set 5(Nasi)

[cyrus1345]

Tuberculosis pearls
Tuberculosis

TB treatment:
- HIV negative: ERHZ or SRHZ for 2 months then RH for 4 months
- Pregnant and lactating woman: PZA and Streptmycin CI. ERH (increased doses) for 4-8weeks, then RH twice Qweek x 7months. If resistance is a concern: ERH x 9months. Add Vit B6 with INH use. Breatfeding is not contraindicated despite presence of small amounts of meds in milk.
- HIV Positive: Same treatment with additional considerations: longer duration, Rifampin interaction with anti-HIV meds, directly-observed TB therapy should be used for all HIV pts, VitB6 mandatory with INH to reduce side effects.
- Drug-resistant patient: Resistance only to INH = RZ with E or S x 6months or ER x 12 months. Others require expert intervention.
- Extrapulmonary TB: 9months with same drugs if miliary, bone, meningeal, or joint TB. If bone: early surgical drainage and debridement of necrotic bone. Steriod therapy prevents cardiac constriction and neurologic complications from meningitis.
- Latent TB: targeted testing to identify candidates, test for HIV, screen for prior TB Rx and current contraindications. Three regimens are considered: 1) Ideally: INH for 9months. Give Vit B6 if at risk to develop neuropathy (Pregnant, DM, HIV, alcoholic, uremia, Seizure disorder). 2) RZ x 2 months. 3) Rifampin x 4 months. Care must be taken if HIV patients on Nonnucleoside RT Inhibitors or Protease inhibitors. If Pregnant or lactating: INH QD or BID + Vit B6.
- BCG Vaccine: recommended only on individual basis: e.g.: Healthcare worker with high % of multiresistant TB patients. CI if immune deficiency/impairement.
- Steriod use in TB Rx: only in TB meningitis and TB pericarditis.

PPD + is when:
- >5mm: HIV+, Recent TB patient contact, CXR TB-like changes, Organ Transplant patients.
- >10mm: Recent immigrant, IV drug user HIV-, TB lab personel, High risk medical personel, High risk medical conditions (Gastrectomy, GI bypass, DM, Silicosis, CRF, Leukemia, lymphoma, CA of HEENT or lung), kids<4yo or teens and adults exposed to TB patients.
- >15mm: if no risk factors to TB.
If PPD – then converts to <10mm => Repeat in 2 weeks (you cannot make a PPD- person become positive by repeated testing).
If PPD is + => CXR: if abnormal => 3 AFB.


TB prophylaxis now called latent TB: PPD + indicates 10% lifetime risk for active TB.
- Exposed adult with PPD - => None
- Exposed child<5yo with PPD - => INH x3months
- PPD conversion but CXR - =>INH x6-12months
- Pregnant woman + HIV+ with PPD+/Conversion/Exposure to TB but no active disease: INHx 6-12months + Vit B6

Side Effects of TB drugs: All are hepatotoxic except Streptomycin.
- INH: Hepatitis – Peripheral neuropathy
- Rifampin: colors body secretions, contact lenses. Hepatitis, Renal Failure – drug interaction with OCP/Coumadin/Digoxin/Oral hypoglycemics/HIV meds
- PZA: hyperuricemia, hepatotoxic,
- ETB: Optic neuritis (reversible)
- Streptomycin: VIII damage, nephrotoxic.


A 69-year-old patient is admitted to the neurology service following a stroke. During the next few days, the staff observes that the patient has developed the clinical picture of mania. Which area of the brain has most likely been affected by the stroke?
A. Left hemispheric lesions including Broca's area
B. Left prefrontal cortex
C. Midbrain lesion
D. Right frontal lobe
E. Thalamus
Answer D.
Is there any correlation between lesion location and the develoment of post-stroke neuropsychiatric sequelae? Possibly. In the case of post-stroke mania, it appears to occur most often with right hemispheric lesions especially when they occur in the right orbito-frontal region or the right thalamus.
Treatment of post-stroke mania: controlled studies have not yet been completed, although case studies have suggested that Lithium, Depakote and Carbamazepine, Clonidine, and neuroleptics, may each be effective in such an entity. Given that anticonvulsant mood stabilizers have shown to be more effective in secondary mania, and given the propensity of convulsions in post-stroke patients, mood stabilizing anticonvulsants may be the agents of choice in post-stroke mania.
Notes:
Controvesy exists in correlating locations with post-stroke depression. It is suggested that it may be related to left frontal cortex, and left frontal basal ganglia. Treatment involves SSRI's (first line), TCA's (risk of ortho hypotension, and cardiac conduction abnormalities), Stimulants (May stimulate during post stroke rehab and stroke is NOT a contraindication) and ECT.
Reference:
Primary Care Companion J Clin Psych.2003;5(2)
http://www.psychiatrist.com/pcc/pccp...2/v05n0205.pdf
Fragile X Syndrome

A- Background:
Fragile X syndrome, also termed Martin-Bell syndrome or marker X syndrome, is the most common cause of inherited mental retardation and, after trisomy 21, is the second most common cause of genetically associated mental deficiencies.
Two to four times as many females carry the gene abnormality as males, but only about one third of females carrying the abnormal gene show decreased intelligence. Males with the disorder are more likely to be sensitive to environmental factors.
The pattern of inheritance most closely resembles X-linked dominant with variable penetrance. Occasionally, because the complex genetics of the disorder, a female will be affected severely.

B- Pathophysiology:
The genetic defect is dynamic and lies at the distal end of the long arm of the X chromosome. Careful examination of the karyotype of affected individuals' lymphocytes, reveals a constriction followed by a thin strand of genetic material extending beyond the long arm of chromosome X. This constriction and thin strand produces the appearance of a fragile portion of the X chromosome, leading to the term fragile X.
The underlying pathology is an unusual high number of repeats of triplets CGG. Unaffected individuals have 5 to 55 CGG repeats. A span of 65 to 230 repeats is known as a premutation, whereas more than 230 repeats is a full mutation. The number of repeats is unstable from generation to generation, making the pattern of inheritance difficult to predict.

• Males with a full mutation have fragile X syndrome.
• Mothers of all males with fragile X syndrome have the premutation or fragile X syndrome themselves.
• Males with fragile X syndrome pass a premutation to their daughters because sperm cells are mosaics.
• Sons are unaffected because they receive the Y chromosome from their fathers.
• Half of females with the full mutation on a single X chromosome are unaffected because of inactivation of the other X chromosome. The other half of females have fragile X syndrome, although with less severe mental retardation than males with the disorder.
• Males with a premutation usually are unaffected to mildly affected and transmit the premutation to their daughters. The mutation is stable; thus, no increase in the CGG triplets exists, when it’s a male transmitting it.
• Females with a premutation usually are unaffected to mildly affected. Unlike their male counterparts, the CGG triplets are unstable and increase in size during oogenesis. If the number of repeats exceeds 230 and the oocyte is fertilized, a male child will have fragile X syndrome, and a female child will have a 50% chance of having fragile X syndrome. The number of repeats is directly proportional to the risk of the disorder in an offspring.
C- Clinically:
Cognitive, behavioral, and neuropsychological difficulties predominate the clinical picture. These signs are especially important in alerting physicians, parents, and teachers to deficits exhibited by preschool and elementary school children—a time when the diagnosis of fragile X syndrome often is made or considered.
Problems include: mild-to-moderate autisticlike behavior (most notably, hand flapping and avoidance of eye contact), attention deficits, depressed affect, mental retardation with IQ typically 35-70, aggressive tendencies, deficiency in abstract thinking, developmental delays after reaching early milestones (especially speech and language delays), and decreasing IQ with increasing age.
In addition, there are physical signs associated with fragile X syndrome; however, these signs are more obvious during adolescence or after puberty and rarely result in disabilities. In addition to the cognitive, behavioral, and neuropsychological findings, the organ systems most frequently involved are craniofacial, genital, and musculoskeletal. They manifest in adolescence as a long thin face with prominent ears, facial asymmetry, a head circumference higher than the 50th percentile, and a prominent forehead and jaw. In addition, the mouth has overcrowding and a high-arched palate. Macroorchidism is universal in adult males. Sometimes, scoliosis may be noted.
D- Work-up
- Cytogenetics (Karyotype) is not as sensitive as molecular testing (Southern Blot and PCR).
- A comprehensive developmental evaluation by a speech/language therapist, physical therapist, and occupational therapist is recommended to assess weaknesses and to identify areas where improvement is needed most. As the patient matures, repeat evaluation may be necessary.
E- Medical Care:
o Workup and diagnosis can be done on an outpatient basis.
o Routine care involves treating the medical problems that these patients experience commonly, including gastroesophageal reflux, sinusitis, and otitis media.
o During infant and early childhood health care maintenance visits, focus examination on possible hip dislocations, hernias, and hypotonia.
o Stimulants (eg, methylphenidate, dextroamphetamine, pemoline) have been used for attention deficits in the doses prescribed for patients with ADHD. Responses are variable.
o Antiseizure and antireflux medications are useful for patients with these symptoms.

