Diabetes + Thyroid Flashcards
What is an alternative to Hba1c and when is it used?
Fructosamine reflect glucose in last 2-3 weeks
Used in any condition that affects age of RBCs - haemolytic anaemia, sickle cell anaemia, blood loss
What is the thyrogastric cluster of autoimmune diseases?
Hashimoto’s/Graves, Coeliac, Vitiligo, Primary sclerosing cholangitis, pernicious anaemia
What is the HLA association for Type 1 Diabetes?
Class II MHC most important
HLADR4 > HLADR3 confers risk
HLADR2 is protective
Present as a polymorphic region on chromosome 6
Difference between Type 1 and 2 diabetes
Type 1 diabetes mellitus is caused by autoimmune destruction of the Beta-cells of the pancreas. Identical twins show a genetic concordance of 40%. It is associated with HLA-DR3 and DR4. It is inherited in a polygenic fashion
Type 2 diabetes mellitus is thought to be caused by a relative deficiency of insulin and the phenomenon of insulin resistance. Age, obesity and ethnicity are important aetiological factors. There is almost 100% concordance in identical twins and no HLA associations.
Auto antibodies associated with T1DM?
- Anti-GAD
- Anti IA2
- Zinc transporter 8
- Anti GAD ab
- Anti tyrosine phosphatase related islet antigen
- Islet cell surface antibody
- Decreased C peptide levels indicate an absolute insulin deficiency - type 1 diabetes
- Increased C peptide levels indicate insulin resistance and hyperinsulinaemia - type 2 diabetes
C-peptide is a substance, a short chain of amino acids, that is released into the blood as a byproduct of the formation of insulin by the pancreas
MOA of metformin + SE
- Biguanide: reduce hepatic glucose production and increase peripheral glucose utilisation
- Reduce fasting BSL by 20%, decrease Hba1c by 2%
- Reduced mortality when added early with sulfonylureas
SE
- Lactic acidosis
- Long term use can cause vitamin B 12 deficiency
- Weight neutral
- GIT symptoms: diarrhoea, abdo crams
Contraindications
- CKD eGFR < 30
MOA + SE of sulfonylurea
Examples of sulfonylurea:
gliclazide, glimepiride
- MOA: Increase insulin secretion from beta cells
Binding to the SUR subunit of the ATP sensitive potassium channel and inducing channel closure - Decrease Hba1c by 1-2%
- SE: hypoglycaemia, weight gain
- ## Concomitant use with metformin can increase cardiovascular events
Which of these hormones acts via an intracellular receptor? A. Insulin B. Glucagon C. Cortisol D. ACTH E. TSH
Answer: cortisol
- Hormones activate targets by diffusing through the plasma membrane of the target cells (lipid soluble hormones) to bind a receptor protein within the cytoplasm of the cell (intracellular receptor) or by binding a specific receptor protein in the cell membrane of the target cell (water-soluble proteins)
- Lipophobic hormones: are not lipid soluble and therefore cannot diffuse through the cell membranes and so their receptors are localised to the cell plasma membranes, eg: TSH, FSH, LH, insulin
- Lipophilic hormones: pass through the cell and nuclear membrane and so their receptors are normally intracellular, eg: steroid hormones (cortisol, aldosterone, testosterone, estrogen) and thyroid hormones (T3, T4)
What are the stages of diabetic nephropathy?
Stage 1: hyperfiltration (increase in GFR), may be reversible
Stage 2 (silent or latent phase): most patients do not develop microalbuminuria for 10 years, GFR remains elevated
Stage 3: microalbuminuria (albumin excretion 30-300mg/day, dipstick negative)
Stage 4 (overt nephropathy): persistent proteinuria (albumin excretion >300mg/day, dipstick positive), HTN present, histology shows glomerulosclerosis and focal glomerulosclerosis (Kimmelstiel-wilson nodules)
Stage 5: end stage renal disease GFR< 10ml/min
.
Histological changes in diabetic nephropathy
- Mesangial expansion
- Thickening of GBM
- Glomerulosclerosis (later stage) - nodular glomerulosclerosis (Kimmelstiel wilson nodules)
Treatment of diabetic nephropathy
Stringent glycemic control
Antihypertensive treatment: ACEi or ARB
Findings for diabetic retinopathy
- Non proliferative retinopathy: microaneurysms, cotton wool spots, visual loss due to macular oedema
Proliferative retinopathy: preretinal neovascularisation
Treatment for diabetic peripheral neuropathy
- Anticonvulsants: pregablin (most effective), gabapentin, sodium valproate
- Antidepresants: amitriptylline (TCA), duloxetine (SNRI)
Autonomic neuropathy of diabetes
- Erectile dysfunction
- Bladder dysfunction, eg: urinary retention
- Gastroparesis - prokinetic agents (metoclopramide, erythromycin, domperidone)
What are causes of hypokalaemia and hypertension?
