MD

 Abetalipoproteinemia: decrease ApoB-48, Apo B-100; pigmentary degeneration of retina, acanthocytes, steatorrhea, cerebellar ataxia.
   
 Acute Fatty Liver of Pregnancy: microvesicular steatosis in the liver, mitochondrial dysfunction in the oxidation of fatty acids leading to an accumulation in hepatocytes
   
  Alkaptonuria: homogentisate oxidase deficiency, increase homogenistic acid, ochronosis, dark blue urine.
   
  AcylCoA Dehydrogenase deficiency (MCAD): fasting hypoglycemia, no ketone bodies, dicarboxilic acidemia.
   
  Bernard Soulier Sd: gp1b deficiency, prolonged bleeding time
 
  Bloom Sd: chromosome 15, Ashkenazi Jews, BLM gene.
 
  Carpenter Sd: craniosynostosis, acrocephaly, craniofacial asymmetry, increased ICP, cutaneous syndactyly, polydactily, mild-profound MR.
 
  Chediak Higashi Sd: Lyst gene mutation, microtubule polymerization defect, no phagolysosome formation, albinism.
 
  Chondrodystrophy: normal-sized trunk and abnormally short limbs and extremities (dwarfism)
 
  Congenital Adrenal Hyperplasia: 17alpha or 21beta or 11 beta hydroxylase deficiency; enlargemente od adrenal glands due to increase ACTH
 
  Congenital Hepatic Fibrosis: hepatic (periporta) fibrosis, irregularly shaped proliferating bile duct, portal hypertension, renal cystic disease.
 
  Cystic Fibrosis: CFTR gene, Phe508, defective Chloride channel, chromosome 7.
 
  Dubin-Johnson Sd: direct hyperBbnemia, cMOAT deficiency, black liver
 
  Endocardial Fibroelastosis: restrictive/infiltrative cardiomyopathy, thick fibroelastic tissue in endocardium of young children, <2yo
 
Familial Mediterranean Fever: chromosome 16, recurrent autoinflammatory disease, characterized by F°, PMN disfx, sudden attacks pain/inflammation (7 types of attacks (abdominal, joints, chest, scrotal, myalgias, erysipeloid, fever). Complication: AA-amyloidosis
 
  Fanconi Anemia: genetic loss of DNA crosslink repair, often progresses to AML, short stature, ↑incidence of tumors/leukemia, aplastic anemia
 
  Friedreich’s Ataxia: GAA triplet repeat, chromosome 9, neuronal degeneration, progressive gait & limb ataxia, arreflexia, hypertrophic cardiomyopathy, axonal sensory neuropathy, kyphoscoliosis, dysarthria, hand clumsiness, loss of sense of position, impaired vibratory sensation.
   
 Gaucher’s disease: glucocerebrosidase deficiency, glucocerebroside accumulation, femur necrosis, crumpled paper inclusions in macrophages.
   
Ganzman’s thromboasthenia: gpIIbIIIa deficiency, deficient platelet aggregation.
   
Hartnup Disease: tryptophan deficiency, leads to niacin deficiency, pellagra-like dermatosis
   
Hemochromatosis: HFE gene, C282Y MC mutation, chromosome 6, unrestricted reabsorption of Fe+ in SI, iron deposits in organs, bronze diabetes, DM1, malabsorption, cardiomyopathy, joint degeneration, increased iron, ferritin, TIBC. Complications: liver cirrhosis, hepatocelullar carcinoma
 
Homocystinuria: due to B6 deficiency (defective Cystathionine synthase) or due to B9,B12 deficiency (defective Homocysteine Methyltrasnferase), dislocated lenses (in & down), DVT, stroke, atherosclerosis, MR.
 
Krabbe's Disease: Galactocerebrosidase deficiency, galactocerebroside accumulation, gobloid cells, optic atrophy, peripheral neuropathy.
 
Leukocyte Adhesion Defect (LAD): CD-18+ deficiency, omphalitis in newborns, chronic recurrent bacterial infxs, increase WBC count, no abscess or pus formation.
 
