Unit 1 SIGS Flashcards
What are the CFTR gene mutation classes?
Class I - no protein - channel not made at all
Class II - no transport - channel not transported to cell membrane
Class III - no function - channel on cell membrane but doesn’t work
Class IV - less function - channels work but poor/decreased function
Class V - less protein - not enough channels made
Class VI - not stable - channels work but aren’t stable, need frequent replacement
Describe the Class I CFTR gene mutation pathophysiology
The result of a nonsense, frameshift or splice-site mutation leads to premature termination of the mRNA sequence –> no protein made –> absence of Cl- channel
Describe the Class II CFTR gene mutation pathophysiology
Abnormal post-translational processing of the CFTR protein –> channel unable to move to proper location
Describe the Class III CFTR gene mutation pathophysiology
Diminished protein activity in response to intracellular signaling –> fully formed channel but non-functioning
Describe the Class IV CFTR gene mutation pathophysiology
CFTR protein has been produced and correctly localized to the cell surface, but rate of chloride ion flow and duration of channel activation after stimulation is decreased from normal
Describe the Class V CFTR gene mutation pathophysiology
Decreased concentration of CFTR channels in the cell membrane as a result of rapid degradation.
Describe the Class VI CFTR gene mutation pathophysiology
Channel instability leads to rapid turnover and decreased net function
Describe the pathway of glycogenesis
Glucose –> (Glucokinase) –> G6P –> Glucose-1-Phosphate –> UDP-Glucose –> linear glycogen –> (branching enzyme) –> branched glycogen –> (Glycogen phosphorylase) –> Limit Dextrin –> (4-a-D-glucanotransferase) –> Modified Limit Dextrin –> (a-1,6-glucosidase) –> Glycogen
Discuss the function of Glucose-6-Phosphatase
Converts Glucose-6-Phosphate into glucose
What is the inheritance pattern of glycogen storage disease?
Autosomal recessive
Describe the importance of dietary therapy in the management of von Gierke disease
Foods rich in fructose or galactose need to be avoided - they need to be converted to G6P before they can be utilized
Cornstarch helps prevent hypoglycemic events
Outline the pathophys and clinical presentation of Type I GSD
Von Gierke Disease - mutation on G6PC gene for G6Pase - diminished G6Pase can’t convert Glucose-6-Phospohate into glucose
Clinical presentation:
Hepatomegaly, renomegaly from increased glycogen and lipids
Hypoglycemic tremor, confusion, seizures
Gout
“Doll-like” faces
Outline the pathophys and clinical presentation of Type II GSD
Pompe disease - impaired glycogenolysis - defective Lysosomal acid a-1,4 glucosidase –> decrease of branch hydrolysis –> increase glycogen in cardiac muscle - affects tissue
Clinical presentation
Progressive
Failure to thrive, proximal myopathy, exercise intolerance
Hypertrophic cardiomyopathy
Respiratory failure
Early death
Outline the pathophys and clinical presentation of Type III GSD
Cori’s disease - impaired glycogenolysis, functional gluconeogenesis
Defective AGL gene –> decrease in debranching enzymes –> increase limit dextrin
Clinical presentation:
Failure to thrive, muscle weakness, cramps
Hepatomegaly, possible cirrhosis or cardiomyopathy
Needs high protein diet with cornstarch supplementation
Outline the pathophys and clinical presentation of Type IV GSD
Anderson disease - impaired glycogenesis - defective GBE1 gene –> branching enzyme depletion –> decreased branched glycogen - affects tissue and liver
Clinical presentation:
Failure to thrive
Hepatosplenomegaly
Hypotonia, cardiomyopathy
Peripheral neuropath
Early death
Outline the pathophys and clinical presentation of Type V GSD
McArdle disease - impaired glycogenolysis - defective PYGM gene –> decreased muscle phosphorylase
Clinical presentation
Older child/adolescent
Muscle weakness, cramps, exercise intolerance
Rhabdomyolysis, myoglobinuria
Outline the pathophys and clinical presentation of Type VI GSD
Hers disease - Impaired glycogenolysis - defective PYGL gene - decreased hepatic phosphorylase –> no debranching of glycogen
Presentation:
Hepatomegaly, hepatic fibrosis
Poor metabolic control –> short stature, delayed puberty, osteopenia, osteoporosis
How does Type I GSD affect serum levels of glucose, lactate, uric acid, and lipids?
