I think this question is not clearly in the Infectious Diseases syllabus, and may overlap with OFT and DERMA, but as I understand it, in an immunocompromised patient and also with data of ocular involvement, admission for intravenous treatment would be indicated due to the high risk of possible complications.

A 71-year-old woman with a history of rheumatoid arthritis on sulfasalazine, prednisone and etanercept. She goes to the emergency room for 72 hours of clinical manifestations compatible with facial herpes zoster affecting the right hemiface, auricular pavilion, respecting the forehead and conjunctival chemosis. What would be the appropriate treatment?

Outpatient treatment with acyclovir, valacyclovir or oral famciclovir.

Hospital admission and treatment with acyclovir or famciclovir iv.

Treatment of herpes zoster ophthalmicus: a systematic review and Canadian cost-comparison.

A systematic review and cost comparison were conducted to determine the optimal treatment of active herpes zoster ophthalmicus (HZO) in immunocompetent adults. A literature search of MEDLINE, EMBASE, CINAHL, Cochrane Library, BIOSIS Previews and Web of Science, ClinicalTrials.gov, International Clinical Trials Registry Platform, Networked Digital Library of Theses and Dissertations, and Canadian Health Research Collection was performed. The search period was from January 1990 to March 2017. Collectively, 516 immunocompetent patients with active HZO treated with oral antivirals were included. Randomized controlled trials (RCTs) investigating treatment of active HZO in immunocompetent adults, with one oral acyclovir monotherapy arm, were included. Studies fulfilling inclusion criteria were subjected to quality assessment and data extraction. Provincial drug formularies were consulted to extrapolate cost comparison for investigated treatment regimens. A total of 1515 titles and abstracts and 9 full-text articles were assessed. Three RCTs met the inclusion criteria. Treatment with oral acyclovir (800 mg 5 times daily for 10 days) was superior to placebo in the prevention of ocular manifestations. Oral famciclovir (500 mg 3 times daily for 7 days) and valacyclovir (1000 mg 3 times daily for 7 days) resulted in comparable rates of ocular manifestations relative to oral acyclovir (800 mg 5 times daily for 7 days). According to provincial drug formulary data, famciclovir and valacyclovir are more affordable across Canada with the recommended dosing schedules. Oral famciclovir and valacyclovir are reasonable alternatives to oral acyclovir for treatment of active HZO in immunocompetent individuals. Their simpler dosing schedules are associated with a cost benefit that is consistent across Canada.

Shingles

Zoster ophthalmicus Treatment for zoster ophthalmicus is similar to standard treatment for shingles at other sites. A trial comparing acyclovir with its prodrug, valacyclovir, demonstrated similar efficacies in treating this form of the disease. The significant advantage of valacyclovir over acyclovir is its dosing of only three times/day (compared with acyclovir's five times/day dosing), which could make it more convenient for people and improve adherence with therapy.

Herpes zoster ophthalmicus

Treatment Treatment is usually with antivirals such as acyclovir, valacyclovir, or famcyclovir by mouth. There is uncertainty as to the difference in effect between these three antivirals. Antiviral eye drops have not been found to be useful. These medications work best if started within 3 days of the start of the rash. Cycloplegics prevent synechiae from forming. References External links Varicella zoster virus-associated diseases Ophthalmology Wikipedia medicine articles ready to translate

Postherpetic neuralgia

Secondary prevention A 2013 Cochrane meta-analysis of 6 randomized controlled trials (RCTs) investigating oral antiviral medications given within 72 hours after the onset of herpes zoster rash in immunocompetent people for preventing postherpetic neuralgia (PHN) found no significant difference between placebo and acyclovir. Additionally, there was no significant difference in preventing the incidence of PHN found in the one RCT included in the meta-analysis that compared placebo to oral famciclovir treatment within 72 hours of HZ rash onset. Studies using valacyclovir treatment were not included in the meta-analysis. PHN was defined as pain at the site of the dermatomic rash at 120 days after the onset of rash, and incidence was evaluated at 1, 4, and 6 months after rash onset. Patients who are prescribed oral antiviral agents after the onset of rash should be informed that their chances of developing PHN are no different than those not taking oral antiviral agents.

Herpes zoster antivirals and pain management.

Evaluation of evidence-based strategies for managing herpes zoster (HZ) and the pain of postherpetic neuralgia (PHN). Approximately 20% of the world's population suffers from herpes zoster at least once in a lifetime, with 10% to 20% having ophthalmic involvement. Treatment of the acute disease with oral antivirals may reduce the incidence and severity of complications but does not reliably prevent PHN or postherpetic itch (PHI). The acute pain abates as the acute phase resolves; the long-term pain of PHN or PHI may be severe and difficult to manage. Although many therapeutic agents have efficacy in the management of these complications, relief is frequently partial for months to the remainder of the lifetime. Literature review was performed using the resources of the Harvard Medical School/Massachusetts Eye and Ear Infirmary Ophthalmic library as well as the National Library of Medicine and the National Institutes of Health PubMed service searching by pertinent topics, authors, and journals. If started within 72 hours of the onset of the acute HZ rash, the oral antiviral agents acyclovir, valacyclovir, and famciclovir significantly shorten the periods of acute pain, virus shedding, rash, acute and late-onset anterior segment complications, and, in the case of valacyclovir and famciclovir, the incidence and severity of PHN. However, these medications do not prevent PHN, which remains a common and debilitating complication of HZ in older patients, requiring assiduous pain management. Tricyclic antidepressants, antiseizure drugs, opioids, and topical analgesics all offer some pain relief, and may be combined. Options are available to manage HZ and reduce the pain of PHN. However, prevention, now possible with the HZ vaccine, is preferable to treatment.

Varicella zoster virus

The mutation rate for synonymous and nonsynonymous mutation rates among the herpesviruses have been estimated at 1 × 10−7 and 2.7 × 10−8 mutations/site/year, respectively, based on the highly conserved gB gene. Treatment Within the human body it can be treated by a number of drugs and therapeutic agents including acyclovir for the chicken pox, famciclovir, valaciclovir for the shingles, zoster-immune globulin (ZIG), and vidarabine. Acyclovir is frequently used as the drug of choice in primary VZV infections, and beginning its administration early can significantly shorten the duration of any symptoms. However, reaching an effective serum concentration of acyclovir typically requires intravenous administration, making its use more difficult outside of a hospital. Vaccination

[Management of herpes zoster infection].

Approximately 10 to 30% of the population will suffer from herpes zoster (HZ) during their lifetime. Prompt treatment of acute HZ with acyclovir, valacyclovir or famciclovir is recommend, if patients are over 50 years old or have severe or moderate pain or severe or moderate rash or they are immonocompromised or suffer from herpes zoster ophtalmicus. Zoster lesions contain high concentrations of Varicella zoster virus that can spread, and cause chicken pox. There is no universal recommendations for varicella vaccination. It has been shown that zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults.

Herpes Zoster Ophthalmicus -- Treatment / Management

Antiviral agents: Ideally, treatment with systemic antiviral agents should begin within 72 hours of disease onset. Initiation should not be delayed while awaiting definitive diagnosis or ophthalmology follow-up. Topical antiviral agents may be considered, but there is limited evidence regarding their utility in managing HZO. Immunocompetent adult dosing (choose single agent): Acyclovir 800 mg orally five times per day for at least 7 days Valacyclovir 1000 mg orally every eight hours for at least 7 days (may require renal dosing) Famciclovir 500 mg orally three times per day for at least 7 days (may require renal dosing) Immunocompromised adult dosing (choose a single agent): Acyclovir 10 mg/kg of ideal body weight (IBW) intravenously (IV) every eight hours for at least 7 days Foscarnet 90 mg/kg IV every 12 hours (typically reserved for severe or acyclovir-resistant disease)

Antiviral treatment in outpatients with herps zoster in six major areas of China, 2010-2019.

The objective of this study was to assess the status and trends of antiviral treatment in outpatients with herpes zoster in China. Prescription data on antiviral drugs were extracted from the database of the Hospital Prescription Analysis Program of China according to the inclusion criteria. Yearly prescriptions and costs were calculated, and trends were analyzed. The trends were further stratified by age, sex, and specific drug use. The distribution of defined daily costs (DDCs) of valaciclovir and famciclovir were analyzed, and trends in the median DDCs were identified. A total of 132,911 prescriptions from 49 hospitals located in six major areas of China were included in the analysis. The yearly prescriptions containing antivirals increased from 8,819 in 2010 to 16,361 in 2019. The percentage of prescriptions for patients aged 65 years and above also increased (27.7% in 2010 to 31.0% in 2019), and the number of prescriptions for females was higher than those for males (<iP</i < 0.001). The average cost of antivirals per prescription decreased; thus, the yearly cost showed no increasing trend. The main prescribed antivirals were valaciclovir and famciclovir, which progressively increased in prescriptions. The use of acyclovir decreased during the study period. Prescriptions containing topical formulations, acyclovir and penciclovir, both increased. The DDCs of valaciclovir and famciclovir decreased dramatically. The use of antivirals has increased over the decade, while the cost has not. Antiviral treatments adhere well to recent recommendations, except for the use of topical antivirals. The findings of this study may benefit the healthcare source allocation and management of herpes zoster in China.

