Endo Flashcards
Dx on CXR?
Rachitic rosary
Calcipenic ricketts
Expect low Ca/vit D, elevated PTH
Dx on CXR?
Osteopetrosis
Skeletal dysplasia = hardening of the bones
- Altered bowel gas pattern & hepatosplenomegaly also consistent
Patterns of hypoglycemia (inc insulin/ketones)
Low BSL/ketones & high insulin
- Hyperinsulinemia
(congenital)
- Insulin prevents breakdown fat > FFA = low ketones
Low BSL/insulin, high ketones
- Indequete substrate (fasting)
- Defect in counter regulatory hormones
- Defecits iin glycogenolysis/GNG
Low BSL, ketones & insulin
- FAO defect
Features of 21-OH CAH?
CYP21a2 mutation
Lack 21-OH enzyme =
build up of 17OHP
↓ Cortisol
↓ Aldosterone
↑ Sex steroids
Classic
- Simple virilising 25% (enough aldosterone, lack sex steroids)
- Severe salt wasting 75%
(no sex steroids or aldo)
Hypotension, hyponatremia & hyperkalemia
Metabolic acidosis
Ambiguous genitalia in females
Virilisation in males/females
Non-classical
- Late onset
- Androgen excess without genital ambiguity
(pubarche, hirstutism etc)
Features of 17a-OH CAH
CYP17A1 mutation
Normal cortisol
↑ Aldosterone
↓ Sex steroids
(Inc DOC/corticosterone)
Hypertension, hypernatremia, hypokalemia,
Metabolic alkalosis
Sexual infantilism
Features of 11b-OH CAH
CYP11B1 mutation
↓ Cortisol
↑ Aldosterone
↑ Sex steroids (androgens), ↓ Oestrogen
(inc DOC, 11-DOC)
Hypertension, hypernatremia, hypokalemia
Metabolic alkalosis
Ambigous genitalia (female)
Virilisation (M&F)
Features of 3b-OHS CAH
HSD3B2 mutation
↓ Cortisol
↓ Aldosterone
↓ Androgens (males, ↑ in females)
(increased DHEA)
Hypotension, hyponatremia, hyperkalemia
Metabolic acidosis
Ambiguous genitalia in males, mild in females
Genetics of 21-OH CAH- what correlates to disease severity?
2 steroid 21-hydroxylase genes
– CYP21P
- CYP21(pseudogene with 9 mutations)
> 90% of mutations causing 21-hydroxylase deficiency are recombinations between CY21 and CYP21P
20% are deletions generated by unequal meiotic crossing over
Gene conversion – caused by non-reciprocal transfer of deleterious mutations
Disease severity correlates with mutations – ie. salt wasting disease results from mutations on both alleles that completely destroy enzymatic activity
Outline types of Cushing’s Syndrome
CS= glucocorticoid excess
CD = caused by pituitary adenoma
Moon facies, buffalo hump, obesity, impaired growth
HTN, hyperglycemia, osteoporosis
ACTH dependent (central)
1. Pituitary adenoma
- Most common >7yrs
- Assoc MEN1
- Ectopic ACTH production
- Pancreatic Ca, neuroblastoma
- HTN more common
ACTH independant (adrenal)
1. Iatrogenic
2. Adrenal adenoma
3. Syndromic
- Primary pigmented nodular adrenocortical disease
- McCune Albright
Ix: Elevated midnight cortisol (usually nadir), urinary free cortisol,
- Elevated dexa supression test >5 (not supressed in ACTH independant, only larger dose supresses in ACTH dependant)
- CRH: IV bolus of CRH
ACTH-dependent Cushing’s = exaggerated ACTH and cortisol response
ACTH-independent (eg. adrenal tumour) = no increase to ACTH
Epi/genetics of T1DM?
