Hepatitis

A B C D ESource and transmission

Fecal-OralInternational travelDay CareCommon in kids

BirthBody fluids (STD)Parenteral

Parenteral (needles, tattoos, transfusions, transplants, sex, birth, accidentally falling into a sharps container-oops)

Blood, Body fluidsIV and dialysisNeed HBV first

Fecal-OralWater

Duration (Incubation and Chronic/Acute?)

Acute onlySelf limiting6 week incubationLasts 2-3wks

Acute is commonFulminant=necrosis1-6 month incub.Liver cell cancerChronic= 15-20% mortality

Chronic(<5 yrs majority)

Acute or Chronic(peak= 6-8 wks)2-26 week incub.

Severe acute diseaseChronic- won’t resolve

Acute onlySelf limitingIncubation- 40 days

Symptoms JaundiceAlcoholic stools

Same as Hep A Can be asymptomaticFever, Jaundice

Prevention and Treatment?

ImmunizationHand washing

ImmunizationHBsAg screeningSafe sexHB immune glob.

Prevent by screening baby boomers and donorsTreatment <3No immunity for reinfection

ImmunizationPrevent HBV

Safe water(IG doesn’t prevent infection)

Complications Fulminant, Cholestatic, Relapsing Hepatitis

Glomerolunephritis* See below

Cirrhosis (20%), Death

>60% develop cirrhosis

High risk for death with preggos

* Chronic Hep B:1. Immune tolerant- viral replication, HBeAg and HBV DNA in serum2. Immune clearance- elevated AST/ALT, liver inflammation3. Inactive HBsAg Carrier state- anti HBe, low risk for cirrhosis 4. Reactivated chronic Hep B- sucks to suck! Increase in HBV DNA, cirrhosis, liver cell cancer, mutations of HBV

Hepatitis G- not a real thing.

Cirrhosis- Final phase of chronic liver disease, fibrosis and scarring, poor liver function (do not confuse with ^LFT unless you want to fail the exam)Causes: *Alcohol, *Hep B/C, *Non alcoholic fatty liver disease (common in the US)Epidemiology: 12th leading cause of death, common in the USSymptoms: Hepatomegaly (enlarged liver), pruritus, jaundice, palmar erythema, spider angiomata, ascites, edema, painful tense abdomen, confusion, asterixis (hand flapping)

Ascites “Beer gut”

Portal Hypertension and Variceal Bleeding

SBP Hepatic Encephalopathy

Pathology Most commonHigh mortality (liver transplant?)Caused by portal hypertension**

Complications: AscitesVariceal bleeding- Dilated vessels in stomach and esoph. from shunting blood away from liver and into splanchnic vessels

Bacteria in ascitic fluidFrom GI Gram (-)sBacteria from gut to lymphReduced host defense

Toxins from crap liverPortal-systemic blood shunting away from liverToxins=ammoniaAmmonia levels NOT correlated with severity

Risk Group Alcoholics Cirrhotics (1/3= death from variceal bleeding)

Variceal bleeders Patients with a TIPS

Symptoms Bulging abdomen Black stool, low hemoglobin, low platelet count

Altered mental status

Treatment Na+ restrictionDon’t fluid restrictAldosterone antag + loop diuretics Large vol. paracentesis for diuretic refractory ascites (temporary help) TIPS for refractory ascites

Prevent bleeding by treating portal hypertensionNon- selective Beta blockersTIPS (transjugular intrahepatic portosystemic shunt)- through liver to relieve pain from pressure in portal vein

Antibiotic therapy(cephalosporins or cipro)

Increase ammonia excretionLactuloseDecrease animal protein (use dairy and vegetable)

Diagnosis UltrasoundParacentesis (drain)SAAG^ = portal hypertension

SAAG >1.1 g/dLHVPG > 5 mmHg= portal HTN(diff b/w portal vein and inferior vena cava)

Elevated ascitic WBC^ PMN+ for bacteria in ascitic fluid

**Portal Hypertension: damage/scarring of liver cellsincreased sinusoidal pressureblood backs up into portal vein and splanchnic vessels =^pressure N.O. released to vasodilate splanchnic vessels less blood into liver and heartbaroreceptors increase SNS (ADH, RAAS) cause fluid retention from the kidneys increased lymph and splanchnic vessel permeability fluid and lymph into peritoneal cavity…. Cycle continues

Cirrhosis lab markers:Low albumin, increased bilirubin, increased INR (decrease in clotting factors), decreased platelets

