Endocrinology

Question 1

How is thyroid hormone made?

Answer 1

There are six steps in the synthesis of thyroid hormone, and you can remember them using the mnemonic ATE ICE:

Active transport of iodide into the follicular cell via the sodium-iodide symporter (NIS). This is actually secondary active transport, and the sodium gradient driving it is maintained by a sodium-potassium ATPase.
Thyroglobulin (Tg), a large protein rich in tyrosine, is formed in follicular ribosomes and placed into secretory vesicles.
Exocytosis of thyroglobulin into the follicle lumen, where it is stored as colloid. Thyroglobulin is the scaffold upon which thyroid hormone is synthesised.
Iodination of the thyroglobulin. Iodide is made reactive by the enzyme thyroid peroxidase. Iodide binds to the benzene ring on tyrosine residues of thyroglobulin, forming monoiodotyrosine (MIT) then diiodotyrosine (DIT).
Coupling of MIT and DIT gives the triiodothyronine (T3) hormone and coupling of DIT and DIT gives the tetraiodothyronine (T4) hormone, also known as thyroxine.
Endocytosis of iodinated thyroglobulin back into the follicular cell. Thyroglobulin undergoes proteolysis in lysosomes to cleave the iodinated tyrosine residues from the larger protein. Free T3 or T4 is then released, and the thyroglobulin scaffold is recycled.
T3 and T4 are the active thyroid hormones. They are fat soluble and mostly carried by plasma proteins – thyronine binding globulin (TBG) and albumin. While T3 is the more potent form, it also has a shorter half-life due to its lower affinity for the binding proteins. Less than 1% of T3 and T4 is unbound free hormone.

At the peripheries, T4 is deiodinated to the more active T3. T3 and T4 are deactivated by removing iodine. This happens in the liver and kidney. As T4 has a longer half-life, it is used in the treatment of hypothyroidism over T3 as its plasma concentrations are easier to manage.

Question 2

What are the features of hyperthyroidism and hypothyroidism.

Answer 2

Both conditions can have a goitre.

Hyper tends to have muscle tremors, aches, weakness, lid lag/ retraction, proptosis, sore +/- diplopia on lateral gaze.

Hypo tends to also have hoarseness, dry skin.

Question 3

What tests are used for assessing thyroid function?

Answer 3

TSH is assessed for screening. (Decreased in Hyper, elevated in Hypo)

Free T3 and T4 (May be normal, or may increase / decrease for hyper / hypo)

Thyroid receptor antibodies TRAb specific

Antithyroid Abs are frequently positive but non-causative.

Technetium nuclear scan
Ultrasound if clinically nodular gland.

Question 4

What are the common causes of hyperthyroidism?

Answer 4

Graves disease (elevated TRAB)
Toxic nodules
Postpartum
Drug induced (Amiodarone, Lithium, T4)
Thyroiditis from immune therapies

Subacute thyroiditis (Includes Hashimoto’s which start with elevated thyroid hormone levels, they then drop and become hypothyroid)

Question 5

What are some differentials for a clinically identifiable solitary thyroid nodule?

Answer 5

Colloid nodule or simple thyroid cyst
Benign follicular adenoma
Thyroid cancer
Nodular area of thyroiditis
Rare (intrathyroidal branchial cleft cyst)

The most common pathology is a dominant nodule in an otherwise inapparent multinodular goitre.

Question 6

What is the treatment for hyperthyroidism?

Answer 6

Treating:
Graves disease:

Anti-thyroid drugs
- NMZ (NEO-MERCAZOLE - active ingredient carbimazole)
- PTU (propylthiouracil)

Radioactive iodine 131

Surgery

Toxic nodules:
- Drugs or I131

Subacute thyroiditis
- Aspirin, steroids, beta blockers

Question 7

What drug is first line for hyperthyroidism?

Answer 7

Carbimazole (NMZ) is first line. It is initiated as a big dose in 1st month, then tapered to min effective dose for 12-18 months minimum duration. May cause rash, leucopenia, abn LFTs, rarely agranulocytosis. Continue whilst TRAb remain positive.

Propylthiouracil is only used as first line in pregnant women or if NMZ is contraindicated. PTU is contraindicated in kids.

Question 8

What is the moa of Carbimazole (NMZ) and Propylthiouracil (PTU)?

Answer 8

Mechanism of Action of Carbimazole and Propylthiouracil
Both carbimazole (which is converted to its active form, methimazole) and propylthiouracil (PTU) are antithyroid medications used to treat hyperthyroidism. They work by inhibiting the synthesis of thyroid hormones, but they have different specific mechanisms and additional actions.

Carbimazole (Methimazole)
Primary Mechanism:

Carbimazole is a prodrug that is converted in the body to methimazole, its active form. Methimazole inhibits the enzyme thyroid peroxidase (TPO). TPO is crucial in the thyroid gland’s production of thyroid hormones (thyroxine (T4) and triiodothyronine (T3)).
By inhibiting TPO, methimazole prevents the iodination of tyrosine residues on thyroglobulin and the coupling of iodotyrosines, which are critical steps in the synthesis of T3 and T4.
Specific Actions:

Inhibition of Iodine Oxidation: Methimazole inhibits the oxidation of iodide to iodine, a necessary step in hormone synthesis.
Inhibition of Iodotyrosine Coupling: It also prevents the coupling of monoiodotyrosine (MIT) and diiodotyrosine (DIT) to form T3 and T4.
Propylthiouracil (PTU)
Primary Mechanism:

Similar to methimazole, PTU inhibits the enzyme thyroid peroxidase (TPO), thereby blocking the synthesis of thyroid hormones by preventing iodination and coupling of tyrosine residues in thyroglobulin.
Additional Mechanism:

Inhibition of Peripheral Conversion: PTU has an additional action of inhibiting the peripheral conversion of T4 to T3. It does this by inhibiting the enzyme 5’-deiodinase, which converts T4 (the less active hormone) into T3 (the more active hormone) in peripheral tissues.
Specific Actions:

Inhibition of Iodine Oxidation and Iodotyrosine Coupling: Like methimazole, PTU inhibits both the oxidation of iodide and the coupling of iodotyrosines, which are necessary steps in the synthesis of T3 and T4.
Summary of Effects
Reduced Thyroid Hormone Synthesis: Both drugs decrease the production of thyroid hormones by inhibiting thyroid peroxidase, leading to reduced levels of circulating T3 and T4.
Decreased Peripheral T3 Levels (PTU-specific): PTU uniquely decreases the conversion of T4 to T3, resulting in lower levels of the more active thyroid hormone, T3.
Clinical Considerations
Onset of Action: The clinical effects of these drugs may take several weeks to become evident because they do not affect preformed thyroid hormone stores but rather inhibit new hormone synthesis.
Use During Pregnancy: PTU is often preferred during the first trimester of pregnancy due to its lower risk of teratogenic effects compared to methimazole. However, methimazole may be preferred in the second and third trimesters due to the risk of liver toxicity associated with PTU.
Carbimazole (methimazole) and PTU are effective in managing hyperthyroidism by reducing the production of thyroid hormones, with PTU offering the added benefit of decreasing peripheral conversion of T4 to T3.