Decreased plasma glucose levels
Elevated lactic acid levels
Elevated triglyceride levels
Elevated uric acid levels
Clinical presentation of Barrett’s Esophagus
Retrosternal burning
Regurgitation with water brash
Worse when supine and after eating
How does smoking increase the risk of Barrett’s Esophagus?
Nicotine relaces smooth muscle –> relaxing the lower esophageal sphincter allows gastric juices to get through
Reduced amount of HCO3 in saliva –> decreased acid neutralizing compound
Induces inflammation –> decrease peristalsis –> disrupts clearance of stomach acid from esophagus
When does GERD turn into Barret Esophagus?
When there is metaplasia of the distal esophageal –> change from squamous to columnar
Explain the pathophysiology of treatment options for Barret esophagus
Antacids - increase pH of stomach acid (neutralize)
Histamine blockers - prevents increase of gastric acid after meals
Proton pump inhibitors - decrease amount of H+ ions pumped into stomach
Inheritance pattern of Sickle Cell Disease
autosomal recessive
Explain the pathogenesis of Sickle Cell Disease
Sickle cell disease - ɑɑSS (homozygous)
Hemoglobin SC disease - ɑɑSC (double mutation)
Sickle cell trait - ɑɑβS (heterozygous)
Globin S chain –> B missense mutation on C11 (Glu(-) –> Val(0))
Globin C chain –> B missense mutation on C11 (Glu(-) –> Lys(+))
Describe the Sickle Cell Disease pathophysiology
In the deoxygenated form of HbS, the valine becomes buried in a hydrophobic pocket on an adjacent beta-globin chain. This joines the molecules together to form insoluble polymers. When enough of these form, it gives rise to the classic sickled shape
Outline the clinical presentation of Sickle Cell disease
General anemia features
Vaso-occlusive events - hallmark
Asplenia
Hematuria
Recurring infections (due to loss of splenic function)
Most distinguishing clinical feature of Sickle Cell Disease
Acute vaso-occlusion pain
Sickle cells lack elasticity –> adhere to endothelium –> causes vasoocclusion –> stroke, acute chest syndrome (pulmonary hypertension), splenic sequestration
How does Sickle Cell Disease affect vital signs?
Lower blood pressure than normal reference ranges
Higher blood pressures are at risk for stroke
Diagnostic tests of Sickle Cell Anemia
Hemoglobin electrophoresis - checking for fetal hgb
PBS
Justify the use of hydroxyurea therapy for Sickle Cell Disease
Hydroxyurea therapy uses an antineoplastic drug to inhibit ribonucleotide reductase
This inhibits DNA replication and causes cell cycle arrest in S phase
Increased nitric oxide levels and cGMP signaling lead to an increase in HgbF
What is the inheritance pattern of hereditary spherocytosis?
** Autosomal dominant **
List the laboratory values of HS, and what unique lab finding will you find in a patient with HS?
normal MCV
Increased reticulocytes
Decreased haptoglobin (binding to free-floating hemoglobin)
Increased indirect bilirubin
Increased MCHC
Describe the pathogenesis and pathophysiology of HS
Deficiency in one or more proteins - spectrin, ankyrin, band 3, or and/or band 4.2 - within the RBC membrane/cytoskeleton lead to misshapen and fragile RBC.
