Acromegaly

Acromegaly

Basics

Excess secretion of growth hormone results in the clinical syndrome known as acromegaly. This is an endocrine condition that develops insidiously over decades.

Epidemiology

Patients with the condition usually present between the ages of 40 and 45. However, diagnosis is usually delayed 7–10 years after the onset of symptoms (1). Children and adolescents who have excess growth hormone before the epiphyseal growth plates are fused can develop pituitary gigantism.

Incidence

3 cases per 1 million persons per year (1)

Prevalence

60 per million (1)

Risk Factors

The most common cause is a growth hormone-secreting adenoma of the anterior pituitary or somatotroph. More than 90% of acromegaly patients have such a lesion.

Genetics

• The genetics of this disorder are still under investigation. However, it appears that most somatotroph adenomas overexpress pituitary tumor transforming gene, which plays a role in tumor invasiveness. In addition, 40% of these tumors have an activating mutation of the alpha subunit of the guanine nucleotide stimulatory protein gene.
• Rare causes of acromegaly include ectopic secretion of growth hormone-releasing hormone by nonendocrine tumors (small-cell lung cancers, carcinoid tumors), an excess secretion of this hormone by hypothalamic tumors, and ectopic GH secretion by nonendocrine tumors.

General Prevention

There are currently no preventative strategies for this condition.

Etiology

Excess secretion of GH stimulates the liver to secrete insulinlike growth factor-I (IGF-1), which causes most of the condition's clinical features.

Commonly Associated Conditions

• Rarely, the disease is associated with familial syndromes, including Carney syndrome, McCune-Albright syndrome, familial acromegaly, and multiendocrine neoplasia type I (1).
• Associated with increased risk of colon polyps and cancer of the colon, esophagus, stomach
• Associated with increased risk of melanoma (2)

Diagnosis

• Associated with cardiovascular abnormalities, including cardiomyopathy characterized by diastolic dysfunction and arrhythmias, hypertension, and left ventricular hypertrophy
• Sleep apnea (1/3 of cases are central and 2/3 are obstructive) occurs in 50% (2)
• Associated with hyperinsulinism, insulin resistance, diabetes
• Bone density may be increased.

History

• Often, onset is recognized by looking at old photographs.
• Enlarged, swollen hands and feet:
  • Enlarging shoe and glove size and need to enlarge rings are typical signs.
• Coarse facial features:
  • Enlarged jaw (macrognathia), nose, and frontal bones
  • Teeth spread apart
  • Enlarged tongue (macroglossia)
• Deepened voice
• Hand numbness
• Fatigue, weakness
• Headache, vision changes may be the result of local tumor effects

Physical Exam

• Neurologic:
  • Bitemporal hemianopsia in 10% of patients
  • Headaches in 60% of patients
  • Hand paresthesias:
    • Carpal tunnel syndrome presents in 20% of patients.
• Musculoskeletal:
  • Hypertrophic arthropathy of spine, hips, knees, ankles
  • Prognathism
  • Gigantism
  • Jaw malocclusion
• Skin:
  • Skin thickening
• Endocrine:
  • Menstrual dysfunction in females, galactorrhea, hyperprolactinemia may occur if the somatotroph macroadenoma decreases secretion of other pituitary hormones
  • Goiter
• Visceromegaly: Enlarged prostate in men, kidneys, liver, heart, thyroid may occur

Diagnostic Tests & Interpretation

Lab

• Hyperphosphatemia seen in 70%.
• Hypercalciuria, increased 25-hydroxyvitamin D₃

Initial lab tests

• Initial testing (1):
  • Serum IGF-1 will be elevated.
  • Serum GH will be elevated and changes little throughout the day, unlike in normal subjects, whose concentrations range from 2–10 ng/mL and change with food or exercise.
• Follow-up testing:
  • An oral glucose tolerance test with 75 g of glucose will not suppress serum GH concentrations.
  • In normal subjects, this glucose load would cause a GH fall to 1 ng/mL or less within 2 hours, but the postglucose values are greater than 2 ng/m in acromegaly.

Imaging

Pituitary magnetic resonance imaging (MRI) is the next step in confirmation of the disease:

• Such a study will detect tumors as small as 2 mm in diameter.
• Study does not differentiate between functioning and nonfunctioning tumors

Follow-Up & Special Considerations

If the initial MRI is normal, chest and abdominal computed tomography should be performed to look for extrapituitary causes of acromegaly and GHRH should be measured.

Treatment

Goals of treatment:

• Lower the serum IGF-1 to within the reference range for the patient's age and gender
• Lower serum GH <1 ng/mL as measured after glucose load

Medication

• Pharmacologic treatment is only utilized if surgery alone has not reduced the serum IGF-1 and GH to normal:
  • Primary therapy is with long-acting somatostatin analogs (2)[B].
  • If somatostatin analogs are ineffective, a dopamine agonist may be used (2)[C].
  • If both or a combination is ineffective, pegvisomant may be tried (2)[B].
• Patients with continued increase in adenoma size despite medications may be candidates for radiotherapy or repeat surgery (2)[B].

First Line

Somatostain analogs (3):

• Mechanism of action: Inhibit GH secretion
• Forms:
  • Octreotide: Initial dose: 100 mcg SC q.8h. If the serum IGF-1 concentration does not decrease to normal within 1–2 months, the dose can be increased up to maximum of 400 mcg SC q.8h. Long-acting form: 10 mg IM once monthly up to 40 mg IM once monthly
  • Lanreotide: Initial dose: 30 mg IM q.20–14 days or 60–120 mg SC q.4 weeks

Second Line

• Dopamine agonists (cabergoline):
  • Mechanism of action: Inhibit GH secretion
  • Less efficacious than somatostatin analogs
  • Dose: 1–4 mg p.o. every week
  • Side effects: Nausea
• GH receptor antagonist (pegvisomant):
  • Used if acromegaly has not responded to other treatments
  • Dose: 10 mg SC every day up to a maximum of 40 mg/day
  • Side effects: Elevated serum aminotransferases

Additional Treatment

Radiotherapy:

• Used if acromegaly is uncontrolled by surgery or medical therapy
• Conventional, proton beam, and stereotactic radiotherapy have been used.
• Complication: Hypopituitarism (50%) (1)

General Measures

A multidisciplinary team approach experienced in managing pituitary tumors is essential.

