Kamis, 29 November 2007

Actinomycosis

Background: Many infectious and inflammatory diseases affect the skin and the oral mucosa. Actinomycosis is one such characteristic and persistent infection. It is a subacute, chronic, cellulitic invasion of the soft tissues that causes the formation of external sinus tracts that discharge sulfur granules. This process spreads unimpeded by traditional anatomic barriers after the endogenous oral commensal organisms invade the tissues of the face and neck. The infection may spread to the pulmonary and GI systems as well (Schaal, 1984).

Actinomycosis is caused by various bacterial species of the actinomycete group. Usually, the disease is caused by Actinomyces israelii, an anaerobic gram-positive organisms that enters the tissue through a break in the mucosa (Eastridge, 1972). The Actinomyces genus of bacteria includes other species that normally inhabit the oral cavity but are seldom pathogenic. The infection begins as an inflammatory soft tissue mass, which can enlarge into an abscesslike swelling, with penetration of the overlying skin and the development of recognizable draining fistulae.

The term actinomycosis is misleading. Because of the derivative term mycosis (from the Greek mykes), some believe that actinomycosis is a fungal infection, although it is not a fungal infection. Aktino referred to the radiating organism in the sulfur granule as ray fungus. Human actinomycosis was first described in the medical literature in 1857, although a similar disease in cattle had been described in 1826. In 1877, Bollinger found Actinomyces bovis in granules from cattle with a condition called lumpy jaw. In 1878, Israel discovered granules in human autopsy material and described actinomycosis in humans in 1885 (Richtsmeier, 1979). Israel further discovered that Actinomyces species do not survive outside mammalian hosts and that they are not found exogenously in plants or soil.

Prior to the antibiotic era, actinomycosis was a common illness and easily recognized at clinical examination. However, the microbiologic features of the etiologic organisms were not fully clarified until the 1940s (Erikson, 1940). The therapeutic outcome of surgical management was variable, and even if healing occurred, sequelae and complications were common (Waksman, 1943; Georg, 1974). The disease often became lifelong, and death was not unusual. At the dawn of the antibiotic era, morbidity resulting from actinomycosis decreased, and a general lack of familiarity with the disease process resulted (Brock, 1973). Subsequently, diagnoses of actinomycosis were often delayed because of a lack of microbiologic techniques.

strong>Pathophysiology: The pathogen is a filamentous bacterium. Historically, actinomycosis has been confused with a fungal disease because of its appearance and the slowly progressive nature of the lesions, which mimics mycotic illness. Confusion was so great that, for many years, some investigators placed Actinomyces species in an intermediate status between fungi and bacteria (Eastridge, 1972). The unique nature of the organism is the absence of a nuclear membrane, which places Actinomyces species among the higher prokaryotic bacteria. The lack of chitin and gluten, coupled with the presence of muramic acid in the cell walls and the absence of mitochondria, is another distinct feature (Behbehani, 1983).

All species of Actinomyces are normal commensal inhabitants of the oral and buccal cavities in humans and certain other mammals. They cannot be classified as symbiotic organisms because they do not have a mutually beneficial relationship with their host. They are not true parasites because they usually do not cause harm to the host; however, they definitely assume a parasitic role when they result in an infection with an inflammatory tissue response. Similar to Mycobacterium tuberculosis, actinomycetes survive phagocytosis by host cells, and they may be characterized as facultative intracellular parasites.

Actinomycosis does not appear to be an opportunistic infection because it is not common in patients who are immunosuppressed or in patients with AIDS. One of the authors has experience in producing a bone infection in animals that leads to osteomyelitis; however, actinomycosis could not be induced in the tibias and mandibles of rabbits. This outcome may have been the result of the avirulent nature of the organisms. Perhaps the presence of other infectious bacteria is required in addition to the Actinomyces species to initiate the infection in experimental models (Najjar, 1980).

Frequency:

  • In the US: The incidence of human actinomycosis has been decreasing in the United States. Weese and Smith reported prevalences of 1 case per 12,000 admissions in the 1930s and 1 case per 21,000 admissions in the 1950s. Bennhoff reported a prevalence of only 1 case per 63,000 admissions in the 1970s. Actinomycosis can still be found in inner-city populations of the United States.
  • Internationally: Actinomycosis remains a problem in underdeveloped countries (Coleman, 1969).

Mortality/Morbidity: No evidence of long-term morbidity is observed in patients treated with antibiotics and surgical excision of the necrotic tissue.

Race: Actinomycosis affects persons of all socioeconomic levels and all races, and the disease is not limited to any single segment of the population.

Sex: A male-to-female predominance in a ratio of approximately 3:1 has been observed (Eng, 1981). This predominance is postulated to reflect the greater likelihood for facial and oral trauma and the lack of oral hygiene in males compared with females.

Age: The incidence of actinomycosis is higher in persons aged 30-60 years than in others, and the disease is rare in children. This difference may reflect the increased incidence of periodontal disease in elderly individuals.

Treatment
Medical Care: The presence of associated bacteria appears to be fundamental to the development of clinical infection. Therefore, antibiotic coverage should be aimed at all associated organisms in patients with actinomycosis. An aerobic environment is an unfavorable condition for the growth of Actinomyces species and thus halts the infection (Schaal, 1983; Lewis, 1978; Hennrikus, 1987; Lerner, 1974; Deshpande, 1985).

With the combined use of penicillin and surgery, cure has become the rule rather than the exception.

  • The treatment of choice includes large doses of antibiotics and prolonged therapy coupled with drainage of the abscesses or radical excision of the sinus tracts. High penicillin concentrations are necessary to penetrate areas of fibrosis and suppuration and possibly the granules themselves. Occasionally, extensive disease may respond to intravenous penicillin alone, rendering surgery unnecessary.
  • If recognized early, cervicofacial infection has an excellent prognosis with the use of antibiotics alone. In the treatment of this infection, tetracyclines are as effective as penicillin. Intravenous penicillin G (10-20 million U/d for 2-6 wk) followed by oral penicillin (2-4 g/d for an additional 3-12 mo) is the typical therapy for the most deep-seated infections (Holmberg, 1977).
  • Actinomyces organisms are also susceptible to chloramphenicol, erythromycin, tetracyclines, and clindamycin but not to metronidazole or aminoglycosides.
  • When tuberculosis is suspected, the effects of rifampin therapy can mask the signs of undiagnosed pulmonary actinomycosis.
  • Because the bacterial species do not vary in terms of their susceptibility to first-line drugs (eg, penicillin, tetracyclines, erythromycin, first-generation parenteral cephalosporins, clindamycin), infection with strains other than A israelii should also respond to adequate courses of treatment with penicillin G or any of its alternatives. Serum concentrations of sulfonamides (4-8 mg/dL) inhibit some strains of A israelii; therefore, proven cases of actinomycosis (that are not mistaken instances of nocardiosis) may occasionally respond to sulfonamides. Oral cephalosporins and semisynthetic penicillins (eg, oxacillin, dicloxacillin) are less active in vitro and are best avoided (Boand, 1949).
  • The acquired resistance of Actinomyces species to antimicrobials, particularly to penicillin G, has not been confirmed in vivo. When the response to penicillin is poor, consider an undrained abscess or an associated infection with a resistant bacterium. European investigators favor the use of ampicillin for initial therapy because associated bacteria are less susceptible to penicillin G in vitro, and they use metronidazole or clindamycin as a secondary agent when Bacteroides fragilis or Bacteroides thetaiotaomicron is present. Imipenem produces an impressive response in extensive, complicated, and relapsing abdominothoracic infections that fail to respond to several surgical procedures and trials of penicillin G (Edelmann, 1987).