Lack of adherence between the cytoskeleton and the cell membrane –> RBC loses biconcave shape –> decrease surface area –> anemia
Howell-Jolly bodies –> extravascular hemolysis
Lack of plasticity –> splenic trapping
Outline the clinical features of HS
Mild: asymptomatic
Moderate: General anemia features, Jaundice, Splenomegaly, Cholelithiasis
Severe: hydrops fetalis, skeletal deformities, delayed puberty
Explain the role of parvo B19 in HS
Parvo B19 infects the bone marrow and uses erythroid progenitor cells to replicate, thus taking them from producing RBC –> causes aplastic crisis in patients with hemolytic anemias who need RBCs to replicate rapidly to replace the damaged RBCs
How does HS effect energy levels
RBC hemolysis –> less O2 carrying capacity and distribution throughout the blood –> less O2 available for aerobic metabolism –> decreased ATP production
Define the clinical utility and significance of osmotic fragility testing and eosin-5-maleimide (EMA) studies in the diagnosis of HS.
Eosin-5-maleimide binding test - test of choice –> looking for decreased binding between E5M dye and RBC membranes –> binding is quantified using flow cytometry
Osmotic fragility test - measures ability of RBCs to resist hemolysis when exposed to different degrees of salt dilution –> HS more vulnerable to osmotic stress –> will explode in hypotonic solution
How do spherocytes differ from normal RBC on PBS
Spherocytes don’t have the biconcave shape so they don’t have the central pallor seen in RBC
Spherocytes may have Howell-Jolly bodies
Signs and symptoms of acetaminophen overdose
Nausea, vomiting, pallor, lethargy
Progressive liver impairment
Jaundice
Outline pathophysiology of acetaminophen overdose
Majority of acetaminophen metabolized to bile –> rest (normally small amount) processed via CP450 into NAPQI –> glutathione inactivates NAPQI –> too much acetaminophen depletes glutathione stores –> NAPQI build up –> oxidative stress –> hepatocyte injury/liver necrosis
How does treatment prevent acetaminophen overdose
N-acetylcysteine provides sulfur to aid in glutathione synthesis
Activated charcoal absorbs newly ingested acetaminophen to prevent absorption into blood stream
Why does acute alcohol intake delay acetaminophen metabolism/overdose?
How does chronic alcohol intake accelerate acetaminophen metabolism?
Alcohol is a competitive inhibitor to acetaminophen of the CP450 enzyme.
Chronic alcohol use induces hepatic microsomal enzymes that result in the accelerated metabolism of acetaminophen.
What is the virulence factor of Staphylococcus aureus
Protein A - binds to macrophage-binding section of IgG antibody which prevents the macrophage from binding and destroying the pathogen
Pt presents with a poorly defined lesion with cutaneous lymphatic edema. The area is warm, tender, and red around the lesion. Pt states it started as an itchy bug-bite but has turned into this over the last 2 or 3 days.
Labs show increased neutrophils with decreased monocytes, and a negative Catalase test. What is the DDx and what is the treatment?
Cellulitis treated with broad spectrum ABX
What cancers are most common in children with Down Syndrome and why?
Under 5yo - Acute myelogenous leukemia (AML)
Older than 5yo - Acute lymphoblastic leukemia (ALL)
Describe the clinical presentation of Cystic Fibrosis
Infants: meconium ileus, failure to thrive, malabsorption
Adults: distal intestinal blockages, pulmonary emphysema - dilation of air spaces, male infertility (vas deferens doesn’t form), finger/toe clubbing, poor growth
Identify and describe the tests used for diagnosis of CF
X-ray of abdomen with contrast - Neuhauser sign (soap bubble appearance)
Chest X-ray - pulmonary emphysema (dilation of alveoli)
Sweat chloride test - defective ATP-gated Cl- channels can’t reabsorb Cl- from sweat glands, causes excess Cl-, Na+ and water –> 60mmol/L or greater of NaCl
CF screening panel
Why might a newborn with CF show a false negative on neonatal CF screening?
Screening checks for increased IRT, which may also be increased if babies are premature, a carrier of the mutation, or had a stressful delivery.
Describe the pathogenesis of CF
Mutation of the CFTR gene on Chromosome 7 causes mutation of the ATP-gated Cl- channel proteins on the surface of epithelial cells.