Pancreatitis

Exocrine function:Acini ducts that secrete juice (zymogenic enzymes that secrete and absorb food once activated) from pancreas to duodenum Exocrine pathophysiology: Inflammation Neoplasms (tumors)Duct obstruction- stone or mucus

------------------------------Acute Pancreatitis: ----------------------------------------------------------------------------------------------

Activated Trypsin= Kallikrein-kinin ^ = edema and inflammation Chymotrypsin^ = edema and vascular damage Elastase^ = hemorrhage and vascular damage Phospholipase A2^ = coagulation necrosis Lipase^ = fat necrosis

Alcohol Pancreatitis: Biliary Induced: 1. ^ enzymes in pancreas: 1. Obstruction of Ampulla of Vater

acinar cells sensitized 2. Reflux into pancreatic duct (parenchyma injury)2. CCK release zymogens activated 3. Inflammation (^ injury) 3. Acetaldehyde ^ = trypsin^ 4. Sludge4. Inflammation of sphincter of Oddi 5. Microlathiasis passage 5. Zn and Se deficiencies

Symptoms of Acute Pancreatitis: Ab painN/VFever^ WBC^ Amylase ^ Lipase^ Triglycerides (Alcohol use)

-------------------------------------------Chronic Pancreatitis--------------------------------------------------------------------------

1.2. Long term obstruction 3. Fibrosis/ Atrophy of acini4. Stenosis/ dilation of ducts5. Pseudocysts6. Calculi (stones)

7. Inflammation= exocrine sucks= decreased bicarbonate= malabsorption (decreased cholesterol)

8. Calcifications and no dilation for small duct9. Dilated large duct10. CCK = pancreas stimulation

Symptoms: Amylase and Lipase are pretty normal (unless relapsing disease), N/V, Ab pain

Hematology

Random CrapPlasma and formed elements (RBCs mostly)- 50% depends on:

Hormones Diet Environmental factors Metabolic demands Vitamins

Plasma proteins- 7-8% plasma volume Reticulocyte- 1% total RBC count (no nucleus) (right before maturity) – depends on IronLess mature cells depend on erythropoietin RBC are mature when they’re disk shaped and filled with hemoglobin Hematopoiesis- cell differentiation Bone marrow stem cells make up blood components Most active stem cells in vertebrae, sternum, ribsTransplant patients with chronic renal disease get erythropoietin exogenously b/c their kidneys can’t sense or produce EPO

Erythropoiesis- hormone that stimulates RBC production From low O2 in tissues kidney= increased erythropoietin and RBC maturation increased O2 in tissues decrease in EPO (negative feedback- when more red cells produced, hemo levels rise, tissues have better oxygenation)Causes of low O2:

Decreased hemoglobin (anemia) Hemorrhage Tissues using a lot of O2

chemoR = brain ^ O2R on kidney peritubular cells= ^ RBC

Leukocytes- ^ in response to steroids, exercise, seizures, stress, and depletion of WBC in marrow

Decrease in WBC (leukopenia = bacterial infections) Active infection = neutrophilia (leukocytosis)- increased less mature cells (bands) - left shift

Phagocytes:o Granulocytes (Neutrophil, basophil (hypersensitivity), eosinophil)

Neutrophil- most common, first line of defense, use NADPH oxidase to produce free radicals, myeloperoxidase, immature neutrophil= bandleft shift

Leukopenia from meds, transplants, chemoo Agranulocytes (in skin tissues)

Monocytes Macrophages Lymphocytes

o T cells o B cells

Platelets*Inactive until needed for clotting Activation controlled by endothelial cellsIncreased platelets= vasoconstrictionSpleen removal= increased thrombocytosis= increased platelets b/c body can’t filter well

Role: 1. Regulation of blood flow to damaged site (impacts vasoconstriction)2. Platelet interaction to form platelet plug3. Coag. Cascade (stabilizes platelet plug) 4. Repair process (clot retraction and dissolution- fibrinolysis)

Life span: 10 daysMostly located in the spleen

AAA:1. Activation- Degranulation: collagen exposure (key in external cascade) triggers pathway, thrombin, ADP, platelet activation

4), TXA (*new platelets and increases platelet aggregation), serotonin, PAF2. Adhesion- coverage at site of injury- Platelet factor IV, release of Von willowbrands factor (important for hemophilia A-

where pt has decrease in Factor 8 and Von willowwhatever’s factor- treat with giving von willow factor)

