disaccharides must Deficiency in pancreatic amylase​ be broken down into their constituent (pancreatitis, CF) monosaccharides prior to absorption​ Reduced disaccharidase activity Both salivary and pancreatic amylase in the small intestinal epithelium​ contribute to their digestion. ​ Decreased absorptive At the brush border intestinal surface area (eg. coeliac enzymes hydrolyze and broken- disease)​ down nutrients are absorbed.​ Unabsorbable carbohydrates Carbohydrates that are not digested (eg sorbitol)​ and absorbed in the small intestine Congenital; lactase deficiency undergo bacterial degradation in and sucrase-isomaltase deficiency. the colon. Symptoms: flatulence, abdominal cramps and pain, diarrhoea VITAMINS, MINERALS, TRACE ELEMENTS Mechanism Causes of malabsorption​ The proximal half of the small intestine is Proximal small bowel resections.​ the predominant site for the absorption of Distal small bowel resections; typically, distal most vitamins and minerals.​ ileum will result in vitamin B12 deficiency. ​ Distal small intestinal and colonic disease Vitamin B12 is absorbed in the ileum​ can cause hypomagnesemia​ Calcium, iron and folate (vitamin B9) Fat-soluble vitamins – The fat-soluble vitamins are predominantly absorbed in the upper (A, D, E, and K). Factors that impact fat absorption small intestine will usually affect absorption of these vitamins​ The excess fatty acids present in the intestinal lumen of patients with untreated fat malabsorption bind to divalent cations, such as calcium and magnesium, causing malabsorption of these minerals. Calcium depletion in this setting is further magnified if vitamin D deficiency is also present.​ Vitamin B12 – Extensive ileal disease or resection decreases B12 absorption and often leads to a deficiency state. Eg Crohn's disease. Diminished intrinsic factor leads to reduced absorption of B12 eg pernicious anaemia.  Gluten is the water-insoluble protein mass present in wheat, rye and barley and is used widely in food processing to add flavours and improve texture. COELIAC Pathophysiology: Immune disorder triggered by an environmental agent (gluten) in DISEASE genetically predisposed individuals. (HLA DR3-DQ2 and/or DR4-DQ8)​ Immune response to gliadin (gluten fraction) promotes an inflammatory reaction, characterized by infiltration of the lamina propria and epithelium with chronic inflammatory cells, ultimately causing destruction of villi, seen microscopically as villous atrophy.​  Prevalence: High rates in European populations, however now becoming increasingly more prevalent in Northern Africa, the Middle East, India, and Northern China. Other individuals at increased risk for coeliac disease include (among several other autoimmune diseases): Type 1 diabetes, Autoimmune thyroiditis COELIAC Symptoms: Classically: Diarrhoea, signs and symptoms of malabsorption DISEASE (eg, steatorrhea, weight loss, iron deficiency anaemia, other signs of nutrient or vitamin deficiency eg ADEK vitamins), and resolution of symptoms upon withdrawal of gluten- containing foods, usually within a few weeks to months. Dermatitis herpetiformis – common among patients with coeliac disease, multiple intensely pruritic papules and vesicles that occur in grouped ("herpetiform") arrangements, particularly over elbows, dorsal forearms, knees, scalp, back, and buttocks. Dermatitis Herpetiformis  Diagnosis: Anti-TTG antibody positive is supportive, gold standard for diagnosis is OGD with D2 biopsy showing villous atrophy. Tissue transglutaminase, an enzyme which deamidates gluten peptides, increases their immunogenicity. Tissue transglutaminase is released by inflammatory and endothelial cells and fibroblasts in response to mechanical irritation or inflammation. COELIAC DISEASE Treatment: Gluten Avoidance  Pathophysiology: The pancreas secretes approximately 1.5 liters of alkaline, enzyme-rich fluid every day for the digestion of fats, starch, and protein. Issues can be due to failure of gland to produce fluid, blockage of ducts which can lead to PANCREATIC auto-digestion, reduced CCK/secretin stimulus, nerve impairment. EXOCRINE Symptoms: Maldigestion of fat leads to steatorrhoea, INSUFFICIENCY maldigestion of protein leads to weight loss, bloating, flatulence, cramping. Deficiency of fat-soluble vitamins A,D,E,K. Exocrine: secretion of substances via ductules Differentials: Chronic pancreatitis: Most common cause of pancreatic exocrine insufficiency in adults, prolonged inflammation and scarring results in permanent structural damage and an inability to produce pancreatic fluid. o Pancreatitis presents as severe pain in LUQ/epigastrium, improved by leaning