  Metachromic Leukodystrophy: Aryl-sulfatase A deficiency, sulfatides accumulation, Demyelination (central & peripheral), Ataxia, Demantia (DAD)
 
  Niemann-Pick Disease: sphingomyelinase deficiency, sphingomyelin accumulation, HSM, cherry-red macula, foam cells.
   
Phenylketonuria (PKU): phenylalanine hydroxylase deficiency, Phe accumulation, MR, microcephaly, diet low in Phe!!! also in pregnancy, avoid aspartame, musty odor.
 
Polycystic Kidney Disease (children): ARPKD, rogressive & fatal renal failure, multiple enlarged cysts perpendicualr to renal capsule, association with liver cysts. Bilateral palpable mass.
 
  Rotor Sd: direct hyperBbnemia, cMOAT deficiency, no black liver
 
Shwaman Diamond Sd: exocrine pancreatic insufficiency (2°MCC in children after CF), bone marrow dysfunction, skeletal abnormalities, short stature.
 
Situs inversus: assoc w/ Kartagener sd
 
Sicke Cell Disease and Trait: Hb S, beta globin chain, chromosome 11, position 6, nucleotide codon change (glutamic acid --> valine), vaso-occlusive crisis (pain), autosplenectomy, acute chest pain sd, priapism, hand-foot sd, leg ulcers, aplastic crisis, drepanocytes & Howell-Jolly bodies, hemolytic anemia, jaundice, bone marrow hyperplasia
 
 Tay-Sachs Disease: Hexoaminidase A deficiency, GM2 accumulation, cherry-red macula, onion skin lysosomes.
 
Thalasemia: alpha (chromosome 16, gene deletion), beta (chromosome 11, point mutation)
 
Werner Disease: adult progeria
 
  Wilson’s Disease: Chromosome 13, WD gene, ATP7B gene (encondes for Copper transporting ATPase), copper accumulation in liver, brain (putamen), eyes (Descemet membrane - Kayser-Fleischer ring), decreased ceruloplasmin.
 
  Xeroderma Pigmentosa: defective excision endonuclease, no repair of thymine dymers caused by UV radiation, excessive freckling, multiple skin cancers.

Thalassemia

Thalassemias are a heterogeneous group of hereditary blood disorders characterized by faulty globin chain synthesis resulting in defective hemoglobin, which can lead to anemia

Thalassemia provides partial resistance against malaria.

Beta thalassemia

Clinical features

Minor variant (heterozygous): unremarkable symptoms (low risk of hemolysis, rarely splenomegaly)

Major variant (homozygous) Severe hemolytic anemia, Hepatosplenomegaly ,Growth retardation ,Skeletal deformities (high forehead, prominent zygomatic bones, and maxilla)

Alpha thalassemia

most commonly seen in people of Asian and African descent

Clinical features

Silent carrier: asymptomatic

Alpha thalassemia trait: mild hemolytic anemia with normal RBC and RDW

Hemoglobin H disease

Jaundice and anemia at birth

Chronic hemolytic anemia which may require transfusions

Hb-Bart's hydrops fetalis syndrome (most severe variant of alpha thalassemia)

Intrauterine ascites and hydrops fetalis, severe hepatosplenomegaly, and often cardiac and skeletal anomalies

Incompatible with life (death in utero or shortly after birth)

Diagnostics

Microcytic hypochromic anemia

Blood smear: target cells , teardrop cells

Bone marrow biopsy: reactive hyperplasia

Confirmatory tests

Hb-electrophoresis Alpha thalassemia can usually only be detected if ≥ 3 alleles are defective.

DNA analysis: to test for alpha thalassemia minor and minima (< 3 alleles defective)

Skeletal deformities -high forehead, prominent zygomatic bones and maxilla can be seen on all imaging modalities.

