exam_3_20150304203003 Flashcards
What are the two types of nephrons?
Cortical (85%) and Juxtamedullary (15%)-juxtamedullary have longer distal tubules that extend into the medulla (lower oxygen level here)
What is the glomerulus and Bowman’s Capsule?
glomerulus is a tuft of capillaries and the Bowman’s capsule is over the glomerulus-the parietal epithelium is the outermost layer of the Bowman’s capsule
What is the visceral epithelium and podocytes of kidneys?
visceral epithelium is also called podocytes. These are cells with radiating rootlike processes, form a network of intercellular clefts called filtration slits and the foot like process are connected by proteins
Glomerular basement membrane
-negatively charged-selectively permeable network of glycoproteins and mucopolysaccharides *allow water and small solutes through *small pores and filtration slits make the glomerular basement membrane less permeable to larger molecules like proteins *the membrane repels proteins because protein molecules are negatively charged
What happens when there is a loss of the negative charge on the basement membrane of the glomerulus?
loss of negative charge or injury to podocytes causing larger pores and slits will allow protein through the glomerular basement membrane
What is the function of the mesangium?
-contains mesangium cells that have macrophages, intrinsic glomerular cells-form mesangial matrix-have contractile and proliferative function
Juxtoglomerular apparatus
contains juxtoglomerular cells-smooth muscle cells in the afferent arteriole next to the distal tubule; sense stretch; manufacture, store and release renin
What does the Macula densa cells do?
distal tubular cells nearest the glomerulussense Na content
Renal blood flow
-25% of CO-from cortex to medulla
Why is PaO2 less in the medulla?
it is less in the medulla because it goes to the cortex first. however more O2 is needed in the medulla to generate ATP for transporting substances—>makes it more susceptible to injury
What does the juxtaglomerular cells do?
assesses perfusion pressure
Autoregulation is provided by tubuloglomerular feed back by which two cells?
- macula densa=decreased Na triggers renin->afferent arteirole vasodilation and efferent arteriole vasoconstiction-increased Na= afferent arteriole vasoconstriction and efferent arteriole vasodilation2. juxtaglomerular cells=assess perfusions press ion-increased MAP (stretch) causes constriction of afferent artierole-decreased MAP stimulates renin release and afferent arteriole vasodilatation
Neural Regulation and Humoral Regulation of kidneys
SNS: vasoconstrict, renin production NO PNS innervationvasoconstriction from angiotensin II, vasopress (ADH), endothelia’svasodilation from NO, adenosine, prostaglandins, dopamine
What is the best indicator of renal function?
creatinine clearance-amount of creatinine excreted in the urine per minute -slightly overestimates GFR-Normal GFR= 120 ml/min, pregnancy 120-160 ml/min-Failure<20ml/min
Serum Creatinine and BUN for renal function
-serum creatinine is common method of estimating trending GFR (normal: 0.8-1.0)*if double then GFR is about 50% of normal and if it is 3x high then GFR is about 25% of normal-BUN: levels increase as glomerular filtration drops-about 50-60% of renal function must be lost before a significant rise in BUN occurs
Excretion of Na in kidney
normal: over 99% of filtered Na is reabsorbed and 1%
What are casts and how are the important in UA?
casts are tube shaped particles of leukoproteins of tubular epithelial cells and whatever blood cells that are in there.RBC do not pass through filtration process-So when you have Red cell casts it indicates bleeding in the tubules-white cell casts are associated with inflammatory process-epithelial cell casts indicate degeneration of the butler lumen on necrosis of the renal tubules
Terms: GF, filtrate, compensatory hyperfiltration
GF: movement of fluids from capillaries across basement membrane and to the tubules (then called filtrate)filtrate is usually free of cellular elements and essentially protein freeloss of nephrons results in compensatory hyper filtration => increased GFR per nephron
Where does the concentration of tubular fluid occur?
occurs in loop of Henle
Where does the concentration of urine occurs?
collecting duct under influence of ADH and aldosterone
What is vitamin D made from?
