Download Addisons disease and Congenital Adrenal Hyperplasia (CAH)

Addisons disease and
Congenital Adrenal Hyperplasia
(CAH)
Dr. Géza Nagy
Semmelweis Univ.
2nd Dep. Of. Int. Med
2015.04.22.
Physiology
Addisons
History
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Thomas Addison
(1793-1860)
Addison kór
· 1714 Eustachius (mellékvese morfológiai leírása)
· 1849 Addison (”Anemia – disease of the suprarenal
capsules in which the disease is not distincly separated
from a new form of anemia” London Medical Gazette, )
• · 1855 Addison (Monograph, ”On the constitutional and
local effects of disease of the suprarenal capsule”
Warren & Son, London)
• ·Trousseau (1801-1867)
Definition
· primary chronic insufficiency os the suprarenal gland
Prevalence
· 1960-1970: 4.5–39/million
· 1990-2000: 117–140/millio (aprox. incidence: 4.2–
6.7/millio/year
· tuberculotic adrenalitis is down from 70% to 0-33%-ra)
Famale/male ratio
· more prevalent in females
Etiology
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• Autoimmune adrenalitis (isolated or as part of APS)
• Infective adrenalitis (tuberculosis, fungal, HIV)
• Inherited (genetic) diseases (X-linked ADL, X-linked
AHC, Xp21 contiguous gene deletion syndrome, SF1linked AHC, mitochondrial deletion, Smith-Lemli-Opitz
syndr, Kearns-Sayre syndr, IMAGe syndr, ACTH
Insensivity syndr)
• Malignant tumours, metastasises
• Iatrogenic drug induced/bilateral adrenalectomy
• Suprarenal apoplexy or thrombosis
• Other (sarcoidosis, amyloidosis, histiocytosis,
hemochromatosis)
Autoimmun polyendocrin syndroma type 1 (APS 1)
(autoimmun polyendocrinopathia-candidiasis-ectodermalis dysplasia –
APECED)
Prevalence: 1:9000 – 1:80000
Main symptoms:
• mucocutan candidiasis
• hypoparathyreosis
• autoimmune Addison syndr.
Onset:
Childhood and adolescents
Inheritance:
autosomal recessive
Gene affected:
AIRE gene (21q22)
Autoimmun polyendocrine syndrome type 2. (APS 2)
Prevalence: 1:20000
Main syndromes:
• autoimmun Addison disease
• diabetes mellitus type 1
• autoimmun thyreoiditis
Other autoimmun syndromes:
• gonad insuff. , vitiligo, alopecia, pernicious anemia, celiac
disease, chronic hepatitis, hypophysitis, rheumatoid arthritis
Age of onset:
30-35 y
Heritability:
Familial forms are rare
Defective genes:
HLA, CTLA4 (HLA-DR3, DR4, DR5)
Acute suprarenal insufficiency
•Life threatening, fatal without treatment
- Addison patient (treated or untreated)
• - acut bilateral destruction of suprarenal gland
(haemorrhage, trauma, anticoagulant treatment, infection
– Waterhouse-Friderichsen sy)
• • Symptoms:
• - severe hypotension, hypovolaemic shock, azotemia
• - gastrointestinal symptoms (acute abdominal pain,
vomiting, etc,)
• - fever
• • Hyponatraemia (and serum K+)
• • CT scan in dg of haemorage
(chronic) Symptoms
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• Weakness 100%
• Weight loss 100%
• Gastro-intestinal symptoms 95%
• Vomiting 85%
• Nausea 80%
• Abdominal pain 30%
• Constipation 30%
• Diarea 25%
• Hyper pigmentation 95%
• Hypotension or orthostatic hypotension 90%
• Hypoglycaemia 50%
• Anaemia 40%
• Salt craving 20%
• Vitiligo 15%
• Muscle pain 15%
• Joint pain 10%
Diagnosis
• National Adrenal Disease Foundation (USA) survey:
At least 60% of Addison patients were „seen” by more
thantwo phisicians befor the suspicion of addison was raised.
