Endocrinology😍

ENDOCRINOLOGY

Acromegaly

Gigantism vs. Acromegaly

Etiology

• GH Excess (95% of cases)
• Pituitary adenoma:
• Most common
• Ectopic GH-secreting adenoma:
• Pancreatic islet cell tumor

• GHRH Excess
• Hypothalamic GHRH-secreting tumor
• Ectopic GHRH-secreting tumor:
• Bronchial carcinoid

• PIT1 gene

• Carney's complex

• McCune Albright syndrome

• MEN I syndrome

• Acromegaly → Big Men → No. 1 (MEN 1) → Bright () → travel in Car (Carney complex) → Fall in Pits (PIT1)

Clinical features

• Coarse facial appearance

• Spade like hands
• Increase in size of hands

• Large tongue, Prognathism

• frontal bossing, prominent supraorbital ridge

• Increased foot size
• X-ray foot: ↑↑ heel pad thickness

• Galactorrhea

Cells involved

• Most abundant: Somatotrophs (Anterior pituitary)

• Also involved: Lactotrophs

Diagnosis

• Screening test: Elevation of IGF-1 levels

• IOC: Glucose challenge test
• Oral glucose suppression test.
• Normally 100g glucose → suppresses GH
• In pituitary adenoma: Test fails, GH > 1 ng/ml

• Gadolinium-enhanced MRI
• Most are macroadenomas.

Acromegaly radiology

• Spade phalanx
• Overgrowth of distal phalanx.

• Increased heel pad thickness

• Increased growth hormone.

• Increased growth of bones and soft tissue.

• Prognathism

• Expanded sinus

Complications

• Hypertension,

• Diabetes mellitus (>10%),

• Cardiomyopathy (asymmetrical LVH, heart failure with preserved EF),

• Increased CAD,

• Colonic polyps,

• Increased colorectal/other cancer risk

• Angle closure glaucoma,

• Obstructive sleep apnea
• Breathing stops for ≥ 10 seconds during sleep.
• Caused by
• Obstruction from relaxed pharyngeal muscles &
• Tongue falling back.

• Hypertriglyceridemia,

• Hypercalcemia, hypercalciuria (kidney stones)

Investigation of Choice (IOC)

Prolactinoma

Fluid & Sodium Disorders

• Diabetes insipidus (loss of water)

• SIADH (gain of water)

• Psychogenic polydipsia

• Adipsic hypernatremia
• defect in thirst center
• Organum vasculosum laminae terminalis/OVLT

Plasma osmolality and Sodium

• TBS: Total body salt

• TBW: Total body water

• If TBS normal & TBW ↑
• Dilutional /Euvolemic hyponatremia
• SIADH: Increased V2 receptors activity
• Blocked by VAPTANS

• If TBS ↑ & TBW ↑
• Hypervolemic hyponatremia
• Due to aldosterone
• Neutralize with spironolactone/eplerenone

Nephrogenic diabetes insipidus:

• Lithium induced

• Rx
• Amiloride
• Thiazide diuretics
• Thiazides suppress osmoreceptor activity at OVLT, reduce polydipsia

Diabetes Mellitus

Diagnosing criteria

ADA criteria for Diagnosis of Diabetes Mellitus

• Any ONE of the following is sufficient:
• Symptoms of diabetes + RBS ≥ 200 mg/dL
• Fasting plasma glucose ≥ 126 mg/dL
• [Fasting = no caloric intake for ≥ 8 hours]
• HbA1C ≥ 6.5%
• 2-hour plasma glucose ≥ 200 mg/dL
• During OGTT

Additional

• High Adipokines: Promotes weight gain

• ↓ Adiponectin: Guardian against obesity

Metabolic syndrome: NCEP-ATP III

Wrong statement regarding life style modification to management of systemic hypertension is :

• Good glycemic control can reduce Microvascular complications
• Mortality → No change → d/t CVS causes

