More severe: Stevens-Johnson syndrome and Toxic epidermal necrolysis

More severe: Stevens-Johnson syndrome and Toxic epidermal necrolysis

acute, self-limited or recurrent / duration: 1-4 weeks from onset to healing / Symmetrically-distributed, fixed lesions lasting > 7 days / discrete, round, erythematous rings or blisters / concentric color changes / target or iris lesions (concentric circles, middle white, outer red) / mucous membrane involvement absent or limited to one surface, usually the mouth / hands [pic] / feet / arms [pic] / legs / back [pic] / palms (back) / soles (top) / extensor

abrupt onset, high fever, prostration followed by extensive lesion eruption, widespread bullae [pic] / involvement of two or more mucosal membranes (oral, lips [pic], ocular, nasal, genital, rectal) (severe oral involvement distinguishes from TSST)

> 25% of epidermis / 25-50% mortality / treat at burn center / daily opthalmological exams

purpura (90%), urticaria (10%) / infection, drugs, autoimmune, malignancy / includes Henoch-Schönlein Purpura (children) / complement attracts neutrophils (fibrinoid necrosis of vessels), increases permeability

dystrophic nail changes, sterile cellulitis, phlebitis, ulceration of pressure areas, urticaria, angioedema, exfoliative dermatitis, flagellate hyperpigmentation from bleomycin [pic]

Argyria from silver [pic]

Hyper-pigmentation from amiodarone [pic]
Specific Drug Reactions
Morbilliform [pic][pic][pic]

7-10 morbilliform drug reaction– skin/drug-morbilliform / skin biopsy differentiates from viral exanthem / eosinophils

symptoms that may indicate more serious drug reaction: duration, fever, itching, affected areas, sore throat (SJS), red eyes, painful skin

Drugs: gold, tetracyclines, bromides – work them up for HCV

Drugs: Dilantin, penicillin, tetracyclines, lithium, imipenem, antimalarials, norfloxacin

occurs within 3 wks / generalized eruptions, patient feels sick / missing epoxide hydrolase?

Dilantin hypersensitivity [pic] / more likely with high loading dose

Common: fever, periorbital facial edema, lymphadenopathy

Complications: hepatitis, nephritis, pneumonitis

Labs: elevated WBCs, LFTs

exfoliative dermatitis, eczema, photosensitivity or even a lupus like syndrome, even TEN

fever (100%), eosinophilia (20%), DIC (10%), LAD (12%), liver > renal > musculoskeletal

rash: exanthomatous (75%), more severe (20%), SJS (5%), TEN (10%) (higher risk with combined use of Lamictal and VPA)
Warfarin - coumadin necrosis

0.7% of coumadin users / women > men / 3-5 days onset / most frequently affects fatty

areas (single/multiple thighs, breasts, buttocks, shoulders) / localized pain then erythema,

bullae [pic], necrosis [pic] / happens in patients with protein C deficiency (< 50% normal

levels) as vitamin K block lowers PrC levels before other clotting factors / fibrin thrombi in

venules / can this mimic classic SC fat necrosis?

can cause the whole gambit / even TEN

not that common, but do happen / urticaria, morbilliform, photosensitivity, onycholysis,

fixed drug reaction, lichenoid / minocycline is an exception for causing skin pigmentation

changes (common) and serum sickness (~ day 16), hypersensitivity syndrome of hepatitis,

pneumonitis, cellulitis, folliculitis et al (~ day 24), drug-induced lupus (2 yrs)
Congenital Disorders (Skin Involvement)

• 
  Ehlers-Danlos syndrome / NF1 / Tuberous Sclerosis / Sturge-Weber / KTW
  

10 types of faulty collagen synthesis / stretchy skin with poor wound healing, hypermobile joints AD (type IV) - ecchymoses, arterial rupture (acute aortic insufficiency)

1 in 3000/4000 (NF 2 is 1 in 50,000), AD, 50% of cases are new mutations, variable expression, paternal age effect

Must meet 2 of diagnostic criteria: café au lait, Crowe’s sign, more…

Skin – hyperpigmentation or café au lait spots (97%) (more than 6 big ones, shape is variable), freckling (81%) (Crowe’s sign) in axillary areas?, which is pathognomonic [pic]

CNS – neurofibromas, plexiform neurofibromas (more aggressive invasion, rare), CNS tumors (5-10%), optic gliomas, astrocytomas, acoustic neuromas (classic NF-2 tumor), neurilemmomas, meningiomas, neurofibromas, intracranial tumors usually detected in first decade

Opthalmological – Lisch nodules (30%) (balls of tissue on iris that do not impair vision, get a consult)