Conjunctivitis -- Treatment / Management

Treatment of herpes zoster conjunctivitis includes a combination of oral antivirals and topical steroids; however, steroids should only be part of therapy in consultation with ophthalmology. Antiviral doses differ from those used for herpes simplex and consist of acyclovir 800 mg PO 5 times a day, famciclovir 500 mg PO 3 times a day, or valacyclovir 1 g PO 3 times a day, each for 7 to 10 days.

Herpes gladiatorum

Treatment Herpes outbreaks should be treated with antiviral medications like Acyclovir, Valacyclovir, or Famcyclovir, each of which is available in tablet form. Oral antiviral medication is often used as a prophylactic to suppress or prevent outbreaks from occurring. The recommended dosage for suppression therapy for recurrent outbreaks is 1,000 mg of valacyclovir once a day or 400 mg Acyclovir taken twice a day. In addition to preventing outbreaks, these medications greatly reduce the chance of infecting someone while the patient is not having an outbreak.

Herpetic whitlow

In adults, it is more common for the primary source to be the genital region, with a corresponding preponderance of HSV-2. It is also seen in adult health care workers such as dentists because of increased exposure to the herpes virus. Contact sports are also a potential source of infection with herpetic whitlows. Treatment Although it is a self-limited illness, oral or intravenous antiviral treatments, particularly acyclovir, have been used in the management of immunocompromised or severely infected patients. It is usually given when the condition fails to improve on its own. Topical acyclovir has not been shown to be effective in management of herpetic whitlow. Famciclovir has been demonstrated to effectively treat and prevent recurrent episodes. Lancing or surgically debriding the lesion may make it worse by causing a superinfection or encephalitis.

A comparative study to evaluate the efficacy and safety of acyclovir and famciclovir in the management of herpes zoster.

Over the years, acyclovir has been the oral antiviral agent approved for the treatment of patients with acute herpes zoster,Its effectiveness in lessening the acute signs and symptoms of herpes zoster has been established but the effects on post herpetic neuralgia are less clear cut. Famciclovir is a new member of guanine nucleoside family of drugs. It is a well absorbed oral form of penciclovir with longer half life. This was a open comparative randomized study carried out to compare the safety and efficacy of famciclovir administered at 250mg thrice daily with acyclovir 800mg five times daily for the treatment of acute uncomplicated herpes zoster in immunocompetent individuals aged above 40 years. To assess the clinical profile of Herpes zoster, compare the efficacy and safety of acyclovir and famciclovir in the treatment of herpes zoster and to describe the effectiveness of acyclovir and famciclovir preventing post herpetic neuralgia. A total of 100 newly zoster were randomized in 1:1 ratio into acyclovir and famciclovir groups after inclusion criteria were satisfied.Treatment was initiated within 72 hrs of onset of symptoms and was continued for 7 days and evaluated at the end of each week up to six weeks period for full crusting of the lesions, complete healing of the lesion and loss of acute pain. It was observed that famciclovir was as effective as acyclovir with no significant difference in time taken for full crusting, complete healing of lesions or loss of acute pain. Famciclovir was well tolerated with a better safety profile comparable to that of acyclovir. Constipation, headache, nausea and vomiting were the most commonly reported adverse effects, but constipation was considered to have a possible relationship to treatment. In conclusion, oral famciclovir administered three times daily for 7 days during acute zoster infection is as effective as acyclovir, administered 800mg five times daily.In addition it offers significant benefit by providing a well tolerated, cost effective, convenient dosage regime and accelerated rate of lesion resolution and a reduced duration of PHN.

Acute retinal necrosis

Treatment Medication Currently treatment of ARN consists of antiviral therapy administered orally. Typical antiviral agents used include famciclovir, valganciclovir, and valacyclovir. While on these medications, a patient's kidney function should be watched. Some physician's also may administer the antiviral agents via intravitreal delivery. Though controversial, some physicians administer steroids (prednisone) and antithrombotic therapy (aspirin). Some commonly administered antiviral agents are as follows: Acyclovir Famciclovir Valacyclovir Gancicilovir Valganciclovir Research In a study done published by the British Journal of Ophthalmology, the cases of ARN/BARN reported in 2001-2002 in the UK, Varicella Zoster Virus was the most common culprit for the disease and presented mostly in men than in women.

Herpes esophagitis

Differential diagnosis CMV, VZV as well as HIV infections of the esophagus can have a similar presentation. Tissue culture is the most accurate means of distinguishing between the different viral causes. Caustic esophagitis, pill-induced esophagitis as well as yeast esophagitis can have a similar clinical presentation. Prevention Herpes simplex virus is commonly found in humans, yet uncommonly results in systemic manifestations. Suppression of HIV with antiretroviral medications, careful monitoring of immunosuppressive medications are important means of prevention. Antiviral prophylaxis such as daily acyclovir in immunocompromised individuals may be considered. Treatment Antivirals such as acyclovir, famciclovir, or valacyclovir may be used. Intravenous acyclovir is reserved for individuals who cannot swallow due to the pain, individuals with other systemic manifestations of herpes or severely immunocompromised individuals. References

InternalMed_Harrison

lymphoproliferative malignancies), both chickenpox and herpes zoster (including disseminated disease) should be treated, at least at the outset, with IV acyclovir, which reduces the occurrence of visceral complications but has no effect on healing of skin lesions or pain. The dose is 10 mg/kg every 8 h for 7 days. For low-risk immunocompromised hosts, oral therapy with valacyclovir or famciclovir appears beneficial. If medically feasible, it is desirable to decrease immunosuppressive treatment concomitant with the administration of IV acyclovir. Patients with varicella pneumonia often require ventilatory support. Persons with zoster ophthalmicus should be referred immediately to an ophthalmologist. Therapy for this condition consists of the administration of analgesics for severe pain and the use of atropine. Acyclovir, valacyclovir, and famciclovir all accelerate healing. Decisions about the use of glucocorticoids should be made by the ophthalmologist. The management of acute

Valacyclovir versus acyclovir for the treatment of herpes zoster ophthalmicus in immunocompetent patients.

Herpes zoster ophthalmicus affects the eye and vision, and is caused by the reactivation of the varicella zoster virus in the distribution of the first division of the trigeminal nerve. An aggressive management of acute herpes zoster ophthalmicus with systemic antiviral medication is generally recommended as the standard first-line treatment for herpes zoster ophthalmicus infections. Both acyclovir and its prodrug valacyclovir are medications that are approved for the systemic treatment of herpes zoster. Although it is known that valacyclovir has an improved bioavailability and steadier plasma concentration, it is currently unclear as to whether this leads to better treatment results and less ocular complications. To assess the effects of valacyclovir versus acyclovir for the systemic antiviral treatment of herpes zoster ophthalmicus in immunocompetent patients. We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register; 2016, Issue 5), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2016), Embase (January 1980 to June 2016), Web of Science Conference Proceedings Citation Index-Science (CPCI-S; January 1990 to June 2016), BIOSIS Previews (January 1969 to June 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 13 June 2016. We considered all randomised controlled trials (RCTs) in which systemic valacyclovir was compared to systemic acyclovir medication for treatment of herpes zoster ophthalmicus. There were no language restrictions. Two review authors independently selected trials, evaluated the risk of bias in included trials, and extracted and analysed data. We did not conduct a meta-analysis, as only one study was included. We assessed the certainty of the evidence for the selected outcomes using the GRADE approach. One study fulfilled the inclusion criteria. In this multicentre, randomised double-masked study carried out in France, 110 immunocompetent people with herpes zoster ophthalmicus, diagnosed within 72 hours of skin eruption, were treated, with 56 participants allocated to the valacyclovir group and 54 to the acyclovir group. The study was poorly reported and we judged it to be unclear risk of bias for most domains.Persistent ocular lesions after 6 months were observed in 2/56 people in the valacyclovir group compared with 1/54 people in the acyclovir group (risk ratio (RR) 1.93 (95% CI 0.18 to 20.65); very low certainty evidence. Dendritic ulcer appeared in 3/56 patients treated with valacyclovir, while 1/54 suffered in the acyclovir group (RR 2.89; 95% confidence interval (CI) 0.31 to 26.96); very low certainty evidence), uveitis in 7/56 people in the valacyclovir group compared with 9/54 in the acyclovir group (RR 0.96; 95% CI 0.36 to 2.57); very low certainty evidence). Similarly, there was uncertainty as to the comparative effects of these two treatments on post-herpetic pain, and side effects (vomiting, eyelid or facial edema, disseminated zoster). Due to concerns about imprecision (small number of events and large confidence intervals) and study limitations, the certainty of evidence using the GRADE approach was rated as low to very low for the use of valacyclovir compared to acyclovir. This review included data from only one study, which had methodological limitations. As such, our results indicated uncertainty of the relative benefits and harms of valacyclovir over acyclovir in herpes zoster ophthalmicus, despite its widespread use for this condition. Further well-designed and adequately powered trials are needed. These trials should include outcomes important to patients, including compliance.

Genital herpes

In people experiencing their first episode of genital herpes oral acyclovir may reduce the duration of symptoms and lesions but the risk of adverse effects is not certain. There may also be little or no difference between topical acyclovir and placebo in terms of duration of symptoms and lesions and the risk of adverse effects. Valacyclovir is a prodrug that is converted to acyclovir once in the body. It helps relieve the pain and discomfort and speeds healing of sores. It only comes in caplets and its advantage is that it has a longer duration of action than acyclovir. An example usage is by mouth twice per day for ten days for primary lesion, and twice per day for three days for a recurrent episode. Famciclovir is another antiviral drug that belongs to the same class. Famciclovir is a prodrug that is converted to penciclovir in the body. The latter is the one active against the viruses. It has a longer duration of action than acyclovir and it only comes in tablets.