• M/c microvascular complication → Neuropathy
• M/c → Glove and stocking → sensorimotor neuropathy
• B/L peripheral distal

Management

• Type 1 DM:
• Insulin

• Type 2 DM:
• Initially OHA;
• after beta cell exhaustion → insulin

• Drug for both T1 and T2 DM:
• Insulin
• Pramlintide
• affects stomach motility,
• Regulate amount of sugar entering small intestine
• controls post-prandial sugar

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Drugs causing DM:

• Steroids

• Thiazide (also gout) > Loop diuretics

• Niacin (also gout)

• Phenytoin

• IFN alpha

• Protease Inhibitors

• Clozapine → atypical

• β Agonists (opp. to β blockers)

---

Insulin

• Indications:
• All patients with type 1 DM.
• Uncontrolled patients with type 2 DM.
• Diabetes in pregnancy.
• Diabetic Ketoacidosis.
• Hyperkalemia

• Routes of Administration:
• Subcutaneous (MC route):
• Self-administration possible.
• All insulin preparations can be given.
• Site of administration:
• Entire abdomen (except around umbilicus).
• Anterior thigh.
• Lateral thigh.
• Arm.
• Intravenous:
• Only regular insulin can be given.
• Insulin of choice in diabetic Ketoacidosis → Regular insulin.
• Inhalational:
• Afreeza → Short acting insulin → Given before every meal.

Methods of Insulin Delivery

• CSII (Continuous subcutaneous insulin infusion) / Insulin Pump
• most preferred

• Insulin pen (dose adjustable)

• Multi-dose vial

• Pre-filled syringes

Sites of Injection

• Upper outer arms

• Abdomen

• Buttock

• Upper outer thighs

Insulin pump (Best)

• Mimics artificial pancreas
1. Basal insulin → continuous secretion
2. Bolus insulin → mealtime, proportionate to carbohydrate intake

Insulin injection at same site

• lipoatrophy

Insulin Analogues:

• Rapid/Ultra short acting:
• LISPRO
• ASPART
• GLULISINE

• Ultra-Long/Long Acting:
• GLARGINE
• DETEMIR
• DEGLUDEC (Longest Acting)
• These are peakless insulins.
• Have low risk of hypoglycemia.

• Side Effects:
• Hypoglycemia
• Hypokalemia

Important

• Most preferred site:
• Anterior abdominal wall (2cm from umbilicus)

• Most preferred route:
• CSII

• MC side effect:
• Hypoglycemia

• β-blockers contraindicated
• they mask hypoglycemia

Types of Insulin

Type of Insulin	Duration	Examples	ㅤ
Inhaled	2–3 hours	Afrezza	Postprandial hyperglycemia C/I → COPD, Asthma
Rapid acting	3–4 hours Onset: 10-15 min	Aspart (NovoRapid) Glulisine (Apidra) Lispro (Humalog)	ㅤ
Short acting	6–8 hours	Regular	Inject at 15-30 min before meal IV in emergencies like • DKA • hyperosmolar coma • dangerous hyperkalemia
Intermediate acting	10–16 hours	NPH, Lente Isophane/zinc	NPH → Cloudy ↳ Humulin-N ↳ Novolin-NPH Used between meals. Can combine with short-acting
Long acting	12–24 hours	Detemir (Levemir) Glargine(Lantus, 24 hrs)	Bedtime, "Peakless," [taken once daily]
Ultra-long acting	42 hours	Degludec	ㅤ

• Composed of two polypeptide chains:
• A-chain: 21 amino acids
• B-chain: 30 amino acids
• First protein:
• Completely sequenced (By Sanger).
• Produced by recombinant DNA technology.
• Zinc stabilizes insulin structure.
• Prolong insulin action