Surgical Care: Surgical management has consisted of various treatment modalities, including excision of sinus tracts, drainage of the abscess cavities, removal of the bulky infected masses, and irrigation and curettage of the osteomyelitic bony lesions.

The abscesses should be drained, or sinus tracts should be radically excised. With the combined use of penicillin and surgery, cure has become the rule rather than the exception.

Consultations: An oral and maxillofacial surgeon should be consulted because the jaws are involved.

Medication
The goals of pharmacotherapy in the treatment of actinomycosis are to eradicate the infection, reduce morbidity, and prevent complications.
Drug Category: Antibiotics -- Therapy must cover all likely pathogens in the context of this clinical setting. Antibiotic selection should be guided by blood culture sensitivity whenever feasible.
Drug Name
Penicillin G (Pfizerpen) -- Interferes with synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms.
Prolonged therapy, including >1 year, may be necessary.
Adult DoseCervicofacial: 1-6 million U/d IV for 2-6 wk
Thoracic and abdominal: 10-20 million U/d IV (administer slowly) for 2-6 wk; administer penicillin VK thereafter
Pediatric Dose<1>
1-4 weeks: 25,000 U q8h IV (1.2-2 kg) or q6h (>2 kg)
<12>1 month: for mild/mod disease use 25,000-50,000 U/kg/d IV divided qid; for severe disease use 250,000-400,000 U/kg/d IV in 4-6 divided doses
>12 years: Administer as in adults
ContraindicationsDocumented hypersensitivity
InteractionsEffects are increased by coadministration with probenecid and decreased by coadministration with tetracyclines and other bacteriostatic antibiotics
Pregnancy B - Usually safe but benefits must outweigh the risks.
PrecautionsCaution in impaired renal function and newborns; rash; anaphylaxis; opportunistic infections with prolonged use; electrolyte imbalances with high doses (above 10 million U/d) if not administered slowly, frequently check electrolytes, renal function, and hematopoietic function (risk of positive Coombs' hemolytic anemia); black hairy tongue; Warner Chillcott's penicillin VK powder contains aspartame (if patient has PKU)
Drug Name
Penicillin VK (Beepen-VK, Betapen-VK, Pen-Vee K, Robicillin VK, Veetids) -- Interferes with synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms. Has better GI absorption than penicillin G
Adult Dose2-4 g/d PO in 4-6 divided doses (best if 1 h before or 2 h after meals) for 6-12 mo
Pediatric Dose<1>
>1 month: 15-62.5 mg/kg/d PO in 3-6 divided doses for 6-12 mo; not to exceed adult doses
ContraindicationsDocumented hypersensitivity
InteractionsProbenecid may increase effectiveness by decreasing clearance; tetracyclines are bacteriostatic, causing a decrease in the effectiveness of penicillins when administered concurrently
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsCaution in renal impairment

Actinic Purpura

Background

Actinic purpura is a benign clinical entity resulting from sun-induced damage to the connective tissue of the dermis. Actinic purpura is characterized by ecchymoses on the extensor surfaces of the forearms and the dorsa of the hands that usually last 1-3 weeks.

Bateman first described the condition in 1818 when he noted dark purple blotches and determined that they were due to the extravasation of blood into the dermal tissue. Hence, it is sometimes called Bateman purpura.

It is common in elderly individuals and usually occurs after unrecognized minor trauma to the respective areas.

Pathophysiology

The purple macules and patches of this condition occur because red blood cells leak into the dermal tissue. This extravasation is secondary to the fragility of the blood vessel walls caused by ultraviolet radiation–induced dermal tissue atrophy. This atrophy renders the skin and microvasculature more susceptible to the effects of minor trauma and shearing forces. The insult to the skin is typically so minor that isolating it as a cause of the ecchymoses can be difficult.

Notably, no inflammatory component is found in the dermal tissue. The absence of a phagocytic response to the extravascular blood has been postulated to be responsible for delaying resorption for as long as 3 weeks.

Actinic purpura may be, along with osteoporosis, a sign of collagen loss in skin and bone.2 This causal loss of skin collagen has been confirmed when collagen was expressed absolutely, instead of as a percentage or ratio. That is, women have less collagen than men and it decreases by 1% a year in exposed and unexposed skin. These changes in skin collagen may correspond to changes in bone density. The hypothesis is that the changes in skin collagen also occur in bone collagen, leading to the associated changes in bone density.

Frequency

United States

Actinic purpura is an extremely common finding in elderly individuals, occurring in approximately 11.9% of those older than 50 years. Its prevalence markedly increases with years of exposure to the sun.

International

Data are not available.

Mortality/Morbidity

The ecchymoses may be cosmetically distressing and may leave dyspigmentation or scarring, but the lesions are not associated with any serious complications.

Race

The effects of chronic sun exposure with the resultant ultraviolet radiation–induced skin changes occur more often and are more pronounced in fair-skinned individuals than in others.

Sex

Both sexes are equally affected.

Age

  • Actinic purpura occurs almost exclusively in the elderly population, though it may sporadically occur in younger people.
  • The incidence varies with respect to age.
  • Approximately 2% of those aged 60-70 years and as many as 25% of those aged 90-100 years can have the purpuric lesions.
Treatment

Medical Care

  • Actinic purpura does not require extensive medical care.
    • To prevent further ultraviolet-induced damage to the skin, sunscreens that provide both UV-A and UV-B protection should be applied daily, especially to areas affected by the purpuric lesions.
    • Patients should also use barrier protection (eg, clothing).
    • Inform patients that sunscreens help prevent but do not reverse the photodamage.

  • Tretinoin has been observed to reverse many changes that occur with photodamage.
    • The use of tretinoin may be beneficial in actinic purpura because photodamage is ultimately responsible for this disorder.

    • Tretinoin increases the amount of dermal collagen and decreases the amount of abnormal elastin when applied topically. However, to the authors' knowledge, no results demonstrate that actinic purpura lesions improve with the topical application of tretinoin.

Activity

  • Advise patients with actinic purpura to limit their sun exposure by applying sunscreen daily or by avoiding sun exposure altogether.
  • Instruct patients to minimize any trauma to the skin where the purpuric lesions are present.

Actinic Prurigo

Background

Actinic prurigo (AP) is a chronic, pruritic skin disease caused by an abnormal reaction to sunlight. In 1954, Escalona first described it in Mexico. Lesions appear hours or days following sun exposure, contrary to what happens in solar urticaria where skin lesions appear minutes after UV exposure. It is commonly associated with cheilitis and conjunctivitis.

Pathophysiology

No systemic or local photosensitizer is known in patients with AP, and a hypersensitivity implicating immunoglobulin E (IgE) has not been demonstrated.