-made from cholesterol in our skin by the action of ultraviolet light; source of inactive vitamin D includes dietary source-inactive vitamin D is transported to the liver and converted to an inactive compound -intermediate compound is taken to kidneys and under two step process activated under influence of PTH -active vitmain D stimulates the absorption of Ca and Ph by small intestine and stimulates osteoclasts to reabsorb bone to increase Ca
Water/Na reabsorption occurs in…
proximal tubule, descending thin limb of the loop of Henle, distal tubule and collecting ducts (Cl passively follows in the ascending limb, proximal tubule and distal and collecting ducts)
Aldosterone controls water and Na absorption in the Vasopressin (ADH) secreted by hypothalamus increases reabsorption of water in the
distal tubule and collecting duct collecting duct
Final place for reabsorption…
distal tubule and collecting ducts
K reabsorption occurs in
proximal, loop of Henle, distal final excretion determined by the rate at the collecting ducts
Regulation of K excretion by kidneys is influenced by…
influenced by plasma levels, acid-base balance, plasma osmolality, aldosteroneacid-base balance (H replaced by K) (acid=^H=K ^ as it goes out of cell) decreases section (base=lowH=low K as it goes into cell and H out)increases secretion
Ca regulation of Kidneys
-mostly reabsorbed by proximal and distal-reabsorption in loop of Henle is tied to Na and K-influenced by PTH and calcitonin and acid base balance
Bicarbonate buffer system or bicarbonate conservation system
H secretion takes place in proximal tubule mostlyH secretion by tubular cells causes Na reabsorption and the H is recycle to make more bicarb when needed
Renal response to alkalosis
decrease H secretiondecrease ammonia productionincrease HCO3 production
Renal response to acidosis
increase Hproduction of ammonia to accommodate H excretionIncrease HCO3 reabsorption
What drugs can cause pre renal disorders
1 ACE inhibitors: loss of efferent vasoconstriction; when combined with decreased glomerular blood flow it will decrease GFR2 NSAIDS: inhibit prostaglandin synthesis; therefore decreased vasodilation and allows afferent vasoconstriction and decreases GFR3 vasoconstrictive drugs
Glomerular disease etiology
hereditary, secondary to other d/oor common immune mechanisms:1 circulating antigen-antibody complex disposition 2 antibodies against planted antigens in the glomerulus3 autoantibodies against normal glomerular components4 T cell mediated immunity
Glomerular injury patho
1 complement activation: neut and macs are recruited and are responsible for opsonizaiton; MAC (membrane attack complex) causes epithelial injury, swelling and loss leading to detachment of epithelium2 neut and mac: release protease that cause GBM degradation, ROS more damage, mac activate fibroblasts; secrete more cytokines to stimulate more cells to come3 increased numbers of activated T lymph and NK cells (NK and T cells release cytokines) (NK lysis of affected cells)4 platelet aggregation: activates coagulation system and fibrin5 vasodilation6 alteration in endothelium permeability, change in GBM charge, allows for greater passages of protein and RBC across membrane 7 messangial cell activate and proliferate; produces inflammation, growth factors, accumulation of ECM, activate fibroblasts; sclerosis of mesangium8 BM and glom thickening, and change in charge9 podocyte injury cause epithelium swelling, stimulates secretion of inflam mediators, podocyte foot stretch/effacement cause abnormal protein filtration and podocytes are not replaced
What happens when podocytes are affected?
loss of foot process (GBM denuding)altered membrane charge and abnormal protein filtrationeventually decreases GFR and nephron loss
What is the compensatory process of glomerular injury
compensatory hypertrophy of remaining glom-from hemodynamic changes in glom blood flow, transcapillary HTN, and filtration volume-causes injury to remaining glomeruli-inflammation-fibrosis-sclerosis of glom-inflammatory process and protein cause tubular injury and interstitial fibrosis
Acute Nephritic Syndrome and Nephrotic Syndrome manifestations
1 acute nephritic syndrome: Hematuria/RBC casts, decreased GFR, Azotemia (increased BUN, Cr), HTN, variable proteinuria (not severe), fluid and Na retention; edema2 nephrotic syndrome: increased glomerular permeability to plasma proteins characterized by proteinuria, hypoalbuminemia (hypoproteinemia), edema, hyperlipidemia and lipiduria
Why is hyperlidemia and lipiduria a result of nephrotic syndrome?
compensatory synthesis of proteins by liver
What are long term risks associated with nephrotic syndrome?
immunosuppressed because of loss of IgG, thrombotic complicates because antithrombin III deficiency and reduced levels of Protein C and S, vitamin D deficiency and hyperparathryoidism due to loss of Vitmain D binding proteinsand renal failure
Acute Glomerulonephritis etiology
usually caused by streptococcal infection and in children-deposition of immune complexes -thought that Compliment activation at C3 or alternative pathway which initiates inflammatory process -leukocytes infiltration, mesangial cells proliferate, immune complexes may be degraded or phaocytosed by leukocytes
Acute Glomerulonephritis manifestations
abrupt onset of acute nephritic syndrome, mild oliguria 7-10 days ager the infectious disease, gross hematuria, elevation of anti streptococcal antibody if present, systemic response to Il-1 and TNFa
Etiology and path of Rapidly Progessive glomerulonephritis
immune complexes deposited -proliferation of parietal cells in Bowman’s Capsule, appear as CRESCENT SHAPE, nephritic syndrome to chronic RF
IgA Nephropathy etiology and path
IgA antibodies deposited in mesangium usually IgA 1 subtype-activation of complement system; inflammatory response-mesangial cell proliferation, release of oxidants and protease, and leads to gomerulosclerosismanifestation: nephritic, hematuria, progresses to CRF
Minimal change disease
frequent cause of nephrotic syndrome in children-t-cell injury causes podocyte damage and diffuse effacement of podocyte foot processes-change in charge, proteins slip through-usually preserve renal function
Membranous nephropathy
usually older adults -usually antibody response to antigens expressed by podocytesand sometimes with other inflammatory d/o-present of deposition of immune complexes in sub epithelium along GBM; complement system activation, diffuse thickening of capillary wall, effacement of foot processes, thinkening of GBM, sclerosis-manifestations; nephrotic syndrome, end-stage RF
Chronic glomerulonephritis leads to
continued injury and obliteration of the glomerulus and marked interstitial fibrosis
Acute tubular injury (ATI) etiology
most common acute kidney inure-destruction of tubular epithelium cells -etiology: ischemia ATI, nephrotoxic ATI (drugs, NSAIDS, gentamycin, radiographic dye, poisons, rhabdomylosis)
Acute tubular injury (ATI) patho
1 ischemia: decreased perfusion>renin secretion>renal medullary hypoxia>endothelial injury>secretion of endothelin and NO and PG12>vasoconstriction>vasoconstriction2 nephrotoxic: tubule cell injury causes disturbance in blood flow>decreased NO and PG12>hypoxia and loss of polarity and adhesion of cells> sloughing of cells, cast formation, cell edema, obstruction, intratubular pressure increase and decreases GFR-altered Na reabsorption increases Na in tubule>afferent vasoconstriction and decreased GFR -damage to tubule causes leaking into interstitium> increases interstitial pressure and collapses tubule>cell damage and inflammatory>eventually irreversible cell injury and necrosis and apoptosis
Acute tubular injury (ATI) manifestations
ARFfocal/pathcy tubular cell necrosis-epithelium cell casts-fractional excretion of Na less than 99%-urine osmolality <200 (normal 200-800)(getting rid of more Na than we should)-usually affected in the proximal and thick descending (ischemia) or proximal (nephrotoxic)
Cystic Disease of Kidney
-characterized by dilation of tubular structures and cyst formation-when epith cells are unable to sense flow of urine the cells lose polarity and will start to divide uncontrollably and in all directions and form a cyst
What are cilium?