Surgery/Other Procedures

• Selective transphenoidal surgical resection by neurosurgeon is the treatment of choice for patients with somatotroph adenomas that are resectable (4).
• If serum IGF-1 is normalized after surgery (within 7–10 days after resection), no further therapy is recommended (2)[B].

Ongoing Care

Follow-Up Recommendations

Patient Monitoring

• At baseline (4):
  • Echocardiogram
  • Colonoscopy
• Every 3–4 months:
  • Evaluation by clinical exam to include cardiovascular exam and measurement of blood pressure to look for hypertension
  • Labs:
    • Measurement of serum GH after glucose load
    • Measurement of serum IGF-1
• Annually:
  • MRI of brain
• Patients with complications (cardiomyopathy, sleep apnea, colon polyps) should be followed appropriately according to guidelines for these conditions.

Patient Education

Patients can learn more about acromegaly from the Pituitary Patient Resource Guide, published by the Pituitary Network Association (www.acromegaly.org).

Prognosis

• Patients with GH levels <2.5 after treatment have a mortality similar to the general population (4).
• Death is due primarily to cancer (15%) and respiratory (25%) and cardiovascular (60%) diseases (2).

Complications

• Diabetes mellitus
• Sleep apnea
• Cardiac:
  • Cardiovascular disease
  • Arrhythmia
  • Cardiomyopathy
• Colon cancer

Acoustic Neuroma

Acoustic Neuroma

Basics

Description

• Slow-growing benign tumor, most often arising from the vestibular division of 8th cranial nerve
• Originates from Schwann cells of the nerve sheath (“schwannoma”)
• Usually arises in the internal auditory canal near the cerebellopontine angle
• Often has extracanalicular portion into the cerebellopontine angle, but may also stay purely intracanalicular
• Most are unilateral; bilateral only seen in neurofibromatosis type II

Epidemiology

• 6–10% of all intracranial tumors
• 80–90% of cerebellopontine angle tumors
• 95% of cases are unilateral.
• Present most commonly in the 5th–6th decade
• Female predominance
• Bilateral acoustic neuroma occurring in neurofibromatosis II present before age 30

Incidence

• 1/100,000 per year
• Asymptomatic lesions may be more common.

Prevalence

3,000 diagnosed annually in the US

Risk Factors

• Pregnancy and epilepsy may increase risk (1).
• Smoking may decrease the risk (1).

Genetics

• Unknown for unilateral acoustic neuroma (AN)
• Neurofibromatosis type II: Bilateral ANs:
  • Autosomal dominant
  • Gene located on chromosome 22q1

Pathophysiology

• Exerts pressure on the surrounding structures
• Compression of acoustic and facial nerve when located within internal acoustic canal
• Compression of brainstem, 4th ventricle, and trigeminal nerve when tumor at the cerebellar pontine angle

Etiology

Unknown

Commonly Associated Conditions

• Neurofibromatosis type II
• Pregnancy may accelerate the growth of the tumor.

Diagnosis

History

• Common:
  • Sensorineural hearing loss (unilateral), often progressive
  • Loss of speech discrimination
  • Tinnitus
  • Balance problems are common, but vertigo is less common.
• Less common:
  • Weakness/loss of facial muscle functions
  • Headache with hydrocephalus and increased intracranial pressure
  • Trigeminal nerve involvement when tumor is large and compressing on cranial nerve (CN) V
  • Ataxia due to cerebellar or brainstem compression from very large tumor

Physical Exam

• Examination with otoscope to exclude other causes of hearing loss (e.g., middle ear effusion, infection, wax, cholesteatoma, or tympanic membrane rupture)
• Detailed neurologic exam concentrating on the cranial nerves
• Weber and Rinne tests to confirm sensorineural hearing loss
• Evaluation of the contralateral ear in patients <30 years; suspect neurofibromatosis type II

Diagnostic Tests & Interpretation

Lab

Initial lab tests

• Pure-tone and speech audiometry (asymmetrical, high-frequency sensorineural hearing loss)
• Speech discrimination
• Stacked auditory brainstem response (ABR): 95% sensitivity and 88% specificity (2). Can detect tumors <1 cm.
• Standard ABR: Can only detect tumors >1 cm

Imaging

Initial approach

• Magnetic resonance imaging (MRI) with gadolinium (gold standard):
  • 100% specificity
  • Detects tumors starting at 2 mm
  • Tumor has marked enhancement with gadolinium
• Noncontrast T2-weighted fast spin-echo MRI:
  • 98% specificity
  • Cheaper than MRI with gadolinium
• Computed tomography (CT):
  • Detect tumors as small as 1 cm
  • Up to 37% false-negatives
  • Provides good information of surrounding bony structures of the tumor

Pathological Findings

• Well-demarcated and encapsulated mass attached to neural structures without direct invasion
• Can be dense or cystic
• Microscopic: Densely packed spindle cells (Schwann cells) mixed in with myxoid and collagenous matrix:
  • Zones of alternatively dense and sparse areas of Antoni A and B

Differential Diagnosis

• Cerebellopontine lesions:
  • Meningioma
  • Glioma
  • Facial nerve schwannoma
  • Epidermoid
  • Hemangioma
  • Arachnoid cyst
• Sensorineural hearing loss:
  • Ménière disease
  • Ototoxicity
  • Presbycusis
  • Cerebellar pathology

Treatment

Medication

Chemotherapy has not yet been explored sufficiently.

Additional Treatment

General Measures

• Conservative management is suitable for elderly patients with contraindications to surgery and radiotherapy.
• Up to 57% of acoustic neuromas may show zero growth or shrinkage (3)[B].
• Up to 70% of extracanalicular tumors may never have growth rate exceeding 2 mm per year (4)[B].
• Growth rate of enlarging acoustic neuromas decreases over time:
  • From 4.9 mm/yr in the 1st year of detected growth to 0.75 mm in 4th year.
• Up to 20% of patients may eventually fail conservative management and require intervention.
• More likely to preserve hearing than radiotherapy or surgery (5)[C]
• 69% of patients with 100% speech discrimination at diagnosis have maintained good hearing even after 10 years of observation (6)[B]

Issues for Referral

• Yearly MRI follow-up for slow-growing tumors
• If an asymptomatic tumor becomes symptomatic, this is often indication for intervention.