InternalMed_Harrison

Application at initial symptoms reduces healing time by 1 d. Therapy should be undertaken in consultation with an ophthalmologist. Valacyclovir may be more effective than acyclovir for pain relief; otherwise, it has a similar effect on cutaneous lesions and should be given within 72 h of rash onset. The duration of postherpetic neuralgia is shorter than with placebo. Famciclovir showed overall efficacy similar to that of acyclovir in a comparative trial. It should be given ≤72 h after rash onset. Acyclovir causes faster resolution of skin lesions than placebo and provides some relief of acute symptoms if given within 72 h of rash onset. Combined with tapering doses of prednisone, acyclovir improves quality-of-life outcomes. Antiviral Chemotherapy, Excluding Antiretroviral Drugs

Ramsay Hunt syndrome type 2

Treatments for Ramsay Hunt Syndrome Type 2 are used to reduce further damage causes by the viral infection. These medications will not reverse any damage that has already occurred at the time that they are prescribed. Initial treatment with a corticosteroid such as prednisone and the antiviral drug such as acyclovir (500 milligrams five times a day), valacyclovir (1000 mg three times a day) or famciclovir (500 mg three times a day) for 5 to 7 days is standard, however some studies have shown later damage to the facial nerve and recommend 21 days of antivirals. Studies indicate that treatment started within 72 hours of the onset of facial paralysis improves the chances of the patient experiencing significant recovery. Chances of recovery appear to decrease when treatment is delayed. Delay of treatment may result in permanent facial nerve paralysis. However, some studies demonstrate that even when steroids are started promptly, only 22% of all patient achieve full recovery of facial

InternalMed_Harrison

Because VZV is generally less sensitive to acyclovir than is HSV, higher doses of acyclovir must be used to treat VZV infections. In immunocompromised patients with herpes zoster, IV acyclovir reduces the frequency of cutaneous dissemination and visceral complications and—in one comparative trial—was more effective than vidarabine. Acyclovir, administered at oral doses of 800 mg five times a day, had a modest beneficial effect on localized herpes zoster lesions in both immunocompromised and immunocompetent patients. Combination of acyclovir with a tapering regimen of prednisone appeared to be more effective than acyclovir alone in terms of quality-of-life outcomes in immunocompetent patients over age 50 with herpes zoster. A comparative study of acyclovir (800 mg PO five times daily) and valacyclovir (1 g PO three times daily) in immunocompetent patients with herpes zoster indicated that the latter drug may be more effective in eliciting the resolution of zoster-associated pain.

Efficacy of famciclovir in the treatment of herpes zoster.

Although vidarabine was the first systemic antiviral drug for the treatment of acute herpes zoster, the agent now used most frequently is acyclovir, a far safer drug that became available a decade ago. However, even with widespread use of acyclovir, postherpetic neuralgia (PHN) remains a principal cause of postinfectious morbidity. Newer antiviral agents, such as famciclovir and valacyclovir, have recently been introduced for the treatment of uncomplicated herpes zoster. In a double-blind, randomized study, 500 mg of famciclovir three times daily for 7 days was compared with placebo; in a second study, 500 mg of famciclovir three times daily for 7 days was compared with 800 mg of acyclovir five times daily for 7 days. Famciclovir significantly reduced duration of viral shedding (P = 0.0001) and accelerated lesion resolution compared with placebo. Famciclovir was comparable to acyclovir for these acute parameters. Most importantly, famciclovir recipients lost PHN two times faster than those receiving placebo (P = 0.02 all patients; P = 0.004 patients > or = 50 years) resulting in a reduction in the median duration of PHN (56 days all patients; 100 days patients > or = 50 years). This reduction translated to a 3.5-month reduction in the median duration of PHN for patients 50 years or older, those at greatest risk for developing the most common complication of herpes zoster. Famciclovir 500 mg administered three times a day for 7 days is an effective and well-tolerated treatment for acute herpes zoster, and is the only oral antiviral agent proven to reduce the duration of PHN when administered during acute zoster infection.

Neonatal infection

Women with a history of genital herpes, can be treated with antiviral drugs to prevent symptomatic lesions and viral shedding that could infect the infant at birth. The antiviral medications used include acyclovir, penciclovir, valacyclovir, and famciclovir. Only very small amounts of the drug can be detected in the fetus. There are no increases in drug-related abnormalities in the infant that could be attributed to acyclovir. Long-term effects of antiviral medications have not been evaluated for their effects after growth and development of the child occurs. Neutropenia can be a complication of acyclovir treatment of neonatal HSV infection, but is usually transient. Treatment with immunoglobulin therapy has not been proven to be effective and is not recommended. Epidemiology

Aciclovir

A related prodrug form, valaciclovir came into medical use in 1995. It is converted to aciclovir in the body after absorption. In 2009, acyclovir in combination with hydrocortisone cream, marketed as Xerese, was approved in the United States for the early treatment of recurrent herpes labialis (cold sores) to reduce the likelihood of ulcerative cold sores and to shorten the lesion healing time in adults and children (six years of age and older). Society and culture Names Aciclovir is the International Nonproprietary Name (INN) and British Approved Name (BAN) while acyclovir is the United States Adopted Name (USAN) and former British Approved Name. It was originally marketed as Zovirax; patents expired in the 1990s and since then it is generic and is marketed under many brand names worldwide. Notes References

Acyclovir -- Indications

Despite the long-term use of acyclovir to treat HSV encephalitis, there has not been a systematic review regarding the efficacy of this disease/treatment combination. Current systematic reviews addressing its safety and efficacy are ongoing, with the primary outcome being the mortality rate. A secondary outcome measure is the quality of life. [4] HSV keratitis has been shown to respond to oral acyclovir and topical steroids in pediatric patients. [5]

Efficacy of valacyclovir and famciclovir in herpes zoster: A comparative study.

The objective was to evaluate the efficacy of antiviral agent valacyclovir compared with famciclovir in the treatment of herpes zoster. A comparative study was conducted over a period of 1 year. Data relevant to the study were collected from 60 patients, with active herpes zoster presenting to the outpatient department within 72 hr of the first occurrence of zoster rash. They were divided in to two groups of 30 patients each. The first group of patients received valacyclovir tablet 1000 mg thrice daily, whereas those in the second group were given famciclovir tablet 500 mg thrice daily. Both the drugs were given for 7 days. Periodic follow-up till 29<supth</sup day was done for assessment of the effects of given drugs. Significant decrease was observed on comparison of pain scores between the two groups using the visual analog scale, with the drug valacyclovir, than in the famciclovir group at day 29. Furthermore, valacyclovir treatment accelerated the resolution of zoster associated pain in more number of patients compared with famciclovir. Oral valacyclovir administered during acute zoster infection for a period of 7 days offers significant benefit compared to famciclovir by providing a well tolerated and greater resolution of pain while maintaining the favorable safety profile, making valacyclovir more efficacious and a better drug in management of Herpes Zoster in comparison to famciclovir.

Nongenital herpes simplex virus.

Nongenital herpes simplex virus type 1 is a common infection usually transmitted during childhood via nonsexual contact. Most of these infections involve the oral mucosa or lips (herpes labialis). The diagnosis of an infection with herpes simplex virus type 1 is usually made by the appearance of the lesions (grouped vesicles or ulcers on an erythematous base) and patient history. However, if uncertain, the diagnosis of herpes labialis can be made by viral culture, polymerase chain reaction, serology, direct fluorescent antibody testing, or Tzanck test. Other nonoral herpes simplex virus type 1 infections include herpetic keratitis, herpetic whitlow, herpes gladiatorum, and herpetic sycosis of the beard area. The differential diagnosis of nongenital herpes simplex virus infection includes aphthous ulcers, acute paronychia, varicella-zoster virus infection, herpangina, herpes gestationis (pemphigoid gestationis), pemphigus vulgaris, and Behçet syndrome. Oral acyclovir suspension is an effective treatment for children with primary herpetic gingivostomatitis. Oral acyclovir, valacyclovir, and famciclovir are effective in treating acute recurrence of herpes labialis (cold sores). Recurrences of herpes labialis may be diminished with daily oral acyclovir or valacyclovir. Topical acyclovir, penciclovir, and docosanol are optional treatments for recurrent herpes labialis, but they are less effective than oral treatment.

Varicella vaccine

weeks, because live vaccines that are administered too soon within one another may not be as effective. It may be usable in people with HIV infections who have a good blood count and are receiving appropriate treatment. Specific antiviral medication, such as acyclovir, famciclovir, or valacyclovir, are not recommended 24 hours before and 14 days after vaccination.

Lawrence Corey

In the early 1980s, Corey worked with Nobel Prize-winning biochemist and pharmacologist Dr. Gertrude Elion to demonstrate that an antiviral that was selective and specific for a viral-specified enzyme could be safely and effectively administered to control a chronic viral infection (herpes simplex virus type 2 or HSV-2). Corey first conceived of and demonstrated the core concepts and direct line association between quantitative viral load reduction and clinical benefit using topical, intravenous and oral formulations of acyclovir in classic studies performed between 1980 and 1984. Acyclovir was the first antiviral drug to get rapid approval from the FDA, and it was Corey's studies that defined its use in genital herpes. These studies led to the licensure for acyclovir in a wide variety of infections such as HSV-1, HSV-2 and varicella chickenpox virus, including the first use of an antiviral for daily long term use. Acyclovir and its derivatives valacyclovir and famciclovir are the

InternalMed_Harrison

and valacyclovir (1 g PO three times daily) in immunocompetent patients with herpes zoster indicated that the latter drug may be more effective in eliciting the resolution of zoster-associated pain. Orally administered acyclovir (600 mg five times a day) reduced complications of herpes zoster ophthalmicus in a placebo-controlled trial.