-cilium is on every tubular epith cell-regulate the growth of the kidney cells and the direction they are formed-all epith cells have polarity and cilium always forms on interior or apical side so urine passing through the tubules on its way to the bladder can flow ove the cilium and bend it in the direction of the flow-calcium channel mechanosenso at the base of the cilium senses bending-it sends Ca into cilium which signals the okay-sensing also important in directing kidney cells to grow in proper direction-gene mutations prevent cilium’s signal from reaching the cell-no longer able to sense normal flow of urine the epith cell loses is polarity and starts dividing uncontrollably in all directions to form a cyst
Polycystic kidney disease
-gene mutations will cause sustained cellular proliferation of tubular epith cell>abnormal cell differentiation> development of cystic epithelium and altered cell adhesion>production of cyst and cyst fluid>compress surrounding vasculature and other tubules>calyces pelvis-the fluid contains inflam mediators> fibrosis and enhance fluid secretion
Pyelonephritis patho and manifestations
-infection and inflammation of kidney tubules, interstitial and renal pelvis-acute: patchy interstitial inflammation, intratubular aggregates of neutrophils, formation of pus and abscesses within the interstitial tissue and tubules>tubular necrosisfever, chills, flank pain, dysuria, CV tenderness, leuko casts, bacterial casts, WBC positive-chronic: predominent interstitial inflammation, progressive interstitial firbrosis and diffuse scarring>tubular atrophy>deformation and sclerosis of the renal calicoes and pelvisrecurrent infection, defects in tubular funciton, renal failure
Arterionephrosclerosis
HTN produces hyaline thickening of the arterial and arteriole walls-decrease renal blood flow, ischemia-ongoing>structural thickening and remodeling and decreased renal blood flow-HTN produces microvascular injury, inflammatory response, plasma proteins enter vessel walls, ischemia of glom and post glom structures>stimulates Renin, vasoconstriction, reduces GFR,
Diabetic nephropathy
impairment in the auto regulation of the glomerular microcirculation form DM-glom HTN and hyperfusion>injury-GBM theckening, mesangial expansion and sclerosis from increase in mesangial matrix/proliferation of cells, activation of fibroblasts and mesangial sclerosis>loss of charge GBM, tubular interstitial injury and fibrosis*microalbinuria, proteinuria, renal insufficiency and RF
Postrenal Disease Patho
-dilation of renal pelvis and calyces-compression of vasculature -back up in tubule>initially filtrate diffuses into interstitial and circulatory system but eventually will alter tubular function, impair ability to concentrate urine and diminish GFR-reduced froward tubular flow stimulates renin production and causes HTN-obstruction triggers inflam process>interstitial fibrosis>atrophy
types of kidney stones
-struvite: Mg and ammonium phosphate, very large, occur in alkaline urine due to UTI-cystine stones: inherited d/o affecting reabsorption of certain amino acid produces cystine stones
Azotemia
-increased BUN, Cr and other nitrogenous wastes in the blood-hallmark sign of ARF
ARF
phase 1: initiating eventphase 2: maintenance; azotemia, sustained decrease in UO>oliguria (less than 1 ml/kg/h infants and less than 400 ml/day in adults), anuriaphase 3: recovery: last for months, polyuria, gradual dissipation of azotemia, gradual improvement in ability to filter/conserve ions and fluids
CRF stages
-loss of nephrons increase functional burden of remainders; HTN of nephron; hyper filtration-subsequent fibrosis, scarring and increased rate of nephron destruction and lossstage 1: GFR is 50% normalstage 2: GFR is 20% to50% normalstage 3: GFR less than 20% normalstage 4: GFR is less than 5% normal
CRF manifestations
Cannot secrete enough H or generate enough buffers>kussmaul respirations to “blow off” CO2 and compensate for =ACIDOSIS-impaired water and Na balance, increased blood volume>pulmonary and peripheral edema-stimulation of renin-angiotensin-aldosterone> more HTN and edema -increased K plasma because decreased secretion in tubule-decreased Vitamin D activation because remaining cannot activate enough V D and less calcium absorption and breaks down from bone to get calcium-hyperhosphatemia from calcium reabsorption form bone-GI n/v, PUD=suppresses bone (platelet, leukocytes), wastes build up and affect all systems (K affects heart)
Exocrine pancreas
1 Acini-80%-85%-surround lumen, contain intracellular zymogen granules which contain digestive enzymes-pancreatic duct cells2 pancreatic islets 15-2%
Neuronal control of pancreas
1 neuronal -PSN stimulates secretions/discharge of zymogen granules-SNS inhibits secretions2 Hormonal Regulation-Cholecystokinin (CCK): secreted by cells in the duodenum, stimulated by exposure to luminal fats and protein, causes release of enzymes from zymogen granules in acinar cells-secretin: secreted by duodenal cells, stimulated by gastric acid and protein products, acts on the pancreatic duct cells to produce a watery solution of bicarbonate
pancreatic duct cells secrete…
1 pancreatic duct cells-bicarbonate solution: secrets 1.5L a day, to maintain pH of 6.0-7.0-mucin
acinar cells secrete…
2 acinar cells-amylase: secreted in active form that breaks down complex carbs into simple sugars-lipase: secreted in active form to break down triglycerides into fatty acids and glycerol -trypsin: secred in inactive form which is converted to trypsin in the duodenum, coverts all other inactive acinar cells secretions to active state and breaks down amino acids-phospholipase secreted in inactive form (phospholipase A) that is converted to phospholipase in the duodenum by trypsin, splits fatty acids-chymotrypsin secreted in inactive form (chymotrypsinogen) that is converted to chymotrypsin in the duodenum by trypsin and it digests protein-elastase secreted in inactive form (proelastase) conerted to elastase in the duodenum by trypsin and digests elastin-trypsin inhibitor prevents activity of proteolytic enzymes while in the pancreas, inhibits activity of proteolytic enzymes if activated while in the pancreas
Whast pH range do pancreatic enzymes function optimally in?