Insulin Analog	Modification
Lispro	Proline (28) ↔ Lysine (29) in B-chain are interchanged
Aspart	Proline (28) in B-chain → Aspartic acid
Glulisine	Asparagine at B3 and Lysine at B29 → Lysine and Glutamic acid
Glargine	Asparagine (A21) → Glycine; 2 extra Arg residues added at B-chain (positions 31, 32)
Detemir	Threonine (B30) removed; C 14 fatty acid added at position B29

 

Somogyi Effect

• So much insulin at Night

• 4 AM: Sugar falls
• Early morning hypoglycemia
• d/t excess insulin at bedtime/less food

• Release of counter-regulatory hormone (Glucagon)

• Pre-breakfast hyperglycemia

• Red: Insulin levels in Somogyi effect

• Green: Insulin in Dawn phenomenon

Dawn Phenomenon

• Insulin sensitivity down in middle of night

• Decreased insulin receptor sensitivity (4–7 AM)

• 4 AM: Blood sugar rises (↓ GLUT-4 in T2DM)

• 7 AM: Pre-breakfast hyperglycemia

Diabetic Ketoacidosis (DKA)

General

• More common in Type 1 DM > Type 2 DM

• Often due to negligence or missed insulin doses

Pathogenesis

• Insulinopenia → body burns fat

• Fat breakdown → Free Fatty Acids (FFA) → converted to ketones

Investigation of Choice

• Plasma β-Hydroxybutyrate level

Precipitating Factors

• Infections: Pneumonia, UTI

• Stress events: MI, Stroke
→ Cause increased energy demand
→ In absence of insulin → fat breakdown → ↑ ketones → Metabolic acidosis

Compensation

• Metabolic acidosis → Respiratory alkalosis
• ↓ pH stimulates respiratory center → Kussmaul breathing

Euglycemic DKA

• Stress

• Illness

• SGLT2 ⛔

ISPAD

• Add IV potassium if serum K ≤5.2 mEq/L

• Hold insulin if serum K <3.3 mEq/L

• HCO3 if pH <6.9

Hyperosmolar Hyperglycemic State (HHS)

General

• More common in Type 2 DM

• Indolent onset → often diagnosed late

• Blood glucose > 600 mg/dL

• Patient often presents unconscious & unresponsive

Initial Action

• Check capillary blood glucose in all unconscious patients

Investigations

• Capillary glucose: >600 mg/dL

• VBG and RBS: essential

• Urine dipstick: Ketones negative

• ABG findings:
• pH: 7.40
• HCO₃⁻: 24 meq

Pathophysiology

• Severe hyperglycemia → neurotoxicity and coma

• No significant ketoacidosis

Treatment

• Normal saline only

• Insulin drip:
• Lower dose than DKA
• No insulin bolus (unlike DKA)

Important

• Plasma β-Hydroxybutyrate elevated: DKA

• Normal β-Hydroxybutyrate with acidosis: Lactic acidosis

Kussmaul sign

• Increased JVP on inspiration
• Seen in: Constrictive pericarditis, Restrictive cardiomyopathy, Right-sided CHF

DKA Severity

• Determined by: Bicarbonate levels

DM Severity

• Determined by: HbA1c

ABG in metabolic acidosis

• pH ↓

• HCO3 ↓

• pCO2 ↓

DKA Management Scenario

• First line: Normal saline, then insulin drip

• Before insulin drip, check K+.

• If K+ <3.5meq/l, correct first
• Insulin moves K+ into cells:
• Risk of respiratory failure,
• Torsades de pointes
• If K+ normal:
• start insulin drip

• TOC: Insulin drip

Long Term Complications of Diabetes

Diabetic Retinopathy

• Earliest: Microaneurysm (inner nuclear layer)

• Manifestation:
• Type 1 DM: 5 years
• Type 2 DM: 15–20 years

• Gross findings:
• Non-proliferative: Macular edema
• Proliferative: Neovascularization (may detach retina, blindness)

