Endocrine Flashcards
What is CAH?
Mutation in CYP21A2 gene
= deficiency in 21 hydroxylase
21 hydroxylase converts 17-OH progesterone to 11 deoxycortisol
Lack of 21 hydroxylase = raised 17-OH progesterone (this is what we test to confirm CAH
2 types -salt losing form with virilisation - simple virilisation Girls present with ambiguous genitalia Boys present either at birth with salt losing adrenal crisis (low Na, high K, FTT) or as toddlers in precocious puberty
What is MELAS?
Mitochondrial myopathy Encephalopathy Lactic acidosis and stroke - mitochondrial -short, deaf, developmental delay - Fhx death -associated with diabetes (type 2 like picture) - can have pyroxidine anaemia --> treat with pyroxidine and resolves
Do you get lactic acidosis with monogenic diabetes?
No
What is monogenic diabetes (MODY)
1x inherited gene
Failure of B cell development +/- decreased insulin transcription (primary defect in insulin secretion)
Onset <25 years old. Often pre-pubertal
Don’t always need insulin
Non-ketotic
Absence of autoantibodies
Fhx- autosomal dominant
MODY2 static (glucokinase defect), rest progressive
Can affect expression of many other genes in several organs
e. g MODY (1,2,3,5 most common)
e. g neonatal diabetes
What does insulin do to glucagon levels?
Inhibits glucagon synthesis = low
IF low insulin levels glucagon is high!
Why is glucagon low in CFRD?
NOT because of lower insulin (normally increases glucagon if low)
Glucagon storage in low in CF
Why do you rarely get ketoacidosis in CFRD?
Poor absorption of fatty so less stores to mobilise to FFA
What can cause a widespread bullous rash, insulin resistance then sudden hypoglycemia, haematuria and marked acanthosis? (Rash, haematuria, diabetes)
SLE with antibody against insulin receptor (Type B insulin resistance, IgG Ab against receptor)
If treat with prednisone get sudden hypoglycaemia as treating SLE with immunosuppression
What test can you do to confirm MODY 2?
Glucokinase
What is the condition affecting neonates which causes diabetes, IUGR, seizures and muscle weakness?
DEND syndrome
-Defect in SUR channel
What is needed to lay down fat antenatally?
Insulin!
What is transient neonatal diabetes?
-Low insulin levels antenatally, IUGR, poor fat layers. Normal placental function. Initial hypoglycemia (low BW, no glycogen stores) Super sensitive to insulin. Then recovers well with sky rocketing growth. -At increased risk of insulin deficient (abnormal beta cells) diabetes later on in life (around age 10years) -70% chromo 6q24, paternal imprinted genes -Overexpression of ZAC and HYMAI genes (methylation defect- one of two copies should be silenced but this doesn't happen)
What methylation defect can cause transient neonatal diabetes
Loss of imprinting of ZAC or HYMAI genes
Maternal copy is not silenced
How does MODY 3 often present?
Adolescence ICA, GAD and IA2 antibody negative Often have kidney issues Family history HNF1 alpha mutation (exon 4) Treat with sulphonylurea
What are sulphonylureas?
Increase Beta cell secretion
Used in T2DM and MODY 3, and DEND syndrome
Can cause hypoglycemia
I.e Gliclazide
What are Biguanides?
Theory is reducing insulin resistance
Can be used in type 2 or in type 1 in combination with insulin
Can cause GI upset, very rare in lactic acidosis
i.e Metformin
What are Thiazolidinediones?
Reduces circulating FFA so use more glucose
Reduces insulin resistance
Increases appetite. Can cause oedema and heptatitis
i.e Pioglitazone
What is MODY 2?
Glucokinase enzyme defect. Non progressive so don’t usually get complications unlike other MODY
In the cytoplasm
Where do all MODY defects occur except type 2?
Endoplasmic reticulum of Beta cells
Part of transcription factors
Often progressive
What is the most common MODY?
MODY type 3 - 65%
What is MODY 3?
Most common monogenic DM
Progressive B cell failure
Presents with symptomatic hyperglycemia in adolescence or in 20’s
Later develops secondary insulin resistance
Do those at risk of MODY 3 have normal insulin secretion?
Yes. But can’t increase excretion of insulin with increased glucose levels
What is DEND syndrome? (developmental delay, epilepsy, and neonatal diabetes)
Defect in K ATP channel (controls release of insulin from B cells)- reduced sensitivity to ATP.