F- Complications:
o Scoliosis
o Mitral valve prolapse (most frequently encountered cardiac defect)

G- Special Concerns:
• Prenatal screening: Because fragile X syndrome is underdiagnosed, has a high prevalence, and is inheritable, preconceptual and antenatal molecular genetic screening is encouraged for women as outlined below.
References:
- Emedicine: http://www.emedicine.com/ped/topic800.htm Updated March 2003
ERCP or HIDA Scan
HIDA scans have sensitivity (94%) and specificity (65-85%) for acute cholecystitis. They are sensitive (65%) and specific (6%) for chronic cholecystitis.
On the other hand, ERCP provides both endoscopic and radiographic visualization of the biliary tract. It can be diagnostic and therapeutic by direct removal of common bile duct stones.
Ultrasound is 50-75% sensitive for choledocholithiasis. CT and HIDA scans are not better. Therefore, when a dilated common bile duct is found or elevated LFTs are present, suspicion should remain high for common bile duct stones, and an ERCP should be considered.
Debate exists as to when an ERCP should be performed. In general, since cholecystitis is caused by obstruction of the ducts, the risk of common bile duct stones is approximately 10%.
Some studies have classified people as low risk for common bile duct stones based on (1) lack of jaundice, (2) elevated transaminases, and (3) a common bile duct diameter of less than 8 mm. In this population, the risk of common bile duct stones may be as low as 1%. In patients with any of the risk factors, the rate of stones was 39%. Therefore, in general, people with any of the risk factors for common bile duct stones should undergo operative or ERCP evaluation of the common bile duct.
Major complications of ERCP include pancreatitis and cholangitis.
Reference:
http://www.emedicine.com/emerg/topic98.htm
Is a dog/cat's mouth cleaner than a human mouth?
Animal and human bites carry a high risk of infectious complications. Human bites and in particular clenched-fist injuries as well as cat bites are highly prone to infection as are wounds that involve the hand or deep structures including joints, bones and tendons. The management of bite wounds consists of intensive irrigation with large volumes of normal saline and a cautions debridement of devitalized tissues. Generally, it appears prudent to leave the wounds open, however, in cases carrying a low risk of infection, a primary surgical closure might be appropriate. If a bite wound is infected, an antibiotic course with amoxycillin/clavulanic acid (first choice) or tetracyclines (second choice) for 10-14 days is recommended. In patients who present early after the injury, an antibiotic prophylaxis for 3-5 days is appropriate, particularly when the risk for the development of infection is high. Furthermore, a tetanus booster and in case of possible transfer of rabies, a rabies vaccination with immunoglobulins and inactivated virus preparation is recommended.
Human bite wounds have long had a bad reputation for severe infection and frequent complication. However, recent data demonstrate that human bites occurring anywhere other than the hand present no more of a risk for infection than any other type of mammalian bite. The increased incidence of serious infections and complications associated with human bites to the hand warrants their consideration and management in three different categories: occlusional/simple, clenched fist injuries, and occlusional bites to the hand.

References:
1)Dog, cat, and human bites
Schweiz Rundsch Med Prax. 1998 May 20;87(21):716-8.
2)Dog, cat, and human bites: a review.
J Am Acad Dermatol. 1995 Dec;33(6):1019-29.
3)Diagnosis and treatment of bites by cats, dogs and humans
Dtsch Med Wochenschr. 2003 May 9;128(19):1059-63.
Q that remained unanswered about antiarrhythmics.
Here is my input.
They are classifed into:
Class I: Blocks Na Channels
Class II: are the beta-blockers
Class III: Block K channels
Class VI: Calcium channel blockers.
Class V: Cardiac Glycosides.
ClassI:
* Ia = Phase 0 = Slow rhe rise of action potential = Make it longer thus more refractory. These agents are used only for chemical conversion. They alter the electrophysiologic mechanisms responsible for arrhythmia.
Examples: Quinidine, Procainamide (Lupus, Fatal blood dyscrasias first 3 months!!), Disopyramide (Urinary retention!!), Moricizine
Note: Can expect increased levels of procainamide metabolite NAPA in patients taking CIMETIDINE, RANIDITINE, beta-blockers, amiodarone, trimethoprim, and quinidine;
Indications: SVT, VTach, Prevention of VFib, Symptomatic PVC
Ib = shorten action potential
Examples: Lidocaine, Mexiletine(Leukopenia!!), Phenytoin
Indications: VTach, Prevention of VFib, Symptomatic PVC's.
Ic = Phase 0 = slow the rise of action potential/refractoriness but more than Ia. These agents are used only in patients with structurally normal hearts (ie, absence of coronary artery disease or cardiomyopathy).
Examples: Flecainide, Propafenone (Weak CaBlock+BetaBlock)
Indications: Life threatening VTach/VFib, Refractory SVT.
Class II:
Beta Blockers: These agents slow the sinus rate in addition to decreasing AV nodal conduction.
Side effects: bronchospasm.
Note: Esmolol (Brevibloc) -- Ideal for use in patients at risk of complications from beta-blockade. short half-life of 8 min
Note: First line of treatment in Asthma secondary to beta blockers: ANTICHOLINERGICS/IPRATROPIUM (NOT BETA2 AGONISTS AS IN REGULAR ASTHMA).
Class III:
Blocking K channels results in widened QRS and longer QT interval. They pronlong action potential.
Examples: Amiodarone (Pulm Fibrosis, Hyper/Hypothyroidism, Corneal and skin depostis, Neurotox!!!!!), Sotalol (noncardiac selective beta blocker), Dofetilide, Ibutilide, Bretylium.
Class IV:
Block Calicum from entering slow channels or voltage-sensitive areas of vascular smooth muscle and myocardium. They reduce rate of AV nodal conduction and control ventricular response in A Fib.
Examples: Verapamil, Diltiazem, Nifedipine.
Relevant Indication: DOC for longterm control of A Fib (better than Dig if long term)
Class V:
Cardiac glycosides -- These drugs slow AV nodal conduction primarily by increasing vagal tone. They are used primarily in the setting of AF with CHF.
Examples: Adenosine (Flushing, AV Block, S brady!!!), Digoxin (CI in idiopathic hypertrophic subaortic stenosis, constrictive pericarditis, Watch out for AV Block, GI problems, Visual changes, PAT with a 2:1 block!!!!)hypercalcemia and hypercalcemia predisposes patient to digitalis toxicity predispose patient to digitalis toxicity.