Question 9

Who should and shouldn’t use I131 (RAI)?

Answer 9

Older patients who are unsuitable for surgery can use it.
Younger patients can if they avoid pregnancy during use.
Unsuitable for patients with eye disease or large goitre.

It commonly causes permanent hypothyroidism.

Steroid cover is needed in patients with eye disease.
Frequent TFTs in 1st 6 months to monitor need for T4 replacement.

Question 10

Should patients with hyperthyroidism who receive surgery get partial or total thyroidectomy?

Answer 10

Total thyroidectomy to avoid relapse.
Best for big goitres.
May cause damage to parathyroid glands or recurrent laryngeal nerve.

Question 11

In toxic thyroid nodules what is the preferred treatment?

Answer 11

Toxic nodules are associated with constitutive activation of Gs alpha pathway which drives cell production.

Small doses of radioactive iodine. Usually curative as they are taken up into the hot nodule and hopefully the rest of the thyroid remains untouched.

Drugs if used may need to be used lifelong.

If T4 and T3 are normal treatment may only be needed if TSH <0.1 mIU/L

Question 12

What are the features of subacute thyroiditis?

Answer 12

Subacute Thyroiditis
Subacute thyroiditis, also known as De Quervain’s thyroiditis or granulomatous thyroiditis, is a self-limiting inflammatory disorder of the thyroid gland. It is typically characterized by a painful enlargement of the thyroid gland and is often preceded by a viral infection. The exact cause is not well understood, but it is believed to be triggered by viral infections or post-viral inflammatory reactions.

Features of Subacute Thyroiditis
Clinical Presentation:
Pain: The hallmark of subacute thyroiditis is pain in the thyroid region, which may radiate to the jaw, ears, or chest. The pain is often described as dull and aching.
Tenderness: The thyroid gland is usually tender to palpation.
Enlargement: The thyroid gland may be diffusely enlarged and firm.

Systemic Symptoms:
Fever: Mild to moderate fever may be present.
Malaise: Patients often experience general malaise, fatigue, and myalgia.
Pharyngitis: Some patients report symptoms similar to a sore throat.

Thyroid Function Changes:
Hyperthyroid Phase: Initially, there may be a transient hyperthyroid phase due to the release of preformed thyroid hormones from the inflamed thyroid gland. Symptoms may include:
Palpitations
Heat intolerance
Weight loss
Nervousness or anxiety
Hypothyroid Phase: After the hyperthyroid phase, some patients may enter a hypothyroid phase due to depletion of thyroid hormone stores. Symptoms may include:
Fatigue
Cold intolerance
Weight gain
Constipation
Euthyroid Recovery: Eventually, most patients return to a euthyroid (normal thyroid function) state as the inflammation resolves.

Laboratory Findings:
Thyroid Function Tests:
Early Phase: Elevated free T4 and suppressed TSH during the hyperthyroid phase.
Later Phase: Decreased free T4 and elevated TSH during the hypothyroid phase.
Erythrocyte Sedimentation Rate (ESR): Typically elevated, reflecting inflammation.
C-reactive Protein (CRP): May also be elevated, indicating inflammation.
Thyroglobulin: Often elevated during the hyperthyroid phase due to thyroid tissue destruction.

Imaging:
Radioactive Iodine Uptake (RAIU): Low uptake during the hyperthyroid phase, distinguishing subacute thyroiditis from conditions like Graves’ disease, where uptake is typically increased.

Course and Prognosis:
Subacute thyroiditis is usually self-limiting, resolving spontaneously over weeks to months. Some patients may require symptomatic treatment during the hyperthyroid and hypothyroid phases, but permanent thyroid dysfunction is uncommon.

Management
Pain Relief: Nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids may be used to manage pain and inflammation.
Aspirin.
Steroids if severe.
Thyroid Hormone Management: Beta-blockers may be used to control symptoms during the hyperthyroid phase. In cases of symptomatic hypothyroidism, temporary thyroid hormone replacement therapy may be necessary.

Question 13

How do we treat hypothyroidism?

Answer 13

Levothyroxine (T4)
First-line Treatment: Levothyroxine, a synthetic form of thyroxine (T4), is the most commonly prescribed medication. It is preferred because it has a consistent potency and long half-life, allowing for once-daily dosing.
Dosage: The dosage of levothyroxine is individualized based on factors such as the patient’s age, weight, severity of hypothyroidism, and presence of comorbid conditions.
Typical Starting Dose: For most adults, the starting dose is usually around 1.6 mcg/kg/day. Elderly patients or those with cardiovascular disease may require lower starting doses (e.g., 25-50 mcg/day).
Adjustment: Dosage is adjusted based on TSH levels, typically checked 6-8 weeks after starting therapy or following dosage changes.
Administration: Levothyroxine should be taken on an empty stomach, ideally in the morning, 30-60 minutes before breakfast. Certain foods, supplements (like calcium and iron), and medications can interfere with absorption.

Liothyronine (T3)
Less Commonly Used: Liothyronine is a synthetic form of triiodothyronine (T3). It is used less frequently because it has a shorter half-life and requires multiple daily doses, which can lead to fluctuations in hormone levels.
Combination Therapy: In some cases, a combination of levothyroxine (T4) and liothyronine (T3) is used, but this is generally reserved for patients who do not feel well on levothyroxine alone.

Desiccated Thyroid Extract
Alternative Option: Derived from animal thyroid glands, this extract contains both T4 and T3. It is less commonly used today due to variability in hormone concentrations and concerns about standardization and safety.

2. Monitoring and Follow-Up
   TSH Levels: TSH is the primary marker used to monitor and adjust therapy. The goal is to keep TSH within the normal reference range, typically between 0.4-4.0 mIU/L, though the target range may be narrower (e.g., 1.0-2.5 mIU/L) in some patients.
   Symptom Relief: Symptom improvement should be assessed alongside TSH levels. It may take several weeks to notice improvement after starting or adjusting therapy.
   Regular Monitoring: Once the appropriate dose is established, TSH should be checked annually or if symptoms change. More frequent monitoring is required during pregnancy, after significant weight loss or gain, or when starting or stopping medications that interact with thyroid hormone metabolism.
3. Special Considerations
   Pregnancy: Hypothyroidism in pregnancy requires careful management. Levothyroxine dosage typically needs to be increased due to increased thyroid hormone demands during pregnancy. TSH levels should be monitored closely, with the goal of maintaining TSH within trimester-specific reference ranges. Avoid letting patients become hypothyroid in pregnancy.
   Elderly Patients: Older adults, particularly those with cardiovascular disease, may require lower starting doses to avoid precipitating angina or arrhythmias.
   Drug Interactions: Certain medications (e.g., calcium and iron supplements, antacids, certain cholesterol-lowering drugs) can interfere with the absorption of levothyroxine. These should be taken several hours apart from thyroid hormone replacement.
4. Treatment of Specific Forms of Hypothyroidism
   Primary Hypothyroidism: Managed with levothyroxine alone.
   Secondary Hypothyroidism: This occurs due to pituitary or hypothalamic dysfunction, resulting in low TSH. Treatment involves levothyroxine, but monitoring relies on free T4 levels rather than TSH.
   Subclinical Hypothyroidism: Treatment may be considered if TSH is mildly elevated (4.5-10 mIU/L) with normal T4, particularly if the patient is symptomatic, has a goiter, or is at risk for cardiovascular disease. In pregnant women or those planning pregnancy, treatment is generally recommended.