AP has many features of a type IV hypersensitivity reaction. Skin lesions associated with AP are infiltrated with T lymphocytes, mostly CD4+, and some of the T-cells express activation markers. AP falls in the category of autoimmune diseases because lymphocytes from patients have been proven to be stimulated in a thymidine incorporation assay when confronted with their own UV-irradiated keratinocytes or UV-irradiated epidermal homogenates.

At this point, the antigen that provokes the inflammatory reaction is not clear, but an epidermal protein is believed to be transformed by UV exposure. In the series by Santos-Martinez et al, the presence of transforming growth factor-beta interleukin 13, and interleukin 10 was demonstrated in a non–type-TH1, non–type-TH2 pattern, similar to what has been shown in lesions of psoriasis and in the synovial fluid of rheumatoid arthritis.

Another potentially important finding in the pathogenesis of AP may be the fact that Langerhans cells in persons with AP show resistance to UV exposure when compared with those in healthy individuals.This same finding has been shown in patients with a similar disease, polymorphous light eruption (PLE). Because these cells are resistant to their demise after UV exposure, they might handle and deliver UV-modified cutaneous antigens to T cells in larger amounts or in a more persistent way; this process could cause or augment the inflammatory phenomenon that is observed in the skin of patients with AP. The apoptotic mechanism in these cells may be somewhat altered, facilitating their survival.

On the other hand, the polyclonal cellular immune response found in biopsy samples from Mexican patients through Southern blot analysis may involve an imbalance linked to a specific hyperimmunity, in which the proportion of autoimmune cells is increased and the proportion of other cells is decreased.

Although different series are searching for a specific HLA, studies have shown associations with B40 and CW3 alleles in some populations, especially Amerindians. For instance, in the Chimila Indians from Colombia,a high frequency of HLA-Cw4 was found. However, in Cree Indians from Saskatchewan, Canada, the most common antigens were HLA-A24 and HLA-Cw4.

Other studies have shown a strong association with HLA-DR4. The more precise finding appears to be in the Mexican series, in which HLA-DR4 DRB1*0407 is found in more than 90% of patients with AP.Another series also found HLA-DR4 DRB1*0407 in Colombian patients. Related alleles such as DRB*0407 have been found in British populations,and DRB1*14 has been found in the Inuit Indians of Canada.

English patients with polymorphic light eruption (PMLE) have not shown an association with any HLA, which suggests that HLA-DR4 (DRB1*0407) could be used as a marker to distinguish PMLE from AP. Therefore, the association with HLA in AP but not in PLE suggests that AP represents an immunologically mediated disease with strong genetic determinants for its expression.

Frequency

United States

AP occurs in persons of all skin types, but its prevalence in the general population is unknown. It probably represents less than 5% of referrals to photodermatologic clinics.AP is well known in the United States among Native Americans.

International

In Mexico, AP represents 1.34% of consultations with pediatric dermatologists and 4% of consultations with general dermatologists. AP is common in Mexico, Central America, and South America, and it is well known in Canada among Native Americans.AP rarely occurs in Europe and Asia, where PLE (a disease with pathogenetic features similar to AP) is more regularly seen. Isolated cases have been reported in France,Germany, Japan, Singapore, Thailand,and Australia. However, the prevalence rate of AP in photodermatology clinics around the world varies from 0-5%.

Mortality/Morbidity

AP is not associated with mortality.

Race

AP frequently affects mestizos of Latin America and American Indians with skin phototypes IV or V.

Sex

In children and adolescents, no differences in prevalence exist between the sexes. However, in adults, women are more frequently affected than men, with a female-to-male ratio of 2:1.

Age

AP can occur at any age; however, one third of patients are children.

Treatment

Medical Care

  • The cornerstone of pharmacologic treatment is 100 mg/d of thalidomide. Studies have shown that this drug modulates its effect on PA through suppression of tumor necrosis factor-alpha synthesis and modulation of interferon-gamma–producing CD3+ cells.Thalidomide can be gradually reduced and then reinstituted in cases of relapse. Women in their childbearing years must use contraceptives because of the teratogenic potential of thalidomide. On some occasions, topical steroids or immunosuppressors are indicated, especially in acute exacerbated cases. Once the skin lesions remit, sunscreens should be used.
  • Other medications frequently used with moderate results, because of their anti-inflammatory action, are antimalarials and pentoxyphilline,although these drugs are more useful as topical corticosteroid-sparing agents.
  • Less favorable results are obtained with antihistaminics, beta-carotenes, and psoralen plus UV-A light.
  • If complications (eg, secondary infection, eczema) occur, patients can be treated with oral antibiotics or topical Burow solution.

Activity

Patients affected by AP should not have restrictions in any areas, such as employment and education. However, changing from outdoor to indoor occupations is important if the patient is not improving with treatment.

Medication

Treatment is mainly aimed at avoiding sun exposure. However, oral and topical corticosteroids are frequently used for short periods. Thalidomide is used, either alone or with topical corticosteroids, for resistant or multiple relapse cases.

Drug Category: Immunosuppressant agents

These agents inhibit key steps responsible for initiating immune activity.

Drug NameThalidomide (Thalomid)
DescriptionImmunomodulatory agent that may suppress activated lymphocytes or prevent their activation. Also down-regulates excessive production of tumor necrosis factor-alpha and selected cell-surface adhesion molecules involved in leukocyte migration.
Adult Dose100-300 mg/d PO qd with water, preferably hs and at least 1 h pc
<50>
Pediatric Dose0.5-2.5 mg/kg/d PO qd with water
ContraindicationsDocumented hypersensitivity
InteractionsMay increase sedation of alcohol, barbiturates, chlorpromazine, and reserpine; because of teratogenic effects, women must use 2 additional methods of contraceptives or abstain from intercourse
PregnancyX - Contraindicated in pregnancy
PrecautionsPerform pregnancy test within 24 h prior to initiating therapy (weekly during the first month, followed by monthly tests in women with regular menstrual cycles or q2wk in women with irregular menstrual cycles); bradycardia may occur; use protective measures (eg, sunscreens, protective clothing) against exposure to sunlight or UV light (eg, tanning beds); prescribing physician must enter STEPS program established by manufacturer

Drug Category: Corticosteroids

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Drug NamePrednisone (Orasone, Meticorten, Sterapred, Deltasone)
DescriptionImmunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocytes.
Adult Dose0.5-2 mg/kg/d PO; taper as condition improves; single morning dose is safer for long-term use, but divided doses have more anti-inflammatory effect
Pediatric Dose4-5 mg/m2/d PO; alternatively, 0.05-2 mg/kg PO divided bid/qid; taper over 2 wk as symptoms resolve
ContraindicationsDocumented hypersensitivity; viral, fungal, connective tissue, or tubercular skin infections; peptic ulcer disease; hepatic dysfunction; GI bleeding or ulceration
InteractionsCoadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
PregnancyB - Usually safe but benefits must outweigh the risks.
PrecautionsAbrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Drug NameBetamethasone (Diprolene, Maxivate, Alphatrex)
DescriptionFor inflammatory dermatoses responsive to steroids. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing capillary permeability. Affects production of lymphokines and has inhibitory effect on Langerhans cells.
Adult DoseApply thin film bid/qid until response
Pediatric DoseApply as in adults with caution
ContraindicationsDocumented hypersensitivity; paronychia; cellulitis; impetigo; angular cheilitis; erythrasma; erysipelas; rosacea; perioral dermatitis; acne
InteractionsNone reported
PregnancyC - Safety for use during pregnancy has not been established.
PrecautionsDo not use in skin with decreased circulation; can cause atrophy of groin, face, and axillae; may cause striae distensae or rosacealike eruption; may increase skin fragility; rarely may suppress HPA axis; if infection develops and is not responsive to antibiotic treatment, discontinue until infection is under control; do not use monotherapy to treat widespread plaque psoriasis

Drug Category: Antimalarial agents

These agents are used for their anti-inflammatory and photoprotective effects.