References:
- CMDT p363
- emedicine
most common brain t/m in children
To let you know why it gets confusing, this question has to be classified by the location of the tumor:
1- Supratentorial (40%)
- Astrocytoma (8-12%)
- Glioblastoma (<5%)
- Craniopharyngioma (5-8%)
- Ependymoma (3-5%)
- Choroid Plexus papilloma (2-3%)
- Pituitary tumor (<1%)
- Pineal tumor (2%)
- Meningioma (<1%)
2- Infratentorial (60%)
- Medulloblastoma (18-25%)
- Cerebellar Astrocytoma (15-20%)
- Brain stem glioma (8-10%)
- Ependymoma (4-6%)
- Schwannoma (<1%)
- Meningioma (<1%)

Overall, in peds, the most common brain tumors are:
- #1: Medulloblastoma
- #2: Astrocytoma
- #3: Ependymoma
Reference:
- Familypracticenotebook.com
http://www.fpnotebook.com/HEM147.htm
Old Question on Neuroblastoma Vs Wilms: CT or IVP?
Facts:
- Solid masses are ominous in a child as opposed to cystic ones, and may represent Wilms tumor, neuroblastoma, congenital mesoblastic nephroma, or other less common tumors, such as malignant rhabdoid tumors.
- Wilms tumor arises from the kidney and most often is detected as a large asymptomatic abdominal mass. Neuroblastoma, which commonly arises from the adrenal gland, often presents with a mass and constitutional symptoms (eg, fever, weight loss).
- Wilms tumor commonly displaces and compresses vessels. Neuroblastoma also displaces and compresses vessels but more often is infiltrative.
- Ultrasound with Doppler can reveal inferior vena cava (IVC) invasion. CT scan plays an important role in the management of Wilms tumor and neuroblastoma for staging (3).
Neuroblastoma Fact: At initial presentation, ultrasound is useful for diagnosing intra-abdominal tumors and can display calcifications, but ultrasound interpretation requires skilled expertise. Falsely negative studies are misleading for the clinician unless an alternate imaging study such as a CT scan is done to make the diagnosis (1).
Wilms Tumor Fact: Ultrasound or CT helps localize the mass, identifies associated genitourinary abnormalities, confirms function of the contralateral kidney, and indicates if there is extension to the inferior vena cava. CT scan is better at detecting subtle intra-abdominal abnormalities such as tumor spread, lymph node enlargement, vascularity (1).
Additional Fact: In a recent study, radiologists were accurate at diagnosing Wilms' tumors using modern imaging methods (IVP was not included in it, nor in any theoretical review I found), however, care should be taken in children who are less than 1 year of age as a mesoblastic nephroma may have identical imaging characteristics (2).
References:
1- Case Based Pediatrics For Medical Students and Residents
http://www.hawaii.edu/medicine/pedia...xt/s12c03.html
2- With advances in medical imaging can the radiologist reliably diagnose Wilms' tumours?
Clin Radiol. 1999 May;54(5):321-7.
3- Radiographic Evaluation of the Pediatric Urinary Tract
http://www.emedicine.com/ped/topic2751.htm
the next step in mgt in the below q....
1.40 yr M , come with pain from 1 hr, severe, constant.
he lies motionless, is diaphoretic, rapid shallow breathing. p/e- rigid abd, tenderness to palpaion, guar
ding+, rebound tenderness+
a. plain x-ray
b. emergency laparotomy
c. r/o other causes of acute abd- amylase, c-xray, ecg
2.in the 2 week of post-op for multiple gunshot wounds to the abdomen, patient becomes unresponsive and progressively disoriented. po2-65 on 40% o2.
a. ABG
b. c-xray
3.50 yr M, h/o smoking+, drinking+, progressive machanical dysphagia, wt loss+
a. barium swallow
b. endoscopy and biopsy
Answers:
1.emergency laparotomy - pt. presents with peritonitis, needs acute Mx,
2.CXR, pt. most likely has ARDS -- occurs in pts after trauma, infections, massive transfusions, onset is acute several hrs. to several days post injury but could be variable, the most typical is several hrs. to several days after event, pt.has hypoxemia refcractory to oxygen, the PaO2/FiO2 ratio < 200 mmHg,
65/0.4= 162.5 - characteristic for ARDS, pt. can have lethargy followed by obtundation, other symptoms are not noted here due to the altered mentation, like tachypnea, etc. - CXR will show bilateral pulm. infiltrates and/or consolidation, CXR is fast to get...
if CXR is -ve , or normal then it could be PE, so then get ABG. get ABG in either case after the CXR, see the A-a gradient , etc...correct me on this one if i am wrong
3.barrium swallow - usually the first Dx test in Pt w/ suspected esoph.CA especially if they have symptoms of dysphagia, can also Dx one of the most serious compl. - TE fitule,...then do EGD , then CT scan to do staging ,look for Mets
Old Request about summary of treatment of Asthma
Asthma is defined primarily as an INFLAMMATORY DISEASE with mostly MAST CELL degranulation.
Classify Asthma first:
- Asthma variant cough: Cough without wheezing with atopic history. Treat as mild intermittent.

- Mild intermittent:
* Pt asymptomatic
* Diurnal symptoms 1x or 2x/week
* Nocturnal symptoms 2x/month
- Mild persistent:
* Diurnal symptoms >2x/week / <1x/day
* Nocturnal symptoms >2x/month
* Exacerbations affect activity
- Moderate persitent:
* Symptoms daily
* Night symptoms each week
* Exacerbations affect activity >2x/week - Can last days
- Severe persistent:
* Continuing symptoms/exacb, mostly at night
* Limited activity
Treat the acute episode with Ox and Beta2 adrenergic short acting. Steroids are used in the exacerbations that needs admission. Long term use is the follwing:
- Mild intermittent:
* No long term Rx
- Mild persistent:
* Inhaled Steroids OR Inhaled Cromolyn
- Moderate Persistent:
* Inhaled steroids low/med dose AND Long acting beta adrenergic = SAlmeterol
* OR!!!!!: Inhaled Cromolyn AND Salmeterol
- Severe Persistent:
* Inhaled Steroid high dose AND Salmeterol AND Steroids Tablets.
* OR!!!!!: Inhaled Cromolyn AND Salmeterol AND PO Steroids.
In clinical scenarios, you step up the long term Rx from one level to the other when:
- Mild intermittent to moderate persistent WHEN Pt USES Beta2INHALER MORE THAN TWICE A WEEK
- Mild persistent to Moderate persistent WHEN PT USES INHALER DAILY.
- Moderate persistent to Severe persistent WHEN PT USES INHALER DAILY AND INCREASES DOSE (MORE THAN 2 PUFFS AT A TIME).
Note: Review treatment with Pt every 1 to 6 months and either step down or step up. This change will depend on the failure of other supporting measures (Technique of using inhaler, adherence, and environmental control).
Note2: Beta2 adrenergics are first line in treatment of asthma.
Ipratropium (anticholinergics) are first line of treatment of bronchospasm secondary to beta blockers, or in CI of beta adrenergics.
Steroids Inhaled are first line in treatment of PERSISTENT ASTHMA. 2nd line of treatment out-pt after familure of beta2adrenergics
Steroids systemic (PO) are first line in treating exacerbation in-patient and in control of severe persistent. (GIve Calicum and Vit D in chronic use. Watch out for Adrnela insufficiency. Scenario of Pt undergoing accident or surgery and post-op clinical scnerio of adrenal insufficiency. H/o of persistent asthma. Or Pt with h/o of asthma who develops recurrent oral candidiasis).
References:
- Swanson
- CMDT
Mercury poisoning

A 2 yo – peeling, erythematous rash – hands and feet. Mother says child has become ill tempered and refuses to walk. PE – irritable, pale child with photophobia. T = 99F, P=90, RR = 23. Tremor of the tongue evident. Further history reveals child’s elder brothers have been playing with household thermometers.
What is the likely diagnosis?
How do you confirm the diagnosis?