Laboratory testing
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Hormone tests
• morning plasma kortizol and ACTH
(plasma kortisol and plasma ACTH)
• standard short corticotropin test (plasma kortisol measurement
at 0, 30 és 60 min. after administering 250 mg ACTH iv
• (normal response: peak plasma kortisol >20 mg/dl)
• • (plasma aldosteron, PRA, DHEAS)
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Other tests based on etiology
• Suprarenal gland autoantibodys
• APS: autoantibody testing
• Males: very long chain fatty acids
• Oncology patients: bilateral suprarenal metastasis (imaging)
Most comonly used drugs for hormone substitution
Treatment of chronic suprarenal
gland insufficiency
• Glukokortikoid substitution
• – Hydrocortison (Cortef) tabl. Total daily dose: 15-25 mg, divided into 2-3
times or
• – Prednisolon tabl 5-7.5 mg/day
• • Mineralokortikoid substitution (rarely needed in secunder hypadrenia)
• – Fludrocortison (Asztonin H) tabl. 0.1-02 mg/day 2 times/day
• • In case of fever or any other stress situation
• – Dose of Hydrocortison (Cortef tabl) should be increased (2x-3x)
• • If oral treatment is not possible (i.e. vomiting)
• – 100 mg hydrocortison (SoluCortef) in evry 6-8 houres slow iv. infusion
• • Treatment of hypadrenic crisis
• – 100 mg hydrocortison (SoluCortef) in evry 6-8 houres slow iv. infusion
• – treatment of Hypovolaemia, hyponatraemia 0,9% saline infusion
• – glucose, antibiotics
• • Anaesthesia, operation
• –High dose iv. hydrocortison kezelés infusion during the operation
• • 50-100 mg hydrocortison (SoluCortef) evry 6-8 hours slow infusions
• •usually 2-3 days
Testing for hormone substitution
therapy
Glucocorticoid
• – Plasma ACTH és cortisol test (jelentősége kicsi)
• – Urine 24-hour cortisol excretion (non-complience?)
• – Symtoms of under and over dose
• – Adherence to stress situations
• – Body weight BP, seNa, seGlucose
• Mineralocorticoid
• – Bp (orthostasis)
• – Symptoms of fluid retention oedemas
• – Serum sodium, potassium, PRA
Case report
47 y female patient
• Anamnesis:
– Tonsillectomy
– 2006 Hypothyreosis (unknown origin)
– 2013 bronchial asthma
• Family history:
– Father: DM, PAD; Brother: DVT, Emb. Pulm.
† 37y
• Medication: L-thyroxin, Bisoprolol
(2014.01.20)
• Significant weight loss 1 y. 10 kg
• Fatigue, weakness, loss of appetite,
nausea.
• Menstrual period: First at 16 y, used to be
regular, 1 y irregular
• Hypotension
Physical examination
findings:
Cachexia (44 kg)
Hyperpigmentation of
periorbital, buccal, gingival
and palmar region
BP: 90/60 hgmm
Family history is important!
Laboratory findings
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WBC: 14.6 Giga/L;
vvt sz: 5.36 Tera/L; Hemoglobin: 150 g/L; Hematokrit: 0.44 L/L; MCV: 82.1
fL;
THRCY: 576 Giga/L;
Süllyedés: 7 mm/h;
INR: 1.15 INR; APTI: 43.4(H) sec;
Glükóz: 5.9 mmol/L;
Triglicerid: 1.32 mmol/L;
HDL-chol: 1.13 mmol/L; LDLC: 2.90 mmol/L; Cholesterin: 4.7 mmol/L
T.bilirubin: 10.8 umol/L; DBIL: 1.2 umol/L;
AP: 179 U/L; LDH: 345 U/L; GOT: 47 U/L; GPT: 36 U/L; GGT: 17 U/L;
CN: 12.9 mmol/L; Kreatinin: 90 umol/L; GFR: 66.4(L) ml/min/1.73 m2;
Nátrium: 126 mmol/L; Kálium: 6.5 mmol/L;
Kalcium: 2.63 mmol/L; Foszfát: 1.93 mmol/L;
Összfehérje: 77.6 g/L; Albumin: 50.5 g/L;
Viezelet: negatív
Hormon tests
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TSH Supersens. 0.005 mU/L,
ATPO 525.20 U/mL
Kortizol <0.1 ug/dL
Ösztradiol meghat. 15.4 pg/mL L;
FSH meghat. 49.58 IU/L H; LH meghat.