- Conn’s syndrome (primary hyperaldosteronism)
- Liddle’s syndrome
Genetic autosomal dominant disorder charactersied by hypertension, low renin, metabolic alkalosis, hypokalaemia, normal to low levels of aldosterone.
Liddle’s syndrome mimics the symptoms of mineralocorticoid excess, causing hypokalemia, hypertension, and metabolic alkalosis, but with suppressed aldosterone and renin levels. It is caused by gain of function mutations to SCNN1A, SCNN1B, and SCNN1G which encode the α, β, and γ subunits of ENaC, respectively - 11-beta hydroxylase deficiency + 17a hydroxylase deficiency in congenital adrenal hyerplasia
- Carbenoxolone, an anti-ulcer drug, and liquorice excess can potentially cause hypokalaemia associated with hypertension
What are causes of hypokalaemia without hypertension
- diuretics
- GI loss (e.g. Diarrhoea, vomiting)
- renal tubular acidosis (type 1 and 2**)
- Bartter’s syndrome
- Gitelman syndrome
What is Bartter Syndrome?
-Autosomal recessive disorder causing defective chloride absorption at the Na+K+2CL-contransporter in the ascending loop of henle causing
Serum: hyponatremia, hypokalaemia, hypochloremia.
Urine there are increased Na, K, Cl, Ca levels and polyuria.
- Mimics loop diuretics
- B for baby - childhood onset
- Gives secondary hyperaldosteronism picture - hypokalaemia, metabolic alkalosis
- Affect growth and mental retardation
What is Gitelman syndrome?
-Autosomal recessive disorder causing defective chloride absorption at the Na+/Cl- symporter in the distal convoluted tubule
- Serum: low K and Mg, high Ca
- Urine: high K, High Mg, low Ca and polyuria
- Act as thiazide diuretics
- G = grownup/adulthood
Cause cramps in limbs, polyuria, fatigue.
How is Bartter syndrome and gitelman syndrome managed?
Electrolyte replaecement
NSAID to block PGE2 levels (prostaglandins are increased in both especially Bartter)
What are the pharmacotherapies approved for obesity?
LOP if off
- Liraglutide
MOA: GLP1 agonist, increase glucose dependent insulin secretion and decrease glucagon secretion. Delays gastric emptying, slow glucose absorption and decrease appetite.
SE: Pancreatitis, nausea, increased risk of gallstones.
- Orlistat: inhibit pancreatic and gastric lipase, reduce fat absorption by 30%, 5-10% weight loss
SE: steatorrhea, flatulence - Phentermine: centrally acting adrenergic agonist that suppresses appetite, 5-10% weight loss
SE: tachycardia, HTN , insomnia, dry mouth
-Naltrexone - Buproprion: opioid antagonist + selective catecholamine (noradrenaline, dopamine) reuptake inhibitor
>10% weight loss
Risk of neuropsych SE
Topiramate - can be used as off-label
Most effective when used with lifestyle management
Hormones that regulate appetite include ghrelin and neuropeptide Y. Where are they produced and their effects
Ghrelin (hungry hormone):
Produced in stomach
Increases appetite and promotes GH release.
Neuropeptide Y
Hypothalamus, increase appetite
Where is the source of leptin and effects
- Source: adipose tissue
- Regulates satiety
- Reduces appetite long-term
- Functions to suppress food intake and thereby inducing weight loss
- Reduces neuropeptide Y release
- Leptin gene mutation = obesity
What is a thyroid follicle composed of?
Thyroid gland is composed of thyroid follicles:
- Thyroid follicular cells – responsible for the synthesis of thyroid hormones
- Thyroid colloid – proteinaceous material including thyroglobulin, which contains the thyroid hormones thyroxine (T4) and triiodothyronine (T3)
- Parafollicular cells or C cells lie between follicles and produce the hormone calcitonin, which helps regulate calcium homeostasis (↓ plasma Ca2+).
Thyroid hormone synthesis
- The thyroid hormones T3 (triiodothyronine) and T4 (thyroxine, tetraiodothyronine) are synthesized by thyrocytes in the thyroid follicles.