neutral 6.0-7.0
Acute pancreatitis etiology and patho
-reversible damage-autodigestion of enzymatic tissue-caused by anything that causes the escape of activated proteolytic enzymes form ducts; usually alcohol and biliary disease1 biliary disease: obstruction causes free bile acid delivery to pancreas via lymphatis with inflammationa nd release of granules-duct obstruction>cell injury>release of pro-inflammatory enzymes which include TNFa and IL-1, TNFa amount correlate witht the severity>inflammation and edeman>vascular insufficiency and ischemia to acinar cells>release and activation of enzymes2 alcohol: induced alterations in intracellular transport of exocrine pancreatic enymes; causes inflammation of the sphincter of Oddi which leads to retention of enzymes and activation 3 acinar injury> causes release of intracellular proenzymes and lysosomal hydrolases are inappropriately packaged together for transport within acinar cell; lysosoal hydrolases convert trypsinogen to tryspin which converts all the other proenzymes to their active state4 autodigestion of the pancreas by inappropriately activated pancreatic enzymes
Complications of Acute pancreatitis
1 shock: massive exudation of plasma andhemorrhage into the retroperitoneal space and accumulation of luid in the gut secondary to increased vascular permeability and vasodilation2 coagulopathy: inflam can activate plasma coagulation cascade systemically > DIC3 pulmonary complications: pleural effusion common on L side, pulm edema, from leakage of fluid from panc to pleura4 hypocalcemia: primarily d/t lipolysis of fat; releases free fatty acids that combine with calcium to for soaps5 destruciton of pancreatic islets> hyperglycemia and acidosis6 pancreatic mass, pseudocyts7 abcess and peritonitis form bacterial infection of necrotic tissue in and arround inflammed pancreas
Chronic pancreatitis etiology and patho
-irreversible damage-recurrent acute panc-alcohol-long standing obstruction-genetic mutations or idiopathic1 ongoing ischemia and attack on acinar cells; inflammation induces scarring and fibrosis with ductal distortion and obstruction; vascular damage, stasis of panc fluid, protein plug and stone formation; 2 acinar protein hypersecretion: thick visocous panc fluid, combined with Ca> forms ductal plugs; pluse cause ijury and formation of fibrotic ductal strictures and eventually cells atrophy3 oxidative stress: acinar cell injury by free radicals, inflammation and development of fibrosis4 alcohol abuse form toxins including alcohol, directly injure acinar cells leading to acinar cell loss and fibrosis
What is the result of enzyme deficiency in intestines resulting in malabsorption of fats, proteins, and CHO?
steatorrhea and wt loss
Pancreatic insufficiency etiology
-chronic panc, tumor, CF, zollinger-ellison syndrome (excessive gastric acid secretion inactivates panc enzymes), gastric surgery (mistiming of enzyme secretion
Manifestations of pancreatic insufficeincy
-maldigestion of fats, prteins, carbs-maldigestion of fat soluble vitmains, and proteins-steatorrhea-hyperCa-wt loss-edema form hypoproteinemia
Pancreatic CA
1 tumor supressor genes-P53 mutation, P16 inactivated in most cases, SMAD4 inactivated in half of cases2 proto-oncogene-point mutations on oncogene K-ras in most cases3 location usually in the head of pancreas4: sx: abd pain, anorexia, DM, jaundice
What controls the gallbladder?
-sphincter of Oddi1 neuronal:-PNS-vagus nerve> timulates GB contraction and sphincter of Oddi relaxation-SNS stimulatin inhibits emptying2 Hormonal-CCK secreted in duodenum, stimulates for release of fat in intestines, functions to contract GB and sphincter of ODDI relaxation
What are the two types of GB stones?
1 cholesterol 2 pigmented (calcium bilirubin salts)
Patho of GB cholesterol stones
1 altered bile composition-cholesterol concentrations exceed the solubilitizing capacity of bile (called saturation)> nucleates into cholesterol crystals-estrogen raises cholesterol levels thus concentrations in the bile-mucin production is very thick and can become trapped creating crystals-prostaglandins decrease mucus production which helps to preven (NSAIDS inhibit prostaglandins)-increased water and electrolyte absorption2 decreaed GB muscular wall motility by estrogen, SNS or decreased sphincter of Oddi relaxation
Patho of GB pigmented stones
1 increased unconjugated bilirubin2 biliary tract infections3 intravascular hemolysis (increases the amount of unconjugated bilirubin)
What is biliary atresia?
