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LPL
- Lipoprotein Lipase
- endothelial cells lining blood vessels of adipose(storage) and muscle(beta oxidation)
- STIMULATED BY INSULIN
- ApoCII is cofactor (surface of TG rich chylomicrons and VLDL)
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LPL deficiency
- Hyperchylomicronemia and/or hypertriglyceridemia
- Type I diabetics->acute pancreatitis & eruptive xanthomata from loss of LPL activity
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Liver Lipid metabolism
- Endocytes chylomicron remnants
- repackages & secretes VLDL(triglycerides and CE) or further to LDL (cholesterol ester-rich)
- LDL cleared by liver (endocytosis after LDLR bound)
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Statins
- indirectly upregulate hepatic LDL receptor through HMG-CoA Recductase inhibition
- increase SREBP2 (transcription factor) processing and hepatic LDL rector expression
- lowers plasma LDL 25-50%
- DO NOT WORK FOR familial hypercholestrolaemia(receptors don't bind LDL) homozygotes
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How long does it take for chylomicrons (TG-rich) to clear from blood and fasting?
12 Hours
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Plasma HDL
- secreted into blood from liver (75%) and intestine (25%)
- Niacin & exercise increase HDL
- High HDL-reduced MI/athersclerosis risk
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LDL vs HDL
- LDL in intima is oxidized and taken into macrophage depositing lipid CE into cells = FOAM CELLS
- FOAM CELLS die and release nipid->becomes placque
- HDL prevents LDL oxidation (ANTIOXIDANT) & removes excess toxic choleserol from foam cells
- Lower LDL=diet, statins
- Raise HDL=exercise, niacin (low compliance), limit alcohol
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Beta Oxidation
- Mitochondrial matrix
- increased, fasting, starvation, TYpe 1, some Type 2
- produce ketone bodies
- require carnitine, CPTI,CPTII (transerases for each membrane in mitochondria)
- blocked by malonyl CoA
- High Beta-ox->excess acetyl CoA->ketone bodies (only in liver)
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Keto acidosis
- problem in fasting and TYpe 1 diabetes
- acidify blood->coma death
- breath contains acetone-sweet smelling
- ketonuria-ketone bodies in urine
- associated with acute pancreatitis,eruptive xanthomata, severe hypertriglyceridemia
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Portahepatis
- hepatic artery (30%) systemic circ
- portal vein (70%) from GI and spleen (largest)
- bile duct
- Travel along TRACTS (other vessel is Central Vein)
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Liver anatomy
- Hepatocytes with bile (brown) canuliculs between them (store glycogen PAS stain)
- Sinusoids lined with endothelial cells
- Kupffer cell-macrophages inside sinusoids
- stellate cells between endothelium and hepatocytes store VITAMIN A
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Stellate cells
Btwn endotheliumand hepatocytes->store Vitamin A
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hepatocyte pathology
- swelling when injured
- inflammatory infiltrate (deep blue)
- steatosis
- apoptosis (deep pink)
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hepatocellular plates
usually onecell thick, widened in regeneration and neoplasia
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cirrhosis
large bands of (blue)fibrosis surrounding nodules of hepatocytes
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Steatosis
fatty accumulation in hepatocytes
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hepatitis
- infection
- autoimmune
- drugs
- steatohepatits-fatty liver disease
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viral hepatitis
- systemic-herpes, adeno, CMV, Rubella
- Epstein Barr- MONO
- Hepatitis A-G= acute (somechronic (> 6 months)
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Hepatitis A
- fecal oral
- day care, military water, seafood
- most self limiting
- no chronic
- vaccine
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Hepatitis B
- most (90%) self limited
- ubiquitous body fluid
- vertical, STD
- most kids get chronic
- Vaccine available
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Hep C
- blood borne-transfusions, needless
- CHRONIC INFECTION-80-90%
- no vaccine
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Acute viral hepatitis
- lobular inflammation
- hepatocye injury-apaptosis, necrosis, swelling
- NO FIBROSIS
- hepatic failure when 80-90 % of hepatocytes necrose
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Chronic Viral hepatitis
- inflammation in portal areas extended beyond in parenchyma
- Regeneration evidence
- fibrosis (scarring) -beginning in portal areas, periportal septa->BRIDGING FIBROSIS
- cirrhosis(end stage liver disease)
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Bridging fibrosis
- fibrosis connecting portal tracts->CIRRHOSIS
- Transplant only option