The culprit: what is mercury?
Mercury is an elemental metal. At room temperature it is a silvery, odorless liquid which vaporizes easily. These properties have given it the common name quicksilver. Mercury's most well known use is in medical thermometers found in the home, but it is also used in electric switches, propellant and fluorescent lamps. Mercury use in diuretics, antiseptics, perservatives and pesticides has greatly declined becuase effective substitutes have been found. Mercury was previously used in paint, but no longer is.
Mercury exists in 3 forms: (1) elemental mercury, (2) inorganic salts, and (3) organic compounds. Perhaps the most deadly form of mercury is methyl mercury. Only 2-10% of the ingested mercury is absorbed from the gut, and ingested elemental mercury is not absorbed at all; however, 90% of any methyl mercury ingested is absorbed into the bloodstream from the gastrointestinal tract.
Mercury posoning by eating Fish:
Japan, North Carolina, New Jersey, New york State, Puerto Rico, Amazon and virgin islands.
Ritual Use of mercury:
in haitian and carribean-american communities, particularly of spiritist faith such as Santeria. The ritual consists in the sprinkling of mercury about the home. Mercury is purveyed by some herbal medicine or botanical shops to consumers unaware of the dangers of the substance. This causes intoxication by mercury vapor.
Some History:
Methyl mercury poisoning, better known as Minamata disease, is one of the most devastating forms of mercury exposure. It is named for Minamata Bay, a body of water in Japan where, in the early 1950s, the fish contained high concentrations of methyl mercury from the polluted waste of a nearby industrial plant. Local villagers ate the fish and began to exhibit signs of neurologic damage such as visual loss, extremity numbness, hearing loss, and ataxia. Babies exposed to the methyl mercury in utero were the most severely affected members of the village. Furthermore, because mercury was also discovered in the breast milk of the mothers, the babies’ exposure continued after birth.
The setting:
- When inhaled or absorbed through the skin, mercury accumulates in the liver, kidneys, brain and blood, causing both immediate and long term health effects.
- Mercury taken into the body through air, water and food is absorbed in varying amounts depending on the route of intake. The major food sources of mercury are fish and shell fish.
- Exposure to mercury also may occur by moving into a mercury-contaminated home, children playing with mercury, or exposing oneself through a hobby.
Pathophysiology:
Mercury is an element and cannot be broken down into harmless components.
Because mercury binds to the body's ubiquitous sulfhydryl groups, toxicity involves multiple organ systems. Structural proteins, membranes, and enzymes are all disrupted.
Methyl mercury exerts its most devastating effect on the central nervous system by causing psychiatric disturbances, ataxia, visual loss, hearing loss, and neuropathy. Methyl mercury is lipophilic and readily crosses the blood-brain and placentofetal barriers. Neurologic damage in the form of diffuse and widespread neuronal atrophy is most severe in patients exposed in utero.
Necrosis of the proximal tubules is a common direct renal toxic effect. Unexplained renal abnormalities with neuropsychiatric disturbances should prompt the physician to consider Minamata disease or other forms of mercury poisoning.
The effect:
The most universal effect of mercury is damage to the nervous system. Mental instability, dizziness, numbness in the limbs and personality changes such as nervousness, increased excitability or insomnia may occur after exposure to mercury vapors.
The phrase "mad as a hatter" originated from the often strange behavior of hat makers, caused by exposure to mercury vapor used in making felt hats. The history of mercury and its toxic effects date back to the fifteenth century B.C. Criminals sentenced to work in mercury mines had a life expectancy of three years.
Can mercury affect some people more than others?
Age:
Children are especially susceptible to the adverse effects of mercury. In pregnant women, mercury easily crosses the placental barrier and concentrates in the fetus more readily than in the mother. Thus, a pregnant woman exposed to toxic levels of mercury may not exhibit any signs of mercury poisoning, but her child may be born with brain damage similar to cerebral palsy or autism.
The scenario:
Children develop the symptoms of mercury poisoning more quickly and severely than adults. Neurological symptoms are very similar to those seen in adults. Children also may develop a bright red reash with sheets of peeling skin.
Symptoms include:
- Perioral and facial paresthesias
- Extremity numbness
- Dysarthria
- Headache - Constriction of the visual fields
- Difficulty in hearing
- Memory loss
- Ataxia - problems in walking
Methyl mercury exerts its most devastating effect on the central nervous system by causing the following:
Psychiatric disturbances, Ataxia, Visual loss, Hearing loss, and Neuropathy
Clinical examination typically reveals the following:
* Deficits in the visual field relative to confrontation
* Ataxia
* Tremor
* Psychiatric disturbances such as anxiety
* Seizures
* Respiratory distress and dermatitis can occur acutely.
Neurotoxicity is the most damaging syndrome.
Severe poisoning eventually causes the patient to lie in a mute semirigid posture that is broken only by episodes of crying or primitive reflexive movements.
Unexplained renal abnormalities with neuropsychiatric disturbances should prompt the physician to consider Minamata disease or other forms of mercury poisoning.
The most damaging effect of ingested inorganic mercury (eg, mercuric chloride) is caustic gastroenteritis.
Ingested elemental mercury is considered nontoxic because of its poor absorption in the gut; it is most dangerous as a vapor because it can cause acute lung injury and respiratory failure.
Differential:
Schizophrenia and Other Psychoses
Substance Abuse: Cocaine
Toxicity, Hallucinogens - PCP
Autism: presents very many similarities (see 3)
The Diagnosis:
- Labs: blood, urine, and (sometimes) tissue analyses are required to confirm the diagnosis of mercury intoxication.
Blood Analysis:
Methyl mercury concentrates in red blood cells. Consequently, a direct determination of the blood mercury concentrations is essential.
The normal range of mercury concentrations in whole blood is 0-10 mcg/L. Early signs and symptoms may occur with concentrations greater than 35 mcg/L.
The severity of mercury poisoning is not always correlated with the blood concentration because of the redistribution of mercury in the tissues, specifically those of the central nervous system.
Urinalysis
The detection of mercury in the urine demonstrates that exposure has occurred; however, it does not indicate the severity of mercury poisoning.
Methyl mercury is primarily excreted through the feces; the urinary excretion of mercury is minimal.
Chelated mercury is excreted primarily through the kidneys. Therefore, urinary assays are useful in monitoring chelation therapy.
Histologic Findings: Necrosis of the proximal tubules is a common direct renal toxic effect.
Medical Care:
Medical Care: The general management measures in Minamata disease are the same as in those of any other toxicologic exposure. After initial assessment and stabilization of the patient’s condition, eliminate the patient's exposure to the source of the mercury. Provide general supportive measures, including monitoring, the performance of baseline laboratory studies, and the creation of a differential diagnosis.
Once the neurologic consequences of Minamata disease appear, they are, unfortunately, irreversible. The goal of medical management in Minamata disease is to reduce the total body burden of mercury and minimize further damage.
* Chelating agents (classified Category C = Safety for use during pregnancy has not been established): Because mercury binds to the body's ubiquitous cellular sulfhydryl groups, chelating agents should be administered early in treatment. These agents are thought to competitively bind the mercury by using its thiol groups. Currently, the best agent for the treatment of Minamata disease is 2,3-dimercaptosuccinic acid (DMSA). Its toxicity is low, and animal trials have shown that it is superior to older chelating agents such as dimercaprol (BAL) and d-penicillamine (DPCN). Even in cases of inorganic mercuric salt exposure, DMSA is preferred over DPCN.
* Gastric Lavage: Because of the high propensity for neurologic impairment, patients with acute mercury ingestion should undergo gastric lavage with solutions containing proteins such as those from milk or egg whites. In addition, activated charcoal should be administered even though it does not absorb heavy metals well in general.
Diet:
Because of the high morbidity and mortality rates associated with methyl mercury poisoning, especially in utero, pregnant women and nursing mothers should avoid consuming larger fish (shark, swordfish, and large tuna steaks ) because their mercury concentrations tend to be higher than those in smaller fish.
Outpatient follow-up:
- Monitor Mercury levels for months
- Monitor Renal Function
- Neurological and Psych examinations
Complications:
Acute perioral and facial paresthesias, Respiratory distress and nonspecific dermatitis, Extremity numbness eventually along with headache, fatigue, tremor, Ataxia and dysarthria.
Severe poisoning eventually causes the patient to lie in a mute semirigid posture that is broken only by episodes of crying or primitive reflexive movements.
Babies exposed in utero are the most severely affected (low birth weight, seizure disorders, profound developmental delay, incomplete visual loss (including tunnel vision), total blindness, and hearing loss).
Long-term studies indicate that even prenatal exposure at low concentrations can cause subtle but detectable decrements in the areas of motor function, language, and memory.
Children so affected may have long-term stigmata, including motor impairment, visual loss, hearing loss, developmental delay, and seizure disorders.
Prevention: What should I do if I spill mercury in my house?
If the mercury spills onto a surface, IT SHOULD NOT BE VACUUMED. Vacuuming causes mercury to vaporize and spread easily through the air, causing contamination.
The correct way to dispose of small amounts of mercury is to pick it up with the sticky side of a piece of tape, place it in a sealed container and place it in the trash outside. Do not put mercury down the drain or dispose of it in the house, because it will continue to vaporize. Contact EPA when a spill of mercury would form a pool larger than a quarter.
Medicolegal pitfalls:
* Consider mercury intoxication in the differential diagnosis when unexplained neuropsychiatric disturbances are coupled with renal abnormalities.
* Because of the high morbidity and mortality rates associated with methyl mercury poisoning, especially in utero, pregnant women and nursing mothers should avoid consuming larger fish because their mercury concentrations tend to be higher than those in smaller fish.
Mercury intoxication after eating fish:
What is mercury and how does it get into the environment?
Mercury is a metal that occurs naturally at low levels in rock, soil and water throughout North Carolina. Mercury is also released into the air, water and land when fossil fuels (coal, oil and natural gas) are burned; when municipal solid waste or medical waste is incinerated; during forest fires; and during some manufacturing processes.
Reference:
1) http://www.emedicine.com/ped/topic1461.htm
2) http://www.epi.state.nc.us/epi/fish/...althfacts.html
3) http://www.whale.to/a/table_a.htm
4) http://www.epa.state.oh.us/pic/facts/mercury.html
What is the difference between Cushing Syndrome and Cushing Disease?