Summary
Hypothyroidism is treated primarily with levothyroxine, a synthetic thyroid hormone that replaces deficient T4 levels. The treatment is individualized, with doses adjusted based on TSH levels and patient symptoms. Regular monitoring is essential to ensure adequate hormone replacement and to prevent both under- and overtreatment.

Question 14

What is TmAb testing for?

Answer 14

Thyroid Microsomal Antibody (TmAB) testing is used to detect the presence of antibodies against thyroid peroxidase (TPO), an enzyme critical in the production of thyroid hormones. These antibodies are often referred to as anti-thyroid peroxidase antibodies (anti-TPO antibodies).

Purpose of TmAB Testing
TmAB testing is primarily used to diagnose autoimmune thyroid diseases such as:

Hashimoto’s Thyroiditis:
Most Common Use: TmAB testing is commonly used to diagnose Hashimoto’s thyroiditis, an autoimmune condition where the body’s immune system attacks the thyroid gland, leading to hypothyroidism.
High Anti-TPO Levels: The presence of high levels of TPO antibodies is a hallmark of Hashimoto’s thyroiditis.

Graves’ Disease:
TmAB testing can also help diagnose Graves’ disease, another autoimmune thyroid disorder. Although TPO antibodies are less specific to Graves’ disease compared to other markers like TSH receptor antibodies (TRAb), they may still be present in a significant number of cases.

Other Thyroid Conditions:
TPO antibodies can also be found in other thyroid disorders and sometimes in individuals without apparent thyroid disease, although typically at lower levels. Their presence can indicate an increased risk of developing thyroid dysfunction in the future.

Clinical Implications
Hypothyroidism Risk: Elevated TmAB levels in euthyroid patients (those with normal thyroid function) indicate an increased risk of developing hypothyroidism, especially postpartum.
Autoimmune Monitoring: TmAB levels can be monitored over time in patients with known autoimmune thyroid disease to assess the progression or response to treatment.
Differentiating Causes of Thyroid Dysfunction: TmAB testing can help differentiate between autoimmune causes and other causes of thyroid dysfunction, such as iodine deficiency or thyroid nodules.

Summary
TmAB testing is primarily used to detect anti-thyroid peroxidase (anti-TPO) antibodies, which are indicative of autoimmune thyroid diseases like Hashimoto’s thyroiditis and Graves’ disease. The presence of these antibodies is associated with an increased risk of developing hypothyroidism.

Question 15

In pregnancy, it is recommended to increase the dose of levothyroxine by ….% for patients who are hypothyroidic.

Answer 15

30%

Post natal thyroiditis is quite common in patients with hashimoto’s and it can be confused for post-partum depression.

Question 16

Does Grave’s disease get better or worse during pregnancy?

Answer 16

It actually gets better, because the body already needs more thyroid hormone, the hyperthyroid state that Grave’s disease patients are in actually becomes relatively more euthyroidic during pregnancy. It can get worse after pregnancy.

Question 17

What are the features of papillary thyroid cancer, follicular thyroid cancer, and medullary thyroid cancer, anaplastic thyroid cancer, hurthle cell thyroid cancer, and poorly differentiated thyroid cancer?

Answer 17

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer, accounting for 70-80% of cases. It typically presents as a slow-growing, painless thyroid nodule. Histologically, PTC is characterized by papillae with fibrovascular cores, Orphan Annie eye nuclei (empty-appearing nuclei), psammoma bodies (concentric calcifications), and nuclear grooves with intranuclear inclusions. PTC often spreads to cervical lymph nodes, but it generally has a favorable prognosis.

Follicular thyroid carcinoma (FTC) comprises 10-15% of thyroid cancers and is more common in regions with iodine deficiency. It is characterized histologically by a follicular architecture, with capsular and/or vascular invasion that distinguishes it from benign follicular adenomas. FTC typically spreads hematogenously, often to the lungs and bones, rather than to lymph nodes.

Medullary thyroid carcinoma (MTC), which accounts for 3-5% of thyroid cancers, arises from the parafollicular C cells that produce calcitonin. Histologically, MTC features spindle-shaped or polygonal cells arranged in nests or trabeculae, often with amyloid deposits derived from calcitonin. This type of cancer is associated with Multiple Endocrine Neoplasia (MEN) 2A and 2B syndromes. Clinically, MTC may present with elevated calcitonin levels, and patients may experience paraneoplastic symptoms such as diarrhea and flushing.

Anaplastic thyroid carcinoma (ATC) is a rare but highly aggressive form of thyroid cancer, representing less than 2% of cases. It typically presents as a rapidly enlarging neck mass with local invasion into surrounding structures such as the trachea and esophagus. Histologically, ATC is characterized by undifferentiated cells with pleomorphic giant cells, spindle cells, high mitotic activity, necrosis, and vascular invasion. Due to its aggressive nature, ATC has a poor prognosis with early metastasis.

Hurthle cell carcinoma is a variant of follicular thyroid carcinoma, accounting for about 3-5% of thyroid cancers. Histologically, it is distinguished by the presence of Hurthle cells, which are large cells with eosinophilic, granular cytoplasm, and prominent nucleoli. Hurthle cell carcinoma is more aggressive than typical follicular carcinoma and has a higher risk of recurrence and distant metastasis.

Lastly, poorly differentiated thyroid carcinoma (PDTC) accounts for approximately 5-10% of thyroid cancers. It is considered an intermediate form between well-differentiated thyroid carcinomas like PTC and FTC and anaplastic carcinoma. Histologically, PDTC exhibits an insular pattern with nests of small, uniform cells, as well as necrosis and high mitotic activity. Clinically, PDTC behaves more aggressively than differentiated thyroid carcinomas, leading to a poorer prognosis.

In summary, thyroid cancers vary significantly in their histological features, clinical presentations, and prognosis. Papillary and follicular carcinomas tend to have better outcomes, while anaplastic and poorly differentiated thyroid carcinomas are more aggressive and have worse prognoses. Medullary thyroid carcinoma, associated with MEN syndromes, presents distinct histological features and clinical implications.

Question 18

What is the pathophysiology and management of diabetic ketoacidosis?

Answer 18

Pathophysiology of Diabetic Ketoacidosis (DKA)
Diabetic ketoacidosis (DKA) is a life-threatening complication primarily associated with type 1 diabetes, though it can also occur in type 2 diabetes under certain conditions. DKA arises due to a severe deficiency of insulin, leading to the following pathophysiological events:

Insulin Deficiency and Hyperglycaemia:
Insulin Deficiency: In DKA, a lack of insulin impairs glucose uptake by cells, especially in muscle and adipose tissue. As a result, glucose remains in the bloodstream, leading to hyperglycaemia.
Counterregulatory Hormones: The insulin deficiency triggers the release of counterregulatory hormones (glucagon, catecholamines, cortisol, and growth hormone), which further increase blood glucose levels by promoting gluconeogenesis (new glucose production) and glycogenolysis (breakdown of glycogen) in the liver.

