Hyperlipidemia

1
Hyperlipidemia

• Elevated Cholesterol and/or Triglycerides
• Measured by LDL/HDL and TG
• Type of treatment depends on the number of risk
  factors and CAD risk factors
• 0-1 risk factors LDL lt160
• 2 LDL lt 130
• CAD or equivalent risk factors lt100 or lt70

2
Hyperlipidemia Signs

• Atheroma- plaques in blood vessels

3
Hyperlipidemia signs

• Xanthoma- plaques or nodules composed of
  lipid-layden histiocytes (foamy cells) in the
  skin, especially the eyelids

4
Tendenous Xanthoma
Xanthoma deposits in tendon, commonly the
Achilles
5
Corneal arcus

• Lipid deposit in cornea

6
Psammoma Bodies

• Laminated Calcific spherules seen in
• Papillary adenocarcinoma of thyroid
• Serous papillary cystadenocarcinoma of ovary
• Meningioma- tumors derived from meningothelial
  cells that invest the arachnoid matter
• Mesothelioma- Mesothelial cell tumor of the
  parietal or visceral pleura

7
Psammoma Bodies
8
RBC forms

• Biconcave- normal, no nucleus, central pallor is
  1/3 or cell

9
Spherecytes

• Seen in Hereditary spherocytosis, autoimmune
  hemolysis, transfusions and severe burns, NO
  CENTAL PALLOR

10
Elliptocytes/Ovalocytosis

• Hereditary Elliptocytosis, Thalassemias, Iron
  Deficiency and Megaloblastic anemias

11
Macro-ovalocytes

• Megaloblastic anemia
• Also has hypersegmented PMNs
• BM failure

12
Helmet cell/schistocytes

• Schistocytes are red cell fragments
• Assoc. with DIC, hemolysis, TTP

13
Sickle Cells

• Sickle Cell anemia- HbS inheritance, in AS, ½ of
  the HbA is replaced with HbS, in SS all of HbA is
  replaced
• Valine is sub. for glutamic acid on B-globin gene

14
Teardrop Cell

• Myeloid metaplasia with myelofibrosis (BM
  fibrosis), myelopthisic anemia

15
Acanthocytes

• Abetalipoproteinemia

16
Target cell

• HbC disease, Asplenia, Liver Disease,
  Thalassemias (HALT)

17
Poikilocytosis

• Non uniform shapes
• Seen in TTP- VWf secretion that is not cleaved by
  protease leading to excess platelet
  aggregation/coagulation
• HUS- Hemolytic uremic syndrome is characterized
  by acute renal failure, microangiopathic
  hemolytic anemia, fever, and thrombocytopenia.

18
Burr Cells

• HUS/ TTP, uremia/renal failure

19
HLA SUBTYPES

• B27- psoriasis, ankylosing spondylitis, IBS,
  Reiters symdrome (all are associated rheumatoid
  diseases that sometimes occur together)
• Reiters triad- arthritis, nongonococcal
  urethritis, and conjunctivitis

20
HLA B8

• Graves disease- autoimmune disease with Ig
  stimulation of TSH receptor
• Celiac sprue- gliadin protein in wheat that
  causes immunological rxn that destroys the lining
  of SI

21
HLA DR2

• Multiple Sclerosis
• Hay fever
• SLE
• Goodpastures
• Diabetes protective

22
DR3/DR4/DR5/DR7

• DR3- Type I Diabets
• DR4- Rheumatoid athritis, Type I Diabetes
• DR5- Pernicious anemia (B12 deficiency) due to
  lack of IF production from parietal cells,
  Hashimotos thyroiditis- autoimmune destruction
  of thyroid gland
• DR7- Steroid responsive nephrotic syndrome

23
Reed Sternburg cells

• Giant cell seen in Hodgkins disease, bilobed
  nucleus with owls eye appearance

24
Enzyme Markers

• AST/ ALT(More Liver specific)- these reflect
  hepatic injury NOT FUNCTION, can be normal in
  advanced disease
• MI- elevated AST ONLY
• Viral Hep- ALTgtAST
• Alcoholic Hep- ASTgt ALT sometimes 2X the ALT level