First of all, Answer to your question
- Cushing disease = Pituitary adenoma ACTH secreting. It displays clinical Cushing Syndrome.
- Cushing syndrome is everything else with clinical features except etiology is NOT pituitary.
CUSHING SYNDROME/DISEASE...GENERAL REVIEW
General Considerations:
Cushing syndrome is caused by prolonged exposure to elevated levels of either endogenous or exogenous glucocorticoids.
In an emergency situation, remembering that the most common cause of Cushing syndrome is the use of exogenous glucocorticoids is important. Exogenous steroids may cause suppression of the hypothalamic-pituitary-adrenal (HPA) axis that can last for as long as a year after exogenous steroid administration has ended.
Etiology:
- Adrenal Hyperplasia
* Pituitary adenoma = Cushing Disease
* ACTH or CRH secreting tumor = Ectopic (Oat cell CA - CA of thymus - PAncreatic CA - Bronchial Adenoma)
- Adrenal Neoplasia
- Exogenous/ Iatrogenic causes = MOST COMMON.
Pathophysiology:
Endogenous glucocorticoid overproduction or hypercortisolism that is independent of adrenocorticotropic hormone (ACTH) usually is due to a primary adrenocortical neoplasm. ACTH-secreting neoplasms cause ACTH-dependent Cushing syndrome. 80% are due to Classic Cushing disease = an anterior pituitary tumor. Ectopic sources of ACTH make up the balance of ACTH-dependent Cushing syndrome cases. Ectopic non pituitary = an oat cell, small-cell lung carcinoma, or carcinoid tumor. Rarely ectopic corticotropin-releasing hormone (CRH) secretion.
Sex: female-to-male ratio is 5:1 for Cushing syndrome due to an adrenal or pituitary tumor.
Ectopic ACTH production is more frequent in men than in women, due to the increased incidence of lung tumors in this population.
Age: The peak incidence of Cushing syndrome due to either an adrenal or pituitary adenoma occurs between ages 25 and 40 years.
Ectopic ACTH production due to lung cancer occurs later in life.
History:
- Weight gain, especially in the face, supraclavicular region, upper back, and torso.
- Changes in skin= purple stretch marks, easy bruising, and other signs of skin thinning.
- Irregular menses and hirsutism
- Progressive proximal muscle weakness, patients may have difficulty climbing stairs, getting out of a low chair, and raising their arms.
- Psychological problems (depression, cognitive dysfunction, and emotional lability)
- New onset or worsening of hypertension and diabetes mellitus, difficulty with wound healing, increased infections, osteopenia, and osteoporotic fractures
- Patients with an ACTH-producing pituitary tumor (Cushing disease) may develop headaches, polyuria and nocturia, visual problems, or galactorrhea.
- Mass effect on the anterior pituitary (hyposomatotropism, hypothyroidism, and hypogonadism)
Physical:
- Obesity, moon facies, buffalo hump, and supraclavicular fat pads.
- Central obesity with increased adipose tissue in the mediastinum and peritoneum, increased visceral fat is evident on CT.
- Skin, Facial plethora, Violaceous striae over the abdomen, buttocks, lower back, upper thighs, upper arms, and breasts. Ecchymoses may be present.
Patients may have telangiectasias and purpura.
Cutaneous atrophy with exposure of subcutaneous vasculature tissue and tenting of skin may be evident.
- Steroid acne
- Acanthosis nigricans, which is associated with insulin resistance and hyperinsulinism, may be present. The most common sites are axilla and areas of frequent rubbing, such as over elbows, around the neck, and under the breasts.
- Cardiovascular/renal: Hypertension, Volume expansion (edema from sodium and water retention).
- Atherosclerotic heart disease is caused by lipid abnormalities, while diabetes mellitus and hypertension are caused by Cushing syndrome.
- Gastroenterologic: Peptic ulceration (rare in endogenous hypercortisolism).
- Endocrine: Hypothyroidism may occur from anterior pituitary tumors, which can interfere with proper thyroid-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) function.
- Galactorrhea may occur when anterior pituitary tumors compress the pituitary stalk, leading to elevated prolactin levels.
- Other pituitary function may be interrupted without obvious clinical findings. Possibilities include polyuria and nocturia from diabetes insipidus.
- With severe hypercortisolism, hypokalemic metabolic alkalosis may occur.
- Osteoporosis = incident fractures and kyphosis, height loss, and axial skeletal bone pain. Avascular necrosis of the hip also is possible from glucocorticoid excess.
- Adrenal crisis
Patients with cushingoid features may present to the emergency department in adrenal crisis. This may occur in patients on steroids who stop taking their glucocorticoids or neglect to increase their steroids during an acute illness. It also may occur in patients who have recently undergone resection of an ACTH-producing or cortisol-producing tumor.
Physical findings that occur in a patient in adrenal crisis include hypotension, abdominal pain, vomiting, and mental confusion (secondary to low serum sodium or hypotension). Other findings include hypoglycemia, hyperkalemia, hyponatremia, and metabolic acidosis.
Lab Studies:
- WBC>11,000/mm3
- Hypokalemic (NA IS NORMAL) metabolic alkalosis may occur in patients with urinary free cortisol (UFC) levels higher than 1500 mcg/24-h.
- 20% have Glucose intolerance/DM
OVERVIEW OF EVALUATION OF PT WITH PRESUMED CUSHING SYNDROME:
1- CLINICAL SUSPICION
2- SCREENING TEST = OVERNIGHT DXM SUPPRESSION TEST (EXCLUDES CUSHING SYNDROME WITH 985 OF CERTAINTY).
3- IF ABOVE ABONORMAL = 24H URINE FREE CORTISOL + CREATININE
4- IF ABOVE ABNORMAL = CUSHING SYNDROME
NEXT = HIGH DOSE DXM SUPPRESSION TEST
5- IF SUPPRESSION <50% CONTROL: CUSHING DISEASE (PITUITARY ADENOMA)
IF NO SUPPRESSION: ADRENAL NEOPLASIA VS ECTOPIC TUMOR
6- NEXT = ACTH LEVEL
IF HIGH = ACTH PRODUCING TUMOR => CT CHEST
IG LOW = ADRENAL NEOPLASIA => URNIARY 17KS - DHEA-S - ABDOMINAL CT: ADRNEAL ADENOMA VS ADRENAL CARCINOMA.
DETAILED EXPLANATION:
Diagnosis of excess endogenous cortisol production requires the demonstration of inappropriately high serum cortisol levels or its urinary metabolites.
Because acute illness activates the HPA axis, resulting in increases in ACTH and cortisol, the laboratory workup for Cushing syndrome should not be performed when subjects are acutely ill.
Two common screening tests for Cushing syndrome are the 24-hour UFC test and the overnight (ON) 1-mg dexamethasone suppression test.