Lipolysis and Ketogenesis:
Lipolysis: In the absence of insulin, the body shifts to fat as an alternative energy source. The breakdown of triglycerides in adipose tissue releases free fatty acids (FFAs) into the bloodstream.
Ketogenesis: The liver converts these free fatty acids into ketone bodies (acetoacetate, β-hydroxybutyrate, and acetone) through a process called ketogenesis. Ketones serve as an alternative energy source, particularly for the brain, during periods of glucose shortage.
Ketoacidosis: As ketone bodies accumulate in the bloodstream, they overwhelm the body’s buffering capacity, leading to metabolic acidosis, characterized by a low pH and low serum bicarbonate.

Electrolyte Imbalance:
Osmotic Diuresis: Hyperglycaemia leads to osmotic diuresis, causing significant fluid and electrolyte losses (sodium, potassium, chloride, magnesium, and phosphate) through the kidneys.
Potassium Shifts: Insulin deficiency and acidosis cause potassium to shift from the intracellular to the extracellular compartment, leading to initial hyperkalaemia, despite total body potassium depletion. However, with ongoing diuresis and subsequent treatment, patients may develop hypokalaemia, which can be life-threatening.

Dehydration and Hypovolemia:
Fluid Loss: The osmotic diuresis leads to significant fluid loss, resulting in dehydration and hypovolemia. This can cause hypotension, reduced tissue perfusion, and potential progression to shock.
Management of Diabetic Ketoacidosis
The management of DKA involves several key steps aimed at correcting the metabolic disturbances and addressing the underlying cause:

Fluid Resuscitation:
Initial Fluid Therapy: Begin with 0.9% sodium chloride (normal saline) to restore intravascular volume and correct dehydration. The typical initial rate is 15-20 mL/kg/hour (approximately 1-1.5 litres in the first hour).
Ongoing Fluid Therapy: After initial resuscitation, continue with 0.9% saline or switch to 0.45% saline depending on the patient’s sodium levels. Monitor fluid balance and adjust the rate based on clinical response and electrolyte levels.

Insulin Therapy:
Intravenous Insulin: Start with an intravenous bolus of regular insulin (0.1 units/kg), followed by a continuous infusion at 0.1 units/kg/hour. Insulin administration reduces blood glucose levels and inhibits further ketone production by promoting glucose uptake and reducing lipolysis.
Glucose Monitoring: Monitor blood glucose levels hourly. When blood glucose drops to 200-250 mg/dL (11-14 mmol/L), add dextrose to the IV fluids (e.g., D5-0.45% saline) to prevent hypoglycaemia while continuing to clear ketones and correct acidosis.

Electrolyte Management:
Potassium Replacement: Monitor serum potassium closely. If potassium is <3.3 mmol/L, hold insulin and give potassium replacement until levels are ≥3.3 mmol/L. Potassium is typically added to IV fluids to maintain serum levels between 4-5 mmol/L during treatment.
Bicarbonate Therapy: Bicarbonate is generally not recommended for routine use in DKA, as it can worsen hypokalaemia and may delay the correction of acidosis. However, it may be considered in cases of severe acidosis (pH <6.9) or life-threatening hyperkalaemia.

Monitor and Manage Complications:
Electrolyte Monitoring: Continue to monitor electrolytes, including potassium, sodium, and bicarbonate, and adjust therapy as needed.

Fluid Overload: Watch for signs of fluid overload, especially in patients with heart or kidney disease. Adjust fluid administration accordingly.

Cerebral Oedema: Although rare, cerebral oedema can occur, particularly in paediatric patients. Early signs include headache, altered mental status, and a sudden drop in sodium levels. Immediate intervention with mannitol or hypertonic saline may be necessary if cerebral oedema is suspected.

Transition to Subcutaneous Insulin:
Once the patient is clinically stable, ketosis has resolved, and oral intake is possible, transition from IV insulin to a subcutaneous insulin regimen. This typically involves overlap of IV insulin and the first subcutaneous dose to avoid rebound hyperglycaemia.
Identification and Treatment of the Underlying Cause:

Infection: Common precipitating factors include infection, missed insulin doses, or new-onset diabetes. Treat underlying infections or other precipitating factors (e.g., myocardial infarction, stroke) concurrently.

Summary
DKA is a serious condition requiring prompt recognition and aggressive management. The pathophysiology involves severe insulin deficiency leading to hyperglycaemia, ketosis, and metabolic acidosis, along with significant electrolyte and fluid imbalances. Management focuses on fluid resuscitation, insulin therapy, electrolyte correction, and addressing the underlying cause. With timely and appropriate treatment, most patients with DKA can recover fully.

Question 19

Describe the pathophysiology and management of hyperosmolar hyperglycaemic non-ketotic state.

How does it differ to DKA?

Answer 19

Pathophysiology of Hyperosmolar Hyperglycaemic Non-Ketotic State (HHS)
Hyperosmolar Hyperglycaemic Non-Ketotic State (HHS) is a serious and life-threatening complication of diabetes, typically occurring in older adults with type 2 diabetes. Unlike diabetic ketoacidosis (DKA), HHS is characterized by severe hyperglycaemia, hyperosmolarity, and dehydration without significant ketoacidosis. Here’s how it develops:

Severe Hyperglycaemia:
Relative Insulin Deficiency: In HHS, there is a relative deficiency of insulin that is sufficient to prevent significant lipolysis and ketogenesis but not enough to allow adequate glucose utilization by peripheral tissues.
Impaired Glucose Utilization: The inability to effectively utilize glucose leads to its accumulation in the bloodstream, resulting in extremely high blood glucose levels, often exceeding 33.3 mmol/L (600 mg/dL).

Osmotic Diuresis:
Glucosuria: The kidneys attempt to excrete the excess glucose through the urine (glucosuria). However, the glucose acts as an osmotic agent, drawing large amounts of water into the urine.
Dehydration: This osmotic diuresis leads to significant loss of water and electrolytes (sodium, potassium, and others), causing profound dehydration. The severe dehydration exacerbates hyperglycaemia, creating a vicious cycle.

Hyperosmolarity:
Increased Serum Osmolality: The excessive glucose in the bloodstream, combined with the loss of water through osmotic diuresis, leads to a marked increase in serum osmolality, typically above 320 mOsm/kg.
Cellular Dehydration: The hyperosmolar state causes water to shift out of cells and into the extracellular space, leading to cellular dehydration. This is particularly detrimental to brain cells, potentially causing altered mental status or even coma.