3. Aggregation- Platelet plug: i. TXA(vasoconstrictor) and ADP = ^fibrinogen R

ii. GPIIb- IIIa conformational change = Calcium dependent R

ThrombopoiesisTPO produced in:

Liver Kidneys Skel muscle Marrow stroma1. Initial- endothelial injury uncovers collagen= increased platelets adherence, aggregation, degranulation, phospholipid

availability2. Propagation- platelet plug (tenase and prothrombinase) 3. Amplification- coag cascade getting ready with thrombin4. Fibrinolytic pathway- breaks apart clot

TPO production at a constant rate- the amount free to interact depends on uptake of the c-Mpl (TPO Receptors) Cytokines= ^ TPO in marrow stromal cellsInflammation= Il-6^ = TPO^= ^platelets (acute phase reactant- whatever the hell that means)

Coagulation Cascade: https://www.youtube.com/watch?v=FNVvQ788wzkImmediate hemostasis in normal pt. Localized to site of injury. *Extrinsic pathyway= Factor VIIIntrinsic= Factor XII after collagen Both meet at Factor X Fibrin clotWarfarin works on factors 2, 7, 9, 10, Proteins C, S (INR looks at factor 7)Calcium is important in activating inactive crap

Hemostasis Major components of hemostasis:

Platelets

Endothelial cells Tissue Factor cells (Factor 3) – part of extrinsic pathway Coagulation factors- plasma proteins

Aintothrombin stops 10 to 10A (stop thrombin) Fibrin molecules cross linked with platelets= stop bleedingVonWillowshit= platelets can adhere to endothelium (important in hemophiliacs) Primary hemostasis:

1. Vasoconstriction, platelet adhesion, activation at sites of endothelial injury Collagen and thrombin= ^platelets

Increase in Ca+2 inside cell Platelets secrete granules

Secondary hemostasis: 2. Formation of fibrin

a. Initiation- i. Tissue Factor is released IIIV activated

ii. IX, X activatediii. Xa, Va catalyze conversion of Prothrombin Thrombin

b. Amplification- surface of platelets, thrombin activates V, VIII (von Willow thing), XIc. Propagation- Thrombin Burst! Tenase (need PL and Ca+) and prothrombinase (need Ca+2 and PL) formed (cleaves

prothrombin thrombin)

Fibrinolysis: fibrin breaks down into degradation products (plasmin)Negative feedback of thrombin = ^ plasmin(active)= decreased fibrin

*Ca+2 important for blood transfusionsCitrate is mixed in with blood, citric acid anticoagulates blood bags= decrease in plasma free Ca= inability to convert tenase and the thrombin burst

Lab Testing – seconds to form a clotPT- Prothrombin time- Extrinsic, Tissue Factor dependent

Factor VII falls = decreased thrombin = anticoagulation (Warfarin 2, 7, 9, 10 and proteins C,S)- INR^ with warfarin

aPPT- Activated partial thromboplastin time- Intrinsic, NOT TF dependent Prolonged when 8 or 9 is decreased Sensitive to Heparin+Antithrombin- heparin therapy= aPPT is checked Low Mol Weight Heparin(enoxaparin) +Antithrombin (AT) inhibit 10a= no prolongation in

aPPT, measure anti 10a levels 4 hours later

-----------------------------------Blood Disorders-----------------------------------------Macrocytic Microcytic NormocyticIncreased MCV*Decreased Folic Acid or B12 Liver diseaseAlcohol= low folateHypothyroid NormochromicMegaloblastic (large cells)Premature cell deathAbnormal maturation*Pernicious

Decreased MCV*Decreased FeThalassemias Small cells Demand>SupplyPreggosNSAIDs (GI bleed)Use Fe replacement

Aplastic anemia Anemia of chronic diseaseChronic kidney disease Hemolytic anemia

Macro: Pernicious AnemiaCauses:Abnormal RBC maturation (decreased B12)Too much bacteria growing in intestine (competes with B12) Intestine sucks at absorbing (Crohn’s) GastrectomyDiet sucks Chronic atrophic gastritis- infiltration of plasma cells and lymphocytes= ^ risk for adenocarcinomaLoss of gastric acid and intrinsic factor= B12 absorbtion sucks (b/c you need acidic environment for B12)