Drug NameHydroxychloroquine (Plaquenil)
DescriptionExerts anti-inflammatory activity by suppressing lymphocyte transformation and may have photoprotective effect. Use in AP requires small doses once a day for long periods.
Adult Dose200 mg/d PO qd to bid
Pediatric Dose4 mg/kg/d PO once
ContraindicationsDocumented hypersensitivity to 4-aminoquinoline derivatives; psoriasis; retinal and visual field changes attributable to 4-aminoquinolines
InteractionsCimetidine may increase serum levels of chloroquine (possibly other 4-aminoquinolones); magnesium trisilicate may decrease absorption of 4-aminoquinolones
PregnancyC - Safety for use during pregnancy has not been established.
PrecautionsCaution in hepatic disease, G-6-PD deficiency, psoriasis, or porphyria; not recommended for long-term use in children; perform periodic ophthalmologic examinations; test for muscle weakness; retinopathy, tinnitus, nerve deafness, skin eruption, headache, anorexia, nausea, vomiting, and diarrhea may occur
Drug NameChloroquine phosphate (Aralen Phosphate)
DescriptionInhibits chemotaxis of eosinophils and locomotion of neutrophils, and impairs complement-dependent antigen-antibody reactions. May also have photoprotective effect.
Adult Dose250-600 mg PO qd
Pediatric DoseNot established; 4 mg/kg/d PO can be used
ContraindicationsDocumented hypersensitivity; psoriasis; retinal and visual field changes attributable to 4-aminoquinolones
InteractionsCimetidine may increase serum levels of chloroquine (possibly other 4-aminoquinolones); magnesium trisilicate may decrease absorption of 4-aminoquinolones
PregnancyC - Safety for use during pregnancy has not been established.
PrecautionsCaution in hepatic disease, G-6-PD deficiency, psoriasis, or porphyria; not recommended for long-term use in children; perform periodic ophthalmologic examinations; test for muscle weakness; retinopathy, tinnitus, nerve deafness, skin eruption, headache, anorexia, nausea, vomiting, and diarrhea may occur

Actinic Keratosis

Background: Actinic keratosis (AK) is a UV light–induced lesion of the skin that may progress to invasive squamous cell carcinoma. It is by far the most common lesion with malignant potential to arise on the skin. AK is seen in fair-skinned persons in areas of long-term sun exposure, with an estimated frequency of 40-50% of the adult population older than 40 years in Australia, the country with the highest skin cancer rate in the world.

Although the premalignant nature of AK was recognized almost 100 years ago, the name AK was not introduced until 1958. The name literally means thickened scaly growth (keratosis) caused by sunlight (actinic). These lesions are common in white populations. In the United States, AK represents the second most frequent reason for patients to visit a dermatologist. Although most do not, some of these lesions may progress to invasive squamous cell carcinoma with metastatic potential. They can be safely and effectively eradicated, and therefore therapy is warranted.

Pathophysiology: AKs arise on fair-skinned people in areas of long-term sun exposure, such as the face, ears, bald scalp, forearms, and backs of the hands. However, they may occur on any area that is repeatedly exposed to the sun, such as the back, the chest, and the legs. Long-term UV light exposure is implicated as the cause from both epidemiologic observations and molecular analysis of tumor cells. AK frequency correlates with cumulative UV exposure. Therefore, AK frequency increases with each decade of life, is greater in residents of sunny countries closer to the equator, and is greater in persons with outdoor occupations. DNA analysis of the cells within AKs shows characteristic UV-induced mutations in key genes.

Clinically, AKs range from barely perceptible rough spots of skin to elevated, hyperkeratotic plaques several centimeters in diameter. Most often, they appear as multiple discrete, flat or elevated, keratotic lesions. Lesions typically have an erythematous base covered by scale (hyperkeratosis). They are usually 3-10 mm in diameter and gradually enlarge into broader, more elevated lesions. With time, actinic keratoses may develop into invasive squamous cell carcinoma. Development of actinic keratoses may occur as early as the third or fourth decade of life in patients who live in areas of high solar radiation, are fair-skinned, and do not use sunscreen for photoprotection. Usually, patients demonstrate a background of solar-damaged skin with telangiectasias, elastosis, and pigmented lentigines.

In both histologic and molecular parameters, AKs share features with squamous cell carcinoma. AK is an epidermal lesion characterized by aggregates of atypical, pleomorphic keratinocytes at the basal layer that may extend upwards to involve the granular and cornified layers. The epidermis itself shows an abnormal architecture, with acanthosis, parakeratosis, and dyskeratoses. Cellular atypia is present, and the keratinocytes vary in size and shape. Mitotic figures are present.

This presentation may resemble Bowen disease or carcinoma in situ, and the distinction between the 2 is a matter of degree (extent of the lesion) rather than differences in individual cells. Often, marked hyperkeratosis and areas of parakeratosis with loss of the granular layer are present. A dense inflammatory infiltrate is usually present. The case has been made that AK is the earliest manifestation of squamous cell carcinoma and should be regarded as such rather than as a precancerous lesion. Others have argued that calling AK a carcinoma unduly alarms patients. Cockerell has proposed renaming the lesion keratinocytic intraepidermal neoplasia, in a nomenclature analogous to cervical and vulvar intraepithelial neoplasia.

Frequency:

  • In the US: AK occurs primarily in whites, the frequency of which correlates with cumulative UV exposure. Therefore, frequency increases with age, proximity to the equator, and outdoor occupation. AKs are seen more in men than in women and have also been correlated with a high-fat diet. Overall, the rate in the United States is estimated to range from 11-26%.
  • Internationally: The prevalence is highest in Australia, where a light-skinned population is common and outdoor sports are very popular activities. Overall, AK is estimated to be present in 40-50% of the Australian population older than 40 years.

Mortality/Morbidity: Lesions begin as barely perceivable rough spots of skin, better felt than seen. The early lesions feel like sandpaper. Later lesions become erythematous, scaly plaques that may enlarge to several centimeters. Lesions may remain unchanged for years, may spontaneously regress, or may progress to invasive squamous cell carcinoma. Most AKs do not progress to invasive squamous cell carcinoma; however, most invasive squamous cell carcinomas have evidence of a preexisting AK. Invasive squamous cell carcinoma may produce significant morbidity by direct extension into facial structures. In less than 10% of cases, invasive squamous cell carcinoma may metastasize, with a low 5-year survival rate.