* The 24-hour UFC test is an excellent indicator of overall daily cortisol production. Values higher than 3- to 4-times the upper limit of normal are very suggestive of Cushing syndrome, whereas values 1- to 3-times normal are consistent with either pseudo-Cushing or Cushing syndrome. Ensuring that the 24-hour collection for this test was adequate, by simultaneously measuring urinary creatinine excretion on the same urine sample, is important.
* The ON 1-mg dexamethasone suppression test calls for ingestion of 1 mg of dexamethasone at 11 PM, with measurement of an 8-AM serum cortisol the next morning. In healthy individuals, the serum cortisol should be less than 2-3 mcg/dL. Cushing syndrome may be excluded with a cortisol level less than 1.8 mcg/dL.
Medications that increase corticosteroid-binding globulin, such as estrogen and tamoxifen, may cause appropriate increases in cortisol levels.
Finally, medications that facilitate the metabolism of dexamethasone, such as phenobarbital, phenytoin, and rifampin, may cause false-positive results with the dexamethasone suppression test.
In many instances, additional studies must be performed to establish the diagnosis of excess cortisol production. The 48-hour low-dose dexamethasone suppression test (0.5 mg dexamethasone PO q6h for 8 doses) has been used for many years.
In healthy individuals, 24-hour urinary 17-hydroxycorticosteroids are suppressed to 4 mg or less during the second day of dexamethasone ingestion. Unfortunately, the sensitivity and specificity of this test are only approximately 70%.
A promising new method of detecting mild glucocorticoid excess combines the 48-hour low-dose dexamethasone suppression test with CRH stimulation. Ovine CRH (1 mcg/kg IV) is given 2 hours after the eighth dose of 0.5 mg dexamethasone.
Serum cortisol is measured 15 minutes after ovine CRH administration. A cortisol level of greater than 1.4 mg/dL is very suggestive of Cushing syndrome.
Other tests that may be useful to identify Cushing syndrome are as follows:
In order to institute appropriate therapy, the cause of excess cortisol secretion must be determined. The logical first step involves establishing the differential diagnosis between an ACTH-dependent or ACTH-independent disorder.
A plasma ACTH (measured by an immunoradiometric assay) of less than 5 pg/mL is suggestive of a primary adrenal tumor. An ACTH greater than 10-20 pg/mL is consistent with ACTH-dependent Cushing syndrome.
The 8-mg ON dexamethasone suppression test and the 48-hour high-dose dexamethasone test may be useful when baseline ACTH levels are indeterminate. These studies also help in determining whether a patient who has ACTH-dependent disease has pituitary-dependent or ectopic ACTH disease.
In the ON 8-mg dexamethasone suppression test, individuals ingest 8 mg dexamethasone orally at 11 PM, with measurement of an 8-AM cortisol the next day. A baseline 8-AM cortisol measurement is required. Suppression of serum cortisol to less than 50% of baseline is suggestive of a pituitary source of ACTH rather than ectopic ACTH or primary adrenal disease. However, the diagnostic accuracy is only 70-80%.
With the 48-hour high-dose dexamethasone suppression test, patients ingest 2 mg dexamethasone every 6 hours for 8 doses. A decrease in UFC of greater than 50% is suggestive of an anterior pituitary adenoma, rather than ectopic ACTH or a primary adrenal tumor. Unfortunately, the sensitivity of this test is only 80%, with a specificity of 70-80%. The more stringent criterion of a 90% decrease in UFC levels excludes the diagnosis of ectopic ACTH and has 100% specificity for anterior pituitary disease.
If concern for adrenal carcinoma exists, measurement of 17-ketosteroid or other cortisol precursors (such as serum dehydroepiandrosterone sulfate [DHEAS]) is useful.
Imaging Studies:
An abdominal CT scan is recommended if a primary adrenal problem is suspected. CT-guided fine-needle aspiration then may have a role in management.
If a pituitary source of excess ACTH is suspected, patients should undergo a contrast-enhanced magnetic resonance imaging (MRI) study of the pituitary.
Chest and abdominal CT scans should be performed in patients with suspected ectopic ACTH production.
Octreotide scintigraphy may be helpful in detecting ectopic ACTH tumors because neuroendocrine tumors typically have cell surface receptors for somatostatin.
Differential Diagnosis:
- Alcoholics: high cortisol levels with clinical cushing
- Depression: High cortisol with no clinical features
- Anorexia Nervosa: Same wasting as in Cushing with extraordinary high levels of 24h urine cortisol
- Morbid obesity mimicks results of DXM suppression test but urine free cortisol is normal
- Pts on HAART for HIV-1 develop partial lipodystrophy with thin extremities and central obesity, buffalo hump.
Medical Care:
Overview
Treatment of Cushing syndrome is directed by the primary cause of the syndrome.
A culprit tumor should be removed if possible.
- The treatment of choice for endogenous Cushing syndrome is surgical resection of the causative tumor.
- The primary therapy for Cushing disease is transsphenoidal surgery. Pituitary radiation may be useful if surgery fails for Cushing disease.
- The primary therapy for adrenal tumors is adrenalectomy. When surgery is not successful or cannot be used, as often occurs with ectopic ACTH or metastatic adrenal carcinoma, control of hypercortisolism may be attempted with medication. However, medication failures are common, and adrenalectomy may be indicated in ACTH-mediated Cushing syndrome.
- The treatment for exogenous Cushing syndrome is gradual withdrawal of glucocorticoid.
Cushing syndrome
Agents that inhibit steroidogenesis, such as mitotane, ketoconazole, metyrapone, aminoglutethimide, trilostane, and etomidate, have been used to cause medical adrenalectomy.
These medications are used rarely and often are toxic at the doses required to reduce cortisol secretion. Thus, medical treatment should be initiated cautiously and, ideally, in conjunction with a specialist. Efficacy of these medical interventions can be assessed with serial measurements of 24-hour UFC.
Patients receiving these medications may require glucocorticoid replacement to avoid adrenal insufficiency.
Metyrapone and trilostane are agents that competitively inhibit a single steroidogenic enzyme. Ketoconazole and aminoglutethimide act at several sites. If enzymatic blockade is not complete, ACTH secretion overcomes the blockade so that hypercortisolism persists.