neonatal/infant developmental abnormalitycomplete obstruciton of bile flow caused by destruction or absence of all or part of the extrahepatic bile ducts
Blood flow of liver
-25% of CO-venous flow from portal vein: low pressure system <10mmHg; gives ost of the liver its O2-arterial flow from hepatic artery-sinusoids are combined blood from arterial and venous systmes; fenestrated endothelium, no basement membrane-central vein which drains into the hepatic vein and ultimately the inferior vena cava
the structure of liver that is closet to the blood supply so recieves O2 and nutrients first and shows changes in bile stasis. it is the last to die and first to generate
Acinus zone 1
the structure of the liver that is farthest from incoming blood; first to show signs of ischemia, first to show fat accumulation
Acinus zone 3
Major cells of Liver
a. hepatocytes: one side is next to the sinusoids and the other forms wall of the bile canliculus; tight junction between hepatocytes; they can regenerateb. kupffer cells are special macrophages; in the sinusoidal spacec. stellat cells or lipocytes are fat storing cells involvd in vitamin A metabolism which lie in the space of Disse
Physiology of Liver
a. carb metabolism: stores excess glucose as gycogen; breaks down stored glycogen to gucose through gycogenolysis; converts excess carbs into triglycerides for starge in adipose tissue; synthesizes glucose from amino acids, glycerol and lactic acid through gluconeogenesisb. protien metabolism: degrades amino acids through oxidative deamination and transmination: used for enegery, glucose synthesis, synthesis of plasma proteins and other aminos; broken down to ureac. lipid metabolism: hepatocytes degrade fatty acids into Acetyl Co-A to be used for energy and to synthesize cholesterol; the liver synthesizes triglcerides from fatty acids and makes apolipoproteins (protein components) to transport lipid components into the blood streem (VDL, LDL, HDL)
What are the three apolipoproteins
1 VLDL: distrbute lipids to tissues for use or storage2 LDL: the modified VLDL that is returned to liver3 HDL: scavenger excess cholesterol from peripheral cells and returns it to the liver where they are excreted
What proteins does the liver synthesize
1 plasma proteins-albumin, globulins, hormones-binding proteins: allow for transport of substances in the bloodstream that would otherwise not be soluble and transport of substances in inactive form-clotting factors: fibrogen I, prothrombin II, factors V, VII, IX, and X
How does the liver solubilize, transport, and store many substances?
- bile acids: solubilizes water insoluable lipids, helps to emulsify lipids and trasport fatty acids to intestinal mucosa for absorption in the intestines; they are reabsorped in distal lumen2. bilirubin: in the liver it is unconjugated and moves from plasma into the hepatocyte; in the cells it is made water soluble>conjugated bilirubin-conjugated bilirubin is excreted from the hepatocyte into the bile caniculi>bile duct>duodenum (direct bilirubin)3 drug metabolism and excretion: if they are not hydrophillic then they cannot be eliminated by the kidneys so the liver converts them to a more soluble form carried out by enzymes located in the smooth endoplasmic reticulum of hepatocytes and mitochondria4 stores vitamins A, B12, folic acid for activationof Vitamin D, and uses vitamin K to synthesize clotting factors5. steroid metabolism: uptakes steroids not boud to proteins and inactivates/excretes6. blood resevoir
Phase of drug metabolism and excretion from liver
phase 1: modification of drug through oxidation, reduction and hydrolysis-transformation takes place in hepatocyte-cytochrome P45 are usually the proteins that cause the biochemical reactions phase 2: intermediates form phase 1 are conjugated further to deactivate the chemically active phase 1 products and produces water soluble metabolites for elimination-Need glutathione by hepatocytes; if not enough>oxidative stress and hepatocyte injury
What is the protective and clearance function of liver?
a. kupffer clls help to remove bacteria and antigens in portal blood and to clear cirulcation of endogenously generated cellular debrib. hepatocytes have endocytic funcitons by their special receptors to remove damaged plasma proteinsc. ammonia metabolism to uread. synthesis of glutathione
What is the major cytoplasmic antioxidant in the liver?
glutathione: important in drug metabolism. without it it will have oxidative stress and hepatocyte injury
Jaundice causes/patho
-hyperbilirubinemia or cholestasis (unable to excrete bile)1 hyperbili: CONJugated: decreased bilirubin into bile canculi > heaptocellular damange> dysfunction in canalicular membrane or transporters2 cholestasis: some dysfunction, intraheptatic obstruction; decrease in bile flow decreases excretion of bili thorugh canaliculi or from bile ducts if extrahepatic -injury from bile salts andother compounds>inflammation, apoptosis, degeneration
Neonatal Jaundice
-unconjugated: hepatic ability to conjugate and excrete bili does not mature until about 2 weeks of age
Portal HTN
Pre-portal vien or massive splenomegalyintra-distortion of structures affecting flow and resistance^(cirhosis)post-right sided HF, pericarditis, or hepatic vein thrombi*results in unfiltered blood into venous circulation: acities, splenomegaly, encepalopahty, varices, hyperglycemia
Injury to liver
-results in hepatocyte swelling>decreased funciton and accumulation of substances>cell death, loss of cytoplasm and celldropout>necrosis exhibited by zonal distrubtion>apoptosis-inflitration of leukocytes, kupffer cells hypertrophy and hyperplasia>becomes APC cell for immune system activation-cytokines release=TNFa and IL 1-stellate cell activated and change function to a proliferative, release fibrin and collagen, and can contract
Manifestations/Results of liver injury
=regeneration is triggered, may result in disorganization=may result in altered fat metabolism resulting in fat acuumulation from decreased export of lipoproteins>lipids accumulate as globules and compress structures=altered bili conjugation=impaired drug metabolism=impaired stoage of vitamins (B12>macrocytic anemia)=altered protein metabolism=diminished synthesis/secretion of plasma protein>hypoalbum>decreased clotting>decreased hormonal binding=altered detoxificaiton of ammonia to urea>encephalopathy=decreased hormone clearnace and elevated liver enzymes
Acute Hepatitis drug induced
-alcoholic or drug induced-*tylenol-mechanism: toxicity to hepatocytes usually zone 1, drug metab produces toxic intermediate; injury/necrosis from these products occurs in zone 2 and 3; drug acts as hapten and stimulates autoimmune response to hepatocyte membranes; and it is dependent on host idiosyncrasies-Patho: hepatocyte injury, etc.