Skeletal – pseudoarthroses (bones look bent, osteopenia on XR, common in tibia, use brace to give support), kyphoscoliosis, macrocephaly of post-natal onset (soft signs, absolute or relatively large, not correlated with other features of disease)

GI – constipation

Renal – hypertension (should have BP checks, usually occurs in adulthood)

Associated malignancies: neurofibromasarcomas, malignant peripheral nerve sheath tumors, schwannoma’s (more NF II), Wilm’s tumor, rhabdomyosarcoma, leukemia, pheochromocytoma

Genetics: defective chromosome 17, diagnostic testing usually not necessary
Tuberous Sclerosis Complex (see NF)

1:9000, autosomal dominant, high spontaneous mutation rate, variable expression

skin, brain, retina, heart, kidneys

Prognosis: only small percentage have premature death (often from CNS features, renal failure)

Diagnosis: major/minor criteria

Genetics: chromosome 16 (next to APK gene) / TSC1 on 9q34

Skin – facial angiofibromas (can look like acne), hypomelanotic macules, ungal fibromas, (can be removed, usually grow back), shagreen patch (peau d’orange, pig’s skin), fibrous plaques, dental pitting (5-10%)

CNS – seizures, retardation, brain tumors (astrocytoma et al)

Opthalmological – pigmentary changes, hamartomas (may be associated with peculiar SZ’s)

Renal – angiomyolipomas (renal failure, prognostic factors unknown), cysts similar to APK?

Cardiac – rhabdomyomas (regress with time – unique)

Pulmonary – lymphangiomyomatosis (seen almost exclusively in women)

Other – hamartomas
Sturge Weber syndrome [dermis]

Rare, sporadic, defect arising in limited part of cephalic neural crest

Rare, sporadic, can effect any part of body

Arterial insufficiency (see PVD) toes, heels, anterior shin and extended over malleoli

Venous insufficiency above lateral or medial malleoli

Lymphedema

Neuropathic ulcers under metatarsal head, over toe joints, under heel, on inner

side of first metatarsal head, over malleoli

Thromboangiitis obliterans

Cholesterol embolization

Antiphospholipid antibody syndrome

Vasculitis (cryoglobulinemia, Wegener’s, RA)

DIC

HIT

Osteomyelitis

Necrotizing fasciitis (Clostridium, Group A Strep, Vibrio)

Tb

Fungus (cryptococcus, coccidioides)

PRV

Hydroxyurea

Necrobiosis lipoidica diabeticorum pretibial area

Pyoderma gangrenosum

Sweet’s syndrome

Erythema nodosum

Weber-Christian disease

Cancer (squamous cell carcinoma)

Environmental Pathology / Toxicology

Chronic hemodialysis patients get too much / acute toxicity: obtundation, coma, seizures / Treatment: deferoxamine (carries risk of mucormycosis?)

binds to disulfide group of proteins

Exposure: ceramics, demolition, plumbing, soldering, exposure to leaded fuels

• 
  Acute intoxication: pallor, abdominal pain (lead colic), lethargy, convulsions, coma, renal failure, cerebral edema
  
• 
  Chronic intoxication (anemia, neuropathy, hypertension): CNS impairment (ataxia, memory loss), demyelination (foot and wrist drop), SZ, coma, pyuria, Fanconi’s syndrome, azotemia, chronic interstitial nephritis leading to uricemia, lead lines may be seen at gingiva-tooth border
  

Route of entry: inhalation, ingestion (PICA)

Sources: insecticides, herbicides, wood preserving, smelting, glass manufacturing, microelectronics, contamination of deep water wells, folk remedies)

• 
  acute ingestion: GI necrosis (hypovolemia), fatty change in liver, renal failure, burning, NVD, cyanosis, HT, DT, hemolysis, eosinophilia, ATN, garlic breath, cardiomyopathy (cardiac arrhythmias)
  

• 
  chronic ingestion: 2-8 wks, erythroderma [pic], hyperkeratosis, hyperpigmentation, exfoliative dermatitis, laryngitis/tracheitis/bronchitis, Aldrich-Mees lines (white transverse lines of fingernails) [pic], polyneuritis, predispose for SCC
  
• 
  arsine gas (fatal): hemolysis (binds Hb), abdominal pain, hematuria, jaundice, NVD, tachycardia, dyspnea, acute renal failure (from excessive hemolysis) / development
  

Cause methemoglobinemia / including nitroglycerin, amyl nitrate / can occur in well water / venous blood drawn will be brown and not turn bright red when shaken in air

elemental, salts (topicals, plastics, cathartics), organic (paints, fungicides, seeds, cosmetics)

vapor: interstitial pneumonitis / tremor, amnesia, insomnia, anorexia, weight-loss (hydrophobic: brain and placenta, but quickly oxidized and long-lived in these tissues)