- cobblestone, nodular gross appearance
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Steatohepatitis
- injury due to necroinflammatory activity and fat deposition->Mallory bodies (cytoplasmic inclusions)
- lobular/pericentral fibrosis, chicken wire fibrosis
- chronic hepatitis
- alcohol or non-alcohol (NASH)
- METABOLIC SYNDROME => NASH = insulin resistance, type 2 diabetes, obesity, hyperlipidemia
- or caused by drugs
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Cirrhosis
- Portal HTN
- esophogeal varicies, caput medusae(musclesout at belly button
- ascites-fluid accumulationinabdomen
- hepatic encephalopathy (no detoxification)
- coagulopathy
- hepatocellular carcinoma
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Gall bladder
columnar villiform structures similar to small intestine
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Gall stones
- alteration from stasis or infection
- composed of cholesterol
- bilirubin, bile salts(Calcium) (Pigment stones) less than 50% cholesterol
- females, obese,industrial, old, tribes
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cholecystitis
- gall inflammation-> 90% have gall stones
- yet only 25% of pts w stones develop clinically evident cholecystitis
- acute=calculous 90%, trauma burns etc remainder
- chronic-no history of acute, biliary colic, right upper quadrant pain, fibrotic(thick walls)
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Pancreas
- acinar-exocrine
- islets-endocrine, insulin, glucagon (rich vascularity)
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pancreatitis
- gallsones & alcohol
- AUTODIGESTION
- enzymatic necrosis and inflammation
- hemorrhage, edema and necrosis of fat or parenchyma
- looks like soap
- leads to fibrosis, scaring leaving just islets & fat
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Sulfonylureas
- -amide (1st generation, cardiotoxicity)
- gli-ide (2nd generation, no cardiotoxicity) (1-3 onset, 10,12-24 duration)
- Glimepiride best protection against MI
- A. Insulin Release
- 1. inhibits ATP K+ channels
- 2. depolarize islet Beta cells
- 3. Ca2+ influx and induced insulin secretion
- B. Depress glucogon
- C. Enhance insulin activity
- Side effects: weight gain, teratogenic, impaired liver kidney
- Increase effect-H2 antagonist, Mg salt, oral anticogulants, salicylates, Beta blockers
- Decrease effect-estrogen, thiazide diuretics, thyroid hormones
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Meglitinides
- 1. bind to KATP channel on beta cell on different binding site than sulfonylureas
- 2. depolarize
- 3. Ca2+ influx -> release insulin
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Nateglinide
- D-phenylalanine
- more rapid less sustained
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Repaglinide
benzoic acid derivative
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Biguanides
- phenformin & metformin (glucophage)
- 1. Activates AMP(K) -inhibit hepatic gluconeogenesis
- 2. Increase insulin sensitivity, peripheral uptake
- 3. Decrease glucose GI absorption
- metformin used in combo
- Contraindication - Iodinated radiographic contrast dye impairs kidney function
- Adverse-GI upset, lactic acidosis, increased homocystein levels and B12 maleabsorption
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Thiazolidindiones
- TZDs Rosiglatazone Avandia (increase CHD)
- pioglitazone (no inc CHD)
- 1. insulin-sensitizing through peroxisome proliferator- activated receptor gamma, PPARr -> nucleus production of glucose and lipid homeostasis
- 2. Decrease hepatic gluconeogenesis
- 3. Increase insulin dependent glucose uptake in muscle and fat
- Adverse-risk of hepatitis (monitor liver)
- Fluid retention, edema, weight gain,
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alpha-Glucosidase Inhibitors
- competitive brush border enzyme->less glucose absorption
- acarbose (precose) inhibits alpha amylase
- miglitol (glyset) monosaccharide
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Aborption of glucose drugs
- Alph-glucosidase inhibitors
- biguanides
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Biosynthesis (hepatic gluconeogenesis) drugs
- biguanides
- thiazolidine diones
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Insulin uptake, effect enhancers
- biguanides
- thiazolidine diones
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Pancreas secretion
- slufonylureas
- Meglitinides
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H2 receptor antagonists
- Histamine receptor
- -TIDINES
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Antiemetic Agents
- D2 Antagonists (dopamine
- H1 Antagonists (histamine 1)
- Muscarinic Antagonists
- 5HT3 Antagonists (seratonin)
- Corticosteroids
- Cannibinoids
- Emetic Agents
- Syrop of Ipecac
- Apomorphine
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Domperidone
- Antiemetic and Laxative
- does not cross blood brain barrier unlike other D2 antagonists
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