Additional Therapies

Stereotactic radiosurgery:

• Gamma knife single-dose stereotactic radiosurgery:
  • Performed on an outpatient basis
  • Alternative for those with smaller tumor (<3 cm) or contraindications to microsurgery
  • No discernible significant difference between growth patterns of untreated tumors and those treated radiosurgically (6)[A]
  • Lower-dose radiation has lower complication rates, but evidence is insufficient on whether as effective as high-dose radiation in tumor control (7)[A]
  • Higher-dose radiation significantly influences hearing preservation rates (9)[C]
  • Complications include trigeminal and/or facial nerve neuropathy from radiation damage.
• Fractionated stereotactic radiosurgery:
  • Conformal radiation delivers a higher dose of radiation within the tumor and less damage to surrounding healthy tissue.
  • Requires multiple treatments and the total dose of radiation is higher compared to the single-dose radiation
  • Suitable for all sizes of tumor

Surgery/Other Procedures

• Recommended definitive treatment (8)[A]
• Lowest rate of recurrence, with up to 97.5% complete tumor removal (8)[A]
• Intraoperative facial nerve monitoring is generally used.
• 3 standard approaches, all using operating microscopes:
  • Retromastoid/retrosigmoid: For any size, especially tumor located mostly outside the internal auditory canal and adjacent to the brainstem. May require retraction of cerebellum.
  • Middle cranial fossa: For small tumors with aim of preserving hearing. Involves retraction of temporal lobe and has higher risk of facial nerve injury.
  • Translabyrinthine: For larger tumors. Hearing not preserved. Completely exposes the distal internal auditory canal and has more favorable facial nerve results.
• Endoscopic approach used in some centers
• Surgical complications:
  • Hearing loss
  • Cerebrospinal fluid leakage
  • Facial nerve injury
  • Headache
  • Meningitis

Ongoing Care

Follow-Up Recommendations

MRI and audiometric follow-up for those treated by radiotherapy and conservative management

Complications

Due to pressure effect of a large tumor:

• Cranial nerve compression
• Hydrocephalus
• Brainstem compression
• Cerebellar tonsil herniation

Acne Vulgaris

Acne Vulgaris

Basics

Description

• Acne vulgaris is a disorder of the pilosebaceous units. It is a chronic inflammatory dermatosis notable for open/closed comedones and inflammatory lesions, including papules, pustules, or nodules.
• System(s) affected: Skin/Exocrine

Geriatric Considerations

• Favre-Racouchot syndrome:
  • Comedones on face and head due to sun exposure

Pregnancy Considerations

• May result in a flare or remission of acne
• Erythromycin can be used in pregnancy; use topical agents when possible.
• Isotretinoin is a teratogenic; Class X
• Avoid topical tretinoin, although no good evidence exists that its use is teratogenic.
• Contraindicated: Isotretinoin, tazarotene, tetracycline, doxycycline, minocycline

Pediatric Considerations

• Neonatal acne
• Infantile acne: Increased risk for severe teenage acne vulgaris
• Rare in ages 1–7 years:
  • Check for hyperandrogenemia of adrenal or ovarian origin.
  • Do not use tetracyclines <8 years of age

Epidemiology

• Predominant age: Early to late puberty, may persist into 4th decade
• Predominant sex:
  • Male > Female (adolescence)
  • Female > Male (adult)

Prevalence

• 17–50 million cases in the US
• Nearly 80–95% of adolescents affected. A smaller percentage will seek medical advice.
• 8% of adults aged 25–34 years, 3% of those aged 35–44 years

Risk Factors

• Increased endogenous androgenic effect
• Oily cosmetics: Cleansing creams, moisturizers, and oil-based foundations; pomade
• Rubbing or occluding skin surface (e.g., sports equipment such as helmets and shoulder pads), telephone, or hands against the skin
• Polyvinyl chloride, chlorinated hydrocarbons, cutting oil, tars
• Numerous drugs including androgenic steroids (e.g., steroid abuse, some birth control pills)
• Endocrine disorders: Polycystic ovarian syndrome, Cushing syndrome, congenital adrenal hyperplasia, androgen-secreting tumors, acromegaly
• Stress

Genetics

• Familial association in 50%
• If a family history exists, the acne may be more severe and occur earlier.

Pathophysiology

• Immune changes and inflammatory responses may predate hyperkeratinization
• Androgens (testosterone and dehydroepiandrosterone [DHEA]) stimulate sebum production and proliferation of keratinocytes in hair follicles.
• Keratin plug obstructs follicle os, causing sebum accumulation and follicular distention.
• Propionibacterium acnes, an anaerobe, colonizes and proliferates in the plugged follicle.
• P. acnes promotes chemotactic factors and proinflammatory mediators, causing inflammation of follicle and dermis.

Commonly Associated Conditions

• Acne fulminans
• Pyoderma faciale
• Acne conglobata
• Hidradenitis suppurativa
• Pomade acne
• SAPHO syndrome: Synovitis, acne, pustulosis, hyperostosis, osteitis
• PAPA syndrome: Pyogenic sterile arthritis, pyoderma gangrenosum, cystic acne
• Behçet syndrome
• Apert syndrome
• Dark-skinned patients: 50% keloidal scarring and 50% acne hyperpigmented macules

Diagnosis

History

Ask duration, medications, cleansing products, stress, smoking, exposures, family history. Factors influencing symptomatology:

• Males later onset, greater severity
• Females may worsen prior to menses

Physical Exam

• Closed comedones (whiteheads)
• Open comedones (blackheads)
• Nodules or papules
• Pustules (“cysts”)
• Scars: Ice pick, rolling, boxcar, atrophic macules, hypertrophic, depressed, sinus tracts
• Grading system (American Academy of Dermatology, 1990):
  • Mild: Few papules/pustules; no nodules
  • Moderate: Some papules/pustules; few nodules
  • Severe: Numerous papules/pustules; many nodules
  • Very severe: Acne conglobata, acne fulminans, acne inversa
• Most common areas affected are: Face, chest, back, and upper arms (areas of greatest concentration of sebaceous glands)

Diagnostic Tests & Interpretation

Lab

Labs only indicated if there are additional signs of androgen excess; if so: Free testosterone, dehydroepiandrosterone sulfate (DHEA-S), luteinizing hormone, and follicle-stimulating hormone (1)[A]