Most common form in childhood
Bimodal peak 4-6yrs, 10-14yrs
Genetics:
- 85% have no FHx
- MZ concordance 30% in 10yrs
- Both parents- up to 30%
- HLADR3/4 + DQ2/8 = susceptible (DR2 protective)
Patho of T1DM
Patho:
Trigger in susceptible host (geography, viral infections, diet, SES)
- T cell mediated B cell destruction
- Preclinical autoimmunity
- Symptoms when 90% destroyed
- Decreased gluc uptake in liver, muscle, fat storage
- Shunts to GNG from fat/protein
- Transient remission with therapy
What is the dawn phenomenon in T1DM
Early morning (2-8am) hypoglycaemia due to overnight GH secretion + ↑ insulin clearance
Occurs in peri-pubertal + pubertal years, may result in sub-optimal morning insulin levels
Manage with ↑ evening protophane dose
What is the Somogyi phenomenon in T1DM
Rebound hyperglycaemia from late night/ early AM hypoglycaemia,
Due to exaggerated counter regulatory response
Antibodies in T1DM and progression?
- Anti-insulin antibodies (appears first then disappears with insulin therapy)
- Anti GAD
- Anti- islet cell cytoplasmic ABs (70% prevalence in newly diagnosed)
- Anti-IA2- best predictor for T1DM development
- Anti-ZNT8: lecrease rapidly over time
Autoimmune associations in T1DM
More common in HLADR3 carriers
- 7-15% coeliac disease within first 6yrs
- 6% prevalence of vitiligo (6x background population)
- 2-5% hypo, 1% hyperthyroidism (HLADQB1)
- APS2/IPEX
- Adrenal disease 21OH
Short, intermediate and long acting insulins?
Short: Novorapid/actrapid/ humalog
Intermediate: humulin/protophane
Long: Levemir/lantus
Earliest sign of diabetic nephropathy?
Hyperalbuminuria defined as albumin excretion between 30-300 mg/day (20-200 mcg/min)
What is Mauriac syndrome
Dwarfism associated with glycogen-laden liver
Complication of chronic low insulin levels in T1DM
Mortality of cerebral oedema in T1DM and risk factors prevention?
Cerebral oedema
- 50-60% of T1DM related deaths
- Occurs 6 and 12 hours after starting therapy
- Risk factors = first presentation, long history of poor control, young age (< 5 yr)
Risk factors for T2DM
Obesity, +ve FHx (one parent 40%, two parent 60%, MZ 90%), female/PCOS, gestational, glut2 defect
What percentage of patients with T2DM present with DKA vs HHONK?
5-15% both
What percentage of patients with T2DM present with DKA vs HHONK?
5-15% both
What symptom of T2DM is a good marker of insulin resistance?
Acanthosis nigricans – marker of insulin resistance found in 50-90% of youth with T1DM
Rx T2DM
OHGs:
1. Metformin monotherapy is treatment of choice (metabolic acidosis/GI upset)
2. Sulfonylureas: inc insulin secretion from B cells (low BSL, weight gain)
3. Acarbose: ↓glucose absorption from GI tract (GI Sx)
4. GLP 1 analogues: improve pancreatic islet glucose sensing (N&V)
5. DPP-IV inhibitors: Prolong GLP1 action, leading to improved beta-cell sensing (hypersensitivity/headache)
6. SLGT2 inhibitor (pee out glucose) = risk inc infection
7. Thiazolidinediones: ↑ insulin sensitivity (weight gain significant)
Insulin if:
HbA1c >9%
Severe hyperglycaemia (serum glucose > 15 mmol/L)
Ketosis/ketoacidosis
MODY syndromes & overview
2-5% of DM diagnosis
AD, younger onset
Reduced insulin response to glucose:
MODY 1 (<10%) - HNF4a
- Rx sulfonylurea
MODY 2 (15-30%)- GCK
- Mild/non progressive
- Rx diet
MODY 3 (65%)- HNF1a most common
- Rx sulfonylurea
Pancreatic dysfunction:
MODY 4- IPF1
MODY 5- HNFb
MODY 6- NEUROD
Vitamin D homeostasis
RFs/protective factors for presentation with DKA in T1DM
RFs: <2yrs, delay in diagnosis, minority group, COVID pandemic
Protective: family history, screening programmes
2 week boy presents with lethargy, vomiting
Na 124, K+ 8, glucose 1.8
Dx & Mx?