Absence of Ketosis:
Sufficient Insulin to Prevent Ketosis: Unlike in DKA, where insulin deficiency leads to lipolysis and ketone production, in HHS, there is usually enough insulin to prevent significant lipolysis and ketogenesis. As a result, ketoacidosis is minimal or absent, hence the term “non-ketotic.”
Management of Hyperosmolar Hyperglycaemic Non-Ketotic State (HHS)
The management of HHS focuses on correcting the severe dehydration, hyperglycaemia, and electrolyte imbalances while monitoring for complications:

Fluid Resuscitation:
Initial Fluid Therapy: The first priority in managing HHS is aggressive fluid replacement. Start with 0.9% sodium chloride (normal saline) to restore intravascular volume. The initial rate is often 15-20 mL/kg/hour (approximately 1-1.5 litres in the first hour).
Ongoing Fluid Therapy: Once intravascular volume is restored, the fluid type and rate may be adjusted based on the patient’s serum sodium levels and osmolality. Hypotonic saline (0.45% sodium chloride) may be used if the sodium levels are high, to provide free water and correct hyperosmolarity.

Insulin Therapy:
Intravenous Insulin: Start with a low-dose intravenous insulin infusion after adequate fluid resuscitation has begun. The initial dose is typically 0.1 units/kg/hour. Insulin helps to lower blood glucose levels gradually and reduces hyperosmolarity.
Monitoring: Monitor blood glucose levels hourly. The goal is to lower blood glucose slowly, by 50-75 mg/dL per hour (2.8-4.2 mmol/L per hour), to avoid rapid shifts in osmolality that could precipitate cerebral oedema.

Electrolyte Management:
Potassium Replacement: As with DKA, patients with HHS are often potassium-depleted despite normal or high serum potassium levels at presentation. As insulin therapy drives glucose and potassium into cells, serum potassium levels can drop, so potassium supplementation is usually necessary.
Monitoring Electrolytes: Regular monitoring of electrolytes (especially potassium, sodium, and phosphate) is critical during treatment, and adjustments should be made as needed.

Correction of Hyperosmolarity:
Gradual Reduction: The aim is to reduce serum osmolality gradually to avoid complications such as cerebral oedema. This is achieved primarily through fluid administration and the gradual reduction of blood glucose with insulin.

Management of Precipitating Factors:
Identify and Treat Underlying Causes: Common precipitating factors include infections, myocardial infarction, stroke, or the use of medications that impair glucose tolerance (e.g., steroids, diuretics). Identifying and treating these underlying causes is essential to prevent recurrence.

Monitoring and Supportive Care:
Neurological Monitoring: Given the risk of cerebral oedema, particularly with overly rapid correction of hyperglycaemia, close monitoring of neurological status is essential.
Management of Complications: Patients with HHS are at risk for thromboembolic events due to severe dehydration and Hyperviscosity of the blood. Prophylactic anticoagulation may be considered in some cases.

Summary
HHS is a severe complication of type 2 diabetes characterized by extreme hyperglycaemia, hyperosmolarity, and dehydration without significant ketosis. The pathophysiology involves severe insulin deficiency leading to hyperglycaemia, osmotic diuresis, and subsequent dehydration, causing hyperosmolarity. Management focuses on aggressive fluid resuscitation, gradual reduction of hyperglycaemia with insulin, correction of electrolyte imbalances, and treatment of any underlying precipitating factors. With prompt and appropriate treatment, the prognosis of HHS can be favourable, but the condition requires careful monitoring to prevent complications.

Question 20

Describe the pathophysiology and management of acute hypoglycaemia.

Answer 20

Pathophysiology of Acute Hypoglycaemia
Acute hypoglycaemia occurs when blood glucose levels drop below the normal range, typically defined as less than 3.9 mmol/L (70 mg/dL). The brain relies on glucose as its primary energy source, so hypoglycaemia can lead to significant neurological impairment and, if severe, can be life-threatening. The pathophysiology of acute hypoglycaemia involves several key mechanisms:

Excessive Insulin or Insulin-Like Activity:
Exogenous Insulin: The most common cause of hypoglycaemia, especially in people with diabetes, is the administration of too much insulin relative to the body’s needs. Insulin promotes the uptake of glucose into cells and inhibits glucose production by the liver, leading to a rapid decline in blood glucose levels.
Oral Hypoglycaemic Agents: Sulfonylureas and meglitinides can cause hypoglycaemia by stimulating the pancreas to release more insulin, even when blood glucose levels are low. Note the metabolites of sulfonylureas can last days are are active, so patients may need to stay in with dextrose infusions.
Insulinoma: A rare cause is an insulin-producing tumour (insulinoma), which leads to persistent hyperinsulinemia and recurrent hypoglycaemia.

Inadequate Glucose Production:
Liver Disease: Conditions that impair liver function, such as severe liver disease, can reduce hepatic glucose production, leading to hypoglycaemia.
Glycogen Storage Disorders: Deficiencies in enzymes responsible for glycogenolysis (the breakdown of glycogen into glucose) can also cause hypoglycaemia, particularly during fasting or periods of increased glucose demand.
Alcohol: Excessive alcohol intake can inhibit gluconeogenesis (the production of glucose from non-carbohydrate sources) in the liver, particularly after fasting or low food intake, leading to hypoglycaemia.

Increased Glucose Utilization:
Exercise: Vigorous or prolonged exercise can increase glucose uptake by muscles, leading to hypoglycaemia, especially in individuals with diabetes who are on insulin or insulin secretagogues.
Sepsis: Infections, particularly sepsis, can increase glucose utilization due to the hypermetabolic state and can impair glucose production, increasing the risk of hypoglycaemia.

Counterregulatory Hormone Deficiency:
Adrenal Insufficiency: Cortisol is a key counterregulatory hormone that helps increase blood glucose levels by promoting gluconeogenesis and glycogenolysis. In adrenal insufficiency, the lack of cortisol can lead to hypoglycaemia.
Growth Hormone Deficiency: Growth hormone also has anti-insulin effects, and its deficiency can contribute to hypoglycaemia.

Management of Acute Hypoglycaemia
The management of acute hypoglycaemia focuses on rapidly restoring blood glucose levels to normal and identifying and treating the underlying cause to prevent recurrence. The approach varies depending on the severity of hypoglycaemia and the patient’s level of consciousness.

Mild to Moderate Hypoglycaemia (Conscious Patient):
Oral Glucose: For patients who are conscious and able to swallow, immediate treatment involves the administration of fast-acting carbohydrates. Options include:
Glucose tablets: 15-20 grams of glucose.
Sugary drinks: Such as fruit juice or regular (non-diet) soft drinks.
Candy: Like glucose gels, hard candy, or honey.
Follow-Up: After initial treatment, blood glucose should be rechecked after 15 minutes. If it’s still low, another 15-20 grams of glucose should be given. Once blood glucose levels are normalized, the patient should consume a snack or meal containing complex carbohydrates and protein to maintain glucose levels.

Severe Hypoglycaemia (Altered Consciousness or Unconscious Patient):
Intravenous Glucose: If the patient is unconscious or unable to swallow, administer intravenous (IV) glucose:
50% Dextrose: 25-50 mL (12.5-25 grams) IV bolus, followed by an infusion of 5% dextrose or 10% dextrose to maintain glucose levels.
Glucagon: If IV access is not available, glucagon can be administered intramuscularly (IM) or subcutaneously (SC). The usual dose is 1 mg for adults and children weighing more than 25 kg, or 0.5 mg for those under 25 kg.
Mechanism: Glucagon stimulates glycogenolysis and gluconeogenesis in the liver, raising blood glucose levels.