• 
  mercury triad: excitability, tremors, gingivitis
  

inorganic chronic: nephrotic syndrome (readily absorbed by skin/GI and stored in most tissues)

organic: requires metabolism and mixed excretion (binds cysteine, mimics methionine, actively shuttled across BBB and placenta causing severe CNS toxicity)

Treatment: emesis/lavage, dimercaprol, D-penicillamine (oral, leukopenia causes stomatitis/gingivitis)

Note: organic Hg is NOT chelated (makes it worse), but you can use polythiol resin in GI / hemodialysis is not effective since most of Hg inside RBCs

mining, shellfish, cigarettes / absorbed by lungs (chemical pneumonitis), GI (nausea and vomiting), yellow teeth

cadmium-metalothionin complex gets concentrated in lungs (emphysema) and kidneys (renal tubules)

Treatment: ?EDTA (do NOT use dimercaprol)
Iron (see Iron Deficiency Anemia)

children overdosing on someone else’s Fe supplements / Fe disrupts mucosal cells, penetrates freely (not coupled to Tf)

Stage I: gastroenteritis (abdominal pain, vomiting, bloody diarrhea), CNS (coma, seizures)

Stage II: up to 48 hrs of quiescence

Stage III: shock, acidosis, coma, death (may have hepatic damage), leukocytosis common

Stage IV (late sequelae): pyloric and antral stenosis and hepatic cirrhosis, atrophy of tongue papilla (also occurs with vitamin B deficiency)

Treatment: lavage, carbonate salts (fecal excretion), phlebotomy / deferoxamine (Desferal) has high affinity for Fe (does not remove protein bound Fe, may cause local reaction at injection site, not for chronic use)

Fe ingestion over 25 mg/kg is toxic / 300-500 mg/dL – use chelating agent / > 500 – high risk of shock

prolongs falling phase, neuronal hypersensitivity / tremors, SZ, respiratory depression / increased p450, infertility / cholestyramine, BZs for SZ

irreversibly phosphorylates AChE / muscarinic, nicotinic, CNS

• 
  decontamination (remove clothes, etc.)
  
• 
  anticholinergics (atropine)
  
• 
  anticonvulsants (only benzodiazepines are effective; not other types of SZ meds; may have to give large doses, ~ 40mg)
  
• 
  2-pralidoxime (2-PAM) (effective early, does NOT cross BBB, not effective for carbamates determine dose by pseudocholinesterase activity) / TOCP causes MS-like demyelination
  

benzene linked to acute leukemia, CNS toxicity

hexane peripheral neuropathy
Alcohols
Ethanol (ETOH)

CNS depression, hypoglycemia, vasodilation (CNS depresses peripheral vasculature)

chronic: cirrhosis / FAS

• 
  intoxication or inebriation, 100-150 mg/dL
  
• 
  loss of muscle coordination, 150-200 mg/dL
  
• 
  decreased level of consciousness, 200-300 mg/dL
  
• 
  death, 300-500 mg/dL
  

worse than ethanol, not as bad as methanol / slower oxidation, longer CNS effects

CNS depression (EG), renal failure (oxalate stones), metabolic acidosis (oxalate/formate), hypocalcemia

induces p450 and others by signal transduction pathways / acute: N&V, HA, irritation, burns causes chloracne / chronic symptoms: elevated porphyrin excretion, hyperpigmentation, CNS, PNS, liver, teratogen/carcinogen?

can cause fatal arrhythmias when combined with catecholamines (such as with exercise after inhalant use)

acute radiation sickness

• 
  prodrome: hours to days / nausea, vomiting, diarrhea
  
• 
  latent phase: 2 to 6 wks with dose-dependent and variable effects / bone marrow suppression (at 2-3 weeks), GI (malabsorption), SZ, death
  

Later symptoms  nausea, vomiting, diarrhea, muscle fasciculations, central apnea, status epilepticus

Treatment: see organophosphates
Sarin (tabun, soman, cyclosarin)

organophosphates / onset within minutes to hours

more stable, can last in environment longer than others, symptoms can occur long after exposure

onset 2 hrs to 2 days / skin (erythema), eyes (conjunctivitis, blepharospasm, pain, corneal damage), airway obstruction / late bone marrow suppression (7-21 days) / no antidote / Treatment is supportive

colorless, smell of almonds / eye irritation, flushed skin, confusion, tachypnea, tachycardia, ARDS, hypoxemia, lactic acidosis / Treatment: sodium nitrate, sodium thiosulfate

lack of protein despite sufficient caloric intake / apathy, edema, subcutaneous fat, enlarged fatty liver, low serum albumin / sometimes pigment changes (flaky-paint sign) / anemia due to decreased iron, protein, transferrin

starvation (lack of caloric intake) / alert and hungry (unlike Kwashiorkor) / stunted growth, loss of subcutaneous fat, muscle atrophy / no edema or liver enlargement