K ATP channels are present in brain, muscle and pancreas
In neonatal period develops weight loss, diabetes.
Developmental delay
Epilepsy
Severe muscle weakness
Can prevent morbidity if detect early
Treatment is with Sulphonylurea! (Glibenclamide) which resolves diabetes and prevents/treats all the sequelae!
What inhibits thyroid releasing hormone from the hypothalamus?
Dopamine
What stores thyroglobulin?
Colloid in follicular cells of the thyroid
What are thyroid cells made up of?
- Colloid stores- contains thyroglobulin
- Follicullar cells - surround colloid.
- Parafollicular cells- make and release Calcitonin
IPEX syndrome
see “syndromes”
Congenital hypothyroidism
The Guthrie test is a measure of TSH. An elevated level is abnormal and indicates hypothyroidism
Congenital hypothyroidism:
- most cases from thyroid dysgenesis – 85%
- some cases familial, inborn error of thyroid hormone synthesis – 10%
- transplacental maternal thyrotropin receptor blocking antibody – 5%
- most infants asymptomatic at birth (some maternal T4 crosses placenta)
Clinical features: lethargy, slow movement, hoarse cry, feeding problems, constipation, macroglossia, umbilical hernia, large fontanels, hypotonia, dry skin, hypothermia, prolonged jaundice
Associated congenital malformations: affecting heart, kidneys, urinary tract, GI, skeletal
In dyshormonogensis – goitre is present
Thyroid dysgenesis:
- 50% aplasia
- 50% hypoplasia or ectopic gland
- Unknown cause in most cases
Androgen insensitivity syndrome
*Androgen insensitivity syndrome = undervirilised male. All patients have 46XY chromosomal complement, range from phenotypic females to males with various forms of ambiguous genitals and undervirilization to phenotypically normal appearing males with infertility. In addition to normal 46XY chromosomes, the presence of testes (palpable gonads) and normal to elevated levels of testosterone levels are common to all such children.
DHT normal with normal T:DHT ratio.
Aromatase deficiency
In genotypic females, aromatase deficiency during fetal life leads to 46XX DSD and results in hypergonadotrophic hypogonadism at puberty because of failure of ovary to synthesize estrogen.
Normal genitalia at birth
Bilateral anorchia
Bilateral anorchia is rare, incidence of 1:20,000 males. It is defined as complete absence of testicular tissues in genetically and phenotypically male patients.
Hypophosphatemic rickets.
X-linked (but acts like dominant inheritance – male and female).
Lab findings: slightly reduced Ca++ level (2.24-2.34 mmol/L); moderately reduced serum phosphate (0.48-0.96 mmol/L), elevated ALP, and no evidence of hyperparathyroidism (i.e. normal PTH).
AKA vit D resistant rickets
Pseudohypoparathyroidism
- resistance to PTH
- Patients have hypocalcaemia and hyperphosphataemia despite elevated serum PTH
- hypocalcaemia including carpo-pedal muscular spasms, cramping, tetany, and if the calcium deficit is severe, generalized seizures. IQ is typically mildly depressed or unaffected.
- Additional characteristics include short stature, obesity, developmental delay, and calcification of the basal ganglia in the deep white matter of the brain.
- multiple types
–> type 1a associated with Albrights Osteodystrophy
Individuals with Albright hereditary osteodystrophy exhibit short stature, characteristically shortened fourth and fifth metacarpals, rounded facies, and often mild intellectual deficiency.
Vitamin D deficient rickets
Vitamin D-deficient rickets is the body’s attempt to maintain normal serum calcium.
- In the absence of vitamin D, less calcium is absorbed from the intestine and with only a slight decrease in serum calcium concentration, PTH is secreted leading to an ↑ Ca++ and phosphorus mobilisation from bone.
- Hence Ca++ is maintained, but rickets changes in bone, low serum phosphorus concentration (PTH decreases phosphorus reabsorption in the kidneys), and increased ALP (due to increased osteoclastic activity).