Acute hepatitis alcohol induced
-hepatic breakdown of alcohol produces acetaldehyde>converted to acetic acid>injure cell membranes, inactivates enzymes-ethanol metab impairs mitochondria function: inhibits glucose metab, inhibits fat oxidation, promotes fatty acid synthesis, decreases transport of lipoprotein and accumulation of lipids as globules within hepatocyte>fatty liver and impaired protein synthesis/secretion-patho: alcohol is metab by O2 in phase 1, this increases the need for O2 in hepatocyte, and this may deplete what is left for sinusoidal blood to oxygenate zone 3=hepatocyte swelling, cytokine release from kupffer cells, neut infiltration, endothelin release (vasoconstrict)=ischemia and accumulation of Mallory’s Bodies (tangles of cytokeratin fibers and proteins)=fibrosis
Hepatitis A
*Viral-single stranded RNA virus-fecal-oral spread-replicates in liver, excreted in bile and shed in stool-causes liver disease by T cell mediated damage to infected hepatocytes
Hepatitis B
*Viral-double stranded RNA virus-transmitted by parenteral routes-virus does not kill cells but cell death is the consequence of immune attack = cytotoxic CD8 T cells-can become chronic -^ risk for CA
Hepatitis C
-parenteral transmission-single-stranded RNA virus-^ risk for chronic-strong CD4 and CD8 cell respone associated with self-limited HCV but only a minority of people elicit this type of response-ongoing damage associated with CD4 and CD8 cell response
Hepatitis D
-small RNA virus-route same as hep b-infect only in the presence of hep B core antigen (HBsAg)-most co-infected can clear the virus and recover and small amount become chronic
Hepatitis E
-single stranded RNA virus-enterically transmitted, water-borne-manifestations similar to A-developing countries and younger persons-incubations 6 weeks-^ mortality
Stages of hepatitis
prodrone: onset general clinical manifestations and ends with appearance of jaundice; extrahepatic sx (HA, photophobia, cough, malaise, rash); measurable viral antigenicteric: constitutional sx improve, wt loss, puritis; enzymes leak into plasma and serum antbodies are elevated; jaundice, ligth stool and dark urine; ecchymosis suggest ocagulopathy, encephalopathy with failure to detoxify amoonia and edema; splenomegalyconvalescent phase: resolving sx; persistent abnormalities in liver fx tests
Chronic Hepatitis
-last greater than 6 months-ongoing inflammation, infiltration of inflamm cells especially lymphs and plasma cells; continued hepatocyte necrosis and apoptosis, bridging fibrosis-ongoing activation of kupffer cells, cytokine release, TNFa IL1, -ongoing activation of stellate cells with secretion of fibrin and collagen, replacement of normal low-density matrix with high-density matrix in space of Disse-loss of both endothelial fenestrations and hepatocyte microvilli; gradual bile duct damage and other disruption of normal liver structure, depositoi of firbrous tissue between portal tracts and formation of bands of scar tissue across protal triads and lobules
Cirrhosis Patho
-conintuation from chronic hepatitis-diffuse fibrosis, bands of scar tissue from continued inflammation and immune system, increased number of stellate cells, ongoing deposition of collagen and fibrin with subendothelial spaces-parencymal nodules (proliferating hepatocytes encircled by fibrotic bands)-increased disruption in structure and decreased blood flow and decreased bile flow-coagulopathy: loss of synthesis of clotting fx, and cannot remove factors-hepatocellular carcinoma, increased androgens and estrogens, hepatic encephalopathy-hepatorenal syndrome: functional renal failure with decreased UO, Na and water retention, and rising BUN and Cr; possible due to splachnic vasodilation and systemic vasoconstriction leading to severf reduction in renal flow
Ascites
-lymph fluid backs up from liver in the peritoneal cavity-has high oncotic pressure that causes more fluid to pull into the perineal cavity-increased renal retention of water and sodium, elevated sinsusoidal pressure leads to sequestration of blood in the splanchnic venous bed; underfilling of central vein, decreased volume, decreased renal perfusion, increaSED RENIN SECRETION, increased renal absorption of Na and water, vasoconstriction
Hepatic Enephalopathy
-caused by toxins like ammonia that have bypassed liver-toxins impair blood brain barrier-increased levels of GABA because they have not been removed by damaged hepatocytes> decreases consciousness-altered amino acid metabolism resulting in increase false neurotransmitters/deranged neurotransmission
submucosa
submucosal glands and submucosal nerve plexus
muscularis
circular and longitudinal smooth muscle layers, myenteric plexus
serosa
large nerves and blood vessels and connective tissue
motility types of gi
tonic contraction-valvessegmental contractionperistaltic contraction: permissive relaxation below and contraction above
Neuronal control GI
1 SNS: inhibits motor and secretory activities, increase sphincter contraction, vasoconstriction2. PNS: vagus nerve and pelvic nerves; stimulates the motor and secretory activities of the GI tract and relaxes sphincter
Enteric control of GI
-nerves fibers, ganglion cell bodies, and interneurons network-myenteric plexus: located between layers of muscularis, regulates motility and contraction of muscle, -submucosal plexus: located in the submucosa and regulates the secretions and absorption-controlled by sensory input form SNS and PNS and neurons specialized to detect variations in gut pH, osmolality, wall strecht, glucose, amino acids, temperature etc.> initiate secretory and motor changes to maintain homeostasis
Swallowing function is controlled by
area in reticular formation of brain system
Saliva contains
alpha amylase and IgA, bicarbonate, sodium, potassium
control of the Lower esophageal sphincter`
-alpha adrenergic sympathetic stimulation increases contriction-PNS and enteric system cause relaxation