Race: The prevalence is much higher in individuals with fair skin and blue eyes and is lower in individuals with darker skin types. It is relatively nonexistent in black skin. Patients with AKs tend to have Fitzpatrick type I or II skin, which burns and does not tan. The prevalence is reduced precipitously in persons with Fitzpatrick types III, IV, and V skin and is nonexistent in those with Fitzpatrick type VI skin.

Sex: The prevalence of AK is higher in men than in women. This is theorized to result from a greater likelihood that men have an outdoor occupation and thus have greater cumulative UV exposure.

Age: The frequency of AK is directly related to cumulative sun exposure. The age of occurrence is related to the skin type and the amount of sun damage. AKs can occur in patients aged 20-30 years, but they are more common in patients aged 50 years and older.

Treatment
/a>Medical Care: AKs may remain unchanged, spontaneously resolve, or progress to invasive squamous cell carcinoma. The fate of any one AK is impossible to predict. Although the risk of progression of any one AK to invasive squamous cell carcinoma is small, a patient may have many lesions, and thus the risk of progression becomes significant. Therapy is generally well tolerated and simple; therefore, treatment is warranted.
  • Medical management begins with educating the patient to limit sun exposure. Patients should be cautioned to avoid sun exposure from 10:00 AM to 3:00 PM as much as possible. They also must wear adequate sunscreens and protective clothing daily. One study suggested that a low-fat diet leads to fewer new AKs and greater resolution of old ones.
  • Treatment consists of 2 broad categories: surgical destruction of the lesion and medical therapy. Medical therapy has the advantage of being able to treat large areas with many lesions. The disadvantages of medical therapies include lengthy courses of treatment with irritation and discomfort. Currently, the US Food and Drug Administration has approved 4 medications for the treatment of AKs. These are topical 5-fluorouracil (5-FU), 5% imiquimod cream, topical diclofenac gel, and photodynamic therapy (PDT) with topical delta-aminolevulinic acid.
    • The most experience in topical therapy for AKs is with 5-FU. Several formulations are available, including a 5% cream or solution, a 2% solution, a 1% cream or solution, and, most recently, a micronized 0.5% cream. Although not well studied, efficacy among the various formulations does not seem to differ significantly.
      • The most popular formulation is the 5% cream, which is applied twice daily for 1 month. During the treatment phase, the lesions become increasingly erythematous and cause discomfort; small subclinical lesions become visible. This treatment can be temporarily disfiguring, with erythematous ulcerations and crust formation. However, if the patient completes the treatment, the lesions usually heal within 2 weeks of stopping treatment, the complexion is smooth, and the AKs are improved.
      • The 0.5% micronized cream was developed to increase tolerability because inflammation and discomfort can be a limiting factor in the use of topical 5-FU. The 0.5% micronized cream is applied once daily for 1 month.
    • Imiquimod is a topical medication that up-regulates a variety of cytokines, which, in turn, invoke a nonspecific immune response (interferons, natural killer cells) and an specific immune response (T cells). It is applied 2-3 times a week for up to 4 months, although generally 1 month is sufficient. Reaction to the drug is idiosyncratic, with some patients barely reacting and others developing marked inflammation. Subclinical lesions previously not appreciated may become inflamed during therapy. In patients with a brisk inflammatory response, dosing is reduced to twice or even once a week, with preservation of therapeutic efficacy but increased tolerability. Experimental evidence suggests patients may develop T-cell memory after treatment with this drug and thus may be less likely to develop new AKs in the future.
    • Topical diclofenac is a nonsteroidal anti-inflammatory drug. Its mechanism of action against AKs is unknown. It is effective therapy when applied twice a day for 3 months. A shorter course of therapy is dramatically less effective. Its chief advantage is that it produces little-to-no inflammation and thus is very well tolerated.
    • PDT uses a light-sensitizing compound that preferentially accumulates in AK cells, where it can be activated by the appropriate wavelength of light. Delta-aminolevulinic acid is a component of the heme biosynthetic pathway that accumulates preferentially in dysplastic cells. Once inside these cells, it is enzymatically converted to protoporphyrin IX, a potent photosensitizer. With exposure to light of an appropriate wavelength, oxygen free radicals are generated and cell death results.
      • Patients experience pain in the areas treated, which is similar in scope to the pain resulting from topical 5-FU. The treated lesions may become erythematous and crusted. One treatment with PDT appears to be as effective as topical 5-FU therapy.
      • When used with light sources that have a cosmetic benefit by themselves, such as the pulsed dye laser of intense pulsed light devices, a cosmetic benefit may be seen from the use of topical PDT beyond that of AK eradication.
      • An unknown parameter in the use of topical PDT is the optimal incubation time following application of the topical aminolevulinic acid before light exposure. A second unknown parameter is the optimal light source to use for this treatment. Ongoing studies are addressing these issues.

Surgical Care: The goal of surgical therapy is complete eradication of the AKs, usually by physical destruction, with limited-to-no damage to surrounding normal tissue. When the diagnosis is unclear and invasive tumor is possible, biopsy is indicated. However, biopsy generally leaves a scar.

  • Cryosurgery refers to use of a cryogen to lower the temperature of the skin and produce cell death. The most common cryogen used is liquid nitrogen, with a temperature of -195.8°C. Keratinocytes die when exposed to approximately -40 to -50°C. Other structures in the skin, such as collagen, blood vessels, and nerves, are more resistant to the lethal effects of cold than keratinocytes. Melanocytes are more sensitive than keratinocytes; thus, cryosurgery often leaves white spots. This technique has not been studied in a scientific fashion until recently, when it was demonstrated to produce an overall clearance rate of 67%.
  • Lesions suggestive of invasive cancer may be treated with curettage, shave excision, or conventional excision, all of which provide a sample for histologic evaluation. These treatments require local anesthesia, produce a wound that requires time to heal, and are likely to scar.
  • Cosmetic resurfacing procedures, in which the entire epidermis is removed, sometimes with some portion of the dermis, are effective for AK eradication. Cosmetic resurfacing procedures include medium and deep chemical peels, dermabrasion, and ablative laser resurfacing. All of these are cosmetic procedures unlikely to be covered by insurance, all carry the risk of scarring and infection, and all require experience and expertise on the part of the dermatologic surgeon. They are highly unlikely to be performed solely for AK therapy.

Diet: One study suggested that a low-fat diet in humans leads to greater resolution of existent AKs and the development of fewer new ones during the study period.

Activity: Instruct patients to practice sun safety, such as the use of sunscreen and protective clothing, and to limit outdoor activity from 10:00 AM to 3:00 PM.