Leads to decreased secretion of Cl- and increased resorption of Na+ into cellular space. Sodium reabsorption –> increased water resorption –> thicker mucus secretions
Pathway: Ga(s) –> +Adenylyl cyclase –> cAMP –> PKA –> CFTR
Explain the different karyotypic findings associated with Turner Syndrome
45XO, 45X/46XX, 45X/46XY, 45X/47XXX
Discuss the process of male and female gametogenesis and fertilization
Spermatogenesis : spermatogonium (2n) –> primary spermatocyte (2n) –> secondary spermatocyte (1n) –> spermatid (1n) –> sperm (spermatids with tails)
Oogenesis : Oogonium (2n) –> primary oocyte (2n) –> secondary oocyte (1n) + polar body –> ootid (1n) + polar body (first polar body –> 2 polar bodies) –> ovum (1n) + 3 polar bodies
Describe anaphase lag and how it contributes to chromosomal abnormalities
Anaphase lag is the failure of a spindle fiber to pull a chromatid apart from the midline –> chromatid stays separated from the rest of the chromosomes while nuclear envelope forms –> lagged chromatid stuck outside nuclear envelope –> chromosome destroyed = monosomy
Explain the components and values of the Quad test seen in Down Syndrome
Decreased AFP (alpha fetal protein)
Decreased Unconjugated estriol
Increased Inhibin A
Increased hCG (DS is the only disorder with increase in hCG)
Describe the major medical complications of Down Syndrome
Congenital heart defects - AVSD most common
Hirschsprung’s disease - ENS missing from end of bowel
Hypogonadism, decreased fertility
Cancer
Early onset Alzheimer’s - amyloid production gene upregulated on extra chromosome
Pathogenesis of TTP
95% of cases acquired by IgG autoantibodies of ADAMTS13
5% - gene mutation –> depletion of ADAMTS13 antigen –> Upshaw-Shulman disease –> found in families with consanguinity
Pathophysiology of TTP
ADAMTS13 function is to cleave vWF to regulate clotting
Mutation of ADAMTS13 causes buildup of vWF factor –> vWF accumulates on endothelial cells –> increased platelet adhesion –> microthrombi –> mechanically shearing of RBC and blockage of small vessels –> schistocytes, end organ ischemia
Clinical features of TTP and common complications
Thrombocytopenia
Microangiopathic hemolytic anemia
Petechiae
Jaundice
Neurological defects
Complications: stroke, seizures, hemorrhagic colitis, bowel necrosis, ischemia, renal failure
Lab findings of TTP
↓ platelets (thrombocytopenia)
↓ hemoglobin (hemolysis - free floating hemoglobin)
↓ haptoglobin (hemolysis)
↑ reticulocytes (replenishing RBC)
↑ LDH (hemolysis - RBC use lactic acid pathway to make ATP)
↑ bilirubin (hemolysis - heme metabolism)
↑ D-dimer
Coag: ↑ Bleeding time, Normal PT, normal or slightly ↑ PTT
PBS: schistocytes, low platelets
Lab findings of Disseminated Intravascular Coagulation (DIC)
↓ platelets
↓ Fibrinogen
↑ D-dimer
↑ LDH
Coag: ↑ Bleeding time, ↑ PT, ↑ PTT
PBS: Schistocytes
Lab findings of Hemolytic Uremic Syndrome
↓ platelets (thrombocytopenia)
↓ hemoglobin (hemolysis - free floating hemoglobin)
↓ haptoglobin (hemolysis)
↑ reticulocytes (replenishing RBC)
↑ LDH (hemolysis - RBC use lactic acid pathway to make ATP)
↑ bilirubin (hemolysis - heme metabolism)
Normal D-dimer
↑ WBC
Coag: ↑ Bleeding time, Normal PT, normal or slightly ↑ PTT
PBS: schistocytes, low platelets
Pathogenesis of HUS
Infection of E. Coli Shiga Toxin cause mucosal inflammation –> facilitates bacterial toxins entering circulation –> toxins cause endothelial cell damage, especially in renal structures –> damages endothelial cells secrete cytokines –> vasoconstriction and platelet microthrombus formation (intravascular coagulopathy) –> thrombocytopenia –> RBCs mechanically destroyed by microthrombi –> hemolysis and end organ ischemia
Justify the use of plasmapheresis rather than a plasma transfusion for aTTP
Plasma transfusions would be less effective for acquired TTP because plasma transfusion would only provide ADAMTS13 enzymes to the blood stream, but would not prevent the destruction of the new enzymes by the antibodies.