1. Thyroglobulin, an iodine-free hormone precursor, is stored in the follicular lumen (colloid)
2. Iodide is actively taken up by thyrocytes by the sodium-iodide symporter (Na/I) and transported into the follicular lumen (colloid) via the transporter pendrin in a passive manner
3. In the colloid, thyroid peroxidase oxidises iodide to iodine. Iodine is very reactive and iodinates the tyrosine residues of thyroglobulin, creating precursors monoiodotyrosine (MIT) and diiodotyrosine (DIT) and eventually the thyroid hormones.
4. To release T3 and T4, the iodinated thyroglobulin must be taken up again by thyrocytes (follicular cells) by endocytosis, where it is broken down by lysosomes, thus releasing attached T4 and T3.
5. T4 and T3 are then transported out of the thyrocyte into the blood.
• More T4 is produced than T3 but T3 is more potent than T4.
○ T3 is biologically active that binds nuclear receptors with higher affinity than T4.
○ Peripheral 5’-deiodinase (or type II iodothyronine deiodinase) in the thyroid, pituitary gland, muscle, and brown fat converts T4 into the biologically active T3.
○ Half of the T4 is processed into biologically inactive T3 (reverse T3).
• The half-life of T3 is about one day (∼ 20 hours) and the half-life of T4 is about one week (∼ 190 hours)
T3 and T4 are partially composed of iodine. A deficiency of iodine leads to decreased production of T3 and T4, enlarges the thyroid tissue and will cause the disease known as simple goitre.
What inhibits TSH secretion?
Somatostatin
Dopamine
Which upregulates TRH receptors?
Estrogen up-regulates TRH receptors; cold and stress lead to increased TRH
When do you measure T3 and T4
Measure thyroxine (T4) when the thyroid stimulating hormone is elevated and measure both thyroxine (T4) and triiodothyronine (T3) when the thyroid-stimulating hormone is suppressed. Normal TSH with elevated T3/T4 indicates TSH secreting pituitary adenoma
3 antibodies in thyroid disorders
- TSH receptor ab: Graves
- Thyroid peroxidase ab: hashimoto’s, autoimmune hypothyroidism
- Thyroglobulin ab: monitor thyroid cancer and hashi moto
Tg is sensitive to residual thyroid tissue, after total thyroidectomy and radioactive iodine ablation, persistence of detectable Tg is a possible indicator of residual or recurrent disease.
How can medullary thyroid cancer be monitored?
Calcitonin
Calcitonin (not thyroglobulin) is a good marker of recurrent disease,
which should be identified and resected if possible
Radioactive iodine uptake findings
- RAIU is used to evaluate the cause of hyperthyroidism; it is not indicated in patients with normal or elevated TSH levels. The degree of uptake is useful for distinguishing the various causes of hyperthyroidism.
- Homogenous/diffusely increased uptake: Graves
- Patchy uptake: multinodular goiter
- Low uptake: thyroiditis or exposure to exogenous thyroid hormone.
- The presence of a ·’cold” nodule on isotope scanning is an indication for ultrasonography to help determine if FNA is indicated.
- RAIU is contraindicated during pregnancy and while breastfeeding
- Toxic adenoma: focal uptake
- Hashimoto: patchy and irregular
What is the Wolff Chaikoff Effect
Iodine induced hypothyroidism
- Wolff-Chaikoff effect is an autoregulatory phenomenon, whereby a large amount of ingested iodine acutely inhibits thyroid hormone synthesis within the follicular cells, irrespective of the serum level of thyroid-stimulating hormone (TSH). The development of thyrotoxicosis shortly after receiving iodinated contrast is suggestive of a failure the Wolff-Chaikov effect in stopping the synthesis of thyroid hormones in the presence of high iodine levels. This occurs when there are autonomous parts of the gland which are not regulated – either autonomous/hyperfunctioning nodules or Graves disease. Since examination reveals a nodular goiter, the most likely diagnosis is a hyperfunctioning goitre.
ChaikOFF - thyroid hormone productoin is switched OFF
Medication causes of primary hyperthyroidism
Amiodarone
Tyrosine kinase inhibitors
Alemtuzumab (CD52 inhibitor)
Biotin - need to withhold biotin for 48 hours prior to blood test
Causes of primary, secondary and tertiary hypothyroidism
PRIMARY
- hashimoto’s,
- thyroidectomy or radioiodine therapy
- Antithyroid medications: amiodarone, lithium
- Thyroiditis - subacute thyroiditis/ de Quervain, post-partum thyroiditis, riedel’s thyroiditis
- Ioidine deficiency
SECONDARY
- Pituitary adenoma
- Infiltrative diseases
- Post pituitary surgery
TERTIARY
hypothalamic disorders
What happens in sick euthyroid?