forward. o Elevated amylase. o Low faecal elastase  Differentials continued: Cystic fibrosis: CFTR mutation leads to inappropriate transport of chloride and water across endothelial cell membranes in the lungs and exocrine glands. Approximately 80 percent of patients with cystic fibrosis develop progressive pancreatic damage due to the blockage of ductules with thickened pancreatic secretions. PANCREATIC Gastric, pancreatic, or small bowel resection: loss of sites of secretin and CCK synthesis and inadequate mixing EXOCRINE of chyme with pancreatic enzymes due to rapid gastric emptying. Total or a partial resection of the pancreas or INSUFFICIENCY postoperative pancreatic duct occlusion. Extensive denervation following lymph node dissection can result in decreased pancreatic stimulation. Exocrine: secretion of Rare: Hereditary hemochromatosis can cause progressive substances via ductules iron deposition in the pancreas. Gastrinoma (Zollinger- Ellison syndrome) can cause inactivation of pancreatic enzymes by excessive gastric acid. Small bowel mucosal disease (eg. coeliac disease) can result in decreased CCK release. Treatment: Address underlying cause Pancreatic enzyme replacement: Creon o Taken with meals LEARNING OUTCOME Develop a differential diagnosis for malabsorption DIFFERENTIAL DIAGNOSIS BASED ON MALABSORPTION PATTERN Phase & nature of malabsorptive Example defect Luminal Phase Digestive Enzyme Deficiency Chronic pancreatitis Digestive Enzyme Inactivation Zollinger-Ellison Syndrome Dyssynchrony of enzyme release Post Bilroth II procedure Fat Solubilisation Diminished bile salt synthesis Cirrhosis Impaired bile secretion Chronic cholestasis DIFFERENTIAL Bile salt de-conjugation Increased bile salt loss Bacterial overgrowth Ileal disease or resection BASED ON Luminal Availability of Specific Nutrients DEFECT Diminished gastric acid Atrophic gastritis- B12 Diminished intrinsic factor Pernicious anaemia- B12 Bacterial consumption of Bacterial overgrowth- B12 nutrients Mucosal (Absorptive) Phase A. Brush border Hydrolysis Congenital disaccharide defect Sucrase-isomaltase deficiency Acquired Disaccharide defect Lactase deficiency B. Epithelial Transport Celiac sprue Postabsorptive processing phase Enterocyte processing Abetalipoproteinaemia Lymphatic Intestinal lymphangiectasia LEARNING OUTCOME 4 Outline the common symptoms and signs in malabsorption SYMPTOMS Diarrhoea: 3 or more loose or liquid stools per day. Steatorrhoea: Excessive faecal fat causing bulky, frothy, greasy, yellow or clay-coloured stools. Foul-smelling, difficult to flush. Think the biliary system Chronic malabsorption: o Weight loss o Anorexia o Abdominal distention o Borborygmi o Muscle wasting o Failure to thrive Consequences o Anaemia (iron, pyroxidine, folate, B12) o Bleeding (vit K deficiency) o Osteoporosis (calcium, magnesium, vit D deficiency) o Oedema (protein deficiency) o Nervous system (B12 deficiency): peripheral neuropathy/Subacute combined degeneration of cord PRESENTING COMPLAINT The aetiology and type of malabsorption can often be Important medical history/ risk factors: history of obtained from a history. chronic intestinal disease, intestinal resection, The history should include: bariatric surgery or other surgical interventions or radiation treatments to the abdomen The duration of the symptoms Risk factors for coeliac disease; eg. type 1 diabetes Character of the stool mellitus, family history of coeliac disease, ethnic Timing of bowel motions in relation to meals background. Exacerbating factors Looking at risk factors for pancreatic insufficiency: Presence of associated symptoms (eg, history of excessive alcohol consumption, abdominal pain, bloating, distension) acute/chronic pancreatitis, or pancreatic surgery. Description of stools: STEATORRHOEA Recurrent peptic ulcer disease may be indicative of Excess flatus, and bloating are common when either a gastrinoma or mastocytosis, each of which carbohydrate malabsorption predominates (eg, can cause malabsorption. lactose malabsorption) Symptoms due to carbohydrate malabsorption typically occur within 90 minutes of carbohydrate ingestion. SIGNS Cachexia Koilonychia: spoon shaped nails Angular Stomatitis SIGNS AND SYMPTOMS Malabsorption of: Clinical Features Laboratory Findings Calories Weight loss with normal appetite Fat Steatorrhoea Fractional fat excretion Protein Oedema, muscle atrophy Hypoalbuminaemia, hypoproteinaemia Carbohydrates Watery diarrhoea, falutence Increased breath hydrogen B12 Anaemia, SCDC Macrocytic anaemia, low B12 Folate (vitamin B9 Anaemia Macrocytic anaemia Vitamin B Cheilosis, painless glossitis, acrodematitis, angular