Differential Diagnosis

• Folliculitis: Gram negative and gram positive
• Acne (rosacea, cosmetica, steroid-induced)
• Perioral dermatitis
• Chloracne
• Pseudofolliculitis barbae
• Drug eruption
• Verruca vulgaris and plana
• Keratosis pilaris
• Molluscum contagiosum
• Facial angiofibromas
• Sarcoidosis

Treatment

• Topical retinoid plus a topical antimicrobial agent 1st-line treatment
• Topical retinoid plus antibiotic (topical or p.o.) is better than either alone (2,3)[A]
• Topical retinoids 1st-line agents for maintenance. Avoid antibiotics for maintenance.
• Comedonal acne (grade 1): Keratinolytic agent (2,3)[A]
• Mild inflammatory acne (grade 2): Benzoyl peroxide +/- topical antibiotic. Keratinolytic if needed (3,4)[A].
• Moderate inflammatory acne (grade 3): Add systemic antibiotic to grade 2 regimen.
• Severe inflammatory acne (grade 4): As in grade 3, or isotretinoin (2,3)[A]
• Recommended vehicle type:
  • Cream: Dry or sensitive skin
  • Gel or solution: Oily skin, humid weather
  • Lotion: Hair-bearing areas
• Mild soap daily to control oiliness; avoid abrasives
• Avoid drying agents with keratinolytic agents.
• Use of a gentle cleanser and noncomedogenic moisturizer helps decrease irritation from keratinolytic agents.
• Oil-free, noncomedogenic sunscreens
• Stress management if acne flares with stress

Medication

Keratinolytic agents (side effects include dryness, erythema, scaling, and photosensitivity; start with lower strength; increase as tolerated) (1,2)[A]:

• Tretinoin (Retin-A, Retin A micro, Avita): Apply at bedtime; wash skin and let skin dry 30 minutes before topical application:
  • Retin-A Micro and Avita are less irritating, less phototoxicity
  • May cause an initial flare of lesions. May be eased by 14-day course of oral antibiotics.
• Adapalene (Differin): 0.1%, Apply topically at night:
  • Effective; less irritation than tretinoin or tazarotene (2,4)[A]
  • May be combined with benzoyl peroxide
• Tazarotene (Tazorac): Apply at bedtime:
  • Most effective and most irritating
  • Teratogenic
• Azelaic acid (Azelex, Finevin): 20% topically, b.i.d.:
  • Keratinolytic, antibacterial, anti-inflammatory
  • Reduces postinflammatory hyperpigmentation in dark-skinned individuals
  • Side effects: Erythema, dryness, scaling, hypopigmentation
  • Less effective in clinical use than in studies
• Salicylic acid: Less effective than tretinoin
• Alpha-hydroxy acids: Available over-the-counter
  
  
• Topical antibiotics and anti-inflammatories (2)[A]:
  • Topical benzoyl peroxide:
    • Bactericidal through direct toxic effect
    • No P. acnes resistance noted
    • 2.5% as effective as stronger preparations
    • When used with tretinoin, apply benzoyl peroxide in morning and tretinoin at night
    • Side effects: Irritation; may bleach clothes
• Topical antibiotics (1,2)[A]:
  • Erythromycin 2%
  • Clindamycin 1%
  • Metronidazole gel or cream: Apply once daily.
  • Azelaic acid (Azelex, Finevin): 20% cream: Enhanced effect and decreased risk of resistance when used with zinc and benzoyl peroxide
  • Benzoyl peroxide-erythromycin (Benzamycin): Especially effective with azelaic acid
  • Benzoyl peroxide-clindamycin (BenzaClin, DUAC, Clindoxyl): Effective combined (4)[A]
  • Sodium sulfacetamide (Sulfacet-R, Novacet, Klaron): Useful in acne with seborrheic dermatitis or rosacea
• Oral antibiotics (1,2)[A]:
  • Tetracycline: 500–2,000 mg/d b.i.d.–q.i.d.; high dose initially, taper in 6 months, as tolerated. Side effects: Photosensitivity, esophagitis:
    • Avoid use with antacids, iron
  • Minocycline 50–200 mg/d, q.i.d.–b.i.d. Side effects: Photosensitivity, urticaria, gray-blue skin, vertigo, autoimmune hepatitis, pseudotumor cerebri, lupuslike syndrome. May be more effective than tetracycline (1)[A].
  • Doxycycline 50–200 mg/d, given b.i.d.–q.i.d.; side effects include photosensitivity
  • Erythromycin: 500–1,000 mg/d; given b.i.d.–q.i.d.; decreasing effectiveness as a result of increasing P. acnes resistance
  • Trimethoprim-sulfamethoxazole (Bactrim DS, Septra DS); 1 daily or b.i.d.
• Oral retinoids:
  • Isotretinoin (Accutane) (1,2)[A]: 0.5–2.0 mg/kg/d b.i.d.; 60–90% cure rate; usually given for 12–20 weeks; maximum cumulative dose = 120–150 mg/kg; 20% of patients relapse and require retreatment:
    • Side effects: Numerous (see package insert). Highly teratogenic.
    • Avoid tetracyclines or vitamin A preparations during isotretinoin therapy.
    • Monitor for pregnancy, complete blood count, lipids, and liver function tests at baseline and every month.
    • Should be registered member of manufacturer's iPLEDGE program

Pregnancy Considerations

• Isotretinoin is a teratogenic; Class X
• Medications for women only:
  • Oral contraceptives (1,2)[A]:
    • Norgestimate/ethinyl estradiol (Orth Tricyclen), norethindrone acetate/ethinyl estradiol (Estrostep), drospirenone/ethinyl estradiol (Yaz, Yasmin) are approved by Food and Drug Administration.
    • Levonorgestrel/ethinyl estradiol (Alesse) is also effective.
  • Spironolactone (Aldactone); 25–200 mg/d; antiandrogen; reduces sebum production
  • Flutamide (Eulexin) 250–500 mg/d; potentially hepatotoxic

Additional Treatment

Acne hyperpigmented macules:

• Topical hydroquinones (1.5–10%)
• Azelaic acid (20%) topically
• Topical retinoids as above
• Corticosteroids: Low dose, suppresses adrenal androgens (1)[B]
• Dapsone 5% gel (Aczone): Topical, anti-inflammatory use in patients >12 years

Issues for Referral

Consider referral/consultation to dermatologist:

• Refractory lesions despite appropriate therapy
• Consideration of isotretinoin therapy
• Management of acne scars

Additional Therapies

• Light-based treatments
  • UVA/UVB, blue light, blue/red light, pulse dye laser, KTP laser, infrared laser
  • Photodynamic therapy for 30–60 minutes with 5-aminolevulinic acid × 3 sessions is effective for inflammatory lesions:
    • Greatest utility when used as adjunct to medications or in patient who can't tolerate medications
  • More data needed to define role of light-based therapies in treating acne

Complementary and Alternative Medicine

• Zinc gluconate 30 mg/d may reduce inflammatory lesions (2)[B]:
  • Topical zinc is ineffective.
• Topical tree oil is effective, but has slow onset (1)[B].