96.55 IU/L
• Prolaktin meghat. 70.97 ng/mL
• Parathormon meghat. (PTH) 35 pg/mL
• 25OH D3-vitamin 17.3 ng/mL
Imageing
• Abdomina US: Negative result
• ODM: Osteopenia (L: -2,4; F: -0.8; R: -1,4)
Immunologiai vizsgálatok
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Deam.gliadin pept.at IgA: negatív
Deam.gliadin pept.at IgG: negatív
Glutaminsav dekarboxiláz elle.AT: negatív
Szöveti transzglut.at IgG, IgA: negatív
Mellékvesekéreg elleni AT: erősen pozitív
Pancreas szigetsejt ell. AT: gyengén
pozitív
Therapy
• IV.
– hydrocortisone
– Fluid replacement
• Per os
– Resonium
– Fludrokortizon (2x1/2 tabl.)
– Hydrocortisone (15-10-5 mg)
Control
(2014.02.24)
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Regained strength and bodymass
Status:decreasing of skin pigmentation.
RR: 145/105 Hgmm
Hr: 76/perc
Labs
(2014.02.24)
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Sodium:
134 mmol/L
K:
4.8 mmol/L
TSH:
4.933 mU/L
Total prolaktin:
54.16 ng/mL
– Aktiv prolaktin:
– Makroprolaktin:
30.00 ng/mL
24.16 ng/mL
Laboratóriumi vizsgálat
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Nátrium:
Kálium:
TSH:
FT3:
FT4:
ACTH:
Renin:
136 mmol/L
4.2 mmol/L
93.983 mU/L
2.98 pmol/L
5.85 pmol/L
303.0 pg/mL
0.7 ng/mL/ó
Congenital Adrenal Hyperplasia
Definition
1. It is a familial disorder of adrenal steroid
biosynthesis with autosomal recessive mode
of inheritance.
2. The defect is expressed as adrenal enzyme
deficiency.
3. 5 major Enzymes deficiency are clinically
important
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21-Hydroxylase
11-b-Hydroxylase
17-a-Hydroxylase
3-b-Hsteroid hydrogenese
20,22 Desmolase deficiency
The enzyme deficiency causes reduction in
end-products, accumulation of hormone
precursors & increased ACTH
production.
The clinical picture reflects the effects of
inadequate production of cortisol &
aldosterone and the increased production
of androgens & steroid metabolites.
21-Hydroxylase Deficiency
Enzyme pathway
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• Most common type, accounts for >80%
of cases.
• Incidence is 1:5000 to 1:15000 live
birth.
• Gene is located on the short arm of
chromosome 6 near the C4 locus in
close association with HLA genes.
• Heterozygous carriers can be detected
by ACTH stimulation test.
• It is characterized by reduced production
of cortisol and aldosterone and increased
production of progesterone;
17-OH-progesterone, and sex steroids.
• The urinary steroid metabolites
(17-ketosteroids and pregnanetriol) are
elevated above normal levels.
• Decreased secretion of aldosterone results in
salt loss with hyponatremia and hyperkalemia;
plasma renin activity is therefore elevated.
• In partial enzyme deficiencies, the aldosterone
deficiency is not expressed, and patients
remain normonatremic and normokalemic.
• The excess androgens causes virilization of
girls & ambiguous genitalia & dark scrotum in
boys.
• 2 forms, classic early virilization type
with or without salt-losing crisis and
non-classic type with late-onset
virilization.
• Male babies with non salt-losing nonclassic type remains asymptomatic till
late childhood when they may show
signs of sexual precocity.
11-b-Hydroxylase Deficiency
• Accounts for 5-10% of cases of CAH.
• Gene is located on the long arm of chromosome
8.
• It is characterized by low plasma renin activity &
elevation of serum 11-Deoxycortisol and 11deoxycorticosterone.