Monitoring and Prevention:
Frequent Monitoring: After treating severe hypoglycaemia, frequent blood glucose monitoring is essential to ensure that levels remain stable. This is particularly important if long-acting insulin or oral hypoglycaemic agents were involved, as the risk of recurrent hypoglycaemia may persist.
Identification of Cause: Identifying and addressing the underlying cause of hypoglycaemia is critical to prevent recurrence. This may involve adjusting insulin or oral hypoglycaemic dosages, altering the timing of meals and medications, or treating any underlying conditions such as adrenal insufficiency or liver disease.

Education and Prevention:
Patient Education: Educating patients, especially those with diabetes, about the signs and symptoms of hypoglycaemia, how to prevent it, and how to treat it promptly is crucial. This includes guidance on medication management, dietary adjustments, and monitoring glucose levels during exercise or illness.
Glucagon Kit: Patients with a history of severe hypoglycaemia should be prescribed a glucagon emergency kit and trained, along with their family members, on its use.

Summary
Acute hypoglycaemia results from an imbalance between glucose supply and demand, commonly due to excessive insulin, inadequate glucose production, or increased glucose utilization. Rapid treatment is essential, with oral glucose for conscious patients and intravenous glucose or glucagon for those with altered consciousness. Preventing recurrence involves identifying the underlying cause, adjusting therapy as needed, and educating patients on hypoglycaemia management.

Question 21

Describe the pathophysiology and management of an Addisonian crisis.

Answer 21

Pathophysiology of Addisonian Crisis
An Addisonian crisis, also known as an acute adrenal crisis, is a life-threatening condition that occurs when there is a sudden and severe deficiency of cortisol and, often, aldosterone. This crisis typically occurs in individuals with adrenal insufficiency, which can be either primary (Addison’s disease) or secondary (due to pituitary or hypothalamic dysfunction). The pathophysiology of an Addisonian crisis involves several key mechanisms:

Deficiency of Cortisol:
Impaired Gluconeogenesis: Cortisol is essential for maintaining blood glucose levels, particularly during stress. In its absence, gluconeogenesis (the production of glucose from non-carbohydrate sources) is impaired, leading to hypoglycaemia.
Reduced Vascular Tone: Cortisol has permissive effects on catecholamines, which help maintain vascular tone and blood pressure. A deficiency in cortisol leads to hypotension due to reduced sensitivity to catecholamines and decreased vascular tone.
Impaired Stress Response: Cortisol is a critical component of the body’s stress response. In an Addisonian crisis, the body’s ability to respond to stress (e.g., infection, surgery, trauma) is severely compromised, leading to shock and multi-organ failure if not treated promptly.
Deficiency of Aldosterone (Primarily in Primary Adrenal

Insufficiency):
Hyponatremia and Hyperkalaemia: Aldosterone is responsible for sodium retention and potassium excretion in the kidneys. A deficiency leads to excessive sodium loss and potassium retention, resulting in hyponatremia (low sodium) and hyperkalaemia (high potassium).
Hypovolemia: The loss of sodium and water leads to a decrease in blood volume, contributing to hypotension and shock. This hypovolemia exacerbates the circulatory collapse seen in an Addisonian crisis.

Triggering Factors:
An Addisonian crisis can be triggered by any stressor that increases the body’s demand for cortisol, such as:
Infection: Particularly gastrointestinal infections leading to vomiting and diarrhoea, which can exacerbate dehydration and electrolyte imbalances.
Trauma or Surgery: Physical stress increases the need for cortisol, which cannot be met in patients with adrenal insufficiency.
Abrupt Withdrawal of Glucocorticoids: In individuals on long-term steroid therapy, sudden discontinuation can precipitate a crisis due to adrenal suppression.
Management of Addisonian Crisis
Management of an Addisonian crisis is an emergency that requires rapid and aggressive intervention to prevent death. The key objectives are to replace deficient hormones, correct electrolyte imbalances, restore fluid volume, and treat any precipitating factors.

Immediate Corticosteroid Replacement:
Intravenous Hydrocortisone: Administer 100 mg of hydrocortisone intravenously immediately, followed by 50-100 mg every 6 hours for the first 24 hours. Hydrocortisone has both glucocorticoid and mineralocorticoid effects, making it the drug of choice.
Tapering: After stabilization, the dose of hydrocortisone is gradually tapered over the next few days, transitioning to oral maintenance therapy (e.g., hydrocortisone 20-30 mg/day in divided doses).

Fluid Resuscitation:
Isotonic Saline (0.9% Sodium Chloride): Begin with rapid intravenous infusion of normal saline to correct hypovolemia and hypotension. If the patient is hypoglycaemic, add 5% dextrose to the saline solution.
Monitor and Adjust: Fluid administration should be carefully monitored, and additional boluses may be required based on the patient’s blood pressure and urine output.

Electrolyte Management:
Hyperkalaemia: Monitor serum potassium levels closely. If hyperkalaemia is severe, treatments such as calcium gluconate, insulin with glucose, and sodium bicarbonate may be used to stabilize the cardiac membrane and promote intracellular potassium shift.
Hyponatremia: Correct sodium levels gradually with fluid resuscitation and corticosteroid replacement. Rapid correction of hyponatremia can cause central pontine myelinolysis, so a controlled approach is necessary.

Glucose Management:
Hypoglycaemia: If hypoglycaemia is present, administer IV dextrose along with the fluid replacement to rapidly correct blood glucose levels. Continuous glucose monitoring is essential during the acute phase of treatment.

Identify and Treat Precipitating Factors:
Infection Management: If an infection is suspected as the trigger, empirical antibiotic therapy should be initiated immediately, based on the likely source of infection, while awaiting culture results.
Stress Dose Steroids: If the crisis was precipitated by surgery, trauma, or another physical stressor, stress doses of hydrocortisone (higher than maintenance doses) should be continued until the patient is stabilized.

Long-Term Management:
Maintenance Corticosteroid Therapy: Once the crisis is resolved, patients should continue on maintenance doses of glucocorticoids (hydrocortisone or prednisolone) and, if necessary, mineralocorticoids (fludrocortisone) for primary adrenal insufficiency.
Patient Education: Patients should be educated on recognizing early signs of adrenal insufficiency, the importance of medication adherence, and when to increase steroid doses during illness or stress.
Emergency Steroid Kit: Patients should carry an emergency injection of hydrocortisone and wear medical identification indicating their condition.

Summary
An Addisonian crisis is a medical emergency characterized by acute adrenal insufficiency, leading to severe hypotension, electrolyte imbalances, and hypoglycaemia. Immediate treatment with intravenous corticosteroids, aggressive fluid resuscitation, and electrolyte management is essential. Identifying and addressing the underlying cause, along with long-term hormone replacement and patient education, are key to preventing recurrence and ensuring patient safety.

Note: Adrenal antibodies especially CYP21A2 strongly correlate with adrenal insufficiency.

Note: Doubling steroid doses during acute illness is a good idea to help reduce risk of Addisonian crisis.

Question 22

What is the synthetic ACTH stimulation test?

