Digestion and absorption Flashcards
Luminal phase
hydrolyzation and solubilization of fats, proteins and CHs by pancreatic and biliary secretions
Mucosal phase
terminal hydrolysis of carbohydrates and peptides
Processing and packaging of fats into chylomicrons for cellular export
Transport phase
transportation of nutrients across the intestinal mucosa into systemic body fluids
Essential fatty acids
alpha-linolenic acid (omega-3) linoleic acid (omega-6)
Acinar cells
secrete chloride-rich juice in resting state
secrete pancreatic enzymes when stimulated
centroacinar and duct cells
secrete water and electrolytes containing sodium, HCO3, K, Cl
Secrete large amounts of Na and HCO3- when stimulated
Innervation of exocrine pancreas
PNS: vagus
Sym: celiac and superior mesenteric ganglia
Above itneract with small intrinsic ganglia –> blood vessels, acini, duct cells, islet cells
NT: ACh, VIP stimulate secretion of pancreatic juice
Low rate of HCO3- secretion by duct cell
Mainly relies on CO2 diffusion into cell –> carbonic anhydrase
Acid exported via H-Na exchanger, driven by Na/K ATPase
Bicarb exported by HCO3-/Cl- exchanger
Cl- balanced by CFTR, driven by secretin/VIP stimulation
High rate of HCO3- secretion by duct cell
Import of HCO3- by HCO3/Na co-transporter, driven by Na/K ATPase
Export mainly through CFTR channel, driven by secretin/VIP stimulation
(Minor: HCO3/Cl- exchanger, HCO3- channel)
Acinar cell secretion
Enzymes stored in zymogen granules, then released upon stimulation
Hormones: secretin, CCK
Activation of trypsinogen
Enzyme inactive until it reaches the lumen of duodenum
Trypsinogen activated by brush border enzyme enteropeptidase (enterokinase), by removal of a trypsinogen activating peptide (TAP cleavage)
Trypsin can autocatalyze trypsinogen and also other zymogens
Pancreatic acinar cells produce pancreatic secretory trypsin inhibitor (PST1) proteolytic enzyme inhibitors to prevent autodigestion
Cephalic phase of pancreatic secretion
Sight of food –> activates neural pathways –> pancreas produces small volume of viscid secretion
Purpose: mobilize enzymes so they are within duct lumen, ready to be flushed out when secretion increases significantly
Gastric phase of pancreatic secretion
Distention of stomach –> activates vago-vagal pathway that induces some pancreatic secretion
Intestinal phase of pancreatic secretion
most significant
Chyme enters duodenum –> enzyme secretion at full potential
Regulated by secretin and CCK
Secretin during intestinal phase of pancreatic secretion
Stimulated by pH <4.5
Secreted by duodenum
Stimulates pancreatic duct cells to secrete mostly electrolyte rich fluid (HCO3-)
CCK during intestinal phase of pancreatic secretion
stimulated by broken down FAs, AAs
Secreted by duodenum
Stimulates vagal afferent fibres –> vagal efferent –> intrinsic pancreatic cholinergic neurons –> acinar cell secretion
(may also act through blood, also potentiates secretin-induced fluidsecretion)
To secrete pancreatic enzymes
Carb digestion
- Salivary amylase
- Pancreatic amylase - most responsible
- Brush border carbohydrases perform further hydrolysis (produce glucose, galactose, fructose)
- Colonic bacterial flora - metabolize oligosaccharides that reach colon (produce short-chain fatty acids)
Carb absorption
duodenum and upper jejunum mature villus cells = highest capacity for monosaccharide absorption (glucose, galactose, fructose)
Glucose/galactose via Na-dependent SGLT1
Fructose via Na-independent GLUT5
Monosaccharides transported to basolateral side via GLUT2
Carb metabolism
- Insulin –> GLUT4 translocated to cell surface
- Glucose –> G6p, converted to glycogen
- Glycogenolysis via glycogen phosphorylase –> G1P –> glycolysis
Fat digestion
- Gastric lipase from chief cells
- Gastric mixing, FAs, dietary proteins, lecithin, lysolethicin and bile salts promote emulsification
- Intestinal hydrolysis by pancreatic enzymes in prox. duodenum (lipase, cholisterolesterase, etc)
- Micellar solubilization via bile salts
- Micelles diffuse through “unstirred water layer” on enterocte surface, delivering lipolytic products only (bile salts recycled or excreted)