• Because of the strong mineralocorticoid activity
of deoxycorticosterone, the condition is
characterized by salt retention, hypertension &
hypokalemic alkalosis.
• The elevated plasma androgens may cause
virilization of the female fetus.
17-a-Hydroxylase deficiency
• Genetic defect is on chromosome 10.
• Presents with similar features of those
of 11-Hydroxylase deficiency except
that Androgens are low, so no
virilization in girls & genitalia is
ambiguous in boys.
3-b-hydroxysteroid dehydrogenase
deficiency
• This is a very rare disorder that results
in accumulation of DHEA, which is
converted to testosterone in peripheral
tissues.
• It can cause virilization of female fetus
and leads to ambiguous genitalia in the
newborn.
ESSENTAILS OF DIAGNOSIS
• Increased linear growth with
advanced bone age and eventual short
stature
• Pseudohermaphorditism in girls due
to androgen virilizing effect
• Isosexual precocity in boys with small
infantile testes.
ESSENTAILS OF DIAGNOSIS/2
• Adrenal crisis with salt-loss &
metabolic acidosis or Hypertension &
hypokalemic alkalosis.
• Low cortisol with high androgens,
ACTH and steroid precursors e.g. 17OH-Progest. or 11-Deoxycortisol.
ESSENTIALS OF DIAGNOSIS/3
• Diagnosis is confirmed by measurement
of ACTH, Cortisol, Aldosterone,
17-OH-progesterone, Testosterone &
urinary 17-ketosteroids.
• Needs alertness for the possibility in all
babies with Diarrhea & Vomiting,
hypoglycemia or  BP.
CLINICAL COURSE
• The clinical phenotype depends upon the
nature and severity of the enzyme
deficiency.
• Approximately 50% of patients with
classic congenital adrenal hyperplasia
due to 21-hydroxylase (CYP21)
deficiency have salt wasting due to
inadequate aldosterone synthesis.
• Girls are usually recognized at birth
because of ambiguous genitalia.
CLINICAL COURSE/2
• Non salt losing CAH present late in
childhood with precocious pubic hair
and/or clitoromegaly, often accompanied
by accelerated growth and advanced bone
age.
• Those individuals with mild deficiencies
of the enzyme present in adolescence or
adulthood with varying virilizing
symptoms ranging from oligomenorrhea
to hirsutism and infertility.
GIRLS WITH CAH
• Have ambiguous genitalia at birth:
• complete fusion of the labioscrotal folds
and a phallic urethra. clitoromegaly and
partial fusion of the labioscrotal folds
• In less severe forms, genitalia is normal
at birth. Precocious pubic hair &
clitoromegaly and excess facial or body
hair appear later in childhood, often
accompanied by tall stature.
BOYS WITH CAH
• Are unrecognized at birth because their genitalia
are normal.
• They are not diagnosed until later, often with a salt
wasting crisis resulting in dehydration, hypotension,
hyponatremia and hyperkalemia or later in
childhood with early pubic hair & phallic
enlargement accompanied by accelerated linear
growth and advancement of skeletal maturation.
• High blood pressure & hypokalemia may occur in
those with 11-b-hydroxylase deficiency and 17-ahydroxylase deficiency due to the accumulation of
the mineralocorticoid desoxycorticosterone
Laboratory Findings
• Demonstration of inadequate production of
cortisol and/or aldosterone in the presence of
accumulation of excess concentrations of
precursor hormones is diagnostic.
• In 21-hydroxylase deficiency, very high
serum 17-hydroxyprogesterone is
characteristic together with very high urinary
pregnanetriol (metabolite of 17hydroxyprogesterone).
Laboratory Findings/2
• 11-b-hydroxylase deficiency is
characterized by high serum 11deoxycorticosterone and 11deoxycortisol concentrations with
elevation of its urinary metabolites
(tetrahydrocompound-S).
• Both are accompanied by elevated 24hour urinary 17-ketosteroids, the
urinary metabolites of adrenal
androgens.
Laboratory Findings/3
• Salt wasting forms of adrenal
hyperplasia are accompanied by low
serum aldosterone, hyponatremia,
hyperkalemia and elevated plasma
renin activity indicating hypovolemia.
