Öregedő mellékvese diagnosztikus és klinikai dilemmák Dr Valkusz Zsuzsanna.
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Transcript of Öregedő mellékvese diagnosztikus és klinikai dilemmák Dr Valkusz Zsuzsanna.
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Öregedő mellékvese Öregedő mellékvese diagnosztikus és klinikai diagnosztikus és klinikai
dilemmákdilemmák
Dr Valkusz Zsuzsanna
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Age Related ChangesAge Related ChangesAdrenals -
connective tissue replaces degenerating tissue
age-related decline in cortical secretions
glucocorticoids
decline in aldosterone over 50
no apparent effect on salt and water balance
medullary hormones actually increase
epinephrine
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Disorders of the Adrenal GlandDisorders of the Adrenal Gland
Adrenocortical Insufficiency
A) Primiary Adrenal Insufficiency (Addison’s disease)
-most common cause is autoimmune-mediated destruction of the adrenal glands (>80%)
-secondary to tuberculosis (20%)
-chronic fungal infections, infection by cytomegalovirus (CMV), metastasis to the glands by cancer cells (rare).
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B) Secondary Adrenal Insufficiency:
-Addison’s Disease caused by inadequate secretion of ACTH by the pituitary gland
-may arise due to the prolonged or improper use of glucocorticoid
Example: Glucocorticoid hormones such as prednisone are used to treat chronic diseases such as rheumatoid arthritis, asthma, and other inflammatory illnesses by suppressing the secretion of ACTH and thus the secretion of cortisol.
-tumors may produce ACTH on their own
-less common causes of secondary adrenal insufficiency include pituitary tumors, or damage to the pituitary gland during
surgery or radiation.
Disorders of the Adrenal Disorders of the Adrenal GlandGland
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Adrenocortical Hyperfunction
A) Congenital adrenal hyperplasia:
-is a common inherited form of adrenal insufficiency
-due to mutations in genes for several enzymes needed for the production of adrenal cortex hormones.
-about 95% of cases of are caused by 21-hydroxylase deficiency
-this enzyme is necessary for production of cortisol and aldosterone –-sensing low levels of cortisol, the adrenal, via the hypothalamus and pituitary glands, the adrenal cortex synthesizes androgens.
-thus, while one part of the adrenal functions poorly, making inadequate amounts of cortisol and aldosterone, another portion of the gland
over-produces androgens
Disorders of the Adrenal Disorders of the Adrenal GlandGland
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B) Cushing’s Syndrome
Therapeutic ("iatrogenic": caused by the treatment)
-Cushing's Syndrome is a disease caused by an excess of cortisol production or by excessive use of cortisol or other similar steroid (glucocorticoid) hormones
-unfortunate necessary side effect when high doses of these steroid hormones must be used to treat certain life-threatening illnesses, such as asthma, rheumatoid arthritis, systemic lupus, inflammatory bowel
disease, some allergies, and others
Disorders of the Adrenal GlandDisorders of the Adrenal Gland
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Spontaneous overproduction of cortisol: Two groups
-those due to an excess of ACTH: A pituitary tumor producing
too much ACTH, stimulating the adrenals to grow
(hyperplasia) and to produce to much cortisol (>70%);
"ectopic" ACTH production (30%)
-those not due to excess ACTH: Adrenal cortex tumors that make
cortisol can be benign (an adenoma), or malignant (a carcinoma) and are
usually found on only one side.
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Adrenal Incidentalomas Adrenal Incidentalomas
Increased use of cross sectional imaging has lead to improved detection
Since prevalence of these masses increases with age, and improved detection, appropriate management of adrenal tumours will be a growing challenge in an aging society
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DefinitionDefinition
Non-functioning adrenal tumours discovered on imaging study performed for indications exclusive of adrenal related pathology.
Based on autopsy studies, adrenal masses are among the most common tumours in human
Adrenal mass occurs in at least 3 percent of persons over age 50
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Why are these lesions important?. . When detected, clinically inapparent adrenal masses
raise challenging questions for physicians and their patients Most adrenal masses cause no health problems
Approximately 1 out of every 4,000 adrenal tumours is malignant.