Because ACTH production may persist or increase in patients with Cushing disease, radiation therapy of the pituitary often is required after unsuccessful initial therapy, either surgical or medical. These agents have higher efficacy when used in combination because they may act synergistically.
Ketoconazole probably is the most popular and effective of these agents for long-term use and usually is the agent of choice. It acts on several of the P450 enzymes, including the first step in cortisol synthesis, cholesterol side-chain cleavage, and conversion of 11-deoxycortisol to cortisol. It also may inhibit ACTH secretion when used at therapeutic doses (200-400 mg bid-tid).
Adverse effects of ketoconazole include headache, sedation, nausea, irregular menses, decreased libido, impotence, gynecomastia, and elevated liver function tests. The drug is contraindicated during pregnancy.
Ketoconazole is ineffective in patients on H2 blockers or proton-pump inhibitors because gastric acidity is required for metabolism. If this agent is ineffective at controlling hypercortisolism, the dose may be maintained while another steroid enzyme inhibitor, typically metyrapone, is initiated.
Metyrapone blocks 11-beta-hydroxylase activity (the final step in cortisol synthesis) and, at high doses, may inhibit ACTH secretion. Therapy is begun at 1 g/d divided into 4 doses and increased to a maximum dose of 4.5 g/d. Adverse effects are from increases in androgen and mineralocorticoid precursors, including hypertension, acne, and hirsutism.
Aminoglutethimide is an anticonvulsant agent that blocks cholesterol side-chain cleavage to pregnenolone. It is a relatively weak adrenal enzyme inhibitor at doses that patients can tolerate. Aminoglutethimide typically is initiated at 250 mg twice daily, and increased to 2 g four times daily.
- Adverse effects of aminoglutethimide include somnolence, headache, a generalized pruritic rash, hypothyroidism, and goiter. In rare cases, it may cause bone marrow suppression. Aminoglutethimide increases the metabolism of dexamethasone but not cortisol.
Trilostane is not widely available and is not as well studied. Trilostane inhibits the conversion of pregnenolone to progesterone, which decreases the synthesis of cortisol, aldosterone, and androstenedione. It is not a first-choice agent because it is a weak inhibitor of steroidogenesis. In addition, trilostane interacts with some assays, causing a false elevation of cortisol measurements.
Etomidate, an imidazole-derivative anesthetic agent, blocks 11-beta-hydroxylase. It is used intravenously at 0.3 mg/kg/h. Its use is limited by the requirement for chronic administration by the intravenous route.
Mitotane is an adrenolytic agent that acts by inhibiting 11-beta hydroxylase and cholesterol side-chain cleavage enzymes. This drug also leads to mitochondrial destruction and necrosis of adrenocortical cells in the zona fasciculata and reticularis. For this reason, it is used in treatment of adrenal cancer. Its survival benefit is unclear. It can be used in addition to radiation therapy for treatment of Cushing disease and in combination with metyrapone or aminoglutethimide for treatment of ectopic ACTH secretion.
- Unfortunately, mitotane is expensive, and its utility is limited by adverse gastrointestinal and neurological effects, including nausea, diarrhea, dizziness, and ataxia. Other adverse effects include rash, arthralgias, and leukopenia. It is taken up by adipose tissues and persists in the circulation long after discontinuation. It is a potential teratogen and can cause abortion; therefore, it is relatively contraindicated in women interested in remaining fertile.
Mifepristone (RU 486) is an antiprogestational agent, which, at high doses, competitively binds to the glucocorticoid and progesterone receptors. It currently is used only on an investigational basis for treatment of Cushing syndrome.
Agents that decrease CRH or ACTH release have been studied for the treatment of Cushing disease. Such agents include bromocriptine, cyproheptadine, valproic acid, and octreotide. Currently, use of these agents is investigational.
Surgical Care:
- Cushing disease
Treatment of choice for classic Cushing disease is transsphenoidal surgery by an experienced neurosurgeon. The goal of surgery is to remove the adenoma, preserving as much pituitary function as possible.
Successful amelioration of hypercortisolism occurs in 60-80% of cases. Both open and laparoscopic techniques are possible. If unsuccessful, MRI-guided pituitary surgery, a new procedure, may be indicated.
- Pituitary irradiation is employed when transsphenoidal surgery is not successful or not possible. The procedure is less successful than surgery in adults, with a 45% cure rate in adults and 85% cure rate in children. Late-onset adverse effects include hypopituitarism.
- Bilateral adrenalectomy is an option if transsphenoidal surgery, pituitary irradiation, and medical therapy fail or if rapid normalization of cortisol levels is required. The patient then requires lifelong glucocorticoid and mineralocorticoid therapy.
In individuals who undergo bilateral adrenalectomy, Nelson syndrome, ie, symptomatic enlargement of the pituitary gland and adenoma, may occur in one quarter to one half of adults not treated with pituitary irradiation and in as many as one quarter of patients pretreated with radiation therapy.
- Ectopic adrenocorticotropic production
Surgical resection of the source of ACTH production may not always be possible.
Medical therapy or bilateral adrenalectomy may be required.
* Adrenal source
Adenomas may be removed with unilateral adrenalectomy, often with a laparoscopic approach.
Carcinomas should be resected for palliation.
Micronodular or macronodular hyperplasia causing Cushing syndrome may be treated effectively by bilateral adrenalectomy. Unilateral or subtotal adrenalectomy may lead to recurrence.
- Hormone replacement
Patients with endogenous Cushing syndrome who undergo resection of pituitary, adrenal, or ectopic tumors should receive stress doses of glucocorticoid in the intraoperative and immediate postoperative period.
Typically, hydrocortisone at 200-300 mg is infused intravenously, either continuously or in boluses (60-100 mg every 8 h) starting prior to surgery and for the first 24 hours afterwards.
If the patient does well, intravenous glucocorticoid replacement may be tapered over 1-2 days and replaced with an oral formulation. The rate of steroid taper may be slowed if severe preoperative hypercortisolism was present.
In the event of pituitary destruction or bilateral adrenalectomy, lifelong steroid replacement is necessary.
Complications:

Osteoporosis
Increased susceptibility to infections
Hirsutism
Diabetes mellitus
Hypertension
Risk for adrenal crisis
Panhypopituitarism
Diabetes insipidus
Medical/Legal Pitfalls:

Patients with Cushing syndrome due to exogenous steroid use are at risk for having an adrenal crisis if they do not receive stress doses of steroids during acute illnesses.
Untreated adrenal crises can lead to death.
High levels of endogenous or exogenous glucocorticoids may mask the abdominal symptoms associated with catastrophic abdominal events such as perforated bowel.
Two catastrophic medical crises that occur in glucocorticoid excess states are perforated viscera and opportunistic fungal infections.
References:
1) Emedicine:
http://www.emedicine.com/MED/topic485.htm
2) Kaplan notes
3) CMDT p1126-1128


Gotta go..gotta go.. right now!!
Diabetes insipidus
Hypercalcemia/Hypokalemia: mechanism by which they provoke DI?
First of all, answer to your question:
The actions of ADH are mediated through at least 2 receptors—V1 mediates vasoconstriction, enhancement of corticotrophin release, and renal prostaglandin synthesis; V2 (Aquaporin) mediates the antidiuretic response.
NDI arises from defective or absent receptor sites at the cortical collecting duct segment of the nephron or defective or absent aquaporin, the protein that transports water at the collecting duct. As a consequence of one of these defects, the ducts do not respond appropriately to vasopressin. Normally, vasopressin is transported in the blood to receptor sites on the basolateral surface of the collecting duct membrane. Through a G protein–adenylate cyclase coupling, activation of the vasopressin receptor increases cyclic adenosine monophosphate (AMP) production and stimulates protein kinase A, leading to increased recycling of the protein aquaporin in the plasma membrane. In the presence of vasopressin stimulus, exocytic insertion of aquaporin into the apical, or luminal, surface of the tubule cell occurs. Aquaporin enhances water entry into the cell from the lumen. Absence of the vasopressin receptor does not allow this process to take place, causing inhibition of water uptake and polyuria.
Hypokalemia and hypercalcemia have been shown to suppress cortical Aquaporin 1 (AQP2) as well as to downregulate medullary AQP2, resulting in a reversible nephrogenic DI.
Next: The review
Diabetes Insipidus
Background:
The word diabetes is derived from the Greek verb dia****ein, which means to stand with legs apart, as in urination, or to go through. Insipidus comes from a Latin word meaning without taste. In contrast to diabetes mellitus (DM), which describes the excretion of sweet urine, diabetes insipidus (DI) describes the passing of tasteless urine because of its relatively low sodium content.
Nephrogenic DI (NDI) reached North America in 1761, carried by Ulster Scots who arrived in Nova Scotia, Canada, on a ship named Hopewell. Scottish folklore reports the existence of the disease in Scotland before 1761. According to legend, a gypsy woman traveling with her thirsty son is denied water by a housewife. The gypsy woman curses the housewife, causing the housewife's sons to crave water while condemning her daughters to pass the curse on to future generations.
General Considerations:
- Central diabetes insipidus (DI) is characterized by decreased secretion of antidiuretic hormone (ADH), AKA arginine vasopressin (AVP), that results in polyuria and polydipsia by diminishing the patient's ability to concentrate urine.
Diminished or absent ADH can be the result of a defect in one or more sites involving the hypothalamic osmoreceptors, supraoptic or paraventricular nuclei, or the supraopticohypophyseal tract. In contrast, lesions of the posterior pituitary rarely cause permanent DI because ADH is produced in the hypothalamus and still can be secreted into the circulation.
- Nephrogenic DI is characterized by a decrease in the ability to concentrate urine due to a resistance to ADH action in the kidney. Nephrogenic DI can be observed in chronic renal insufficiency, lithium toxicity, hypercalcemia, hypokalemia, and tubulointerstitial disease.
The rare hereditary form of nephrogenic DI is transmitted as an X-linked genetic defect of the V2 receptor gene. A rare autosomal variant is caused by mutation in the aqua porin gene AQP2, a water-channel exclusively expressed in the collecting ducts of the kidney.
Clinically:
- The most common form of DI is that which follows trauma or surgery to the region of the pituitary and hypothalamus. It may exhibit 1 of 3 patterns—transient, permanent, or triphasic. The triphasic pattern is observed more often clinically.
** First, a polyuric phase = fall in urine osmolality ** Second, an antidiuretic phase from release of stored hormone = urine osmolality rises.
** The third phase can be permanent DI, when stores of ADH are exhausted
Polyuria, polydipsia, and nocturia (from 3-18 liters) are the predominant symptoms.
In infants, crying, irritability, growth retardation, hyperthermia, and weight loss may be the most apparent signs.
In children, enuresis, anorexia, linear growth defects, and fatigability typically predominate.
Patients with a nontraumatic onset typically have a much more indolent course. The daily urine volume is highly variable (3-20 L/d), and patient tolerance of dehydration also varies among individuals.
Note: Pregnancy is associated with increased risk of DI. It's called VASOPRESSINASE-INDUCED DI. IT IS SEEN IN THIRD TRIMESTER AND PUERPERIUM. IT IS OFTEN ASSOCIATED WITH OLIGOHYDRAMNIOS, PRE-ECLAMPSIA, OR HEPATIC DYSFUNCTION. A circulating enzyme destroys native vasopressin; however synthetic desmopressin is unaffected, THEREFORE RESPONDING TO DESMOPRESSIN THERAPY AND SUBSIDING SPONTANEOUSLY THEREAFTER.
Physical Examination: Normal or signs of dehydration
Causes:
- Central: traumatic/surgery, neoplastic or infiltrative of the hypothalamus or pituitary (adenomas, cranipharyngiomas, leukemia, sarcoid histiocytosis), Radiation therapy, HTN, and meningitis. 30% are idiopathic.
- Mephrogenic: idiopathic, hypercalcemia, hypokalemia, Sickle Cell Disease, pyelonephritis, Sarcoidosis, Multiple Myeloma, or drugs (Lithium, demeclocycline, colchicine, foscarnet, methicillin).
Workup:
Perform testing with the patient maximally dehydrated as tolerated, ie, at a time when ADH release would be highest and urine would be most concentrated. Ruling out secondary causes, such as diabetes mellitus, also is important.
1) USUALLY IN THE QUESTION STEM:
*** 24h urine collection (volume, glucose, creatinine, urine specific gravity, urine Na, Uosm)
***Serum: electrolytes and glucose, simultaneous serum and urine osmolality, and ADH levels.
A urine specific gravity of 1.005 or less and a urine osmolality less than 200 mOsm/kg is the hallmark of DI. Random plasma osmolality generally is greater than 287 mOsm/kg.
2) The water deprivation test = compares Uosm after dehydration versus Uosm after vasopressin.
Details: All water intake is withheld and urine osmolality and body weight are measured hourly. When 2 sequential urine osmolalities vary by less than 30 mOsm or if the weight decreases by more than 3%, 5 U of aqueous vasopressin is administered subcutaneously. A final urine specimen is obtained 60 minutes later for osmolality measurement.
In healthy individuals, water deprivation leads to a urine osmolality that is 2-4 times greater than plasma osmolality. Administration of vasopressin results in less than 9% increment in urine osmolality. The time required to achieve maximal urine concentration ranges from 4-18 hours.
In complete central DI, testing reveals minimal ADH levels and activity, with failure of the urine to be concentrated despite excessively concentrated serum. In response to exogenous vasopressin, urine osmolality increases by more than 50%.
Patients with nephrogenic DI have a normal-to-elevated serum ADH level and failure of the kidney to respond to exogenous ADH during the water deprivation test.
3) Measuring Posm and Uosm at intervals and plotting them. Compare with relationship betwen Posm and Uosm in normal individuals. If on the right, it's DI.
4) Vasopressin challenge test: If injection of vasopressin normalizes response, diagnosis of Central DI is made.
5) Consider MRI of pituitary/hypothalamus/skull: T1-weighted images of the healthy posterior pituitary yield a hyperintense signal. In patients with central DI this signal is absent except in the rare familial form of central DI where the signal is still present.
Medical Care:
** In an emergency, most patients can drink enough fluid to replace their urine losses. Replace losses with dextrose and water or IV fluid hyposmolar to the patient's serum. Avoid hyperglycemia, volume overload, and a correction of hypernatremia that is too rapid. A good rule of thumb is to reduce serum sodium by 0.5 mmol/L/h. Water deficit may be calculated based on the assumption that body w