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• In contrast hypertensive forms of
adrenal hyperplasia (11-b-hydroxylase
deficiency and 17-a-hydroxylase
deficiency) are associated with
suppressed plasma renin activity and
hypokalemia.
Other Tests
• A karyotype is essential in the
evaluation of the infant with
ambiguous genitalia in order to
establish the chromosomal sex.
• Prenatal diagnosis of adrenal
hyperplasia is possible through
biochemical and genetic tests.
Imaging studies
• A pelvic ultrasound: in the infant with
ambiguous genitalia to demonstrate the
presence or absence of a uterus or associated
renal anomalies
• A urogenitogram is often helpful to define the
anatomy of the internal genitalia.
• A CT scan of the adrenal gland to R/O bilateral
adrenal hemorrhage in the patient with signs of
acute adrenal failure
• A bone age study is useful in the evaluation of
the child who develops precocious pubic hair,
clitoromegaly, or accelerated linear growth.
TREATMENT PRINCIPLES
• Treatment is life-long
• Treatment goals are:
• to maintain growth velocity & skeletal
maturation.
• to normalize electrolytes & hormone
levels using the smallest dose of
glucocorticoids that will suppress the
ACTH to normal. Mineralocorticoid
replacement may be needed to sustain
normal electrolyte homeostasis.
MODES OF TREATMENT
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Steroid replacement
Supportive therapy when needed
Treatment is life-long
Plastic surgery for ambiguous
genitalia at early age
• Genetic counseling
• Psychological support
Acute Medical Management
• Fluid therapy in babies with salt losing
crisis 0.9% sodium chloride 20 ml/kg as
IV bolus, followed by a continuous IV
infusion of 0.9% or 0.45% saline 3200
ml/m2/day.
• If the patient is hypoglycemic, 2-4 ml of
10% dextrose will correct the
hypoglycemia.
• Patients with 11-b-hydroxylase and 17alpha-hydroxylase deficiency, may be
hypokalemic and require potassium.
Long Term Therapy
• Glucocorticoids Replacement
• Hydrocortisone 10-15 mg/m2/day
divided in 3 oral doses. Dose should
doubled during crisis & stressful
conditions. The goals of therapy are:
• To replace the body's requirement under
normal conditions and during stress.
• To suppress ACTH secretion, which
drives the adrenal gland to overproduce
adrenal androgens in virilizing forms of
congenital adrenal hyperplasia.
Long Term Therapy/2
• Mineralocorticoids Treatment
Fludrocortisone acetate 0.05-0.2 mg
once daily orally is indicated for
patients who have salt-wasting
forms of CAH to replace the
aldosterone that is insufficiently
produced by the adrenal cortex. It
will restore the sodium- potassium
balance.
New Trends of treatment
• glucocorticoid (to suppress ACTH and adrenal
androgen production),
• mineralocorticoid (to reduce angiotensin II
concentrations),
• aromatase inhibitor (to slow skeletal
maturation),
• flutamide (an androgen blocker to reduce
virilization)
Further Outpatient Care
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Monitor patients adequacy of dosing of glucocorticoid
and/or mineralocorticoid.
• Too little glucocorticoid results in symptoms of adrenal
insufficiency (e.g., anorexia, nausea, vomiting, abdominal
pain, asthenia) and will result in progressive virilization
and advancement of skeletal maturation in virilizing forms
of CAH.
• Too much glucocorticoid results in excess weight gain,
cushingoid features, hypertension, hyperglycemia,
cataracts, and growth failure.
PROGNOSIS
Is good and complications like short
stature, sexual precocity & metabolic
effects are not seen with early
adequate therapy.
However, children with CAH are at 
risk of developing mesodermal
tumours e.g. osteogenic sarcoma,
pulmonary liposarcoma, uterine
leiomyomata and brain tumours.
PROGNOSIS /2
• Late diagnosis & inadequate therapy
may cause:
• Death of newborns with salt-losing
types & if patients are not provided
with stress doses of glucocorticoid in
times of illness, trauma, or surgery.
• Psychological problems in girls with
ambiguous genitalia.
• Short stature and infertility.