Diagnostic evaluation is performed to determine: 1.) Is the lesion hormonally active or non-functioning 2.)Is it malignant or benign?
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Radiologists Role?Radiologists Role?
With a little clinical and endocrinological information
the radiologist can make the diagnosis and effect
management
The results from these tests will influence whether the
mass is removed surgically or treated nonsurgically in
most cases.
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AnatomyAnatomy
Named For location : AD_renal = above kidneys
Weights 5g
Has a characteristic Y, V or T shape.
Embryology: Cortex derived from mesoderm
: Medulla derived from neural crest
cells
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AnatomyAnatomy
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AnatomyAnatomy
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AnatomyAnatomy
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PhysiologyPhysiology
Influence or regulate the body's metabolism, salt and water balance, and response to stress by secreting a variety of hormones.
Cortex has 3 layers that secrete cortisol, aldosterone and androgens.
Medulla secretes adrenaline and noradrenaline
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Imaging ModalitiesImaging Modalities
Widespread use of CT scanning has lead to incidentalomas detected in approximately 0.5% of the population scanned CT Scanning CT scanning is used to characterise a large
number of adrenal incidentalomas Several different Strategies used in CT scanning 3 criteria used: Histologic, Physiologic and
Morphologic
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HistologicalHistological
Non Contrast CT
Principle
Both macroscopic fat (myelolipoma or lipoma) of the adrenal gland
as well as intracytoplasmic fat in sufficient concentrations maybe
detectable.
Adrenal cortex and many benign adrenocortical tumours contain
intracytoplasmic fat (mainly cholesterol, fatty acids and neutral fat)
Malignant as well as metastasis lesions do not generally contain fat.
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PhysiologicalPhysiological
Contrast Enhanced CT Scanning (Perfusion CT) Utility Most adrenal incidentalomas are seen on contrast
CT scanning. To permit rapid diagnosis ,prevent repeat
scanning (cost and time inefficient) with a non-contrast CT scan and prevent excess radiation exposure certain strategies can be used with contrast enhanced CT
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PhysiologicalPhysiological
Principle: Adrenal glands (both metastatic and adenomas)
enhance rapidly post contrast to the same degree, which complicates the use of adrenal density values
30 % of adrenal adenomas do not have sufficient fat to be characterised with non-contrast CT. Contrast CT is valuable for these lesions.
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Case Study- PJ (early 2003)Case Study- PJ (early 2003)
56 year old white female presented to medical attention due to a blood pressure of 210/125 discovered at work
Over several months, she had been dealing with worsening diabetes, persistent worsening hypertension, deepening voice and progressive hirsutism. Also noted vaginal bleeding despite being postmenopausal (LMP several years prior)
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Lab StudiesLab Studies
24h urinary studies:– cortisol: 588 (nl 9- 53)
•Serum Studies:–Testosterone 291 (nl 14-76)–Cortisol 41.8–DHEA elevated
–VMA: 2.6–Metanephrines: <40
–Serum ACTH: undetectable
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ImagingImaging
•CT scan revealed a mass involving the adrenal gland, apparently completely contained within. The lesion demonstrated scattered calcification and signal heterogeneity
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Its appearance, coupled with the patient history, physical exam, and laboratory data strongly suggested an adrenocortical carcinoma
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EpidemiologyEpidemiology
Estimated incidence of 0.5-2 per 106 patients per year
Peaks of age distribution at age <5 and in the 4th and 5th decades
Scattered reports of gene associations, but rarity of lesion precludes clear associations
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Functioning LesionsFunctioning Lesions
60-65% of adrenocortical carcinomas are functioning lesions– Cushings– Virilization– Feminization– Hyperaldosteronism
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Hormonal studies can be a first diagnostic test which confirms ectopic steroid hormone secretion, leading to an imaging and tissue diagnosis.
They also can be a “tumor marker” which can be useful for monitoring response to therapy and suspicion of recurrence.
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HypercortisolismHypercortisolism
24 hour urinary cortisol exrection– More than 90% of Cushinoid patients have free
cortisol levels greater than 200mcg/ 24 hours. 97% of normals have levels less than 100mcg/ 24 hours
ACTH measured with serum cortisol will demonstrate ACTH independent nature of hypercortisolism.