Fat absorption
Mostly in jejunum and proximal ileum
Short/med-chain FAs cross via FA binding proteins (without micelles), enter portal blood directly
Long-chain via micelles –> bind cytosolic FA binding proteins –> re-esterified in ER to triglycerides –> lymph
TGs, PLs, cholesterol and apolipoproteins –> chylomicrons –> exocytosis –> central lacteal –> lymph –> thoracic duct –> L. subclavian vein –> systemic circulation
Bile salts reform micelles or recycled
Fat metabolism
Lipoprotein lipase on endothelium hydrolyzes TGs in chylomicrons to FAs and glycerol
FAs enter adipocytes, muscles, hepatocytes
Adipocytes and mucles: esterify FAs –> TGs, or to PLs
Hepatocytes: FAs –> TGs
Glycerol –> gluconeogenesis (liver)
Adipocytes –> release stored lipids via hormone-sensitive lipase - hydrolyze TGs to FAs and glycerol
Hepatocytes: beta-oxidation
Protein digestion
Gastric pepsins Pancreatic enzymes (trypsin, chymotrypsin, elastin, carboxypeptidases A and B) in proximal duodenal lumen
Protein absorption
Di- and Tri-peptides cross via H+-dependent Pept1
Brush border hydrolases hydrolyze larger oligopeptides - cross via Na dependent/independent transporters
AA transporters on basolateral surface of enterocytes
Protein metabolism
Proteins stored in all tissues for structure or function
Excess AA: converted to TGs or glucose then glycogen
Protein is constantly metabolized to accommodate demand
Vit B12 digestion
Released by mastication and gastric acid
- R-proteins from saliva and parietal cells bind free cobalamin at low pH
- Pancreatic enzymes in duodenum hydrolyze R-protein and allow IF to bind cobalamin
Vit B12 absorption
- IF-cobalamin complex resists pancreatic proteolysis, taken up by specific ileal enterocyte receptors
- Complex separated within enterocyte
- B12 accumulates in mitochondria, transported out basolaterally
- B12 immediately binds ileal pool of transcobalamin II, required for transportation in portal/systemic circulation
- Transcobalamin-cobalamin complex endocyted by cells, then enzymatically released
Vit B12 metabolism
Formation of blood and DNA (regenerates folate)
Delivered throughout body
Excess secreted by liver into bile, then recycled
Vit A digestion
micellar solubilization
Dietary retinal esters hydrolyzed to retinol in intestinal lumen before absorption
Vit A absorption
duodenal enterocytes take up retinol via passive and facilitated diffusion
Retinol incorported –> chylomicrons –> leaves mucosa into portal circulation
Vit A Metabolism
Hepatocytes hydolyze retinyl esters to release free retinol –> bind retinol-binding protein and prealbumin in sinusoids, OR stored ins tellate cells as RBP-bound retinol
Retinol may undergo oxidation to retinal –> retinoic acid for phototransduction
Secreted into bile
Vitamin D digestion
Mostly from endogenous synthesis in skin cells as a result of UV radiation
Vit D absorption
Passive diffusion into small intestinal mucosa (facilitated by pH)
absorbed into circulation unchanged in chylomicrons
Vit D metabolism
hydroxylated first in hepatocytes, and then in renal tissue to calcitriol
Promotes intestinal calcium and phosphate absorption
Termination of activity via CYP-450
Vitamin E digestion
esters may be hydrolyzed following micellar solubilization by pancreatic and duodenal esterases
Vit E absorption
passive diffusion across intestinal mucosa
incorporated into chylomicrons
Vit E metabolism
TG hydrolysis
Tocopherol remaining in remnant chylomicrons transported to liver
- resecreted as part of VLDL, or metabolized and excreted by liver
Vit K digestion
K2 produced by intestinal bacteria
K1 dietary in vegetables and beef liver
Vig K absorption
K1: carrier-mediated process, dependent on luminal bile salts
K2: entirely passive
Vit K metabolism
essential for gamma-carboxylation of glutamate residues in coagulation factors
Iron digestion
ingested mainly as myoglobin or hemoglobin
Mucosal ferrireductase reduces dietary Fe3+ –> 2+
Iron absorption
mostly in proximal duodenum
bound to transferrin (made by liver) in circulation
Iron metabolism