Plasmapheresis would replace the entirety of the plasma, including the ADAMTS13 antibodies, which would allow the enzyme to function.
Outline the etiology and pathophysiology of Factor V Leiden
Autosomal recessive inheritance
DNA point mutation (Arg –> Gln) Arg506Gln near the polypeptide cleavage site of Factor V
Gln506 is resistant to the cleavage of Activated Protein C –> TF V remains active in common coagulation cascade –> continues to activate prothrombin (TF II) –> increases thrombotic events (hypercoagulation)
Pathogenesis of DVT
Hypercoagulability, Endothelial damage, and/or venous stasis can cause DVT
Identify the significance of D-dimer levels in thrombotic disorders
D-dimers are fibrin degradation products released when plasmin cleaves cross-linked fibrin
Elevated D-dimers indicate elevated clotting
Justify the use of long-term anticoagulation therapy in patients with Factor V Leiden and explain the MOA
Warfarin is a long term anticoagulant
Because Warfarin inhibits Vitamin K, the zymogens produced by the liver are inactivated, including protein C. Protein C is used to promote anticoagulation. So because Warfarin takes a few days to work, it should be paired with a bridging anticoagulant such as Heparin, as it works on the coagulation cascade immediately. Otherwise it can cause hypercoagulability.
Outline the Ottawa Ankle Rules
- Inability to bear weight for more than 4 steps
- Bone tenderness on posterior lateral malleolus
- Bony tenderness on posterior medial malleolus
- Tenderness at base of 5th metatarsal
- Pain at navicular bone
Outline the pathway that causes NSAIDs to delay wound healing
NSAIDS inhibit enzyme cyclooxygenase (COX)
COX converts arachidonic acid –> thromboxanes (TXA), prostaglandins, and prostacyclins
Inhibited COX –> decreased platelet aggregation
Identify the role of neutrophils in bacterial infections
Production of ROS
Chemotaxis of other inflammatory cells
How does infection cause a fever?
Exogenous pyrogens (bacteria) initiate fever by interacting with macrophages or monocytes –> induces cytokine induction –> cytokines (IL-1 mostly) act on hypothalamus –> synthesis of prostaglandins –> increase of core temperature
Staphylococcus aureus
Structure, epidemiology, virulence factor and mode of transmission
Structure: Cocci - round, found in clusters, Gram (+), catalase +
Epidemiology: anywhere dirty (gym, hospitals, skin)
Virulence factor: Protein A - binds to Fc section of IgG antibody to inhibit phagocytosis
Opportunistic MOT - ingestion, direct, transdermal
Streptococcus pyogenes
Structure, epidemiology, physiology and mode of transmission
Structure: Cocci - round, found in chains, Gram (+), catalase -
Epidemiology: anywhere dirty (gym, hospitals, skin)
Virulence factor: Toxins (exotoxins result in release of IL-1, IFN-y, TNF-a), enzymes (DNase - destroys neutrophils), protein M (prevents opsonization)
Opportunistic MOT - ingestion, direct, transdermal
What test differentiates Staph from Strep
Catalase - staphylococcus has the ability to produce catalase
Pathogenesis of Ewing Sarcoma family of tumors
Translocation of EWSR1 gene on C22
t(11;22)(q24;q12) leads to full expression of fusion protein EWS-FLI1 –> increased cell proliferation
Describe how the Ewing Sarcoma family of tumors is a systemic disease process
There are four different tumor types affecting different aspects of the body
Ewings Sarcoma - bone
Extraosseous ES - soft tissue
Primitive neuroectodermal tumor - brain
Askin’s tumor - chest wall
Explain the significance of LDH levels in Ewing Sarcoma
Ewing sarcoma has rapidly dividing tumor cells, which use aerobic glycolysis of lactate in the presence of oxygen
Increased LDH is indicative of significantly increased cell proliferation