InternalMed_Harrison

c. Suppression of recurrent genital herpes: Oral acyclovir (400–800 mg bid) or valacyclovir (500 mg daily) is given. Patients with >9 episodes per year should take oral valacyclovir (1 g daily or 500 mg bid) or famciclovir (250 mg bid or 500 mg bid). 2. Oral-labial HSV infections a. First episode: Oral acyclovir is given (200 mg 5 times per day or 400 mg tid); an oral acyclovir suspension can be used (600 mg/m2 qid). Oral famciclovir (250 mg bid) or valacyclovir (1 g bid) has been used clinically. The duration of therapy is 5–10 days. b.

Herpes simplex keratitis

Epithelial keratitis Epithelial keratitis is treated with topical antivirals, which are very effective with low incidence of resistance. Treatment of the disease with topical antivirals generally should be continued for 10–14 days. Aciclovir ophthalmic ointment and Trifluridine eye drops have similar effectiveness but are more effective than Idoxuridine and Vidarabine eye drops. Oral acyclovir is as effective as topical antivirals for treating epithelial keratitis, and it has the advantage of no eye surface toxicity. For this reason, oral therapy is preferred by some ophthalmologists. Ganciclovir and brivudine treatments were found to be equally as effective as acyclovir in a systematic review. Valacyclovir, a pro-drug of acyclovir likely to be just as effective for ocular disease, can cause thrombotic thrombocytopenic purpura/Hemolytic-uremic syndrome in severely immunocompromised patients such as those with AIDS; thus, it must be used with caution if the immune status is unknown.


We are presented with a patient with resistant arterial hypertension, assuming that he has primary hyperaldosteronism due to hypokalemic metabolic alkalosis. When the diagnosis is biochemically confirmed, the next test to be performed is a CT scan to determine the subtype and rule out the presence of an adrenal carcinoma (option 3 correct). Therefore, it is necessary to wait for the imaging test to confirm the etiology (option 1 incorrect). The most frequent cause is aldosterone-producing adenoma (option 2 incorrect). Spironolactone is the medical treatment of choice (option 4 incorrect).

We are presented with a patient with resistant arterial hypertension, assuming that he has primary hyperaldosteronism due to hypokalemic metabolic alkalosis. When the diagnosis is biochemically confirmed, the next test to be performed is a CT scan to determine the subtype and rule out the presence of an adrenal carcinoma ([HIDDEN]). Therefore, it is necessary to wait for the imaging test to confirm the etiology ([HIDDEN]). The most frequent cause is aldosterone-producing adenoma ([HIDDEN]). Spironolactone is the medical treatment of choice ([HIDDEN]).

A 58-year-old man with a 6-year history of hypertension consults for poor blood pressure control despite treatment with an angiotensin-converting enzyme inhibitor, a diuretic and a calcium antagonist. On consultation she presented with blood pressure of 149/100 mmHg. Laboratory tests: creatinine 1.2 mg/dl, potassium 2.2 mEq/l and compensated metabolic alkalosis; the rest of the biochemical study, blood count, coagulation and urinary sediment were normal. Point out the correct statement:

The origin of hypertension in this case is excessive secretion of aldosterone caused by autonomic hyperfunction of the adrenal medulla.

In most cases the anatomical substrate is a bilateral hyperplasia of the adrenal cortex.

CT scan is part of the diagnostic study in case of biochemical confirmation.

Spironolactone is contraindicated in the management of this pathology.

Hypokalemia induced myopathy as first manifestation of primary hyperaldosteronism - an elderly patient with unilateral adrenal hyperplasia: a case report.

Primary hyperaldosteronism is only rarely caused by unilateral adrenal hyperplasia. A 73-year-old hypertensive Greek man (on 10 mg amlodipine for the last ten years) presented in the emergency department with severe muscle weakness of all limbs. The initial physical and laboratory examination revealed normal blood pressure, muscle weakness, severe hypokalemia, sinus rhythm and U wave, rhabdomyolysis and metabolic alkalosis. The patient was immediately treated with intravenous administration of potassium-rich solutions, 25 mg spironolactone with progressive dose titration up to 100 mg. Because of high arterial blood pressure, irbesartan was added. On day 6, muscle weakness was completely restored with decrease of arterial blood pressure and further improvement of laboratory tests. The combination of hypokalemia with arterial hypertension raised the suspicion of primary hyperaldosteronism; therefore, we performed abdomen computed tomography scan, which revealed a nodular mass (15 mm in diameter) in the left adrenal gland. Plasma renin activity was in the lower normal range with a three-fold increase of plasma aldosterone concentration. We performed total resection of the left adrenal gland and the histopathological examination revealed hyperplasia of the left adrenal gland. This report presents a rare case of an elderly patient under antihypertensive treatment the last ten years for essential hypertension, who admitted to our emergency department with hypokalemia - induced myopathy as first manifestation of primary hyperaldosteronism due to unilateral adrenal hyperplasia.

[High doses of aldosterone antagonist is a condition of sufficient blood pressure control in bilateral adrenal hyperplasia].

Primary aldosteronism occurs in 1-10% of hypertensive patients and is classified in adenomas or bilateral adrenal hyperplasia. Computed tomography (CT) or magnetic resonance imaging can be used to discriminate these subtypes and in guiding treatment selection. This case report describes a 65-year-old man with hypertension and hypokalaemia during 25 years. Bilateral adrenal hyperplasia was diagnosed based on a CT, and an oral sodium-loading test with measurement of renin and aldosterone confirmed the diagnosis. Blood pressure and potassium in plasma was normalized during treatment with the mineralocorticoid receptor antagonist eplerenon.

Diagnosis and management of primary aldosteronism.

Primary aldosteronism (PA) is the most common form of secondary hypertension (HTN), with an estimated prevalence of 4% of hypertensive patients in primary care and around 10% of referred patients. Patients with PA have higher cardiovascular morbidity and mortality than age- and sex-matched patients with essential HTN and the same degree of blood pressure elevation. PA is characterized by an autonomous aldosterone production causing sodium retention, plasma renin supression, HTN, cardiovascular damage, and increased potassium excretion, leading to variable degrees of hypokalemia. Aldosterone-producing adenomas (APAs) account for around 40% and idiopathic hyperaldosteronism for around 60% of PA cases. The aldosterone-to-renin ratio is the most sensitive screening test for PA. There are several confirmatory tests and the current literature does not identify a "gold standard" confirmatory test for PA. In our institution, we recommend starting case confirmation with the furosemide test. After case confirmation, all patients with PA should undergo adrenal CT as the initial study in subtype testing to exclude adrenocortical carcinoma. Bilateral adrenal vein sampling (AVS) is the gold standard method to define the PA subtype, but it is not indicated in all cases. An experienced radiologist must perform AVS. Unilateral laparoscopic adrenalectomy is the preferential treatment for patients with APAs, and bilateral hyperplasia should be treated with mineralocorticoid antagonist (spironolactone or eplerenone). Cardiovascular morbidity caused by aldosterone excess can be decreased by either unilateral adrenalectomy or mineralocorticoid antagonist. In this review, we address the most relevant issues regarding PA screening, case confirmation, subtype classification, and treatment.

[Primary aldosteronism and pregnancy: report of 2 cases].

Based on two patients, we discuss the difficulties in diagnosing and managing primary aldosteronism in pregnancy, which derive from changes of the renin-angiotensin-aldosterone axis, from the uncertainty regarding blood pressure control along gestation and postpartum, and from the contraindication to the use of spironolactone. The first case is a 27 years old woman with a long standing refractory hypertension, a hemorrhagic stroke with left brachial hemiplegia and crural hemiparesia, two miscarriages, one stillbirth and one offspring with intrauterine growth retardation. Due to hypokalemia, a plasma aldosterone/renin activity ratio of 91, and a negative genetic screening for glucocorticoid remediable aldosteronism (GRA), a primary hyperaldosteronism with normal adrenals in CT scan was diagnosed, and good blood pressure control was attained with spironolactone. After two and a half years of normotension, a fifth pregnancy, managed with methyldopa evolved with satisfactory blood pressures, plasma potassium, fetal growth, uterine and umbilical arterial resistance indexes, and maternal endothelial function. At 37 1/2 weeks of pregnancy the patient delivered a healthy newborn weighing 2,960 g. Blood pressure rose during the 48 hours of postpartum in the absence of proteinuria and required i.v. hydralazine. The second patient is a 37 years old woman, with known refractory hypertension for 7 years, hypokalemia, plasma aldosterone/renin activity ratio greater than 40, normal adrenals in the CAT scan, and a negative genetic screening for GRA. She had normotensive pregnancies 5 and 3 years prior to the detection of hypertension, with hypertensive crisis in both postpartum periods, retrospectively considered as expressions of primary hyperaldosteronism.

[Modern pharmacological aspects of hyperaldosteronism therapy].