stomatitis Iron Anaemia, glossitis Microcytic anaemia, decreased serum iron, ferritin and transferrin saturation Calcium and Parasthesia, tetany, Hypocalcaemia, increased Vitamin D osteomalacia, positive alkaline phosphatase, abnormal chvostek and trosseau signs bone densiometry Vitamin A Follicular hyperkeratosis, night Decreased serum retinol blindness Vitamin K Bleeding/bruising Low vitamin K dependent coagulation factors LEARNING OUTCOME 6 Discuss the assessment and investigative work-up Investigations are led by the history. INVESTIGATION Examples of our approach to testing based on the clinical scenario are as follows: In patients with positive coeliac serologies (Anti-TTG), we perform an upper endoscopy with multiple mucosal biopsies of the 2nd and 3rd portions of the duodenum. In individuals with a history of pancreatitis or excessive alcohol use or a low fecal elastase, investigations include; Faecal elastase Imaging of the pancreas with magnetic resonance cholangiopancreatography (MRCP) Endoscopic ultrasound evaluation. INVESTIGATION If the patient has predisposing risk factors for bacterial overgrowth, (eg. strictures or adhesions, small bowel diverticulosis, blind intestinal loops), can perform breath test for small bacterial overgrowth. In patients without an identifiable cause/risk factors: Upper endoscopy and colonoscopy with multiple mucosal biopsies (eg. To out rule Crohn's disease) Imaging of the small bowel with computed tomography (CT) or magnetic resonance (MR) enterography. D-xylose test can help establish a diagnosis of malabsorption and distinguish mucosal disease from conditions that cause maldigestion. INVESTIGATION Bloods Serologic testing for coeliac disease: Anti TTG, Anti EMA Faecal elastase to exclude maldigestion due to pancreatic insufficiency Endoscopy with biopsy Macroscopic features on endoscopy may suggest the presence of an underlying cause of malabsorption, although intestinal biopsies are usually required to confirm the aetiology. For example, a cobblestone appearance of the duodenal mucosa is seen in Crohn's disease, while reduced duodenal folds and scalloping of the mucosa may be evident in coeliac disease. The unusual finding of multiple jejunal ulcers may indicate the presence of jejunoileitis, a gastrinoma, or infiltrative disease such as lymphoma. Imaging Small bowel — An upper gastrointestinal series with small bowel follow-through, or a CT or MR enterography, wireless video capsule endoscopy can provide important information about the gross morphology of the small intestine and can identify small bowel diverticulae or other anatomic abnormalities associated with bacterial overgrowth. Nevertheless, the radiologic findings in malabsorption are generally nonspecific and contrast studies are relatively insensitive. Pancreas — Pancreatic imaging by CT or MRCP, may be helpful in the diagnosis of chronic pancreatitis and may be critical for distinguishing benign from malignant causes. The secretin stimulation test remains the most sensitive means of diagnosing pancreatic insufficiency. INVESTIGATION Breath tests Small intestinal bacterial overgrowth — The diagnosis of small intestinal bacterial overgrowth (SIBO) is supported by a positive glucose or lactulose breath test, or a positive jejunal aspirate culture; the latter being the gold standard. The accuracy of the breath tests in bacterial overgrowth are limited. Malabsorption of specific carbohydrates — Breath tests are available to assess the integrity of lactose, fructose, and sucrose absorption. Other infrequently performed tests D-xylose absorption test for small bowel mucosal disease – used to determine whether defects in the intestinal mucosa are responsible for malabsorption Protein malabsorption – Testing for protein malabsorption is rarely performed in the clinical setting, intestinal protein loss is more commonly a result of protein-losing gastroenteropathy, which can be demonstrated by measurement of the faecal alpha-1 antitrypsin. Bile acid malabsorption –Evaluation of bile acid absorption with a SeHCAT test can differentiate bile acid diarrhoea from diarrhoea due to fat malabsorption. In the absence of an objective test, patients with diarrhoea due to cholorrhoea can undergo a therapeutic trial with a bile acid-binding resin such as cholestyramine, resolution of symptoms supports the diagnosis of cholorrhoea. Cholestyramine can make the fat malabsorption worse. LEARNING OUTCOME Describe the management MANAGEMENT Goals of management: Treat the underlying disease Optimize control of the diarrhoea that often accompanies malabsorption. Identify and treat nutritional deficits, and then monitor