achalsia is
a d/o of the esophagus in which the LES fails to relax properly during swallowingpatho: 1primary: loss of intrinsic inhibitory innervation of the lower esophageal sphincter; smooth muscle of the lower half to two -thirds of the body of the esophagus does not contract normally2 secondary: myenteric plexus damage from disease; aperistalsis, overly contracted LES, parital or incomplete relaxation with swallowing, progressive dilation of esophagus
GERD patho
-persistant acid exposure, mucosal damage and inflammatory response> esophagitis, injury, hyperplasia, ulcerations, scar formation, sphincter incompetence-prolonged exposure will produce metaplastic columner epithelium containing goblet cells (Barret’s esophagus) leads to CA, stricture and perforation
Mallory-Weiss Syndrome
-longitudinal tears in the esophagus at the esophagogastric juncitonfrom severe retching-patho: inadequate relaxation of the LES at moment of propulsive expulsion of gastric contents; causes stretching and tearing at esophagogastric junction
varices
from portal HTN-dilated veins within submucosa of distal esophagus and proximal stomach-patho: collateral bypass channels develop when portal HTN diverts blood flow through coronary veins of the stomach into esophageal subepithelial and submucosal veins-vessels beocme dilated and tortuous=varices and may ruputure
Stomach structure
-ghrelin is hormone produced mainly by cells lining fundus of the stomach that stimulates hungert-epithelium is simple columnar and have tight junctions-gastric pits: a. mucous: secreting cell that also synthesize prostaglandins from cell membranesb. parietal cells secrete hydrochloric acid and intrinsic factorc. chief cells secrete pepsinogend. G cells within antrum secrete gastrin
Motility control of stomach
- PNS2. enteric nervous system: relaxation and contraction of pyloric sphincter
Hydrochloric acid
secreted by parietal cells-H formed within the parietal cells is pumped by the H-K ATPase pump against high concentration gradient to end up in the GI lumen-Cl is transported across the parietal cell to the GI lumen=HCl-acid secretion by stomach- pH 1-2-HCO3 eliminatrion from the parietal cells create alkaline tide that helps prevent mucosal damage-activates enzyme pepsinogen and releases vitamin B12 from food-stimulated by histamine, gastrin, acetylcholine, PNS vagus nerve, eating
phases of acid secretion by eating
-cephalic: sight smell taste: stimulate PNS to secrete acetylcholine, histamine, gastrin-gastric phase: distention from food: stimulates PNS to release acetylcholine, histamine, and gastrin-intestinal phase: nutrients reach duodenum; gastric secretion is modulated by the duodenal contents
Antagonists of gastric secretion
-somatostatin secreted by D cell sin gastric antrum-GIP secreted by duodenum and down regulates gastric activity-intrinsic factor secreted by parietal cells as well as HCl that is required for B12 absorption-pepsinogen secreted by chief cells, stimulated by acetylcholine, converted by HCl to pepsin and pepsin digests proteins-mucins secreted by surface of mucous neck cells that form gel that adheres to surface of epithelial that help to maintain a pH of about 7 at cell surface and protect from acid and pepsin-bicarbonate secreted by mucous neck cells and secrete to help maintain pH as well-prostaglandins enhance augment bicarbonate and mucous production
Gastritis
patho: increased acid production and or loss of one or more of the defenses> injury to gastric cells>acute inflammation with mucosal edema and infiltrate of neutrophils-possible erosion and hemorrhage-chronic: leads eventually to metaplasia of epithelium or mucosal atrophy and loss of glands
H-pylori
-modulates host immune system to allow colonization of gastric epithelial cells-causes inflammation and immune responses-increases urease which produces ammonia to buffer itself from gastric acid-increases gastric acid production and impairs duodenal bicarb production-urease damages gastric mucosa>more inflamm-leakage of tissue nutrients to surface which sustains bacilli and permits back leakage of acid to the epithelium >more injury-eventually replacement of gastric mucosal epithelium by intestinal metaplasia =increase risk CA and ulcer formation
Autoimmune gastritis
-antibody response to H-K ATPase pump in parietal cells and or intrinsic factorloos of chief cell and parietal cellsdegeneration of gastric mucosa and gastric atrophydiminishes secretion of acid, pepsinogen, and intrinsic factorpernicious anemia
PUD
patho: increased depth of damage at least to the submucosa and possibly into the muscularis mucosa>exposes submucosal areas to gastric secretions and auto digestion
gastroparesis
patho: autonomic neuropathy from poorly controlled DM: causes autonomic neuropathy and loss of PNS, produce gastric outlet obstruction, delayed emptying, release of large boluses of chyme,
gastric tumors
patho: related to H-pylori-T cell driven activation by B cells may be involved
structure of small intestine
-enterocytes: surface epithelial cells contain microvilli that face the intestinal lumen and facilitate absorption-last 4-7 days -crypts of Lieberkuhn: contain stem cells that can differentiate to enterocytes, goblet cells (secrete mucus into lumen), enteroendocrine cells (secrete hormones into blood stream) and paneth cells (produce antimicrobial peptides and growth factors); contain fluid and electrocyte secretions from enterocytes
neuronal control of small intestine
-SNS: celica, superior, inferior mesenteric ganglion: inhibit motor and secretory activities; increase sphincter contraction-PNS: vagus and pelvic: stimulate motor and secretory activities of the GI and relax sphincter
enteric control of small intestine
-myenteric plexus and subucosal plexus (Meissner plexus) exerts most control
humoral control of small intestine
motilin stimulates duodenal motility
what is fasting motility?