The prevalence of primary hyperaldosteronism is 5-10% of all hypertensive patients, and clearly above the estimated prevalence in the past. In nearly 30% of patients with therapy resistant hypertension, primary hyperaldosteronism is detected if they are investigated thoroughly. This will result in 1.5 to 2.5 million people in Germany suffering from primary hyperaldosteronism. Besides efficient diagnostic procedures, an effective treatment is of increasing importance. The aldosterone-producing adenoma (Conn's syndrome) is primarily cured by operation, in most cases performed endoscopically. Bilateral hyperplasia, which is found in two-thirds of primary hyperaldosteronism, is treated primarily by mineralocorticoid receptor antagonist: 12.5-50 mg/day spironolactone (in case of anti-androgenic side-effects alternatively by 50-100 mg/day eplerenone). If the blood pressure can not be lowered by this first-line treatment, an additional treatment with potassium-sparing diuretics, calcium-antagonists, ACE-inhibitors or angiotensin-2-antagonists is necessary. The start of medication should be closely monitored by serum electrolyte and creatinine controls.

[Reninoma: a rare but curable cause of high blood pressure, a case report].

We report a case of a renin secreting tumor, which is a very rare cause of secondary high blood pressure. A 22-year-old woman was hospitalised for exploration of high blood pressure (160/110 mmHg) with severe hypokaliemia (2,7 mmol/l) and secondary hyperaldosteronism. Physical examination was normal except the high blood pressure. Bioassays show increased kaliuresis (66 mmol/24h), plasma renin (89 pg/ml in clinostastism--108 pg/ml in orthostatism), pro-renin (1207 pg/ml in clinostastism--1412 pg/ml in orthostatism) and aldosterone (210 pg/ml in clinostastism--566 pg/ml in orthostatism). The rest of the endocrine tests were normal (cortisol and ACTH at 8:00 am, urinary free cortisol, overnight 1 mg dexamethasone suppression test). Doppler ultrasound method, performed by an experienced radiologist, did not show renal artery stenosis. Abdominal computerized tomography showed a nodular formation at the upper pole of the right kidney, isodense to renal medullary. The size tumor was 15 mm. The renal vein sampling shows high values of renin on both sides whereas, for the pro-renin, the values were higher on the tumor side. In spite of treatment with CEI (Converting Enzyme Inhibitors) and calcium antagonists, the blood pressure was not controlled. Hypokaliemia persisted (3 mmol/l) in spite of high daily potassium intake (64 mmol/l of potassium chloride). After tumor resection, reninoma was diagnosed by the pathology examination and blood pressure, plasma rennin, plasma aldosterone level returned to normal.

Diagnosis Other conditions such as Liddle's Syndrome can mimic the clinical features of AME, so diagnosis can be made by calculating the ratio of free urinary cortisol to free urinary cortisone. Since AME patients create less cortisone, the ratio will much be higher than non-affected patients. Alternatively, one could differentiate between the two syndromes by administering a potassium-sparing diuretic. Patients with Liddle's syndrome will only respond to a diuretic that binds the ENaC channel, whereas those with AME will respond to a diuretic that binds to ENaC or the mineralcorticoid receptor. Treatment The treatment for AME is based on the blood pressure control with Aldosterone antagonist like Spironolactone which also reverses the hypokalemic metabolic alkalosis and other anti-hypertensives. Renal transplant is found curative in almost all clinical cases.AME is exceedingly rare, with fewer than 100 cases recorded worldwide.

[Primary hyperaldosteronism. Apropos of 2 cases].

Primary hyperaldosteronism (PHA) represents less than 1 to 2% of all causes of hypertension (HT). We report 2 cases of primary hyperaldosteronism which emphasize the difficulty of distinguishing neoplastic PHA from idiopathic PHA, observed in a 60-year-old woman and a 42-year old woman, respectively. In both cases, the diagnosis of PHA was suggested by marked hypokalaemia with inappropriate potassium excretion and was confirmed by hyperaldosteronaemia and low and poorly stimulated renin activity. In the first case, computed tomography showed nodular hyperplasia of the 2 adrenal glands. The patient was treated with spironolactone and calcium channel blockers which controlled blood pressure and serum potassium. In the second case, computed tomography and magnetic resonance imaging revealed an adrenocortical adenoma confirmed by pathological examination after the operation. The diagnosis of primary hyperaldosteronism is based on three steps: detection, positive diagnosis and aetiological diagnosis. Detection is essentially based on demonstration of hypokalaemia. Positive diagnosis is based on demonstration of elevated aldosterone secretion with inhibited renin secretion. The aetiological diagnosis is dominated by the differentiation between Conn's adenoma and bilateral adrenal hyperplasia, which has therapeutic implications.

[Clinical characteristics and surgery outcomes of unilateral nodular adrenal hyperplasia in primary aldosteronism: study of 145 cases].

To investigate the clinical characteristics, differential diagnosis, and surgery outcome of unilateral nodular adrenal hyperplasia (UNAH). The clinical data of 145 patients with primary aldosteronism, 67 males and 78 females, aged 37.9 (19-60), including 78 cases of aldosterone-producing adenoma (APA), 14 cases of UNAH, and 55 cases of idiopathic bilateral adrenal hyperplasia (BAH), were collected. Radioimmunoassay was used to examine the blood and urine aldosterone and plasma rennin activity. Automatic biochemical apparatus was used to examine the blood and urine electrolytes, renal functions, and urine microalbumin. Twelve-lead electrocardiography, echocardiography, and plain scanning of enhanced CT scanning of the bilateral adrenals were conducted. Adrenal venous sampling (AVS) was conducted in 62 patients to collect blood samples from vena cava and bilateral suprarenal veins to detect the levels of aldosterone and cortisol. All UNAH patients and 3 BAH patients underwent unilateral adrenalectomy and three APA patients underwent unilateral adrenalectomy or adenoma resection. Then the patients were followed up for 39.2 months. The incidence of UNAH is 9.7% in the primary aldosteronism patients. There were no significant differences in age, gender, duration of hypertension, blood pressure (SBP, DBP), and indexes indicating damages in target organs of hypertension (left ventricular hypertrophy rate, blood creatinine, urine microalbumin, etc) among these three groups. The level of serum potassium of the APA group was significantly lower than that of the BAH group (P < 0.01), and the levels of plasma and urine aldosterone of the APA group were significantly higher than those of the BAH group (P < 0.05 and P < 0.01). The serum potassium of the UNAH group was higher than that of the APA group and lower than that of the BAH group, and the levels of plasma and urine aldosterone of the UNAH group were both higher than those of the APA group and lower than those of the BAH group, however all not significantly (all P > 0.05). The coincidence rate of CT was 50% (7/14) in the UNAH group. The accuracy of AVS for diagnosis of UNAH was 85.7% (12/14). After operation, the serum potassium and plasma aldosterone concentrations returned normal in all the UNAH patients. Blood pressure returned to normal in 50% (7/14) of the UNAH patients, and was improved in the other 50% (7/14) patients. UNAH can be cured by adrenal surgery. The diagnostic values of clinical examination and adrenal CT are limited. AVS is essential in diagnosing UNAH patients.

Pseudohyperaldosteronism

Pseudohyperaldosteronism (also pseudoaldosteronism) is a medical condition which mimics the effects of elevated aldosterone (hyperaldosteronism) by presenting with high blood pressure (hypertension), low blood potassium levels (hypokalemia), metabolic alkalosis, and low levels of plasma renin activity (PRA). However, unlike hyperaldosteronism, this conditions exhibits low or normal levels of aldosterone in the blood. Causes include genetic disorders (e.g. Apparent mineralocorticoid excess syndrome, Liddle's syndrome, and types of Congenital adrenal hyperplasia), acquired conditions (e.g. Cushing's syndrome and mineralocorticoid-producing adrenal tumors), metabolic disorders, and dietary imbalances including excessive consumption of licorice. Confirmatory diagnosis depends on the specific root cause and may involve blood tests, urine tests, or genetic testing; however, all forms of this condition exhibit abnormally low concentrations of both plasma renin activity (PRA) and plasma

[Primay hyperaldosteronism--diagnostic and treatment].

Primary hyperaldosteronism (PHA) is characterized by an increased Aldosterone synthesis which is independent of the Renin-Angiotensin-Aldosterone-System (RAAS). The prevalence of PHA in patients who present in specialized hypertension centers is approx. 10 %. Besides patients with the classical symptoms known as "Conn-Trias" (hypertension, hypokalemia, metabolic alkalosis), the more frequent normokalemic patients with PHA also show a worse outcome compared to patients with essential hypertension. Identifying these patients is an important task in the evaluation of hypertension since targeted treatment options are available. Screening for PHA using the Aldosterone-Renin-Ratio (ARR) should be performed in patients with hypokalemic, severe or resistant hypertension. In addition, young patients with early onset of severe hypertension and/or positive family history should be screened. A positive screening result should be followed by a confirmatory test. The saline infusion test is the preferred clinical test for confirming a suspected PHA since it is accessible and time efficient. Other confirmatory tests are not used on a regular basis. After any confirmatory test, CT- or MRI-imaging and adrenal vein sampling (AVS) is used in order to differentiate between a unilateral adenoma, a bilateral hyperplasia or another cause of PHA. CT or MRI usually cannot discriminate smaller tumors form hyperplasia. Therefore AVS is used to detect lateralization of autonomous aldosterone production. Lateralization of aldosterone production indicates a unilateral adenoma. In these cases, laparoscopic adrenalectomy is the therapeutic option of choice with a hypertension cure rate of up to 60 %. If no lateralization is detectable, bilateral hyperplasia as the underlying cause of PHA is likely. Pharmacological inhibition of the mineralocorticoid receptor is the preferred treatment option in these cases. If Spironolactone is not well tolerated, Eplerenone and potassium-sparing diuretics should be prescribed. Often, however, in order to fully control hypertension, additional antihypertensive therapy is necessary.