Answer 22

The synthetic ACTH (adrenocorticotropic hormone) (SynACTHen) stimulation test, also known as the Cosyntropin test or the short ACTH stimulation test, is a diagnostic procedure used to assess adrenal gland function and to diagnose adrenal insufficiency. This test helps determine how well the adrenal glands can respond to ACTH, which is a hormone produced by the pituitary gland that stimulates the adrenal cortex to release cortisol.

Procedure of the Synthetic ACTH Stimulation Test
Preparation:
The patient is usually instructed to refrain from taking steroids or other medications that could interfere with the test results for a period before the test.
The test is typically performed in the morning when cortisol levels are naturally at their highest.

Baseline Measurement:
A baseline blood sample is taken to measure the initial level of cortisol and sometimes aldosterone in the blood.

Administration of Synthetic ACTH:
Cosyntropin, a synthetic form of ACTH, is administered either intravenously or intramuscularly. The standard dose is 250 micrograms.
Cosyntropin stimulates the adrenal cortex in the same way as natural ACTH, prompting it to produce and release cortisol and, to a lesser extent, aldosterone.

Post-Administration Measurements:
Blood samples are taken at intervals after the administration of cosyntropin, typically at 30 and 60 minutes. These samples are used to measure the cortisol levels after stimulation.
A normal response indicates an increase in blood cortisol levels following the administration of cosyntropin.

Interpretation of Results
Normal Response: An adequate increase in cortisol levels after ACTH administration (usually at least a doubling of the baseline level or a rise to above 18-20 mcg/dL, depending on the laboratory’s reference range) indicates normal adrenal function.

Abnormal Response:
If cortisol levels do not rise appropriately after ACTH stimulation, it suggests adrenal insufficiency. This can be due to primary adrenal insufficiency (Addison’s disease) where the adrenal glands themselves are damaged, or secondary adrenal insufficiency where there is inadequate production of ACTH by the pituitary gland.
The test can help differentiate between primary and secondary causes based on the levels of ACTH and cortisol. In primary adrenal insufficiency, ACTH levels will be high due to a lack of feedback inhibition, while cortisol levels will be low. In secondary adrenal insufficiency, both ACTH and cortisol levels will be low.

Uses of the ACTH Stimulation Test
Diagnosis of Adrenal Insufficiency: This is the primary use of the ACTH stimulation test, helping to confirm whether the adrenal glands are producing enough cortisol.

Evaluating Recovery of Adrenal Function: In patients who have been on long-term steroid therapy, this test can be used to assess the recovery of the adrenal glands’ ability to produce cortisol naturally after cessation of steroids.

Advantages and Limitations
Advantages: The test is highly effective for diagnosing primary adrenal insufficiency and is relatively simple to perform.

Limitations: It may not be as effective for diagnosing secondary or tertiary adrenal insufficiency due to pituitary or hypothalamic dysfunction. Further testing might be necessary in these cases.

Overall, the synthetic ACTH stimulation test is a critical tool in the diagnosis of adrenal insufficiency, providing essential information about the functional status of the adrenal glands.

Question 23

What are the diagnostic requirements for diabetes?

Answer 23

1) Symptoms of diabetes and a casual plasma glucose of 11.0 mmol/L or higher. Casual = not related to any meal time specifically.

2) Fasting plasma glucose of 7.0 mmol/L or higher. Fasting = 8 hours since last caloric intake.

3) 2 hours plasma glucose of 11.0 mmol/L or higher during an OGTT (75g glucose)

4) HbA1c greater than or equal to 6.5% (48 mmol/L) is also diagnostic for diabetes. Also should do a secondary test to confirm.

HbA1c of 6-6.4% indicates pre diabetes status.

Test 2 and 3 should be repeated to confirm the diagnosis.

Symptoms you expect to see in these patients are polyuria, polydipsia, and unexplained weight loss.

Question 24

What is the rationale for the biochemical definition of diabetes?

Answer 24

It is based upon the development of microvascular complications. There is a stark rise in the prevalence of microvascular complications such as retinopathy when the FPG and HbA1c are at those levels, so that is the starting point for what we determine is diabetes.

Question 25

What is the upper limit of a normal fasting glucose reading for non diabetic / pre diabetic patients?

Answer 25

It is 6.1 mmol/L .

Impaired glucose tolerance (IGT) is where blood glucose levels are higher than normal but not high enough to be classified as diabetes. Impaired fasting glucose (IFG) is where blood glucose levels are escalated in the fasting state but not high enough to be classified as diabetes.

Question 26

Assessing for GAD antibodies is useful for what condition?

Answer 26

Antibodies to glutamic acid decarboxylase (anti-GAD) are reliable serological markers of Insulin-dependent diabetes mellitus.

Question 27

Is the age of onset for type 1 and type 2 diabetes more common in younger or older patients.

Answer 27

Type 1 = younger.
But there are some late onset autoimmune diabetes of adulthood cases (LADA)

Type 2 = very strongly associated with aging. More commonly seen in older individuals. It is becoming an issue in obese children and teens.

Question 28

Acanthosis nigricans is commonly associated with what endocrinological disease?

Answer 28

Type 2 diabetes.

Acanthosis nigricans is a skin condition characterized by areas of dark, velvety discoloration in body folds and creases. It typically affects the armpits, groin, neck, and other areas. While it can be associated with several conditions, it is most commonly linked to insulin resistance. Here’s how insulin resistance leads to acanthosis nigricans:

Pathophysiology of Insulin Resistance Leading to Acanthosis Nigricans

Insulin Resistance:
High Insulin Levels: In insulin resistance, the body’s cells do not respond effectively to insulin, a hormone that helps glucose enter cells from the bloodstream. As a result, the pancreas produces more insulin to achieve the desired effect on blood sugar control. This leads to hyperinsulinemia (excessively high levels of insulin in the blood).
Impact on Skin Cells: Insulin and insulin-like growth factors (IGFs) have growth-promoting effects on various types of cells, including keratinocytes and fibroblasts in the skin. High levels of insulin stimulate these cells to proliferate.

Hyperinsulinemia and Cell Growth:
Insulin as a Growth Factor: Insulin can bind to insulin-like growth factor receptors (IGF receptors) on keratinocytes and fibroblasts. This stimulates cellular proliferation and the production of skin pigments (melanin).
Stimulation of Keratinocytes and Fibroblasts: The excessive insulin stimulates these skin cells to grow rapidly and abnormally. The hyperproliferation of keratinocytes leads to the thick, velvety texture of the skin, while increased activity in melanocytes (the cells that produce melanin) leads to the darker pigmentation seen in acanthosis nigricans.

Role of Growth Factors:
Insulin-Like Growth Factors (IGFs): Hyperinsulinemia is often associated with increased levels of IGFs, which further contribute to the proliferation of skin cells. Both insulin and IGFs exacerbate the symptoms of acanthosis nigricans by promoting excessive growth and activity of keratinocytes and melanocytes.

Question 29

Is visceral fat or subcutaneous fat associated with insulin resistance?

Answer 29

It is only visceral fat that has been shown to link closely with insulin resistance.
Subcutaneous fat is not strongly linked.