Salt wasting crisis in setting of 21-OH def (90% of cases)
- XY patients may not have any physical features
- Consider in any child <5wks with high K/low Na
Rx: fluid resuscitation, dextrose if low BSL, glucocorticoid Rx (steroid profile prior)
46XY- ambiguous genitalia, around puberty undergoes significant masculinisation- growth of penis/testes
5a reductase deficiency
SRD5A gene
-AR
-Defective conversion of testosterone to DHT (role in EXTERNAL genitalia during embryogenesis)
- Normal testosterone
- Normal to low DHT
- HIGH ratio testosterone:DHT
46XY with female external genitalia, breasts & primary amenorrhoea, palpable gonads in labia
Complete androgen insensitivity
- AR
- Serum testosterone normal
- AMH present
- Androgen receptor does not sense
46XY no uterus, undervirilised male genitalia with high T/DHT, normal ratios on HCG test T/DHT
Partial androgen insensitivity
46XX, male external genitalia, uterus, high testosterone, high K+, low Na
21-OH
DSDs at increased risk of malignancy
Risk of germ cell malignancy
HIGH
- Gonadal dysgenesis + Y chromosome positive + Intra-abdominal gonad
-Partial insensitivity syndrome + intra-abdominal gonad >50%
INTERMEDIATE
- Turner + Y
- GD + Y + scrotal gonads
- PAIS + scrotal gonads
LOW – No Y
-CAIS
- 46 XX ovotesticular DSD
- Turner, No Y chromosome
Define precocious puberty?
= puberty < age 8 in girls or < 9 in boys
How to differentiate central vs peripheral cause precocious puberty
Peripheral
- High testosterone, low FSH/LH
- Asynchronous development
- Paraneoplastic (HCG stimulates LH receptor)- germ cell tumors- CNS/gonads/liver/mediastinum
Central
- High testosterone, high LH/FSH
Basics of calcium metabolism
99% stored in bone
- Resorption (breakdown): osteoclasts - clasts release calcium
- Mineralisation (bone formation): osteoblasts (blasts build)
1% in serum
- 50% ionised
- 40% albumin/globulin (influenced by pH)
- 10% in complexes- phosphate/citrate etc
10% excreted via urine
90% reabsorbed via PCT/LOH/DCT
- Acidosis increases excretion
- Alkalosis decreases excretion
What receptor governs Ca2+ metabolism and where is it found?
Calcium sensing receptor
- Parathyroid chief cells
- Renal tubular cells
- C cells of thyroid
Regulates PTH/calcitonin release & Ca2+ renal absorption
Differentiate Ricketts from osteomalacia?
Rickets = deficient mineralisation at the growth plate + architectural disruption of this structure
Osteomalacia = impaired mineralisation of the bone matrix
Signs of Ricketts
- Widened growth plate
- Metaphyseal fraying
- Cupping
- Widening of distal metaphysis
Genetic cause of pseudohypoparathyroidism
Pseudohypoparathyroidism = HypoCa,
hyperPhos, and raised PTH.
Allbright’s hereditary osteodystrophy
Imprinting disorder
- Maternally inherited GNAS mutations =
Allbright’s hereditary osteodystrophy +
pseudohypoparathyroidism.
- Paternally inherited = Allbright’s
hereditary osteodystrophy without
endocrinopathy
(pseudopseudohypoparathyroidism).
Most common antibody at Dx T1DM
- ICA: Islet cell antibodies- 90%
- Against cytoplasmic proteins in the beta cell - GAD-65: Antibodies to glutamic acid
decarboxylase- 80% - IAA: Insulin autoantibodies- 75%
- IA2: antibodies to protein tyrosine phosphatase- 70%
Detail these regions of bone development
Distal -> proximal:
Germinal zone
- irregularly scattered chondrocytes
Proliferation zone
- Chondrocytes divide, flatten and form columns
- Creates lengthening
Hypertrophic zone
- Maturation
- Chondrocytes differentiate, enlarge and die
- Bone is calcified
- Regulated by phosphate
Ossification zone
- Matrix formed by chondrocytes becomes template for osteoblasts to build bone
Features of metabolic syndrome
- Diabetes
- Hypertension
- Dislipidaemia
- Abdominal Obesity
Association with other conditions
e.g. NASH, PCOS, OSA