Medication
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Drug Category: Antineoplastic agents -- DOC is topical 5-FU lotion or cream, which inhibits cell growth and proliferation.
Drug Name
Fluorouracil (Fluoroplex, Carac, Efudex) -- Used topically for management of AKs. Interferes with DNA synthesis by blocking methylation of deoxyuridylic acid via inhibition of thymidylate synthetase and, subsequently, cell proliferation. For lesions on bald scalp or extremities, longer treatment is often necessary.
Adult DoseApply topically to affected areas bid for approximately 2-6 wk (has been used as long as 12 wk in some cases)
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; pregnancy
InteractionsNone reported
Pregnancy X - Contraindicated in pregnancy
PrecautionsInflammatory reactions may occur with occlusive dressings; porous gauze dressing may be applied for cosmetic reasons, without an increase in reaction; patients should expect inflammatory reaction with crusting; application to mucous membranes may cause increased inflammation and ulceration; exposure to UV rays (ie, sunlight) may increase intensity of the reaction
Drug Category: Immunomodulators, topical -- Investigation of imiquimod demonstrates it induces interferons alpha and gamma, TNF-alpha, and interleukin 12, among other cytokines. Studies using 5% cream in mice showed significant induction of interferon alpha at the site of application, occurring as early as 2 h after treatment. At 4 h after application, increases in interferon alpha mRNA levels were found, indicating an increase in transcription. Cytokine up-regulation is thought to be activated by imiquimod binding to toll-like receptor VII.
Drug Name
Imiquimod (Aldara) -- Immune response modifier thought to produce a nonspecific anti-AK response (interferon, natural killer cells) and a specific immune response (cytotoxic T cells). Indicated to treat clinically typical, nonhyperkeratotic, nonhypertrophic AKs on the face or scalp.
Adult DoseApply no more than 1 packet to defined area of face or scalp 2 times/wk hs for 16 wk; apply to dry skin (at least 10 min after washing face) and leave on for approximately 8 h; then, wash area with mild soap and water
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsNone reported
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsAvoid exposure to sunlight or artificial tanning devices; regular use of sunscreen is encouraged; avoid contact with lips, eyes, or nostrils; common adverse effects include erythema, edema, vesicles, erosion or ulceration, weeping, exudate, flaking, scaling, dryness, and scabbing, or crusting
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Acropustulosis of Infancy

Background: Infantile acropustulosis is a recurrent, self-limited, pruritic, vesicopustular eruption of the palms and the soles occurring in young children during the first 2-3 years of life. Newly described in 1979, it is probably much more common than the scarcity of reports would imply.

Pathophysiology: The pathophysiology of infantile acropustulosis is unknown. Many cases are preceded by well-documented or suspected scabies infestation, and a scabies id reaction has been suggested. More often, cases occur despite scabies having been thoroughly ruled out. Bacterial and viral culture results are consistently negative, and negative immunofluorescence results suggest that infantile acropustulosis is not an antibody-mediated autoimmune process.

Frequency:

  • In the US: The exact incidence is unknown.
  • Internationally: The exact incidence is unknown. One study from Israel reported 25 cases in a 9-year period, suggesting that this is not as uncommon as once thought.

Mortality/Morbidity: All cases spontaneously resolve in a few months to 3 years.

Race: Early reports suggested a predominance of African Americans. Now, acropustulosis is believed to affect all races equally.

Sex: Early reports suggested a male predominance. Larger series have since shown an equal distribution between males and females.

Age: Although children as old as 9 years have been reported, acropustulosis typically begins between the first 2-12 months of life. Resolution by age 3 years is the norm.

Treatment
Medical Care: Treatment is often unnecessary because of the self-limited nature of this condition.
  • Topical steroids and oral dapsone have been used successfully, if justified in more difficult cases.
  • Topical pramoxine preparations are available without prescription for the treatment of pruritus.
  • Oral antihistamines may be useful.

Consultations: Consult a dermatologist or a pediatric dermatologist.

Activity: Isolation is not warranted.

Medication
High-potency topical steroids (classes 1 and 2) have been used successfully for control of pruritus. Children who are extremely symptomatic may be treated with dapsone.
Drug Category: Topical steroids -- These agents provide symptomatic relief of pruritus.
Drug Name
Betamethasone (Diprolene, Betatrex) -- For inflammatory dermatoses responsive to steroids. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing capillary permeability. Use fluorinated topical steroids with caution in children.
Pediatric DoseApply thin film to affected areas bid; occlusion increases effectiveness; avoid wraps that may present choking hazard
ContraindicationsDocumented hypersensitivity; paronychia; cellulitis; impetigo; angular cheilitis; erythrasma; erysipelas; rosacea; perioral dermatitis; acne
InteractionsNone reported
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsApplication over large surface areas may cause systemic absorption and adrenal suppression; do not use on skin with decreased circulation; can cause atrophy of groin, face, and axillae; if infection develops and is not responsive to antibiotic treatment, discontinue until infection is under control
<Drug Category: Antibiotics -- Diaminodiphenylsulfone antibiotics have been used as anti-inflammatory agents.
Drug Name
Dapsone (Avlosulfon) -- Bactericidal and bacteriostatic against mycobacteria; mechanism of action is similar to that of sulfonamides where competitive antagonists of PABA prevent formation of folic acid, inhibiting bacterial growth. Used mainly to treat leprosy and dermatitis herpetiformis. Has antineutrophil and anti-inflammatory properties.
Pediatric Dose1-2 mg/kg/d PO; not to exceed 100 mg
ContraindicationsDocumented hypersensitivity; known G-6-PD deficiency (assay for G-6-PD activity prior to initiation of therapy)
InteractionsMay inhibit anti-inflammatory effects of clofazimine; hematologic reactions may increase with folic acid antagonists, eg, pyrimethamine (monitor for agranulocytosis during second and third months of therapy); probenecid increases toxicity; trimethoprim with dapsone may increase toxicity of both drugs; because of increased renal clearance, levels may significantly decrease when administered concurrently with rifampin
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsAssociated with a variety of systemic toxicities, including agranulocytosis, anemia, methemoglobinemia, hepatitis, and neuropathy; patients may experience headache and/or GI distress on initiation of therapy; perform weekly blood counts (first mo), then monthly WBC counts (6 mo), then semiannual WBC counts; discontinue if a significant reduction in platelets, leukocytes, or hematopoiesis occurs; caution in methemoglobin reductase deficiency, G-6-PD deficiency, or hemoglobin M because of high risk for hemolysis and Heinz body formation
Caution in patients exposed to other agents or conditions (eg, infection, diabetic ketosis) capable of producing hemolysis; peripheral neuropathy can occur (rare); phototoxicity may occur when exposed to UV light; pancreatitis may occur; various forms of renal complications including acute renal failure, acute tubular necrosis, and oliguria have occurred with dapsone use
<Drug Category: Antipruritics -- These agents may relieve associated itching.
Drug Name
Pramoxine (Tronothane, Prax) -- Blocks nerve conduction and impulses by inhibiting depolarization of neurons. Use 1% lotion or cream.
Pediatric DoseApply to affected area prn; not to exceed 200 mg
ContraindicationsDocumented hypersensitivity; do not apply over large areas; avoid contact with eyes and nose
InteractionsNone reported
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsCaution in patients with trauma in area to be treated


Acromegaly

Background

Excess secretion of growth hormone (GH) induces gigantism in prepubertal children and acromegaly in adults. Acromegaly arises from GH-secreting pituitary adenomas. GH is necessary for normal linear growth. GH is not the principal stimulator of growth, but it acts indirectly by stimulating the formation of other hormones. These hormones are termed somatomedins (SMs, ie, somatotropin-mediating hormones) or insulinlike growth factors (IGFs).

Somatomedin C (SM-C; insulinlike growth factor I [IGF-I]), the most important SM in postnatal growth, is produced in the liver, chondrocytes, kidney, muscle, pituitary, and gastrointestinal tract.