for re-occurrence. Optimize quality of life  MANAGEMENT: MDT approach: Dietician, gastroenterology, SLT Diarrhoea: Antidiarrhoeals (eg. Loperamide) only once you have out ruled infectious cause Dietary modifications: avoidance of triggers eg FODMAPS Supplementation: Fat soluble vitamins, calcium, magnesium, iron, folate, vitamin B12, and zinc. Based on aetiology: Bile acid malabsorption –therapy with exogenous conjugated bile acids can decrease steatorrhoea, cholestyramine. Small intestinal bacterial overgrowth – The mainstay of therapy for small intestinal bacterial overgrowth are antibiotics to reduce (rather than eradicate) small intestinal bacteria. Post-bariatric surgery – Replacement of nutrients Exocrine pancreatic insufficiency –balanced fat intake and administration of exogenous pancreatic enzymes. Short bowel syndrome – enteral and parenteral feeds. Nutrient replacement. Faecal transplant. Coeliac disease – A gluten-free diet Zollinger Ellison syndrome –high-dose proton-pump inhibitor Monitoring: Bone density — Chronic malabsorption, and particularly fat malabsorption, is a risk factor for metabolic bone disease and fractures. Laboratory studies for micronutrient deficiencies LOPERAMIDE/ IMODIUM Synthetic anti-diarrhoeal/ anti-motility agent Mechanism of Action: Binds to opiate receptors in bowel wall, inhibits the release of acetylcholine and prostaglandins, thereby reducing propulsive peristalsis, and increasing intestinal transit time. Reduces daily faecal volume, increases the viscosity and bulk density, and diminishes the loss of fluid and electrolytes. Loperamide increases the tone of the anal sphincter, thereby reducing incontinence and urgency. Tolerance to the antidiarrhoeal effect has not been observed. Metabolism: CYP450, CYP3A4 Side Effects: Common: Gastro-intestinal disorders, nausea, headache, constipation. Rare: CNS toxicity leading to dizziness, impaired consciousness, coordination impairment, increased muscle tone, urinary retention, angioedema. QTc prolongation, torsades de pointes, cardiac arrest with higher than normal doses. Interactions: Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmics, antipsychotics (e.g., chlorpromazine, haloperidol), antibiotics (e.g., moxifloxacin, ciprofloxacin), or any other drug known to prolong the QT interval (e.g., pentamidine, levomethadyl acetate, methadone). LOPERAMIDE/ IMODIUM Contra-indications: **Due to the risk of significant sequelae including ileus, megacolon and toxic megacolon** Patients with acute dysentery, which is characterized by blood in stools and high fever. Patients with acute ulcerative colitis. Patients with bacterial enterocolitis caused by invasive organisms including Salmonella, Shigella, and Campylobacter. Patients with pseudomembranous colitis (e.g., Clostridium difficile) associated with the use of broad-spectrum antibiotics. Cautions: Risk of abuse, dependency due to its' action as a mu-opioid agonist. Overdose: Life threatening cardiac, respiratory and CNS implications  1 2 3 4 5 6 7 8 Adverse Drug Reaction  1 2 3 4 5 6 7 8 Adverse Drug Reaction Answer: B, loperamide and ciprofloxacin are both CYP450 inhibitors, and concomitant use can cause QTc prolongation, leading to torsades de pointes. This is also a risk when patients take over the recommended dose of loperamide.​ This demonstrates several PSA learning points: Planning management, providing information to patients, adverse reactions and drug monitoring. SUMMARY Malabsorption is a broad clinical term which refers to the impaired absorption of nutrients at any point where nutrient absorption takes place. It can be a complication of many disease processes. Clinical history can provide important clues as to the underlying cause. Investigations should be led by the most likely diagnosis. RESOURCES UpToDate. (n.d.). Evidence-Based Clinical Decision Support System| UpToDate | Wolters Kluwer. https://www.uptodate.com/contents/approach-to-the-adult-patient-with-suspected-malabsorption#H1025910224 https://www-uptodate-com.proxy.library.rcsi.ie/contents/overview-of-the-treatment-of-malabsorption-in-adults?sear ch=malabsorption&source=search_result&selectedTitle=3~150&usage_type=default&display_rank=3 School of medicine Handbook of clinical medicine Volume 4th Edition. Gastroenterology – Malabsorption page 258 https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017694s052lbl.pdf https://www-new-medicinescomplete-com.proxy.library.rcsi.ie/#/content/bnf/_892147716 https://www.uptodate.com/contents/exocrine-pancreatic-insufficiency?search=pancreatic%20insufficiency&source =search_result&selectedTitle=1~133&usage_type=default&display_rank=1