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Other SteroidsOther SteroidsOther steroids are elevated:
– androstenediol and adrosetenedione– DHEA and DHEA-S– 11- deoxycortisol– urinary 17- ketosteroids– aldosterone
Many intermediate enzymes are defective or dysregulated, leading to inefficient steroid production and precursor buildup
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Potential Functional AssaysPotential Functional Assays
Serum TestosteroneSerum DHEA and DHEA-S24 hour urinary ketosteroidsPlasma estradiol and/ or estronePlasma aldosterone/ reninUrinary catecholamines/ metanephrines
in all patients
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ImagingImaging
CT detects 98% of adrenal carcinomasMRI scanning can also provide vascular
invasion/ tumor thrombosis information.Also provides many incidentalomas
– Malignant lesions tend to be > 5cm, have irregular shapes/ blurred margins, and be heterogeneously enhancing.
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StagingStaging
Hormonal studies directed at symptoms24h urine studies to r/o pheochromocytomaCT scanning to determine extent and
resectability of lesionMRI if vascular invasion unclear; R sided
lesions have a propensity to form venous tumor emboli
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StagingStaging
Stage I — Disease confined to the adrenal gland and <5 cm in diameter (approx 20%)
Stage II — Disease confined to the adrenal gland and >5 cm in diameter (approx 20%)
Stage III — Local invasion that does not involve adjacent organs or regional lymph nodes (approx 20%)
Stage IV — Distant metastases or invasion into adjacent organs plus regional lymph nodes (approx 40%)
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Gross SpecimenGross Specimen
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Microscopic SpecimenMicroscopic Specimen
Note the mitotic figure
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Prognostic factorsPrognostic factors
In a case review of 46 patients at MSKCC, 3 histologic factors correlated with survival:– tumor> 12cm– 6 or more mitotic figures/ 10hpf– presence of histologic evidence of intratumoral
hemorrhage– 5 year survivals:
0 factors: 83% 1 factor: 42% 2 factors: 33%
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Radiation ApproachRadiation Approach
There are scattered case reports demonstrating improved pain when palliative XRT used for localized lesions
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Chemotherapeutic ApproachChemotherapeutic Approach
Review of the literature reveals case reports, retrospective treatment data, and reviews.
A few phase II trials do exist from some cooperative or national groups
No true modern- design controlled phase III trials exist
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MitotaneMitotane
1,1- dichloro-2-(o-chlorophenyl) ethane (o,p-DDD).
Chemical relative to DDTFound to have adrenolytic activity in dogs
in vivo (selectively destroyed the zonae reticularis and fasciculata)
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inhibits the intramitochondrial conversion of cholesterol to pregnenolone and the conversion of 11-deoxycortisol to cortisol (11B- hydroxylation). It produces selective adrenocortical necrosis in both the adrenal tumor and metastases
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Side effects are major and frequent, including:– CNS disturbance (vertigo, somnolence, ataxia)– Liver Toxicity– Renal Toxicity– Nausea, Vomiting– Diarrhea– Rash
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Selected Mitotane StudiesSelected Mitotane Studies
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Other symptom- palliative Other symptom- palliative OptionsOptions
Metyrapone (11B hydroxylase inhibitor)KetoconazoleAminoglutehamide
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CytotoxicsCytotoxics
Various systemic cytotoxics have been used for advanced disease, usually for those failing mitotane.
Most studied have been Etoposide, cisplatin, and adriamycin.
Paclitaxel and Temozolamide have recently demonstrated antitumor activity in vitro
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SummarySummary
Adrenocortical carcinoma is a rare disease that often presents late
Primary curative therapy is surgicalNo role for adjuvant chemotherapy has
been demonstrated to datePalliative therapy with mitotane may be
useful; its palliative effect may be entirely due to adrenolytic effect
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Reoperation appears to be the only long term curative option in recurrent cases
Cytotoxic chemotherapy in the advanced/ metastatic setting has not been definitively demonstrated to be useful in controlled trials
EDP-M may be useful in metastatic settings; more evaluation is needed
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