hepatocytes take up, secrete, and store iron via specific transferrin receptors
Utilized in intracellular enzymatic reactions
in cell, stored with ferritin (otherwise toxic)
Magnesium absorption
active transport across ileal mucosa
passive diffusion across the rest
Magnesium metabolism
enzyme cofactor
NT, muscular contractions
bone acts as a reservoir
renally excreted
Phosphorus absorption
paracellular diffusion
Vitamin D-promoted transcellular
Phosphorus metabolism
bone acts as reservoir
intracellular metabolism and growth
renally handled
Celiac disease pathophys
- Mucosa primed by previous trigger
- Gliadin derived peptides processed by HLA class II molecules for presentation to helper T cells
- Helper T cells activated, invasion of the surface by CD8
- Direct gliadin toxicity –> release of transglutaminase, CLs with gliadin –> neoepitope target for gliadin
Celiac disease S/S
primarily affects the mucosal layer of the small intestine
intermittent diarrhea, abd pain, bloating, but no “typical” signs and symptoms
can also present with signs and symptoms of vitamin deficiency (also osteoporosis/malacia, peripheral neuropathy, dermatitis herpetiformis, follicular hyperkeratosis/dermatitis)
Chronic pancreatitis pathophys
Intraductal plugging/obs (alcohol, stones, tumors)
Direct toxins: act on acinar cells to release cytokines –> stimulate the stellate cell to produce collagen and to establish fibrosis - also stimulates macrophages, neutrophils, lymphocytes
Oxidative stress (idiopathic)
Necrosis-fibrosis
Ischemia (from obs and fibrosis) - exacerbation rather than initiation
Autoimmune - association with Sjogren’s, primary biliary cirrhosis, renal tubular acidosis
Chronic pancreatitis
chronic abd pain
normal/mildly elevated pancreatic enzyme levels
end stage: DM, steatorrhea
Vit B12 deficiency pathophys
pernicious anemia (megaloblastic, macrocytic anemia) can also cause folate deficiency
Vit B12 deficiency S/S
neuropathy due to demyelination
Vit B1 deficiency pathophys
Wernicke’s encelopathy caused by decrease intake, increased requirement due to liver damage, decreased absorption
Most commonly associated with alcoholism
Vit B1 deficiency S/S
ophthalmoplegia, nystagmus, ataxia, loss of recent memory, confusion
Vit D deficiency pathophys
inadequte exposure to sunlight malabsorption lack of vit D in breast milk medications elevated parathyroid hormone
Low Vit D –> decrease Ca absorption and enhances phosphorus absorption
Vit D –> maturation of osteoclasts –> resorption of bone
Vit D deficiency S/S
Rickets (bowing legs)
Osteomalacia: poorly mineralized skeletal matrix –> chronic muscleaches and pains
Pellagra (B3 def) pathophys
Primary: inadequte niacin/tryptophan in diet
Secondary: adequate intake but other conditions
Pellagra (B3 def) S/S
diarrhea
dementia
dermatitis
death
Zn deficiency pathophys
malabsorption diarrhea acrodermatitis enteropathica chronic liver disease chronic renal disease sickle cell diabetes malignanc nutritional
Zn deficiency S&S
hair loss skin lesions diarrhea wasting acne eyesight/taste/smell/memory malfunctions congenital abnormalities
Refeeding syndrome pathophys
Starvation –> depletion of intracellular minerals (phosphate, Mg, K)
Serum concentration maintained due to intracellular compartment shrinkage
- Glucose administration –> insulin released, glucagon decrease
- Insulin-stimulated protein, glycogen, and fat synthesis - requires minerals and cofactors
- Insulin stimulates K+ absorption into cells via Na/K symporter (to aid in glucose transport)
- Mg/phos taken up into cell, water follows, expansion of intracellular fluid vol
- Reduction in serum phosphate, Mg, and K - already depleted
- Rapid decrease in renal excretion of Na and water due to glucose - expansion of ECFV, TBW
- Fluid repletion to maintain urine output –> may lead to fluid overload, CHF, pulmonary edema and cardiac arrhythmias
Refeeding syndrome mineral depletion sequelae
weakened cardiac muscles
weaked pulm muscles
hypokalemia –> cardiac arrest
hypophosphatemia –> impaired oxygen deliver, hypoxia
Refeeding syndrome management
Start low, go slow!