Megaloblastic changes in each stage of erythrocyte devel.- abnormal RBS are destroyed in the marrowDemyelination of posterolateral spinal columns= neuronal deathManifestation:Slow development b/c there are a lot of B12 storesHemoglobin is 1/3 normalFatigue, dyspnea, dizziness, high output heart failureSwollen tongue…Neuro- numbness, loss of balance/coordination

Micro: Iron Deficiency- Most common (GI or GU (preggos) bleed)Usually chronicPatho: duodenum absorbtion isn’t greatFe export to plasma is regulated by hepcidin and binds to ferroportinFe in body stored as ferritin and hemosiderin and is transported with transferrin*Final step in heme synth is interrupted= decreased heme productionIncreased heme regulated inhibitor= decreased heme synth

Ferrous iron + ferrochelatase= into protoporphyrin 9 Early deficiency- hemoglobin decreases but RBC seem normal, increased platelets Then- Low MCV (microcytic, hypochromic erythrocytes) , more fatigue

Manifestations:Fatigue, weakness, SOBGlossitisAchlorhydria, gastric atrophy*Pica (eat anything….)

Compensations:Pale skinTachycardia

Normocytic AnemiaCaused by:Decreased RBC precursors- primary failure (aplastic anemia)

Replacement of marrow elements- cancer, viral, aplasiaLow EPOChronic inflammatory disease- affects Fe availability

Decreased life span- acute blood loss, autoimmune hemolytic anemia, sickle cell anemia, spherocytosis/elliptocytosis (hereditary)

White cell disorders:

Abnormalities in NUMBERS of wbc

Leukocytosis- acute or chronic infection or inflammation. (persistent= chronic lymphocytic leukemia) Lymphopenia- steroids and immunodeficiencies

Neutrophilia- infection, inflammation, steroidsNeutropenia- overwhelming infection, benign disease, bone marrow tumor, myeldoplastic syndromes, drug therapy

Platelet Disorders

Thrombocytopenia- decreased TPO production by liver (cirrhosis), increased destruction (dialysis, hypersplenism, ongoing clotting, autoantibodies

Thrombocytosis- recovery from Fe deficiency anemia, myeloproliferative disorders, essential thrombocythemia

Functional Disorders- Uremia (renal failure), aspirin therapy, inherited disorders (von Willebrand)

Drug associated- (5-7 days after first exposure) Spleen destroys Ab b/c platelets are seen as abnormal Ex. NSAIDs, quinine, PCN, cephalosporin, gold salts, sulfonamindes…

Heparin Induced Thrombocytopenia (HIT) 1. PF4 released

2. Heparin binds to PF43. IgG bind to heparin-PF44. Complex binds to platelets (Fc R)5. Destruction (spleen)6. Prothrombic state- heparin-PF4 binds to PF4 R on platelets= cross linking, activation, aggregation

Increased platelets= white clots in arteries and veins. *Bleeding unusual (unlike DIC) Treatment- stop heparin, Binds to platelet 4 (PF4) increased platelet activationbinds with high affinity to heparin on vascular endothelium HIT Type 1- platelet binding to fibrinogen and aggregation, mildHIT Type 2- Antigen = ^ IgG*, immune based, increased prothrombotic state w/ increased platelet activation, need anticoagulation

Disseminated Intravascular Coagulopathy (DIC)

Consumptive coagulopathy Widespread activation of clotting cascadeMediator- TF release (binds to 7a), excess thrombin= excess activation of coag cascade and excess fibrinogen cleavage \Coag. Inhibitors are used up= more clotting Thrombocytopenia occurs- platelets consumed and clotting factors consumed= severe bleeding

Coagulation Factor DisordersHemophilia A (Factor 8) Hemophilia B (Factor 9)= excessive post traumatic bleedingVitamin K deficiency- decreased 2, 7, 9, 10 and C and S proteins

Virchow’s Triad- inherited (Thrombosis) - decreased blood flow, vessel injury or inflammation, changes to intrinsic blood properties

Protein C Resistance (increased coag)- V Leiden Factor, single mutation in 5 gene= factor 10a increases conversion of prothrombin to thrombin

Protein C deficiency- 5a^ and 8a^ Less negative feedback of prothrombinase complex

Protein S deficiency- unregulated procoagulant action of 10a

Antithrombin deficiency- increased thrombin, 9a, 10a, 11a, 12a, TF-7 complex

Deep vein thrombosis (DVT)- slow blood flow, more prevalent in extremities Pulmonary Emboli- SOB, hypoxemia, embolic DVT?