Surgery/Other Procedures

• Comedo extraction after incising the layer of epithelium over comedo (1)[C]
• Incision and drainage for abscesses
• Inject large cystic lesions with 0.05–0.3 mL triamcinolone (Kenalog 2–5 mg/mL); use 30-g needle to inject and slightly distend cyst (1)[C].
• Acne scar treatment: Retinoids, steroid injections, cryosurgery, electrodessication, microdermabrasion, dermabrasion, chemical peels, laser resurfacing, grafting, subcutaneous incision, punch excision, punch elevation, subcision, tissue augmentation injections

Ongoing Care

Follow-Up Recommendations

Use oral or topical antibiotics for 3 months; stop if inflammatory lesions resolve. Can switch abruptly from oral to topical without taper. Do not use topical and oral together.

Patient Monitoring

• Pretreatment and monthly lipids, liver function tests, and pregnancy tests when on isotretinoin
• Consider antibiotic resistance (60% overall) or gram-negative folliculitis if treatment fails.

Diet

Special diets do not diminish acne (1)[B].

Patient Education

• There may be a worsening of acne during 1st 2 weeks of treatment.
• Treatment takes a minimum of 4 weeks to show results.
• Topical agents can cause redness and drying of the skin.
• Picking at or popping lesions may increase inflammation and scarring.

Prognosis

Gradual improvement over time (usually within 8–12 weeks after beginning therapy)

Complications

• Acne conglobata: Severe confluent inflammatory acne with systemic symptoms
• Facial and psychological scarring
• Gram-negative folliculitis: Superinfection due to long-term oral antibiotic use; treatment with ampicillin, trimethoprim-sulfa, or isotretinoin

Adenovirus Infections

Adenovirus Infections

Basics

Description

Usually self-limited febrile illnesses characterized by inflammation of conjunctivae and the respiratory tract. Adenovirus infections occur in epidemic and endemic situations.

• Common types:
  • Acute febrile respiratory illness, affecting primarily children
  • Acute respiratory disease, affecting adults
  • Viral pneumonia, affecting children and adults
  • Acute pharyngoconjunctival fever, affecting children, particularly after summer swimming
  • Acute follicular conjunctivitis, affecting all ages
  • Epidemic keratoconjunctivitis, affecting adults
  • Intestinal infections leading to enteritis, mesenteric adenitis, and intussusception
• Conjunctivitis, sometimes called pink eye
• System(s) affected: Cardiovascular; Gastrointestinal; Hemic/Lymphatic/Immunologic; Musculoskeletal; Nervous; Pulmonary; Renal/Urologic

Geriatric Considerations

• Complications more likely

Pediatric Considerations

• Viral pneumonia in infants and neonates may be fatal.

Epidemiology

• Predominant age: All ages
• Predominant sex: Male = Female

Incidence

• Very common infection, estimated at 2–5% of all respiratory infections
• More common in infants and children

Risk Factors

• Large number of people gathered in a small area (e.g., military recruits, college students at the beginning of the school year, day care centers, community swimming pools)
• Immunocompromised at risk for severe disease

General Prevention

• Live type 4 and type 7 adenovirus vaccine orally in enteric-coated capsules reduces incidence of acute respiratory disease.
• Frequent hand washing among office personnel and family members
• 9-valent pneumococcal conjugate vaccine may decrease risk of pneumonia in infants.

Pathophysiology

• Adenovirus (DNA viruses 60–90 nm in size with 47 known serotypes; 3 types cause gastroenteritis); difficult to eliminate from skin and environmental surfaces
• Different serotypes have different epidemiologies.
• Most common known pathogens:
  • Types 1, 2, 3, 5, and 7 cause respiratory illness.
  • Type 3 causes pharyngoconjunctival fever.
  • Types 4, 7, and 21 cause acute respiratory disease.
  • Several other types may cause epidemic keratoconjunctivitis.

Commonly Associated Conditions

• Hemorrhagic cystitis (can be caused by adenovirus)
• Viral enteritis
• Intussusception and mesenteric adenitis

Diagnosis

History

Depends on type (see “Differential Diagnosis”). Common signs and symptoms with most respiratory forms:

• Headache
• Malaise
• Sore throat
• Cough
• Fever (moderate to high)
• Vomiting
• Diarrhea
• Abdominal Pain
• Ear Pain
• Urinary symptoms/hematuria
• Conjunctivitis

Physical Exam

• Mucosa exhibiting patches of white exudates
• Cervical adenitis
• Conjunctivitis

Diagnostic Tests & Interpretation

Cultures and serologic studies, if appropriate

Lab

• Viral cultures from respiratory, ocular, or fecal sources can establish diagnosis:
  • Pharyngeal isolate suggests recent infection.
• Antigen detection in stool for enteric serotypes is available.
• Serologic procedures such as complement fixation with a fourfold rise in serum antibody titer identify recent adenoviral infection.

Imaging

Radiographs: Bronchopneumonia in severe respiratory infections

Diagnostic Procedures/Surgery

Biopsy (lung or other) may be needed in severe or unusual cases.

Pathological Findings

• Varies with each virus:
  • Severe pneumonia may be reflected by extensive intranuclear inclusions.
• Bronchiolitis obliterans may occur.