X-ray: hair-on-end (“crew cut”) sign

ENDOMETRIOSIS

The proliferation and functioning of endometrial tissue outside of the uterine cavity

Incidence: - 15-30% of all premenopausal women, -mean age at presentation: 25-30 years
 
Etiology - unknown

theories

- retrograde menstruation theory of Sampson
- Mullerian metaplasia theory of Meyer
- endometriosis results from the metaplastic transformation of peritoneal mesothelium under the influence of certain unidentified stimuli
- lymphatic spread theory of Halban
- surgical transplantation
- deficiency of immune surveillance


Predisposing Factors

- nulliparity
- age > 25 years
- family history
- obstructive anomalies of genital tract

Sites of Occurrence

ovaries  most common location, 60% of patients have ovarian involvement
broad ligament
peritoneal surface of the cul-de-sac (uterosacral ligaments)
rectosigmoid colon
appendix


Symptoms

there may be little correlation between the extent of disease and symptomatology

pelvic pain - due to swelling and bleeding of ectopic endometrium, unilateral if due to endometrioma

dysmenorrhea (secondary) - worsens with age, suprapubic and back pain often precede menstrual flow (24-48 hours) and continue throughout and after flow

infertility - 30-40% of patients with endometriosis will be infertile, 15-30% of those who are infertile will have endometriosis

dyspareunia  on deep penetration

premenstrual and postmenstrual spotting
bladder symptoms - frequency, dysuria, hematuria

bowel symptoms - direct and indirect involvement diarrhea, constipation, pain and hematochezia

Diagnosis

truly a surgical diagnosis

history - cyclic symptoms - pelvic pain, dysmenorrhea, dyschezia

physical examination

- tender nodularity of uterine ligaments and cul-de-sac
- fixed retroversion of uterus
- firm, fixed adnexal mass (endometrioma)

laparoscopy

- dark blue or brownish-black implants (mulberry spots) on the uterosacral ligaments, cul-de-sac, or anywhere in the pelvis
- chocolate cysts in the ovaries (endometrioma)
- powder-burn lesions
- early white lesions and blebs


Treatment

pseudopregnancy - cyclic estrogen-progesterone (OCP) or medroxyprogesterone (Provera)

pseudomenopause - danazol (Danocrine) = weak androgen, s/e:  weight gain, fluid retention, acne, or hirsutism, leuprolide (Lupron) = GnRH agonist (suppresses pituitary GnRH)

s/e: hot flashes, vaginal dryness, reduced libido, and osteoporosis with prolonged use .these can only be used short term because of osteoporotic potential

surgical

- laparoscopic resection and lasering of implants
- lysis of adhesions
- use of electrocautery
- unilateral salpingo-oophorectomy
- uterine suspension
- rarely total pelvic clean-out
- follow-up with 3 months of medical treatment

Cavernous Sinus

Each cavernous sinus is a large venous space situated in the middle cranial fossa on either side of the body of the sphenoid bone. Its interior is divided into a number of trabeculae or caverns. The floor of the sinus is formed by the endosteal dura mater. The lateral wall, roof and medial wall are formed by the meningeal dura mater.

Structures in the lateral wall of the sinus from above downwards:

  1. Oculomotor nerve
  2. Trochlear nerve
  3. Ophthalmic nerve - in the anterior part of the sinus, it divides into the lacrimal, frontal and nasociliary nerves.
  4. Maxillary nerve - it leaves the sinus by passing through the foramen rotundum on its way to the pterygopalatine fossa.
  5. Trigeminal ganglion - the ganglion and its dural cave project into the posterior part of the lateral wall of the sinus.

Structures passing through the centre of the sinus:

  1. Internal carotid artery with the venous and sympathetic plexus around it.
  2. Abducent nerve, inferolateral to the internal carotid artery.

Tributaries (incoming channels) of cavernous sinus

  1. Superior ophthalmic vein.
  2. A branch of inferior ophthalmic vein or sometimes vein itself.
  3. Central vein of retina (it may also drain into superior ophthalmic vein).
  4. Superficial middle cerebral vein.
  5. Inferior cerebral vein.
  6. Sphenoparietal sinus.
  7. Frontal trunk of middle meningeal vein (it may also drain into pterygoid plexus or into sphenoparietal sinus).