Correct existing deficiencies
Correct volume depletion, monitor renal function
Supplement with thiamine prior to administration of glucose
Monitor levels of phosphate, K, Mg
Prophylactic K and P
gradually increase caloric administration
Tests for fat malabsorption
Fecal fat excretion
Sudan III stain - examination of undigested muscle fiber, as well as neutral and split fats; screening test for steatorrhea
14C-Triolein Breath Test
- test for pancreatic function
- triolein triglyceride releases CO2 when hydrolyzed
- exhaled-radiolabelled 14CO2 measured after ingestion
- low levels of 14CO2 –> lipase deficiency
- could be confounded by pulmonary disease, age-related triolein metabolism changes and the presence of colon bacteria
Tests for CH malabsorption
Lactose/hydrogen breath test
- Absence of lactase –> lactose goes undigested into colon –> bacterial fermentation to release hydrogen gas
- false positives due to may be caused by small intestine bacterial overgrowth
D-xylose test
- measure of maximal intestinal absorption area
- poorly metabolized aldopentose, absorbed in duodenum and jejunum
- ingest D-xylose - 5-hour urine collection for xylose excretion; >4 is normal
- abnormality due to: disorders affecting the mucosa of the proximal small intestine such as celiac disease/tropical sprue
- poor sens, spec
Schilling test stage 1
- Ingest radioactive cobalamin, with im injection of unlabelled cobalamin - saturate liver receptors so that all that is absorbed will be excreted
- Collect urine over 24 hours
Schilling test stage 1 abnormality
Pernicious anemia - IF insufficiency
Pancreatic insufficiency - inhibition of transfer of cobalamin from R factor –> IF
Loss of absorptive surface of the terminal ileum
Bacterial overgrowth (second stage would be abnormal as well)
Schilling test stage 2
- Ingest radioactive cobalamin bound to IF
2. Urine collection
Schilling test stage 2 abnormality
Bacterial overgrowth
Loss of absorptive surface of the terminal ileum
14C-glycocholic acid breath test
- Radiolabelled bile acid
2. If compound is not absorbed in small bowel and reach the colon - de-conjugated by colonic bacteria and release 14CO2
Selenium-75 labelled homotaurocholic acid test
Radioactive compound resistant to bacterial deconjugation
Degree of retention of compound at 7 days following po intake provides an index of absorption
retention - malabsorption
Trial of cholestyramine
binds bile salt, prevents diarrhea
3-day diagnostic test
Definition of malnutrition
imbalance between supply and demand
Usage of nutrients during starvation
- glucose from diet
- glycogen - 1 day
- gluconeogenesis
- Ketones
depletion of fat supply –> muscle breakdown –> death
Marasmus
protein and energy depletion
Kwashiorkor
protein depletion
energy adequate
Edema
Tests for pancreatic exocrine function
Direct: secretin/CCK
Indirect: PABA, pancrealauryl, dual-labelled Schilling test
Secretin/CCK test
- iv infusion of secretin/CCK
- collect pancreatic secretions by a duodenal tube
usually bicarb quantified (easier)
Indirect tests for pancreatic exocrine function
- PABA test: indirect measure of chymotrypsin - PABA cleaved, measured in urine
- Pancreolauryl test: fluoroscein dilaurate given orally hydrolyzed by pancreatic esterases to release fluoroscein –> excreted in urine
- Dual-labelled Schilling test
Parenteral nutrition indication
Indicated for patients expected to have non-functioning GI for >7 days
Patient needs to be able to tolerate large fluid volumes, and be hemodynamically and metabolically stable
Stopped when patient meets 75-100% needs
TPN (central) preferred
TPN complications
infection
occlusions
hyperglycemia, hyperlipidemia
villous atrophy and bacterial translocation
hepatobiliary complications (cholestasis)
metabolic bone disease
Enteral nutrition indication
when oral intake is insufficient/contraindicated
more cost effective
less risks
Pancreatic stellate cell function
deposit ECM to facilitate tissue repair after wounding
hyperactive in chronic inflammatory/fibrotic states
Prevention of autoactivation of trypsinogen
Any accidentally activated trypsin bound by PST1, then degraded by chymotrypsin C
Some hereditary mutations of cleavage sites for chymotrpsin C –> accumulation of activated trypsin in the pancreas –> pancreatitis
Consequences of CFTR mutation
Very thick pancreatic secretions –> obstructions, due to halted alkaline fluid production
Zymogen autoactivation within the duct cells
Leads to loss of acini, replacement by fibrous tissue
CCK function
sphincter of Oddi relaxation
decreased acid secretion
decreased gastric emptying
increased pancreatic enzyme secretion
Impaired fat solubilization clinical presentation
steatorrhea
fat-soluble vitamin deficiencies (ADEK)
Brush border hydrolase deficiency consequences
Non-absorption of carbohydrates
Colonic digestion of carbs by bacteria –> gaseous distention/diarrhea
e.g. lactose deficiency
Tests for celiac disease
endomysial/anti-tissue transglutaminase antibodies (Ab IgA)