Pathophysiology

GH secretion from the pituitary gland is controlled by a combined hypothalamic regulation. Secretion is stimulated by growth hormone–releasing hormone (GHRH) and inhibited by GH release–inhibitory hormone or somatostatin (also termed somatotropin release–inhibitory factor or SRIF).

Syndromes of excessive secretion of GH or acromegaly are caused 95% of the time by a pituitary adenoma of the somatotrophs. A few cases of ectopic GHRH-producing tumors, usually seen in the lung or pancreas, also have been described.

Isolated familial somatotropinoma is a rare disease; at least 2 cases of acromegaly or gigantism has been reported in a family that does not exhibit features of Carney complex or multiple endocrine neoplasia type 1.1 It appears to be inherited as an autosomal dominant disease with incomplete penetrance. Although an association exists between the disease and loss of heterozygosity on 11q13, the responsible gene remains unknown.

Approximately 40% of somatotroph tumors have a mutation in the alpha subunit of a stimulatory G protein. Activation of this G protein is associated with binding of guanosine triphosphate (GTP) to the alpha subunit, which allows the alpha subunit to stimulate cyclic adenosine monophosphate (AMP) production. The normal free subunit has intrinsic GTPase activity, which inactivates GTP, preventing continued cyclic AMP stimulation. The mutant alpha subunit in acromegalic patients does not possess GTPase activity; therefore, continued cyclic AMP stimulation results.

GHRH-induced acromegaly is rare but is clinically indistinguishable from acromegaly caused by pituitary adenomas.

High levels of IGF-I are found in acromegaly, and low levels are found in children with GH deficiency. Insulin and IGF-I are similar peptides, and either can bind to IGF-I receptors.

Activation of this receptor leads to the growth and differentiation of many different cell lines, including keratinocytes, fibroblast, and the pilar unit of the skin.

Epidermal growth factor (EGF) and its homologs, transforming growth factor-alpha and amphiregulin, play a pivotal role in the regulation of keratinocyte growth and differentiation. All 3 growth factors stimulate cell growth by activating the epidermal growth factor receptor (EGF-R) that is expressed on keratinocytes in culture and in situ. Active proliferation of keratinocytes is associated with increased expression of the EGF-R and of its ligands (ie, transforming growth factor-alpha and amphiregulin) in the epidermis.

IGF-I and insulin, both of which stimulate keratinocyte growth through the IGF-I receptor, have been identified as primary keratinocyte mitogens. Proliferation induced by insulin and IGF-I requires the presence of other growth factors (notably EGF), and IGF-I stimulates keratinocyte proliferation in the absence of any other polypeptide growth factor at physiologic concentrations, through the IGF-I receptor. Thus, IGF-I is 1 of the factors inducing the growth factor component of the EGF-R–dependent autocrine loop in keratinocytes.

Frequency

United States

Acromegaly is uncommon, with an incidence of 3-4 cases per million per year. This figure easily may be an underestimation because of the insidiousness of this disease.

Mortality/Morbidity

Acromegaly is a severe disease often diagnosed late. Morbidity and mortality rates are high, in particular, because of associated cardiovascular, cerebrovascular, and respiratory disorders and malignancies.

  • Acromegaly is associated with an increase in left ventricular mass, even in the absence of systemic hypertension. Pathologic studies on acromegalic hearts have shown extensive interstitial fibrosis, suggesting the existence of a specific acromegalic cardiomyopathy.
  • Alveolar hypertrophy or hyperplasia is the mechanism for lung growth in this condition.
  • Increased colon and breast cancers have been associated with acromegaly.

Sex

Male-to-female ratio is equal.

Age

Acromegaly occurs most frequently in middle age. The mean age of diagnosis is 40 years in men and 45 years in women.

Treatment

Medical Care

No single treatment modality consistently achieves control of the disease. A multimodality approach usually requires surgery as the first line of treatment, followed by medical therapy for residual disease. Radiation treatment usually is reserved for recalcitrant cases. The most effective and practical drugs currently in use include somatostatin analogs and dopamine agonists such as bromocriptine.

This chronic debilitating disorder caused by a GH-producing pituitary adenomas is usually treated with transsphenoidal surgery as the treatment of choice; however, radiotherapy and medical treatment are important because surgery cures only approximately 60% in long-term studies.Slow-release formulations of somatostatin are now widely used, also as primary treatment, and appear to be safe and effective in 50-60% of the patients. A GH-receptor blocking agent, pegvisomant, appears to normalize IGF-1 levels in almost all patients

  • Somatostatin is a natural inhibitor of GH secretion. Octreotide is used most extensively.
    • Octreotide binds to the somatostatin receptor subtypes II and V and inhibits GH secretion.
    • Treatment with octreotide reduces GH concentration to less than 5 ng/mL in 65% of patients and less than 2 ng/mL in 40%.
    • Octreotide normalizes the IGF-I concentration in 60% of patients.
    • Tumor shrinkage is seen in 20-50% of patients.
    • Primary treatment with depot octreotide and lanreotide has been found to induce tumor shrinkage in newly diagnosed acromegaly.The best predictor of tumor shrinkage was after treatment with IGF-l.
  • Bromocriptine lowers serum GH in as many as 75% of patients, but in only 20% are the levels reduced to normal.
    • Patients in whom prolactin is elevated are more likely to have a favorable response.

    • GH-secreting tumors usually do not decrease in size with bromocriptine.

    • Bromocriptine has an adjunctive role in patients who fail to achieve a cure by surgical treatment or who are to be treated with radiation.

  • Periodic reassessment of GH production is advisable after treatment.
  • Criteria for cure include a normal basal GH level and normal GH dynamic responses.
  • SM-C levels appear to correlate better with clinical activity than do GH levels; therefore, SM-C levels should be monitored.
  • Radiotherapy takes years to become effective. Approximately 60% of patients have GH concentration of less than 5 ng/mL 10 years after radiotherapy. A similar number develop panhypopituitarism as a result of treatment. Because of the disappointing results and adverse effects, radiotherapy is used as an adjunct treatment for large invasive tumors and when surgery is contraindicated. Some studies suggest that radiation is associated with the development of secondary tumors.

Surgical Care

Surgery is performed as first-line therapy.

  • Transsphenoidal hypophysectomy has the dual advantage of rapidly improving symptoms caused by mass effect of the tumor and significantly reducing or normalizing GH/IGF-I concentrations.
  • Remission rates of 80-85% can be expected for microadenomas and 50-65% for macroadenomas.
  • Carefully monitor patients for enlargement or recurrence of a pituitary mass lesion.
  • The biochemical activity of disease after pituitary surgery in persons with acromegaly has been evaluated. By definition, biochemical cure in acromegaly involves both the normalization of IGF-1 levels and a glucose-suppressed GH level of less than 1 ng/mL. A significant proportion of acromegalic patients were found have a change in biochemical status upon long-term follow-up after surgery. Most of these changes occurred within the first postoperative year and were more likely to occur if the initial GH postglucose and IGF-1 levels were discordant.
Medication

The goal of pharmacotherapy is to reduce morbidity and to prevent complications.