Primary aldosteronism: renaissance of a syndrome.

Great strides have been made in our understanding of the pathophysiology of primary aldosteronism syndrome since Conn's description of the clinical presentation of a patient with an aldosterone-producing adenoma (APA) more than 50 years ago. It is now recognized that the APA is just one of the seven subtypes of primary aldosteronism. APA and bilateral idiopathic hyperaldosteronism (IHA) are the most common subtypes of primary aldosteronism. Although most clinicians had thought primary aldosteronism to be a rare form of hypertension for more than three decades, it is now recognized to be the most common form of secondary hypertension. Using the plasma aldosterone to plasma renin activity ratio as a case-finding test, followed by aldosterone suppression confirmatory testing, has resulted in much higher prevalence estimates of 5-13% of all patients with hypertension. In addition, there has been a new recognition of the aldosterone-specific cardiovascular morbidity and mortality associated with aldosterone excess. Although thought to be daunting and complex in the past, the diagnostic approach to primary aldosteronism is straightforward and can be considered in three phases: case-finding tests, confirmatory tests and subtype evaluation tests. Patients with hypertension and hypokalaemia (regardless of presumed cause), treatment-resistant hypertension (three antihypertensive drugs and poor control), severe hypertension (>or= 160 mmHg systolic or >or= 100 mmHg diastolic), hypertension and an incidental adrenal mass, onset of hypertension at a young age or patients being evaluated for other forms of secondary hypertension should undergo screening for primary aldosteronism. In patients with suspected primary aldosteronism, screening can be accomplished by measuring a morning (preferably between 0800 and 1000 h) ambulatory paired random plasma aldosterone concentration (PAC) and plasma renin activity (PRA). An increased PAC:PRA ratio is not diagnostic by itself, and primary aldosteronism must be confirmed by demonstrating inappropriate aldosterone secretion. Aldosterone suppression testing can be performed with orally administered sodium chloride and measurement of urinary aldosterone or with intravenous sodium chloride loading and measurement of PAC. Unilateral adrenalectomy in patients with APA or unilateral adrenal hyperplasia results in normalization of hypokalaemia in all these patients; hypertension is improved in all and is cured in approximately 30-60% of them. In bilateral adrenal forms of primary aldosteronism, unilateral or bilateral adrenalectomy seldom corrects the hypertension and they should be treated medically with a mineralocorticoid receptor antagonist.

Hyperaldosteronism

Primary Primary aldosteronism (hyporeninemic hyperaldosteronism) was previously thought to be most commonly caused by an adrenal adenoma, termed Conn's syndrome. However, recent studies have shown that bilateral idiopathic adrenal hyperplasia is the cause in up to 70% of cases. Differentiating between the two is important, as this determines treatment. Also, see congenital adrenal hyperplasia. Adrenal carcinoma is an extremely rare cause of primary hyperaldosteronism. Two familial forms have been identified: type I (dexamethasone suppressible), and type II, which has been linked to the 7p22 gene. Features Hypertension Hypokalemia (e.g., may cause muscle weakness) Alkalosis Investigations High serum aldosterone Low serum renin High-resolution CT abdomen Management Adrenal adenoma: surgery Bilateral adrenocortical hyperplasia: aldosterone antagonist, e.g., spironolactone

[Primary hyperaldosteronism--12 clinical cases].

To show clinical, biochemical, and morphological data of 12 patients with primary hyperaldosteronism: eight with an aldosterone-producing adenoma and four with adrenal hyperplasia. To compare clinical and biochemical parameters of the patients with adenoma and hyperplasia. For those with adenoma, to verify clinical and biochemical modifications after adrenalectomy. In the 12 patients with hyperaldosteronism, retrospective analysis of clinical (age, sex, blood pressure), biochemical (plasmatic and urinary potassium, plasmatic aldosterone, plasma renin activity, and plasmatic aldosterone/renin activity ratio), and morphological (computed tomography, magnetic resonance, and norcholesterol scintigraphy) data was performed. 1--In the 12 patients with hyperaldosteronism (seven female), the age was 51.0 +/- 10.2 years (mean +/- standard deviation), the systolic pressure 200.9 +/- 34.5 mm Hg and the diastolic pressure 120.0 +/- 12.3 mm Hg. Hypertension was diagnosed 12.0 +/- 10.1 years before. As biochemical evidence, we found kalaemia of 3.06 +/- 0.28 and urinary potassium of 63.4 +/- 16.5 mEq/l, renin activity 0.98 +/- 1.02 ng/ml/h, plasmatic aldosterone of 49.4 +/- 36.0 ng/dl, aldosterone/renin activity > 30 in 83% of the cases. As morphological evidence, computed tomography allowed diagnosis in nine patients, suggested it in two, being doubtful in one. Performed on four patients, resonance confirmed the tomography in three and was not contributive in one. The scintigraphy performed in four patients visualized two adenomas, was negative in one adenoma and in one hyperplasia. 2--In the eight patients with adenoma (six female), the youngest age and the highest diastolic pressure compared with patients with hyperplasia were statistically significant (p < 0.01 and 0.05). In the adenomas, the biochemical changes were more pronounced, but not statistically significant. The plasmatic aldosterone/renin activity ratio was also higher in the adenoma cases. 3--After the adrenalectomy, blood pressure became normal in five patients and was more easily therapeutically controlled in three. The average systolic and diastolic pressures decreased and the biochemical parameters became normal in all patients. The pre/post surgical modification of these parameters had statistical significance (systolic pressure decrease, p < 0.01; diastolic pressure decrease, p < 0.01; kalaemia increase, p < 0.001; renin activity increase, p < 0.01; aldosterone decrease, p < 0.02). The plasmatic aldosterone/renine activity ratio normalized in all patients. In diagnosing primary hyperaldosteronism, biochemical (kalaemia, urinary potassium, plasmatic aldosterone, renin activity, aldosterone plasmatic/renin activity) and tomography studies were important. On comparing the patients with hyperplasia with those with adenoma, we found that the latter are younger and exhibit higher diastolic pressure, both findings with statistical significance. After adenoma surgery, blood pressure became normal in five patients and improved in three, these findings, and the improvement of the kalaemia, plasmatic aldosterone, and renin activity parameters were statistically significant.

InternalMed_Harrison

In patients with normal adrenal morphology and family history of early-onset, severe hypertension, a diagnosis of GRA should be Disorders of the Adrenal Cortex Clinical suspicion of mineralocorticoid excess Patients with hypertension and Severe hypertension (>3 BP drugs, drug-resistant) or Family history of early-onset hypertension or cerebrovascular events at < 40 years of age Measurement of aldosterone-renin ratio (ARR) on current blood pressure medication (stop spironolactone for 4 wks) and with hypokalemia corrected (ARR screen positive if ARR >750 pmol/L: ng/ml/h and aldosterone >450 pmol/L) (consider repeat off ˜-blockers for 2 wks if results are equivocal) Negative E.g., saline infusion test (2 liters physiologic saline over 4 h IV), oral sodium loading, fludrocortisone suppression Confirmation of diagnosis Rare: Both renin and Aldo suppressed

[Primary hyperaldosteronism in a population of hypertensive patients].

The diagnosis of primary hyperaldosteronism (PHPA) has progressively increased over the last years and some authors consider it as the main cause of secondary hypertension. We studied the prevalence of PHPA in hypertensive patients followed at the Hypertension Unit from July 1999 to July 2017. A total of 2500 patients were included and diagnosis of PHPA was done in 79 of them (3.2%). It was more frequent in women (55.7%) with an increased incidence in the elderly, as compared to previous studies (27.8%). Initial diagnosis was suspected upon the presence of inappropriate kaliuria and metabolic alkalosis, associated to an aldosterone/plasma renin activity ratio > 30 (ng/dl)/(ng/ml/h). After confirmation of the presence of PA, imaging techniques to determine the etiology were performed. In this way, 29 cases (36.8%) of aldosterone-producing adenoma and 5 cases of bilateral adrenal hyperplasia with nodules were identified. Computed tomography identified the adenomas and hyperplasias with bilateral cortical nodules in all patients. Adrenalectomy and/or antialdosteronics were efficient in controlling blood pressure in 69.9% of cases. Of note in this series was the remission of stage 3 chronic renal failure in two cases, the high prevalence of hypercalciuric urinary lithiasis and a case of breast carcinoma after prolonged treatment with spironolactone.

Primary aldosteronism

Primary hyperaldosteronism has a number of causes. About 33% of cases are due to an adrenal adenoma that produces aldosterone, and 66% of cases are due to an enlargement of both adrenal glands. Other uncommon causes include adrenal cancer and an inherited disorder called familial hyperaldosteronism. Some recommend screening people with high blood pressure who are at increased risk, while others recommend screening all people with high blood pressure for the disease. Screening is usually done by measuring the aldosterone-to-renin ratio in the blood (ARR) whilst off interfering medications and a serum potassium over 4, with further testing used to confirm positive results. While low blood potassium is classically described in primary hyperaldosteronism, this is only present in about a quarter of people. To determine the underlying cause, medical imaging is carried out.