Normal TSH, low T3/T4
Occurs in severe illness or severe physical stress
Causes of primary hyperthyroidism
Graves disease Toxic MNG Toxic adenoma Post partum thyroiditis Subacute granulomatos thyroidits (de quervain)
What is De Quervain’s (subacute) thyroiditis
De Quervain’s (subacute) thyroiditis is a painful swelling of the thyroid gland thought to be triggered by a viral infection, such as mumps or flu
What are rare causes of hyperthyroidism/thyrotoxicosis?
- TSH producing pitutary tumours (central hyperthyroidism)
- Excessive production of BHCG (gestational trophoblastic disease - hydatidiform mole, choriocarcinoma)
What is Riedel thyroiditis?
Riedel’s thyroiditis is a rare cause of hypothyroidism characterised by dense fibrous tissue replacing the normal thyroid parenchyma. On examination a hard, fixed, painless goitre is noted. It is usually seen in middle-aged women. It is associated with retroperitoneal fibrosis.
What is subacute thyroiditis?
- Refers to a transient patchy inflammation of the thyroid
- Divided into subacute granulomatous thyroiditis (de quervain) and subacute lymphocytic thyroidtis
- Characterised by triphasic clinical course: hyperthyroid to hypothyroid to euthyroid.
- Diagnosis: raised ESR and reduced uptake on radioiodine uptake study.
- Spontaneous remission seen in about 80 cases, symptomatic treatment
- Thyroid peroxidase ab present
- Diffuse and firm goitre
Subacute granulomatous thyroiditis (de quervain)
- tends to occur post viral URTI
- Cause: Viral and mycobacterial infections causing damage to follicular cells
- PAINFUL
Subacute lymphocytic infiltration
- Causes: postpartum thyroiditis, autoimmune diseases, drugs (a-interferon, lithium, amiodarone, IL-2, tyrosine kinase inhibitors)
- Painless
Characteristics of subacute granulomatous thyroiditis (Dr Quervain Thyroiditis)
- Possible history of URTI prior to onset
- Painful, diffuse firm goitre, jaw pain
- Fever, malaise
- Hyperthyroidism and then hypothyroidism
What is the Joe Basedow Phenomenon
Iodine induced hyperthyroidism
- Thyrotoxicosis in patients with pre-existing iodine deficiency thyroid disorder
- More common in iodine deficient regions
- Causes: iodine excess from diet, contrast or amiodarone
- Painless
- Reduced uptake on radioactive isotype scan
Characteristics of MNG?
toxic multinodular goitre
Chronic iodine deficiency
Painless
Patchy uptake on radioactive iodine uptake scan
Radioactive iodine ablation/surgery is the most common treatment
Characteristics of graves disease
- Most common cause of hyperthyroidism, peak 20-30yo
- Cause: autoimmune due to TSH receptor autoantibodies
- Diffuse and smooth goitre, painless
- Other findings: graves ophthalmopathy (exophthalmos, proptosis, lid lag, chemosis), pretibal myxedema
- Diffuse uptake on iodine scan
- TSH receptor positive, thyroid peroxidase mildy positive.
- Pathognomonic signs: diffuse goitre, ophthalmpathy, pretibial myxoedema
- Antithyroid medications do not correct mortality risk/reduce cardiovascular events
- Definitive therapy is radioactive iodine - correct mortality risk and reduce cardiovascular events
Treatment for hyperthyroidism
- Antithyroid medications, radioiodine ablation, surgery
MOA + SE of carbimazole
Prevents synthesis of new thyroid hormone
- MOA: Carbimazole is a pro-drug as after absorption it is converted to the active form, methimazole. Methimazole prevents thyroid peroxidase enzyme from iodinating and coupling the tyrosine residues on thyroglobulin, hence reducing the production of the thyroid hormones T3 and T4 (thyroxine).
- CMZ is first line due to potential rare fatal hepatotoxicity with PTU
- CMZ causes fetal syndrome if used before 12 weeks (aplasia cutis, choanal syndrome)
- Also has higher intrathyroidal retention (potency)
- Other SE: rash, agranulocytosis, mild neutropenia.
MOA and SE of propylthiouracil.
Prevents synthesis of new thyroid hormone
Also inhibits conversion of T4 to T3
- Inhibits thyroid peroxidase from coupling and iodinating the tyrosine residues on thyroglobulin
- Inhibits 5’ deiodinases which converts T4 to active T3
- PTU associated with ANCA positivity with skin, renal and lung vasculidities
- Used in first trimester of pregnancy as carbimazole has possible teratogenic effect during 1st trimester.