- ALP normally <200 in children, >500 in mild rickets. (ALP may be normal in protein or zinc depleted infants with rickets).
alpha 5 reductase deficiency
- alpha 5 reductase deficiency = undervirilised male
An autosomal recessive disorder in which 46,XY subjects with bilateral testes and normal testosterone formation have impaired external virilisation during embryogenesis due to defective conversion of testosterone to dihydrotestosterone. In this disorder, the ratio of T:DHT is >10:1 The external genitalia usually are predominately female at birth, with the exception of clitoromegaly in some, so that most affected males are raised as females. A variable degree of virilisation occurs at the time of puberty. The internal urogenital tract is male, consisting of epididymides, vasa deferentia, seminal vesicles, and ejaculatory ducts that empty into a blind-ending vagina
CAH and ambiguous genitalia
*Congenital adrenal hyperplasia = virilised female. More than 90% of cases of CAH are caused by 21-hydroxylase deficiency. The most important problem caused by accumulation of steroid precursors is that 17-hydroxyprogesterone is shunted into the pathway for androgen biosynthesis, leading to high levels of androstenedione that are converted outside the adrenal gland to testosterone. This problem begins in affected foetuses by 8-10 wk of gestation and leads to abnormal genital development in females.
Masculinised female genitalia manifest as enlargement of the clitoris and by partial or complete labial fusion. The vagina usually has a common opening with the urethra (urogenital sinus). The clitoris may be so enlarged that it resembles a penis, because the urethra opens below this, some females may be mistakenly presumed males with hypospadias and cryptorchidism.
Normal T:DHT ratio.
Causes of ambiguous genitalia
Either: virilised female or an undervirilised male
CAH if female
In males-
Causes of an undervirilised XY - see below
CAH – the less common forms (non-classical) only. CAH caused by 21-hydroxylase deficiency is also seen in 46,XY children but does not result in genital ambiguity.
Abnormal testicular activity ◾Gonadal dysgenesis ◾Testicular regression syndrome ◾Vanishing testes syndrome ◾Persistent Mullerian duct syndrome
Abnormal androgen synthesis: have abnormal response to hCG stimulation.
◾17-beta-hydroxysteroid dehydrogenase type 3 deficiency
◾Steroid 5-alpha-reductase deficiency (SRD)
◾LH receptor defects
Abnormal response to androgen
◾Androgen insensitivity
◾ MIS receptor defect
◾Endocrine disrupter
Testicular biosynthetic disorder
- Causes of XY undervirilisation in which androgen synthesis is abnormal include 17-beta-hydroxysteroid dehydrogenase type 3 deficiency. In this condition, serum testosterone concentrations are often in the lower normal range
True hermaphroditism
– Ovotesticular DSD (previously termed true hermaphroditism), is characterised by the presence of both functional ovary and testis. It is most often associated with an XX karyotype. However, it can be seen with an XY karyotype, a mixed XX/XY karyotype, or various other sex chromosome patterns
Adrenoleukodystrophy
Adrenoleukodystrophy (ALD) is a peroxisomal disorder of beta-oxidation that results in accumulation of very long chain fatty acids (VLCFA) in all tissues.
ALD is an X-linked disorder. Therefore a female is unlikely to be severely affected.
Female carriers may be symptomatic depending upon the pattern of X-chromosome inactivation. Affected individuals typically present with mild spastic paraparesis in mid-adulthood.
An AMN-like (adrenomyeloneuropathy) syndrome affects up to 50% of female heterozygotes in middle age or later, although cerebral disturbance is uncommon. Adrenal insufficiency is rare in females.
polyglandular autoimmune syndrome
-also referred to as the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome
- AR
- mutations in the autoimmune regulator gene (AIRE) on 21q22.3, which encodes a protein that plays an important role in establishing and maintaining tolerance in the thymus
- APECED is characterized by at least 2 of the following: CMC, hypoparathyroidism, and Addison disease. Other autoimmune disorders may be associated, such as, type 1 diabetes, autoimmune thyroiditis, Graves disease, alopecia areata, vitiligo, hypogonadism, biliary cirrhosis, hepatitis, idiopathic thrombocytopenic purpura, and pernicious anemia.
- Candidiasis is often the first manifestation of APECED, appearing before age 5 years in most cases, followed by manifestations of the other endocrine and nonendocrine conditions, including ectodermal dysplasia. Ectodermal dysplasia manifestations include dental enamel hypoplasia and pitted nail dystrophy. Keratopathy and calcifications of the tympanic membrane also may occur.
- the presence of adrenal autoantibodies has a high positive predictive value for development of adrenal insufficiency, but won’t tell you if they are