Question 30

Explain the biochemical pathways implicated in damage caused by chronic elevated blood glucose.

Answer 30

Chronic elevated blood glucose, often observed in diabetes mellitus, can lead to a wide range of complications affecting multiple organ systems. The biochemical pathways through which hyperglycaemia causes cellular and tissue damage are complex and multifaceted. Here’s a detailed look at the key mechanisms:

1. Increased Polyol Pathway Flux
   Pathway Description: In normal circumstances, glucose is primarily metabolized via glycolysis. However, under hyperglycaemic conditions, excess glucose enters the polyol pathway. In this pathway, glucose is reduced to sorbitol by the enzyme aldose reductase, and sorbitol is subsequently converted to fructose.
   Consequences: This pathway consumes NADPH and can lead to oxidative stress due to the depletion of essential cofactors needed for regenerating glutathione, an important cellular antioxidant. Additionally, sorbitol accumulation can cause osmotic stress and cellular damage, particularly in the lenses of the eyes, nerves, and kidneys.
2. Formation of Advanced Glycation End-products (AGEs)
   Pathway Description: AGEs are formed through a non-enzymatic reaction between reducing sugars and the amino groups of proteins, lipids, or nucleic acids (a process known as glycation). Elevated glucose levels accelerate the formation of AGEs.
   Consequences: AGEs alter the structure and function of proteins, promoting inflammation and cross-linking of extracellular matrix components. This leads to decreased elasticity of tissues, such as blood vessels and skin, and contributes to vascular complications (like atherosclerosis and nephropathy) and diabetic retinopathy.
3. Activation of Protein Kinase C (PKC)
   Pathway Description: High glucose levels increase diacylglycerol (DAG) production, a secondary messenger that activates PKC. Several isoforms of PKC are involved in the regulation of various cellular functions.
   Consequences: Activated PKC can alter blood flow and increase vascular permeability, enhance extracellular matrix production, and induce inflammatory responses. These changes are particularly detrimental in vascular tissues, contributing to microvascular and macrovascular complications.
4. Increased Hexosamine Pathway Flux
   Pathway Description: A portion of the fructose-6-phosphate in glycolysis is diverted to the hexosamine pathway, where it is converted into glucosamine-6-phosphate and eventually into uridine diphosphate N-acetylglucosamine (UDP-GlcNAc).
   Consequences: Increased activity of this pathway leads to the modification of proteins through the process of O-GlcNAcylation, affecting their function. This modification can impact transcription factors, reducing insulin sensitivity and altering endothelial nitric oxide synthase activity, thereby contributing to insulin resistance and endothelial dysfunction.
5. Reactive Oxygen Species (ROS) Generation and Mitochondrial Dysfunction
   Pathway Description: Chronic hyperglycaemia induces excess production of superoxide by the mitochondrial electron transport chain. This overproduction is mainly due to an overload of the electron transport chain with more substrates being processed under high glucose conditions.
   Consequences: Increased ROS production leads to oxidative stress, damaging cellular components such as lipids, proteins, and DNA. This oxidative stress is a central mechanism in the development of diabetic complications, including cardiomyopathy, retinopathy, and nephropathy.
   Management of Hyperglycaemia-Induced Damage

Effective management of chronic hyperglycaemia and minimizing its complications involves:
Strict Glycaemic Control: Maintaining blood glucose levels within normal ranges through medication, dietary management, and lifestyle changes to minimize the activation of harmful biochemical pathways.
Antioxidant Therapy: Use of antioxidants may help reduce oxidative stress.
Inhibitors and Blockers: Certain drugs can inhibit pathways such as the polyol pathway (e.g., aldose reductase inhibitors) or counteract the effects of AGEs and PKC.
Regular Monitoring: Frequent monitoring of blood glucose levels and regular screening for early signs of diabetic complications to initiate timely interventions.

In summary, the damage caused by chronic elevated blood glucose involves multiple biochemical pathways that promote oxidative stress, inflammatory responses, and structural changes in proteins and tissues, contributing to the wide array of diabetic complications. Effective management focuses on controlling blood glucose levels and potentially targeting specific pathways pharmacologically.

Question 31

What are the stages of chronic kidney disease?

Answer 31

Question 32

What is the First-Line Management of T2DM?

Answer 32

First-Line Management
In short - metformin, and if a second agent needed add SLT2 inhibitor.

Lifestyle Modifications
Diet: Emphasizing a balanced diet rich in fruits, vegetables, whole grains, and lean proteins. Limiting high glycemic index foods that cause rapid spikes in blood glucose.
Exercise: Regular physical activity (at least 150 minutes per week of moderate-intensity aerobic activity).
Weight Management: Achieving and maintaining a healthy weight through diet and exercise.

Metformin
First-Line Medication: Metformin is typically the first-line pharmacological treatment for type 2 diabetes unless contraindicated (e.g., in patients with severe renal impairment or metabolic acidosis).
Mechanism of Action: It primarily decreases hepatic glucose production and improves insulin sensitivity, which helps in lowering blood glucose levels without causing significant hypoglycemia.
Benefits: Metformin has been shown to have cardiovascular benefits and is associated with weight stability or modest weight loss.

Second-Line Management
If glycemic targets are not achieved with metformin and lifestyle changes, or if metformin is contraindicated or not tolerated, second-line options are considered based on individual patient needs, preferences, and any comorbid conditions:

Sulfonylureas (e.g., glipizide, glyburide, glimepiride)
Increase insulin secretion from the pancreas.
Often used when cost is a concern, but they may increase the risk of hypoglycemia and weight gain.

DPP-4 Inhibitors (e.g., sitagliptin, linagliptin, saxagliptin)
Enhance the incretin system, which increases insulin release and decreases glucagon levels in a glucose-dependent manner.
Well-tolerated with a low risk of hypoglycemia.

SGLT2 Inhibitors (e.g., canagliflozin, empagliflozin, dapagliflozin)
Reduce blood glucose by blocking glucose reabsorption in the kidneys, promoting glucosuria.
Benefits include cardiovascular risk reduction and weight loss.

GLP-1 Receptor Agonists (e.g., liraglutide, semaglutide, exenatide)
Mimic the incretin GLP-1 that enhances glucose-dependent insulin release, suppresses glucagon secretion, and slows gastric emptying.
Provide substantial glycemic control, promote weight loss, and are associated with cardiovascular benefits.

Thiazolidinediones (e.g., pioglitazone, rosiglitazone)
Increase insulin sensitivity.
Less commonly used due to concerns about weight gain, heart failure risk, and bone fractures.

Insulin Therapy
Considered when there is a significant deficiency in insulin secretion or markedly elevated blood glucose levels.
Various regimens can be used, depending on the extent of hyperglycemia and patient factors.

Additional Considerations
Individualization of therapy: Treatment choices depend on factors like cardiovascular disease, chronic kidney disease, risk of hypoglycemia, and patient preferences.

Regular Monitoring: Regular monitoring of blood glucose levels, HbA1c, and other health parameters is essential to adjust therapy and manage complications.
Patient Education: Education on self-management of diabetes, including diet, exercise, medication adherence, and monitoring of blood glucose levels.