Differential Diagnosis

Early diagnosis depends on clinical evaluation. The following are the primary characteristics of the major adenovirus infections:

• Acute febrile respiratory illness:
  • Nonspecific coldlike symptoms, similar to other viral respiratory illnesses (e.g., fever, pharyngitis, tracheitis, bronchitis, pneumonitis)
  • Mostly in children
  • Incubation period 2–5 days
  • May be pertussislike syndrome (rarely)
• Acute respiratory disease:
  • Malaise, fever, chills, headache, pharyngitis, hoarseness, dry cough
  • Fever lasting 2–4 days
  • Illness subsiding in 10–14 days
• Viral pneumonia:
  • Sudden onset of high fever, rapid infection of upper and lower respiratory tracts, skin rash, diarrhea
  • Occurs in children aged a few days up to 3 years
  • Common; severe illness occurs in subset.
• Acute pharyngoconjunctival fever:
  • Spiking fever lasting several days, headache, pharyngitis, conjunctivitis, rhinitis, cervical adenitis
  • Conjunctivitis, usually unilateral
  • Subsides in 1 week
• Epidemic keratoconjunctivitis:
  • Usually unilateral onset of ocular redness and edema, periorbital edema, periorbital swelling, local discomfort suggestive of foreign body
  • Lasts 3–4 weeks

Treatment

Medication

• Acetaminophen, 10–15 mg/kg PO, for analgesia (avoid aspirin)
• Cough suppressants and/or expectorants
• Antihistamine/decongestant combos may decrease cough.

Additional Treatment

General Measures

• Treatment is supportive and symptomatic.
• Infections are usually benign and of short duration.

Complementary and Alternative Medicine

Echinacea has not been shown to be better than placebo for treatment of viral upper-respiratory infections.

In-Patient Considerations

Admission Criteria

Severely ill infants or those with epidemic keratoconjunctivitis or infants with severe pneumonia:

• Contact and droplet precautions during hospitalization are indicated.

Ongoing Care

Follow-Up Recommendations

Rest during febrile phases

Patient Monitoring

For severe infantile pneumonia and conjunctivitis, daily physical exam until well

Diet

No special diet

Patient Education

• Avoid aspirin in children.
• Give instructions for nasal spray, cough preparations, frequent hand washing

Prognosis

• Self-limited, usually without sequelae
• Severe illness and death in very young and in immunocompromised hosts

Complications

Few if any recognizable long-term problems

Addison Disease

Addison Disease

Basics

Description

• Insufficiency of the adrenal gland from primary disease (partial or complete destruction of adrenal cells) with inadequate secretion of glucocorticoids and mineralocorticoids
• 80% of cases are caused by an autoimmune process, followed by tuberculosis (TB), AIDS, systemic fungal infections, and adrenoleukodystrophy.
• Addison disease can be differentiated from secondary (pituitary failure) and tertiary (hypothalamic failure) causes of adrenocortical insufficiency because mineralocorticoid function usually remains intact in secondary and tertiary causes.
• Addisonian (adrenal) crisis: Acute complication of adrenal insufficiency (circulatory collapse, dehydration, hypotension, nausea, vomiting, hypoglycemia); usually precipitated by an acute physiologic stressor(s) such as surgery, illness, exacerbation of comorbid process, and/or acute withdrawal of long-term corticosteroid therapy
• System(s) affected: Endocrine/Metabolic
• Synonym(s): Adrenocortical insufficiency; Corticoadrenal insufficiency; Primary adrenocortical insufficiency

Epidemiology

• Predominant age: All ages; usually 3rd–5th decade; mean age at diagnosis in adults is 40 years
• Predominant sex: Females > Males (slight)

Incidence

0.6:100,000

Prevalence

4:100,000

Risk Factors

• ∼40% of patients have a 1st- or 2nd-degree relative with associated disorders.
• Chronic steroid use, then experiencing severe infection, trauma, or surgical procedures

Genetics

• Autoimmune polyglandular syndrome (APS) type 2 genetics are complex. Associated with adrenal insufficiency, type 1 diabetes, and Hashimoto disease. More common than APS type 1.
• APS type 1 caused by mutations of the autoimmune regulator gene. Nearly all have the following triad: Adrenal insufficiency, hypoparathyroidism, mucocutaneous candidiasis before adulthood
• Adrenoleukodystrophy is an X-linked recessive disorder resulting in toxic accumulation of unoxidized long-chain fatty acids
• Frequent association with other autoimmune disorders
• Increased risk with cytotoxic T-lymphocyte antigen 4 (CTLA-4)

General Prevention

• No preventive measures known for Addison disease; focus on prevention of complications:
  • Anticipate adrenal crisis and treat before symptoms begin.
• Elective surgical procedures require upward adjustment in steroid dose.

Pathophysiology

Destruction of the adrenal cortex resulting in deficiencies in cortisol, aldosterone, and androgens

Etiology

• Autoimmune adrenal insufficiency (80% of cases in the US)
• Infectious causes: TB (most common infectious cause worldwide), HIV (most common infectious cause in the US), Waterhouse-Fredrickson syndrome, fungal disease
• Bilateral adrenal hemorrhage and infarction (for patients on anticoagulants, 50% are in the therapeutic range)
• Antiphospholipid syndrome
• Lymphoma, Kaposi sarcoma, metastasis (lung, breast, kidney, colon, melanoma); tumor must destroy 90% of gland to produce hypofunction
• Drugs (ketoconazole, etomidate)
• Surgical adrenalectomy, radiation therapy
• Sarcoidosis, hemochromatosis, amyloidosis
• Congenital enzyme defects (deficiency of 21-hydroxylase enzyme is most common), neonatal adrenal hypoplasia, congenital adrenal hyperplasia, familial glucocorticoid insufficiency, autoimmune polyglandular syndromes 1 and 2, adrenoleukodystrophy
• Idiopathic

Commonly Associated Conditions

• Diabetes mellitus
• Graves disease
• Hashimoto thyroiditis
• Hypoparathyroidism
• Hypercalcemia
• Ovarian failure
• Pernicious anemia
• Myasthenia gravis
• Vitiligo
• Chronic moniliasis
• Sarcoidosis
• Sjögren syndrome
• Chronic active hepatitis
• Schmidt syndrome

Diagnosis

History

• Weakness, fatigue
• Dizziness
• Anorexia, nausea, vomiting
• Abdominal pain
• Chronic diarrhea
• Depression (60–80% of patients)
• Decreased cold tolerance
• Salt craving

Physical Exam

• Weight loss
• Low blood pressure, orthostatic hypotension
• Increased pigmentation (extensor surfaces, hand creases, dental-gingival margins, buccal and vaginal mucosa, lips, areola, pressure points, scars, “tanning,” freckles)
• Vitiligo
• Hair loss in females