[Chronic kidney disease after adrenalectomy in a patient with primary aldosteronism].

We report one case of estimated glomerular filtration rate (eGFR) decline after taking unilateral adrenalectomy due to aldosterone adenoma. A 60-year-old male with 23-year history of hypertension was reported to the endocrinologist due to hypokalemia (serum potassium 3.01 mmol/L). Urine microalbumin/creatinine (ALB/CR) was 70.15 mg/g, serum creatinine was 82 μmol/L and eGFR was 89.79 mL/(min·1.73 m<sup2</sup). Random serum aldosterone was 172.2-203.5 ng/L, and random plasma rennin activity was 0-0.17 μg/(L·h). His captopril challenge test suggested that his aldosterone le-vels were suppressed by 8% (< 30%) and the adrenal enhanced computed tomography scan revealed a left adrenal tumor. The patient was diagnosed with primary hyperaldosteronism (PA), aldosterone adenoma and underwent left laparoscopic adrenalectomy. Histological examination confirmed adrenal cortical adenoma. One week after the operation, his serum creatinine was increased to 127 μmol/L compared with preoperative level; eGFR was 32.34 mL/(min·1.73 m<sup2</sup). His systolic blood pressure (SBP) was 110 mmHg and diastolic blood pressure (DBP) was 60 mmHg (hypotensive drugs discontinued), and serum potassium level was 5.22 mmol/L. At the end of the 2-year follow up, the serum creatinine of this patient remained at 109-158 μmol/L and eGFR fluctuated from 63.28-40.12 mL/(min·1.73 m<sup2</sup). PA is one of the most common causes of secondary hypertension. Several studies have reported renal function deterioration of PA patients after unilateral adrenalectomy, like the patient in this article. Age, preoperative plasma aldosterone concentration, albuminuria and preoperative potassium level might be significant predictors of a decrease in the eGFR. Growing evidence suggests that aldosterone could contribute to structural kidney damage, arterial injury and hemodynamic disorder. At the same time, patients with PA exhibit glomerular hyperfiltration and glomerular vascular hypertension, leading to the misinterpretation of renal function in PA patients as subtle kidney damage may be masked by the glomerular hyperfiltration before treatment. After a unilateral adrenalectomy, glomerular hyperfiltration by aldosterone excess is resolved and renal damage can be unmasked. In conclusion, kidney function deterioration after adrenalectomy can be detected in some patients with PA. Thus, accurate evaluation of kidney function in patients with PA may be essential, especially for those with preoperative risk factors for postoperative renal impairment. After unilateral adrenalectomy, close monitoring of renal function and adequate management are required for PA patients.

Amiloride

minimal efficacy. For people with resistant hypertension, already taking a thiazide diuretic, an angiotensin converting enzyme inhibitor (ACE-i) or an angiotensin II receptor blocker (ARB), and a calcium channel blocker, the addition of amiloride (or spironolactone) was better at reducing blood pressure than adding a beta-blocker (bisoprolol) or an alpha-1 blocker (doxazosin). When combined with hydrochlorothiazide, the addition of amiloride had positive effects on blood pressure and blood sugar tolerance. Amiloride may therefore be useful for preventing the metabolic side effects of thiazide diuretics, allowing for the use of higher thiazide doses (in line with how they were originally studied).

Antihypertensive drug

Sodium nitroprusside, a very potent, short-acting vasodilator, is most commonly used for the quick, temporary reduction of blood pressure in emergencies (such as malignant hypertension or aortic dissection). Hydralazine and its derivatives are also used in the treatment of severe hypertension, although they should be avoided in emergencies. They are no longer indicated as first-line therapy for high blood pressure due to side effects and safety concerns, but hydralazine remains a drug of choice in gestational hypertension. Renin inhibitors Renin comes one level higher than angiotensin converting enzyme (ACE) in the renin–angiotensin system. Renin inhibitors can therefore effectively reduce hypertension. Aliskiren (developed by Novartis) is a renin inhibitor which has been approved by the U.S. FDA for the treatment of hypertension. Aldosterone receptor antagonist Aldosterone receptor antagonists: eplerenone spironolactone

Pseudohyperaldosteronism

Treatment Specific treatment of pseudohyperaldosteronism depends on the inciting cause. General management focuses on countering the effects of excess mineralocorticoid activity to achieve adequate blood pressure control and avoid end-organ damage and cardiovascular mortality. In some cases, specific antihypertensive medications may be recommended. In Liddle's syndrome, ENaC-binding potassium-sparing diuretics (e.g. amiloride or triamterene) are used to counter the excess ENaC activity. In AME, the mineralocorticoid receptor-binding potassium-sparing diuretics (e.g. spironolactone or eplerenone) are used to limit aldosterone receptor activity. Other medications such as glucocorticoids are added in AME and CAH to inhibit ACTH and further cortisol production. Lifestyle changes such as a low sodium diet are also used for managing hypertension, and cessation of licorice intake is recommended in cases of licorice overconsumption.

Hyperaldosteronism

Hyperaldosteronism is a medical condition wherein too much aldosterone is produced by the adrenal glands, which can lead to lowered levels of potassium in the blood (hypokalemia) and increased hydrogen ion excretion (alkalosis). This cause of mineralocorticoid excess is primary hyperaldosteronism reflecting excess production of aldosterone by adrenal zona glomerulosa. Bilateral micronodular hyperplasia is more common than unilateral adrenal adenoma. Signs and symptoms It can be asymptomatic, but these symptoms may be present: Fatigue Headache High blood pressure Hypokalemia Hypernatraemia Hypomagnesemia Intermittent or temporary paralysis Muscle spasms Muscle weakness Numbness Polyuria Polydipsia Tingling Metabolic alkalosis Nocturia Blurry Vision Dizziness/Vertigo

Secondary hypertension

11β-hydroxylase deficiency, aka apparent mineralocorticoid excess syndrome, involves a defect in the gene for 11β-hydroxysteroid dehydrogenase, an enzyme that normally inactivates circulating cortisol to the less-active metabolite cortisone. At high concentrations cortisol can cross-react and activate the mineralocorticoid receptor, leading to aldosterone-like effects in the kidney, causing hypertension. This effect can also be produced by prolonged ingestion of liquorice (which can be of potent strength in liquorice candy), by causing inhibition of the 11β-hydroxysteroid dehydrogenase enzyme and likewise leading to secondary apparent mineralocorticoid excess syndrome. Frequently, if liquorice is the cause of the high blood pressure, a low blood level of potassium will also be present. Cortisol induced hypertension cannot be completely explained by the activity of Cortisol on Aldosterone receptors. Experiments show that treatment with Spironolactone (an inhibitor of the aldosterone

Spironolactone

The clinical benefits of spironolactone as a diuretic are typically not seen until 2–3 days after dosing begins. Likewise, the maximal antihypertensive effect may not be seen for 2–3 weeks. Unlike with some other diuretics, potassium supplementation should not be administered while taking spironolactone, as this may cause dangerous elevations in serum potassium levels resulting in hyperkalemia and potentially deadly abnormal heart rhythms. High blood pressure About 1 in 100 people with hypertension have elevated levels of aldosterone; in these people, the antihypertensive effect of spironolactone may exceed that of complex combined regimens of other antihypertensives since it targets the primary cause of the elevated blood pressure. However, a Cochrane review found adverse effects at high doses and little effect on blood pressure at low doses in the majority of people with high blood pressure. There is no evidence of person-oriented outcome at any dose in this group.

The spironolactone, amiloride, losartan, and thiazide (SALT) double-blind crossover trial in patients with low-renin hypertension and elevated aldosterone-renin ratio.

There is continuing variation in diagnosis and estimated prevalence of primary hyperaldosteronism. The higher estimates encourage search for adrenal adenomas in patients with elevated ratios of plasma aldosterone to renin. However, it is more likely that patients with normal plasma K+ and aldosterone belong to the polygenic spectrum of low-renin hypertension rather than have the same monogenic syndrome as classic Conn's. Our primary hypothesis was that in low-renin patients with normal plasma K+ and aldosterone, a thiazide diuretic, bendroflumethiazide, would be as effective as spironolactone in overcoming the Na+ retention and lowering blood pressure. Secondary objectives were to compare the dose response for each diuretic and to evaluate amiloride as an alternative to spironolactone. Fifty-seven patients entered and 51 patients completed a placebo-controlled, double-blind, randomized crossover trial. Entry criteria included low plasma renin, normal K+, elevated aldosterone-renin ratio, and a previous systolic blood pressure response to spironolactone of > or = 20 mm Hg. Two doses each of spironolactone and bendroflumethiazide were compared. The crossover also included amiloride and losartan. Outcome measures were blood pressure, plasma renin, and other biochemical markers of diuretic action. Spironolactone 100 mg and bendroflumethiazide 5 mg caused similar falls in systolic blood pressure, whereas bendroflumethiazide 2.5 mg was 5/2 mm Hg less effective in reducing blood pressure than either bendroflumethiazide 5 mg or spironolactone 50 mg (P<0.005). Amiloride 40 mg was as effective as the other diuretics. Biochemical indices of natriuresis showed bendroflumethiazide to be less effective than either spironolactone or amiloride; plasma renin rose 4-fold on spironolactone but only 2-fold on bendroflumethiazide (P=0.003). In hypertensive patients with a low plasma renin but normal K+, bendroflumethiazide 5 mg was as effective as spironolactone 100 mg in lowering blood pressure, despite patients being selected for a previous large fall in blood pressure on spironolactone. Because this result differs from that expected in primary hyperaldosteronism, our finding argues against low-renin hypertension including a large, undiagnosed pool of primary hyperaldosteronism. However, spironolactone was the more effective natriuretic agent, suggesting that inappropriate aldosterone release or response may still contribute to the Na+ retention of low-renin hypertension.