1. 
   unintentional weight loss > 10% body weight in < 3 months
   
2. 
   body weight < 90% ideal for height (< 80% malnourished, < 70% severely malnourished, < 60% incompatible with life)
   
3. 
   BMI < 18.5
   

precursor of TPP, a cofactor of pyruvate dehydrogenase (alpha-ketoglutarate), transketolase (hexose and pentose phosphate shunt pathways)

Note: coffee/tea reduces levels (by destroying enzyme)

Dosing: can be given IM or IV / always give thiamine to alcoholic before sugar to prevent acute Wernicke’s (from carbohydrate load)
Dry Beri-beri (peripheral neuropathy, Wernicke-Korsakoff)
Wet Beri-beri (peripheral arteriolar dilatation, high output heart failure)

occurs ≥ 3 months of thiamine deficiency

malnutrition, alcoholism / FMN, FAD precursors / dermatitis, neuritis (carpal-tunnel, spinal cord pain, joint pain), mucous membrane

Dosing: oral replacement
biotin, pantothenic acid necessary

choline, carnitine undetermined

severe malnutrition, alcoholism / NAD, NADPH precursors

oral replacement / corn-based diets are low in niacin, tryptophan / high dose treats hyperlipidemias (see pharm) / Symptoms: pruritis, flushing, HA

defect in GI uptake of neutral amino acids, increased renal tubular loss / (tryptophan is a precursor which can be converted to niacin, corn is low in tryptophan) / causes attacks of cerebellar ataxia, which resolve spontaneously / Treatment: can be reversed by nicotinic acid

converted to cofactor in amino acid metabolism (including homocysteine to cysthionine) / increases peripheral DOPA decarboxylase (so contraindicated for Parkinson’s) / found in legumes, nuts, wheat bran, meat

Decreased by: malnutrition, INH, L-Dopa, penicillamine, ethanol

Deficiency: dermatitis, glossitis, stomatitis, cheilosis, neuritis, carpal tunnel, microcytic/hypochromic anemia

Excess: large amounts over time can cause neuropathy
Cyanocobalamin (B₁₂)

Physiology: acid pH in stomach cleaves B₁₂ from binding protein, intrinsic factor (IF) binds B₁₂ which is then absorbed by ileum and distributed to liver et al via transcobalamin / B12 necessary for conversion of methylmalonyl-CoA to succinyl-CoA

• 
  folate trapping  hyperhomocysteinemia
  
• 
  megaloblastic anemia (most commonly macrocytic anemia but can cause pancytopenia)
  
• 
  CNS myelin problems (malonyl CoA carboxylation)  progressive dementia
  
• 
  subacute combined degeneration  ataxia, spasticity, loss of proprioception
  
• 
  degeneration of the corticospinal tracts  (+) Babinski, weakness
  
• 
  degeneration of large sensory fibers  paresthesia, hyporeflexia, absent joint position, vibratory sensation, sensory ataxia
  
• 
  diarrhea
  

deficiency from enterohepatic recycling disease, duodenal/jejunal disease (sprue), surgery, 1st trimester syndrome

hydroxylation reactions (collagen crosslinking) / facilitates Fe absorption in GI tract / anti-oxidant immune function (wound healing, infection) / neurotransmitter synthesis / scurvy (skeletal changes, hemorrhages; perifollicular papules, capillary fragility)

stored in liver / retinol binding protein / eye: 11-cis-retinal plus opsin gives rhodopsin / tissue: retinoic acid (hormone-like action) induces cell growth and differentiation (morphogenesis, epithelial regeneration)

Used for treatment of psoriasis (topical, systemic), acne (topical RA and oral accutane), keratinization disorders, photoaging, acute promyelocytic leukemia, head and neck CA chemoprevention / B-carotene (anti-oxidant) may decrease risk of lung cancer

• 
  Acute: neurological (increased ICP, vertigo, diplopia, seizures), exfoliative dermatitis
  
• 
  Chronic (>15mg/d for months): lymphadenopathy, pseudotumor cerebri, hepatic fibrosis, hepatic fibrosis bone demineralization (hyperostosis, spurs, fusion)
  
• 
  Teratogenic (congenital malformations, spontaneous abortions)
  

anti-oxidant (A,C,E) / reduces cholesterol oxidation, decreases atherosclerosis / deficiency causes spinocerebellar degeneration, skeletal muscle changes, hemolytic anemia in infants

carboxylation of prothrombin (II)-complex proteins, VII, IX, X / made by GI flora Deficiency: malabsorption (including antibiotic-induced deficiency, biliary insufficiency), poor dietary intake, liver disease / transient deficiency of newborn (pre-colonization)