Drug Category: Somatostatin analogs

Reduce blood levels of GH and IGF-I in patients with an inadequate response to surgery, radiation, and bromocriptine.

Drug NameOctreotide (Sandostatin)
DescriptionActs primarily on somatostatin receptor subtypes II and V. Inhibits GH secretion. Also has a multitude of other endocrine and nonendocrine effects, including inhibition of glucagon, VIP, and GI peptides.
Adult DoseInitial: 50 mcg SC tid; may increase to 500 mcg tid
Doses of 300-600 mcg/d or higher seldom result in additional benefit
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsMay reduce cyclosporine effects; patients on insulin, oral hypoglycemics, beta-blockers, and calcium channel blockers may need dose adjustments
PregnancyB - Usually safe but benefits must outweigh the risks.
PrecautionsAdverse effects primarily are related to effect on GI motility and include nausea, abdominal pain, diarrhea, increased incidence of gallstones and biliary sludge; hypoglycemia or hyperglycemia may be seen because of alteration in counter-regulatory hormones, insulin, glucagon, and GH; bradycardia, cardiac conduction abnormalities, and arrhythmias reported; hypothyroidism also may occur because of inhibition of TSH secretion; caution in renal impairment

Drug NameOctreotide LAR (Sandostatin LAR)
DescriptionLong-acting somatostatin analog given q4wk. Similar improvements in GH/IGF-I concentration compared to octreotide, but associated with fewer adverse effects. A trial of short-acting somatostatin analog is necessary to confirm patient's ability to tolerate the compound.
Do not administer in deltoid area because of significant discomfort at injection site.
Gluteal injection sites should be alternated.
Adult Dose10-30 mg IM q28d
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsMay reduce cyclosporine effects; patients on insulin, oral hypoglycemics, beta-blockers, and calcium channel blockers may need dose adjustments
PregnancyC - Safety for use during pregnancy has not been established.
PrecautionsAdverse effects primarily are related to effect on GI motility and include nausea, abdominal pain, diarrhea, and increased incidence of gallstones and biliary sludge; hypoglycemia or hyperglycemia may be seen because of alteration in counter-regulatory hormones, insulin, glucagon, and GH; bradycardia, cardiac conduction abnormalities, and arrhythmias reported; hypothyroidism may occur because of inhibition of TSH secretion; caution in renal impairment; cholelithiasis may occur

Drug Category: Dopamine agonists

Usually added to somatostatin analogs if complete remission is not achieved. Have modest effects if used as single agent.

Drug NameBromocriptine (Parlodel)
DescriptionActs on central dopamine receptors. More effective in tumors that co-secrete prolactin. Dose used to treat acromegaly usually is much higher than for hyperprolactinemia.
Adult Dose1.25 mg PO hs qd initial; increase gradually to 20-30 mg PO qd in divided doses
Safety not demonstrated with dosages >100 mg/d
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; uncontrolled hypertension; ischemic heart disease; peripheral vascular disorders
InteractionsOther ergot alkaloids increase toxicity of bromocriptine; amitriptyline, butyrophenones, imipramine, methyldopa, phenothiazines, and reserpine may decrease bromocriptine effects
PregnancyB - Usually safe but benefits must outweigh the risks.
PrecautionsAdverse effects include nausea, vomiting, headaches, nasal congestion, orthostatic hypotension, and digital vasospasm; patients tend to develop tolerance to adverse effects; caution in renal or hepatic disease

Drug Category: Growth hormone antagonists

The newest class of drugs used to decrease excessive GH effect. Blocks GH binding to receptors, thus, decreases IGF-I, IGF binding protein-3 (IGFBP-3), and acid-labile subunit (ALS).

Drug NamePegvisomant (Somavert)
DescriptionRecombinant DNA analog of human GH structurally altered to act as GH receptor antagonist. Selectively binds to GH receptors on cell surfaces, thereby blocking endogenous GH binding. This action interferes with GH signal transduction, resulting in decreased levels of IGF-I, IGFBP-3, and ALS.
Adult DoseLoading dose: 40 mg SC
Maintenance dose: 10 mg SC qd initially; may increase or decrease q4-6wk by 5-mg increments as determined by IGF-I levels; not to exceed 30 mg/d
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsMay decrease insulin or oral hypoglycemic effects; patients receiving opioid analgesics may require higher doses to suppress IGF-I production to recommended levels
PregnancyB - Usually safe but benefits must outweigh the risks.
PrecautionsVial stopper contains latex; may cause GH-secreting tumors to grow; may increase insulin sensitivity; may induce GH deficiency; may increase liver enzyme levels

Acrokeratosis Verruciformis of Hopf

Lesions identical to those of acrokeratosis verruciformis are also observed in many patients with acral Darier disease (also termed keratosis follicularis). To complicate matters further, lesions of acrokeratosis verruciformis have been reported in relatives of individuals with Darier disease. Considerable controversy surrounds the nature and relationship of acrokeratosis and Darier disease and whether they are manifestations of one genetic abnormality. Acrokeratosis verruciformis and acral Darier disease have been distinguished as 2 distinct entities in the literature. Although clinically similar, acrokeratosis verruciformis is thought to remain nondyskeratotic throughout life, whereas acral lesions of Darier disease show, upon careful histologic examination, various gradations of benign acantholytic dyskeratosis.

Darier disease (keratosis follicularis) is the most important disorder to be distinguished from acrokeratosis. Darier disease, acrokeratosis verruciformis, epidermodysplasia verruciformis, plane warts, and seborrheic keratoses can be differentiated by histologic examination of biopsy samples from individual lesions. The hard nevus of Unna can be differentiated clinically by its late onset.

Pathophysiology: The close similarity of Hopf disease to the acral warty lesion of keratosis follicularis has been noted by Hopf and Darier themselves. The similarities led later observers to postulate a relationship between the two diseases. The exact relationship between acrokeratosis verruciformis and Darier disease has not yet been satisfactorily resolved. A classic case of Darier disease poses no diagnostic problem. However, deciding whether a forme fruste of Darier disease (with atypical acral papules) is identical to acrokeratosis verruciformis remains difficult.

Frequency:

Race: Acrokeratosis verruciformis has been described in individuals of many races.

Drug Name
Tretinoin (Avita, Retin-A) -- Developed to treat acne vulgaris. Alters maturation and differentiation of keratinocytes. Has been used for a variety of conditions, including flat warts, abnormalities of keratinization, and other keratoses.
Available in 0.025%, 0.05%, and 0.1% concentrations in a variety of vehicles, including gels, solutions, and creams.
Adult DoseBegin with lowest tretinoin formulation and increase as tolerated; apply hs or qod; lower frequency of application if irritation develops
Pediatric Dose<12>
>12 years: Administer as in adults
ContraindicationsDocumented hypersensitivity
InteractionsToxicity increases with coadministration of benzoyl peroxide, salicylic acid, and resorcinol; avoid topical sulfur, resorcinol, salicylic acid, other keratolytics, abrasives, astringents, spices, and lime
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsPhotosensitivity may occur with excessive sunlight exposure; caution in eczema; do not apply to mucous membranes, mouth, and angles of nose; pruritus, erythema, and a burning sensation may be noted, especially with higher strengths; hypopigmentation and, rarely, hyperpigmentation, may be noted locally