Mineralocorticoid hypertension.

Hypertension affects about 10 - 25% of the population and is an important risk factor for cardiovascular and renal disease. The renin-angiotensin system is frequently implicated in the pathophysiology of hypertension, be it primary or secondary. The prevalence of primary aldosteronism increases with the severity of hypertension, from 2% in patients with grade 1 hypertension to 20% among resistant hypertensives. Mineralcorticoid hypertension includes a spectrum of disorders ranging from renin-producing pathologies (renin-secreting tumors, malignant hypertension, coarctation of aorta), aldosterone-producing pathologies (primary aldosteronism - Conns syndrome, familial hyperaldosteronism 1, 2, and 3), non-aldosterone mineralocorticoid producing pathologies (apparent mineralocorticoid excess syndrome, Liddle syndrome, deoxycorticosterone-secreting tumors, ectopic adrenocorticotropic hormones (ACTH) syndrome, congenitalvadrenal hyperplasia), and drugs with mineraocorticoid activity (locorice, carbenoxole therapy) to glucocorticoid receptor resistance syndromes. Clinical presentation includes hypertension with varying severity, hypokalemia, and alkalosis. Ratio of plasma aldosterone concentraion to plasma renin activity remains the best screening tool. Bilateral adrenal venous sampling is the best diagnostic test coupled with a CT scan. Treatment is either surgical (adrenelectomy) for unilateral adrenal disease versus medical therapy for idiopathic, ambiguous, or bilateral disease. Medical therapy focuses on blood pressure control and correction of hypokalemia using a combination of anti-hypertensives (calcium channel blockers, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers) and potassium-raising therapies (mineralcorticoid receptor antagonist or potassium sparing diuretics). Direct aldosterone synthetase antagonists represent a promising future therapy.

Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency

The adrenal cortex is hyperplastic and overstimulated, with no impairment of the mineralocorticoid pathway. Consequently, levels of DOC, corticosterone, and 18-hydroxycorticosterone are elevated. Although these precursors of aldosterone are weaker mineralocorticoids, the extreme elevations usually provide enough volume expansion, blood pressure elevation, and potassium depletion to suppress renin and aldosterone production. Some persons with 17α-hydroxylase deficiency develop hypertension in infancy, and nearly 90% do so by late childhood. The low-renin hypertension is often accompanied by hypokalemia due to urinary potassium wasting and metabolic alkalosis. These features of mineralocorticoid excess are the major clinical clue distinguishing the more complete 17α-hydroxylase deficiency from the 17,20-lyase deficiency, which only affects the sex steroids. Treatment with glucocorticoid suppresses ACTH, returns mineralocorticoid production toward normal, and lowers blood pressure.

[Primary hyperaldosteronism. Diagnostic procedure useful in hospital routine].

Personal experience in the management of three cases of primary hyperaldosteronism, in which a cure was obtained by surgical removal of an adrenocortical adenoma, is was used in the elaboration of a diagnostic procedure requiring hospitalisation for 12 days. During 6 days, the patient is kept on a diet containing 100 mEq Na and K, and blood potassium values are repeatedly determined. Other causes of hypertension are ruled out. On the 6th day, baselines for blood renin and urinary aldosterone are calculated. Next, a hyposodic diet is given for 4 days, and a diuretic is administered on the last of these days, after which renin is determined "in response to stimulation". Lastly, two days of i.v. NaCl loading are followed by the determination of urinary aldosterone "during inhibition". If the picture is positive for hyperaldosteronism, the patient is discharged and followed during treatment with spironolactone, and eventually subjected to renal and adrenal arteriography to determine the site of the adenoma. Division of the procedure into increasingly complex steps enables the examination to be halted at any point when evidence in support of the suspected diagnosis fails to appear. This feature, coupled with the simplicity of the procedures adopted, enables all young subjects admitted for unexplained hypertension to be screened for hyperaldosteronism, with the assurance of obtaining certain diagnosis without an excessively long stay in hospital.

Blood pressure

Currently, the RAS is targeted pharmacologically by ACE inhibitors and angiotensin II receptor antagonists, also known as angiotensin receptor blockers (ARBs). The aldosterone system is directly targeted by spironolactone, an aldosterone antagonist. The fluid retention may be targeted by diuretics; the antihypertensive effect of diuretics is due to its effect on blood volume. Generally, the baroreceptor reflex is not targeted in hypertension because if blocked, individuals may suffer from orthostatic hypotension and fainting. Measurement

Hypertension due to a deoxycorticosterone-secreting adrenal tumour diagnosed during pregnancy.

Mineralocorticoid hypertension is most often caused by autonomous overproduction of aldosterone, but excess of other mineralocorticoid precursors can lead to a similar presentation. 11-Deoxycorticosterone (DOC) excess, which can occur in 11-β hydroxylase or 17-α hydroxylase deficiencies, in DOC-producing adrenocortical tumours or in patients taking 11-β hydroxylase inhibitors, may cause mineralocorticoid hypertension. We report a 35-year-old woman who in the third trimester of pregnancy was found to have a large adrenal mass on routine obstetric ultrasound. On referral to our unit, persistent hypertension and long-standing hypokalaemia was noted, despite good compliance with multiple antihypertensives. Ten years earlier, she had hypertension noted in pregnancy which had persisted after delivery. A MRI scan confirmed the presence of a 12 cm adrenal mass and biochemistry revealed high levels of DOC and low/normal renin, aldosterone and dehydroepiandrosterone, with normal catecholamine levels. The patient was treated with antihypertensives until obstetric delivery, following which she underwent an adrenalectomy. Histology confirmed a large adrenal cortical neoplasm of uncertain malignant potential. Postoperatively, blood pressure and serum potassium normalised, and the antihypertensive medication was stopped. Over 10 years of follow-up, she remains asymptomatic with normal DOC measurements. This case should alert clinicians to the possibility of a diagnosis of a DOC-producing adrenal tumours in patients with adrenal nodules and apparent mineralocorticoid hypertension in the presence of low or normal levels of aldosterone. The associated diagnostic and management challenges are discussed. Learning points: Hypermineralocorticoidism is characterised by hypertension, volume expansion and hypokalaemic alkalosis and is most commonly due to overproduction of aldosterone. However, excess of other mineralocorticoid products, such as DOC, lead to the same syndrome but with normal or low aldosterone levels. The differential diagnosis of resistant hypertension with low renin and low/normal aldosterone includes congenital adrenal hyperplasia, syndrome of apparent mineralocorticoid excess, Cushing's syndrome, Liddle's syndrome and 11-deoxycorticosterone-producing tumours. DOC is one intermediate product in the mineralocorticoid synthesis with weaker activity than aldosterone. However, marked DOC excess seen in 11-β hydroxylase or 17-α hydroxylase deficiencies in DOC-producing adrenocortical tumours or in patients taking 11-β hydroxylase inhibitors, may cause mineralocorticoid hypertension. Excessive production of DOC in adrenocortical tumours has been attributed to reduced activity of the enzymes 11-β hydroxylase and 17-α hydroxylase and increased activity of 21-α hydroxylase. The diagnosis of DOC-producing adrenal tumours is challenging because of its rarity and poor availability of DOC laboratory assays.

Bartter syndrome

Bartter syndrome consists of low levels of potassium in the blood, alkalosis, normal to low blood pressures, and elevated plasma renin and aldosterone. Numerous causes of this syndrome probably exist. Diagnostic pointers include high urinary potassium and chloride despite low serum values, increased plasma renin, hyperplasia of the juxtaglomerular apparatus on kidney biopsy, and careful exclusion of diuretic abuse. Excess production of prostaglandins by the kidneys is often found. Magnesium wasting may also occur. Homozygous patients suffer from severe hypercalciuria and nephrocalcinosis.

Surgical management of primary aldosteronism. not everything that shines is gold.

Primary aldosteronism (PA) is a syndrome which includes a group of clinical entities in which aldosterone production is inappropriately high and nonsupressible by sodium loading. The most frequent causes of PA are adrenal adenoma and unilateral or bilateral primary hyperplasia. We report a case of a 55-year-old man with a 10-year history of hypertension in whom functional hormonal studies were indicative of PA. Because adrenal venus sampling was not available at our hospital, the investigation was conducted with a computed tomography (CT) scan and a scan with 131-iodocholesterol (NP-59) which both revealed a left adrenal adenoma. The tumor was excised laparoscopically without any complications and the histological findings confirmed the diagnosis of an aldosterone-producing adenoma. Blood pressure remained normal despite the discontinuation of antihypertensive drugs, further supporting that the adrenal tumor was indeed the cause of high blood pressure. Unfortunately, blood pressure began to rise again 2 months later, and laboratory findings indicated the presence of PA once again. Spironolactone was instituted and blood pressure significantly improved and was finally controlled by the addition of amlodipine. We report this case to underline the difficulties in the discrimination between adenoma and hyperplasia in everyday clinical practice. Although the CT and scintigraphic findings strongly pointed toward an adenoma, the fact that PA re-appeared shortly after the operation, indicated that the underlying cause of the PA was hyperplasia and not adenoma after all.