- SE: rash, agranulocytosis, neutropenia, hepatotoxicity (rare)
Causes of painful thyroiditis
- The causes of painful thyroiditis are inflammatory (de Quervain or subacute granulomatous thyroiditis), infectious (suppurative), and radiation-induced. The pain, typically only present during the thyrotoxic phase, can be quite intense. Treatment is aimed at controlling inflammation with NSAIDs or systemic glucocorticoids if severe.
- Subacute thyroiditis is the most common form and is presumably caused by a postviral inflammatory process; many patients report a recent history of upper respiratory illness preceding the thyroiditis.
- Radiation thyroiditis may occur 10 days after treatment with radioactive iodine. This may be associated with transient exacerbation of the hyperthyroidism. The accompanying pain is usually mild and lasts for up to 1 week.
- Infectious thyroiditis is rare but may be seen in an immunocompromised patient; the most common causative organisms are Staphylococcus and Streptococcus species.
Causes of painless thyroiditis
- Painless thyroiditis is more commonly seen than painful thyroiditis and has several causes, including postpartum thyroiditis, silent thyroiditis, and drug-induced thyroiditis.
- Postpartum thyroiditis may occur up to 1 year after delivery; the frequency is variably reported but may occur in up to 10% of pregnancies.
- The presence of TPO antibodies is nearly universal, and the likelihood of subsequent permanent hypothyroidism is very high. Thyroiditis is also likely to recur in later pregnancies.
Characteristics of amiodarone induced thyrotoxicosis
Amiodarone - Class III antiarrhythmic
Amiodarone may cause:
(A) HYPOTHYROIDISM due to interference of T4 synthesis
Tx: withdraw drug +/- thyroxine
(B) Type 1: IODINE INDUCED THYROTOXICOSIS – increased synthesis of T3 and T4 due to excess of iodine in amiodarone providing substrate for more hormone production. Diffuse or multinodular goitre
Usually occur in abnormal thyroid glands
Treated with ANTI THYROID MEDS
(C) Type II DESTRUCTIVE THYROIDITIS
Release of pre-formed thyroid hormones due to direct cytotoxic effects of amiodarone. Lasts weeks to months and often followed by hypothyroid phase with eventual recovery in most patients. Small or no goitre. Usually occur in normal thyroid glands.
Treat with STEROIDS
Surgery if no response
Iodine not helpful
If both type 1 and II toxicosis, technetium scan is cold
Characteristics of amiodarone induced thyrotoxicosis
- Type I amiodarone induced thyrotoxicosis – increased synthesis of T3 and T4 due to excess of iodine in amiodarone providing substrate for more hormone production. Diffuse or multinodular goitre
- Type II amiodarone induced thyrotoxicosis – thyrocyte cytotoxicity resulting in excess release of T3 and T4 without increased hormone synthesis (destructive thyroiditis). Lasts weeks to months and often followed by hypothyroid phase with eventual recovery in most patients. Small or no goitre
Drug Effects
- Inhibits 5’-monodeiodination of T4 to T3, decreasing T3 production (spurious result)
- Direct toxic effect on thyroid follicular cells (destructive thyroiditis-type 2 AIT)
- Beta-blockade (masking of symptoms of thyrotoxicosis)
Timing of hyperthyroidism
- AIT type 1 more common in the early phase post amiodarone commencement (median 3.5 months)
- AIT type 2 more common in late phase (median 30 months) or following discontinuation
-AIT type 2 is more common than AIT type 1
-Thyroid autoantibodies (e.g. TRAb) -may be positive in AIT type 1
- Nuclear medicine thyroid scan-Often not useful and misleading
-Doppler Ultrasound thyroid? (vascularity reduced in AIT type 2, normal in AIT type 1)
-Consider response to treatment (often prednisolone and carbimazole commenced together)
- Rapid response to prednisolone suggests AIT type 2
-Slow response suggests AIT type 1
- Due to long half life stopping amiodarone may not make any difference
- Surgery if deterioration despite medical treatment
-In the majority of patients, amiodarone causes a temporary reduction in circulating triiodothyronine (T3) and thyroxine (T4) and levels with a minor rise in the thyroid-stimulating hormone that reverses within first 3 months of treatment and requires no intervention.
In 15% of patients, amiodarone may cause either hypo- or hyperthyroidism; those at highest risk for amiodarone-induced hypothyroidism are women with preexisting thyroid peroxidase antibody positivity.