Diagnostic Tests & Interpretation

Lab

Initial lab tests

• Basal plasma cortisol and adrenocorticotropic hormone (ACTH) (low cortisol and high ACTH indicative of Addison disease)
• Standard ACTH stimulation test: Cosyntropin 0.25 mg IV, measure preinjection baseline, and 60-minute postinjection cortisol levels (patients with Addison disease have low-to-normal values that do not rise)
• Insulin-induced hypoglycemia test
• Metapyrone test
• Autoantibody tests: 21-hydroxylase (most common and specific), 17-hydroxylase, 17-alpha-hydroxylase (may not be associated), and adrenomedullin
• Circulating very-long-chain fatty acid levels if boy or young man
• Low serum sodium
• Elevated serum potassium
• Elevated blood urea nitrogen, creatinine, calcium, thyroid-stimulating hormone (TSH)
• Low serum aldosterone
• Hypoglycemia when fasted
• Metabolic acidosis
• Moderate neutropenia
• Eosinophilia
• Relative lymphocytosis
• Anemia, normochromic, normocytic

Follow-Up & Special Considerations

• Plasma ACTH levels do not correlate with treatment and should not be used for routine monitoring of replacement therapy (1)[C].
• TSH: Repeat when condition has stabilized:
  • Thyroid hormone levels may normalize with the treatment of Addison disease.
• Drugs that may alter lab results: Digitalis
• Disorders that may alter lab results: Diabetes

Imaging

Initial approach

• Abdominal computed tomography (CT) scan: Small adrenal glands in autoimmune adrenalitis; enlarged adrenal glands in infiltrative and hemorrhagic disorders
• Abdominal radiograph may show adrenal calcifications.
• Chest x-ray may show small heart size and/or calcification of cartilage.
• Magnetic resonance imaging of pituitary and hypothalamus if secondary or tertiary cause of adrenocortical insufficiency is suspected.

Diagnostic Procedures/Surgery

CT-guided fine-needle biopsy of adrenal masses may identify diagnoses (2)[C].

Pathological Findings

• Atrophic adrenals in autoimmune adrenalitis
• Infiltrative and hemorrhagic disorders produce enlargement with destruction of the entire gland.

Differential Diagnosis

• Secondary adrenocortical insufficiency (pituitary failure):
  • Withdrawal of long-term corticosteroid use
  • Sheehan syndrome (postpartum necrosis of pituitary)
  • Empty sella syndrome
  • Radiation to pituitary
  • Pituitary adenomas, craniopharyngiomas
  • Infiltrative disorders of pituitary (sarcoidosis, hemochromatosis, amyloidosis, histiocytosis X)
• Tertiary adrenocortical insufficiency (hypothalamic failure):
  • Pituitary stalk transection
  • Trauma
  • Disruption of production of corticotropic-releasing factor
  • Hypothalamic tumors
• Other:
  • Myopathies
  • Syndrome of inappropriate antidiuretic hormone
  • Heavy-metal ingestion
  • Severe nutritional deficiencies
  • Sprue syndrome
  • Hyperparathyroidism
  • Neurofibromatosis
  • Peutz-Jeghers syndrome
  • Porphyria cutanea tarda
  • Salt-losing nephritis
  • Bronchogenic carcinoma
  • Anorexia nervosa

Treatment

Medication

First Line

• Chronic adrenal insufficiency:
  • Glucocorticoid supplementation:
    • Dosing: Hydrocortisone 15–20 mg (or therapeutic equivalent) p.o. each morning upon rising and 10 mg at 4–5 p.m. each afternoon (3)[C]; dosage may vary and is usually lower in children and the elderly
    • Precautions: Hepatic disease, fluid disturbances, immunosuppression, peptic ulcer disease, pregnancy, osteoporosis
    • Adverse reactions: Immunosuppression, osteoporosis, gastric ulcers, depression, hyperglycemia, weight gain, glaucoma
    • Drug interactions: Concomitant use of rifampin, phenytoin, or barbiturates
  • Mineralocorticoid supplementation:
    • Dosing: Fludrocortisone 0.05–0.2 mg p.o. per day
  • May require salt supplementation
• Addisonian crisis:
  • Hydrocortisone 100 mg IV followed by 10 mg/h infusion, or hydrocortisone 100 mg IV bolus q.6–8 h.
  • IV glucose, saline, and plasma expanders
  • Fludrocortisone 0.05 mg/d p.o. (may not be required; high-dose hydrocortisone is an effective mineralcorticoid)
• Acute illnesses (fever, stress, minor trauma):
  • Double the patient's usual steroid dose, taper the dose gradually over a week or more, and monitor vital signs and serum sodium.
• Supplementation for surgical procedures:
  • Administer hydrocortisone 25–150 mg or methylprednisolone 5–30 mg IV on the day of the procedure in addition to maintenance therapy; taper gradually to the usual dose over 1–2 days.

Second Line

Addition of androgen therapy:

• Dehydroepiandrosterone (DHEA) 25–50 mg p.o. once daily may be considered in women to improve well-being and sexuality (4)[B].

Additional Treatment

General Measures

Consider the 5 S's for the management of adrenal crisis:

• Salt, sugar, steroids, support, search for a precipitating illness (usually infection, trauma, recent surgery, or not taking prescribed replacement therapy)

In-Patient Considerations

Initial Stabilization

Addisonian crisis:

• Airway, breathing, and circulation management
• Establish IV access; 5% dextrose and normal saline
• Administer hydrocortisone 100 mg IV bolus q.6–8h.; replacement with fludrocortisone is not necessary (high-dose hydrocortisone is an effective mineralcorticoid)
• Correct electrolyte abnormalities.
• Blood pressure (BP) support for hypotension
• Antibiotics if infection suspected

Admission Criteria

• Presence of circulatory collapse, dehydration, hypotension, nausea, vomiting, hypoglycemia
• Intensive care unit admission for unstable cases

IV Fluids

Intravenous saline containing 5% dextrose and plasma expanders

Discharge Criteria

Normal laboratory and stable vital signs

Ongoing Care

Follow-Up Recommendations

Patient Monitoring

• Verify adequacy of therapy: Normal BP, serum electrolytes, plasma renin, and fasting blood glucose level
• Periodically assess for the development of long-term complications of corticosteroid use, including screening for osteoporosis, gastric ulcers, depression, and glaucoma
• Lifelong medical supervision for signs of adequate therapy and avoidance of overdose

Diet

Maintain water, sodium, and potassium balance.