slow waves that sweep along the length of the intestinal tract to keep the GI tract clear of debri
bicarb Secretions of small intestine
-secretin: stimulates secretion of bicarb from pancreas and regulates gastric activity-cholecystokinin (CCK) responds to fat products and stimulates GB/pancreas to secrete bicarb
non-bicarb secretions of small intestine
-gastrin stimulates acid secretion in stomach in presence of peptides and amino acids-GIP stimulates insulin release -mucous goblet cells secrete mucus-enterocytes secrete water and electrolytes-paneth cell produce antimicrobial peptides and growth fx-enzymes that aid in digestion
structure of large intestine
-mucosa is columnar epithelium and mucus secreting goblet cells with no villi and few short irregular microvilli on epithelium-crypts of lieberkuhn: goblet cells, endocrine cells, and absorptive cells-longitudinal muscle layter of muscularis externa is concentrated in three bands-gathered circular muscles are call haustra
control of large intestine`
1enteric control: predominates2 neuronal modulates enteric control-PNS: stimulates function-SNS: inhibits3 humoral is minimal
what initiates propulsive movements in large intestines
gastrocolic and duodenocolic reflexes
secretions of large intestines
mucin secreted by goblet cells contain bicarb, lubricate feces, protects mucosal wall
Zollinger-Ellison syndrome
increased gastrin production from pancreatic or duodenal tumor causes excessive gastric secretion and parietal cell hyperplasialeads to multiple ulcers and inactivates panc enzymes
megacolon
-colonic dilation proximal to the affected segment-hirschprung disease: congenital absence of enteric NS is more distal portions of intestine-organic obstruction: from neoplasm, stricture-secondary to ulcerative colitis or Crohn’s disease-functional psychomotor disorder”holding”
types of diarrhea
-dysentary: low volume, painful, bloody-osmotic:high osmolality of luminal solutes that draws water into lumen; absent on fasting-secretory: excessive mucosal secretion of fluid and electrolytes; greater than absorptive capacity; intestinal fluids are isotonicex: rotavirus, clostridium diff, e-coli-exudative: purulent, bloody stools, frequent, persist during fastingex. infection destroying epithelium layer, IBS, salmonella
malapsorption
patho of lactase deficiency: usually enzyme is on the border membrane of enterocyte; without it inhibits the break down of lactose into monosaccarhides and prevents digestion and absorptioncauses gases, increases osmotic gradient> diarrheaanother cause from reduced small intestinal surface area; example radiation, loss of enterocytes or injury; causes atrophy and blunting of villi with inflamm and infiltrate of lamina propria
IBS
patho: unregulated and exaggerated immune and inflamma response to bacterial antigens or other self antegens in susceptible persons-genetic, immunologic fx, alterations in tight junctions, microbial factors, inflammatory response are causes
Crohn’s disease
patho: inflammatory disease of intestinal mucosa that is transural with fissures and noncaseating granulomas-small and large involved, most common terminal lumen-affects some haustral segments-wall becomes rubbery and thick and the muscularis hypertrophies and becomes fibrotic>narrow lumen
ulcerative colitis
pahto: inflammatory disease of colonic mucosa/submucosa that is nongranulomatous-limited to colon-extends proximally from rectum in a continuous fashion-inflammation causes small reosions, into superficial ulcers-pseudopolyps of normal mucosa -inflammatory infiltrate within the lamina propria and crypt of lieberkuhn abscesses -no hypertrophy of muscularis-regenerated mucosa may be flattened and atrophied. granulation tissue may fill the ulcer crators
diverticular disease
-out pouching of the mucosa and submucosa through the underlying muscularis-patho: focal weakness of colonic wall at areas of nervesw and arterial vas recta > potential herniation-peristaltic contractions increase and increase luminal pressure-continued exaggerated perstaltic contractions produces muscular hypertrophy and increases pressure>mucosal and submucosal herniation
vascular disorders
-hypoperfusion or occlusion of the celiac, superior or inferior arteries-poor or absent circulation results in altered membrane permeability, altered motility, mucosal dysfunction, alterations in absorption and digestion
hemorrhoids
variceal dilations of anal and perianal venous plexuses secondary to increased pressure; can become thrombosed and strangulated leading to infarct
IBS type of deranged motility
-altere3d function with abd pain or discomfort that is not explained by structural or biochemical abnormalities-dysfunction of the extrinsic and intrinsic NS, exagerated small intestinal motor resp[onse to stress and food intake, -increased frequency of peristaltic contractions and migrating motor complexes (fasting motility)>IBS with diarrhea-decreased frequency of peristaltic contractions and migrating motor complexes (fasting motility)>IBS with constipation-visceral hypersensitivity from altered signal trafficking with enteric NS, spinal cord or CNS, peipheral sensitization or centeral amplification of sensory input or altered antinociceptive pathways; causes abnormal distention to be felt as discomfort and bloating-psychosocial fx
Polyps
malignant risk: adenomas double in size within 10 years, cancer rare if < 1cm and higher if >4 cm; the greater the dysplasia the greater the risk
colon CA
-adenoma: carcinoma sequence: mutation in tumor supressor genes APC, protooncogene mutatino most common K-ras, alteration in P53 common-microsatellite instability: no detectable antecedent lesion, mutation in DNA mismatch repair gene leads to accumulation of mutations