Draining channels (communications) of cavernous sinus

  1. Into transverse sinus through superior petrosal sinus.
  2. Into internal jugular vein through inferior petrosal sinusand through a plexus around the ICA
  3. Into pterygoid plexus of veinsthrough emissary veins.
  4. Into facial vein through superior ophthalmic vein.
  5. Right and left cavernous sinus communicates with each other by anterior and posterior intercavernous sinuses and through basilar plexus of veins.

 

Antiplatelet Drugs

Aspirin/ASA

- Works on Cyclo-oxygenase (AA -> thromboxane)

- Low dose (80-160 mg/day) irreversibly inhibits plt COX, and they can’t make new COX b/c they have no nucleus

- Some inhibition of endothelial COX but not much, therefore prostacyclin (anti-coag) synthesis isn’t  affected much
- Benefit is greater after thrombolysis

- SE is bleeding

- Prophylaxis for MI or TIA (80mg/day), higher doses for post-MI/TIA (160-325mg/day)

- Contraindications (bleeding risk):  Vit. K def., Hemophilia, Hypoprothombinemia, pregnancy & childbirth

Clopidogrel/Plavix

- ADP antagonist

- Competes with ADP for P2Y receptor (prevents lowering of cAMP)

- Less incidence of neutropenia/thrombocytopenia

- Used in combo with ASA

 Ticlopidine

- ADP antagonist, prodrug

- Often used in combo with ASA (synergistic)

- May cause severe neutropenia (1%)

 

Dipyridamole

- phosphodiesterase inhibitor (prevents cAMP breakdown)

 

GpIIb-IIIa inhibitors

-  Eptifibatide, Abciximab, Tirofiban

-  Block the receptor for fibrinogen blocking plt Aggregation

 

Heparin (& derivatives)

- Stimulates natural anticoags (antithrombin)

Heparin

- Monitor using aPTT (add negative charges)

- Negatively charged, therefore cannot cross membranes (given IM, IV, parentally)

- Good for pregnancy

- Eliminated by RES & macrophages

- Potentiates AT III (in the plasma) – inhibits IIa, Xa, IXa and VIIa

- Toxicity – hemorrhage

- Antidote – protamine sulfate (1mg for every 100 units of heparin)

Heparin-Induced Thrombocytopenia (HIT) – occurs 5-10 days after, stop heparin immediately;  use alternatives lepirudin/danaparoid

- Good for PE and DVT and during pregnancy

 

LMWH – better bioavailability, can be given subcut. w/o lab monitoring as outpatient, less risk of bleeding

- More expensive, not good in renal failure, not for pregnancy

- DOES NOT inhibit IIa (but inhibit Xa)

- Good for DVT, PE and UA

Danaparoid – promotes inhibition of Xa by AT (for HIT)

Lepirudin – direct thrombin inhibitor (for HIT)

 

Coumarin (Oral) anticoags

Warfarin

- Monitored using PT (add tissue factor)

- Inhibit Vit. K Epoxide reductase in liver

-Prevents carboxylation of Vit.K dependent factors

-Takes 4-5 days to get effective (carboxylated fx’s in plasma need to be cleared before inactive ones take over)

-Small volume of distribution, steep dose-response curve (small therapeutic window)

-Teratogenic

- For DVT and PE, prosthetic heart valves or Afib, MI

-Metabolized by CYP1A and CYP2C9

-Efficacy measured by INR, pt’s PT time divided by PT time in pooled plasma

- INR = (PTpt/PTref)^ISI (target is 2.0 – 3.0)

- Warfarin overdose

- Give Excess Vit.K, goes through a diff  enzyme that isn’t inhibited by warfarin  (Diaphorase)

Fibrinolytics (lyse formed thrombi)

Streptokinase – turns plasminogen -> plasmin

-Plasmin breaks down fibrin (lysis of formed clot) Dissolves clots post-MI/DVT/PE

- SE – bleeding (systemic plasminogen activation), allergy, hTN, fever

- Streptokinase has an additive effect with ASA

Tissue plasminogen activator (tPA) – acts on fibrin and circulating plasminogen -> plasmin

- Less systemic plasmin

- Same indications as streptokinase

- More expensive