Patient Education

• For patient education materials, contact: National Adrenal Disease Foundation, 505 Northern Blvd., Suite 200, Great Neck, NY 11021, (516) 487–4992 (http://www.medhelp.org/nadf)
• Patient should wear or carry medical identification with information about the disease and the need for hydrocortisone or other replacement therapy.
• Instruct patient in self-administering of parenteral hydrocortisone for emergency situations.

Prognosis

Requires lifetime treatment: Life expectancy approximates normal with adequate replacement therapy; without treatment, the disease is 100% lethal.

Complications

• Hyperpyrexia
• Psychotic reactions
• Complications from underlying disease
• Over- or underuse of steroid treatment
• Hyperkalemic paralysis (rare)
• Addisonian crisis

Acne Rosacea

Acne Rosacea

Basics

Description

• Rosacea is a chronic condition characterized by recurrent episodes of facial flushing, erythema (due to dilatation of small blood vessels in the face), papules, pustules, and telangiectasia (due to increased reactivity of capillaries) in a symmetrical, facial distribution. Sometimes associated with ocular symptoms (ocular rosacea).
• System(s) affected: Skin/Exocrine
• Synonym(s): Rosacea

Geriatric Considerations

• Uncommon >60 years of age
• Effects of aging might increase the side effects associated with oral isotretinoin (at present, data is insufficient due to lack of clinical studies in elderly patients aged 65 and above).

Epidemiology

Prevalence

• Predominant age: 30–50 years
• Predominant sex: Female > Male. However, male will often progress to later stages.

Risk Factors

• Exposure to cold, heat, hot drinks
• Environmental trigger factors: Sun, wind, cold

Genetics

People of Northern European and Celtic background commonly afflicted

General Prevention

No preventive measures known

Etiology

• No proven cause
• Possibilities include:
  • Thyroid and gonadal disturbance
  • Alcohol, coffee, tea, spiced food overindulgence (unproven)
  • Demodex follicular parasite (suspected)
  • Exposure to cold, heat, hot drinks
  • Emotional stress
  • Dysfunction of the gastrointestinal tract

Commonly Associated Conditions

• Seborrheic dermatitis of scalp and eyelids
• Keratitis with photophobia, lacrimation, visual disturbance
• Corneal lesions
• Blepharitis
• Uveitis

Diagnosis

History

• Usually have a history of episodic flushing with increases in skin temperature in response to heat stimulus in mouth (hot liquids), spicy foods, alcohol, sun (solar elastosis). Acne may have preceded the onset of rosacea by years; nevertheless, rosacea usually arises de novo without any preceding history of acne or seborrhea.
• Excessive facial warmth and redness is the predominant presenting complaint. Itching is generally absent.

Physical Exam

• Rosacea has typical stages of evolution:
  • The rosacea diathesis: Episodic erythema, “flushing and blushing”
  • Stage I: Persistent erythema with telangiectases
  • Stage II: Persistent erythema, telangiectases, papules, tiny pustules
  • Stage III: Persistent deep erythema, dense telangiectases, papules, pustules, nodules; rarely persistent “solid” edema of the central part of the face (phymatous)
• Facial erythema, particularly on cheeks, nose, and chin. At times, entire face may be involved.
• Inflammatory papules are prominent, and there may be pustules and telangiectasia.
• Comedones are absent (unlike acne).
• Women usually have lesions on the chin and cheeks, whereas nose is commonly involved in men.
• Ocular findings (mild dryness and irritation with blepharitis, conjunctival injection, burning, stinging, tearing, eyelid inflammation, swelling, and redness) are present in 50% of patients.

Diagnostic Tests & Interpretation

Diagnosis is based on physical exam findings.

Pathological Findings

• Inflammation around hypertrophied sebaceous glands, producing papules, pustules, and cysts
• Absence of comedones and blocked ducts
• Vascular dilation and dermal lymphocytic infiltrate

Differential Diagnosis

• Drug eruptions (iodides and bromides)
• Granulomas of the skin
• Cutaneous lupus erythematosus
• Carcinoid syndrome
• Deep fungal infection
• Acne vulgaris
• Seborrheic dermatitis
• Steroid rosacea (abuse)
• Systemic lupus erythematosus

Treatment

Medication

First Line

• Azelaic acid (Finacea) with oral doxycycline is very effective as initial therapy and then Azelaic acid topical alone is effective for maintenance (3,3)[A].

Precautions: Tetracycline may cause photosensitivity; sunscreen is recommended.

Significant possible interactions:

• Tetracycline: Avoid concurrent administration with antacids, dairy products, or iron.
• Broad-spectrum antibiotics: May reduce the effectiveness of oral contraceptives; barrier method is recommended.

Pediatric Considerations

• Tetracycline: Not for use in children <8 years

Pregnancy Considerations

• Tetracycline: Not for use during pregnancy
  • Isotretinoin: Teratogenic; not for use during pregnancy or in women of reproductive age who are not using reliable contraception

Second Line

• Topical erythromycin
• Topical clindamycin lotion preferred
• Possible utility of calcineurin inhibitors (tacrolimus 0.1%; pimecrolimus 0.1%)
• Permethrin 5% cream (5)[A] similar efficacy compared to metronidazole
• Topical steroids should not be used, as they may aggravate rosacea.
• For severe cases, isotretinoin p.o. for 4 months

Additional Treatment

General Measures

• Use of mild, nondrying soap is recommended; local skin irritants should be avoided.
• Reassurance that rosacea is completely unrelated to poor hygiene
• Treat psychological stress if present
• Avoid oil-based cosmetics:
  • Others are acceptable and may help women tolerate the symptoms.
• Electrodesiccation or chemical sclerosis of permanently dilated blood vessels
• Possible evolving laser therapy
• Support physical fitness

Surgery/Other Procedures

Laser treatment is an option for progressive telangiectasias or rhinophyma.

Ongoing Care

Follow-Up Recommendations

Outpatient treatment

Patient Monitoring

• Occasional and as needed
• Close follow-up for women using isotretinoin

Diet

Avoid alcohol, excessive sun exposure, and hot drinks of any type.

Prognosis

• Slowly progressive
• Subsides spontaneously (sometimes)

Complications

• Rhinophyma (dilated follicles and thickened bulbous skin on nose), especially in men
• Conjunctivitis
• Blepharitis
• Keratitis
• Visual deterioration