25
GGT (?-glutamyl transpeptidase)

• Highest activity in bile ducts, kidney and
  pancreas
• Sensitive for occult alcoholism
• Not very specific for liver disease but very
  sensitive

26
Alkaline phosphatase

• Cholestasis
• Biliary obstruction- stones, cirrhosis, ca,
  Cholangitis
• In absence of Liver DZ.- Pagets disease- soft
  porous bone that can bend and shorten the limbs
  or parts of body affected

27
Amylase/Lipase

• Amylase
• Acute pancreatitis, mumps
• Lipase
• Acute pancreatitis

28
Creatine Phosphokinase

• Duchennes muscular dystrophy-absence of
  dystrophin protein that keeps muscular cells
  intact
• MI with CPK-MD

29
Lactate Dehydrogenase

• Tetrameric protein with M and H proteins based on
  the content of M/H
• Liver specific are LDH 4 and LDH 5
• Non-specific, located in many tissues
• MI if LDH-1gtLDH-2
• CHF
• Acute viral or drug induced hepatitis
• Cirrhosis
• Extra-hepatic obstruction

30
Immunohistochemical Stains

• Vimentin- Connective Tissue
• Desmin- Muscle
• Cytokeratin- epithelial cell
• Glial fibrillary acid proteins (GFAP) Neuroglia
• Neurofilaments- Neuron

31
Pharmacokinetics

• Volume of distribution (Vd)- relates the amount
  of drug in the body to the plasma concentration
• Vd amount of drug in the body
• plasma drug concentration

32
Clearance

• Relates the rate of elimination to the plasma
  concentration
• Rate of elimination
• plasma drug concentration
• CLVd x Kel

33
Half Life

• The amount of time required to change the amount
  of the drug in the body by ½
• Drug reaches the steady state between the 4th and
  5th half lives
• T ½ 0.7 x Vd
• CL

34
Dosage calcuations

• Loading dose target plasma concentration(Cp) x
  (Vd)/ bioavailability (F)
• In patients with renal or hepatic insufficiency
  the loading dose is the same and the maintenance
  dose is lowered

35
Order of elimination

• Zero-order elimination- rate of elimination is
  constant regardless of concentration meaning a
  constant AMOUNT will decrease from Cp linearly
  with time
• First Order- rate of elimination is proportional
  to the drug concentration meaning a constant
  FRACTION will decrease over time

36
Phase of elimination

• Phase I- oxidation, hydrolysis, reduction- P450
  mxns- ends with the addition of functional groups
  COOH, OH, NH2, SH
• Mostly inactivates, but can activate some, and
  have no effect on others
• Yields slightly polar, water-soluable metabolites

37
Phase II

• Synthetic Rxns- conjugations, acetylations,
  glucuronidations
• Almost all become biologically inactive
• Energy for Rxn, and conjugate must be supplied by
  the body
• Yields very polar, inactive metabolites, secreted
  renally

38
Drug Development

• Years 0-2 PRECLINICAL TESTING Chemical synthesis,
  biologic products, compound to be tested is
  developed
• Years 2-4 ANIMAL TESTING
• Pharmacokinetics, pharmacodynamics, toxicological
  safety, production and distrubition,

39
Drug Development

• Years 4-8- INVESTIGATIONAL NEW DRUG
• Must pass the three phases of testing to apply
  for new drug to be approved by FDA
• It is possible to shorten these phases with
  treatment of disease with high mortality

40
Phase I

• Tested in healthy normal subject
• Compares pharmacokinetics with the animal model
  in previous testing
• Evaluates safety, dosage range, and side effects

41
Phase II

• Double blind test conducted in those with the
  target disease
• Establish therapeutic effect vs. side effects

42
Phase III

• Very controlled setting on those with targer
  disease
• Larger number of individuals tested
• Establish the most relevant problem vs. clinical
  benefit

43
Drug development

• Years 8-9
• New Drug Application, if passed then the drug is
  continually monitored (postmarket surveillence)