• Prevention:
• PRP (Nd YAG Laser)
• intravitreal Bevacizumab
• control sugars

• HbA1c >7%:
• Progresses to retinopathy/nephropathy

Diabetic Nephropathy

• Leading cause:
• Chronic kidney disease, progression same as retinopathy

• Can progress to ESRD (GFR <15 ml/min)

• Monitoring:
• Homocysteine ↑ (contributes to atherosclerosis, stroke)
• Creatinine clearance ↓
• Serum creatinine ↑

• Screening:
• Urine albumin/creatinine ratio (UAC),
• Normal <30mg/g
• Albumin excretion rate
• >300 mg/g creatinine

• Treatment:
• Low-dose ACE inhibitors (increase survival)

Diabetic Dermopathy

• MC: Delayed wound repair (Non-healing ulcer)

• Acanthosis nigricans:
• Type 2 DM + hyperpigmentation (extensors/back of neck)
• Seen in: Dermopathy, PCOD, Metabolic syndrome, Ca Pancreas/stomach

• Foot ulcer:
• Due to neuropathy & angiopathy

• Glucagonoma skin:
• Necrolytic migratory erythema

• Necrobiosis Lipoidica Diabeticorum:
• Shin ulcer (T1DM-Females, Glucogonoma)

Important

• MC long term complication: Diabetic neuropathy

• M/C HPE finding:
• Diffuse glomerulosclerosis

• MC HPE HIV nephropathy: FSGS

Lesions on Shin (anterior aspect)

• Necrobiosis lipoidica diabeticorum

• Pyoderma gangrenosum (IBD/Crohn's)

• Pretibial myxedema (Grave's)

• Martorell ulcer (HTN)

Conn's syndrome

• Tumor: Adrenal adenoma
• Aldosterone ↑

• Clinical features:
• Metabolic alkalosis (loss of K+ & H+ in urine)
• Hypokalemia → Muscle cramps, interstitial atony, Nephropathy.
• Hypertension: Due to Na⁺ & H₂O retention → Increased ECF → Increased BP.

• Aldosterone escape:
• Pressure diuresis (D/T ↑ BP) → Atrial natriuretic peptide: Natriuresis → Na⁺ & H₂O excretion (in spite of ↑ aldosterone) → No edema

Screening: ARR (Aldosterone renin ratio)

• Low renin HTN

• High Aldosterone Renin Ratio
• Aldosterone ↑ → Renin ↓

IOC:

• Saline infusion test

Others

• CT Scan and Adrenal vein sampling

Treatment:

• Spironolactone

Addison disease

• M/c cause in developed countries: Autoimmune

• M/c cause in developing countries: TB

• M/c cause in infectious cause in children: Neisseria Meningitidis

• Autoimmune destruction

• Aldosterone ↓

• Cortisol ↓

Clinical features

• Salt wasting

• Postural hypotension
• (tilt table, sudden standing, after 3 min)
• Fall in
• SBP >20mmHg,
• DBP >10mmHg

• Hypoglycemia (cortisol deficiency)

• Hyperpigmentation (cortisol deficiency → ↑ ACTH)
• Key feature Primary Addison




• Proopiomelanocortin (POMC → Precursor of ACTH and MSH)
• gamma MSH with ACTH.
• Gamma MSH causes hyperpigmentation.

• Loss of pubic hair
• sex steroid deficiency

• Dextrose fever
• Dextrose infusion is used as treatment.
• Low cortisol → water retention → hypoosmotic circulation.
• Water enters thermostat cells of the hypothalamus.
• This causes dysregulation of hypothalamus and dextrose fever.

Screening

• Basal plasma ACTH

• Basal serum cortisol, glucose, urea, electrolytes
• High ACTH, Low cortisol

IOC:

• ACTH stimulation/Cosyntropin test (no response)

Treatment

• Fludrocortisone (postural hypotension; mineralocorticoid)

• Dexamethasone (hypoglycemia, glucocorticoid)

Important

• Autoimmune destruction:
• MC cause for
• T1DM, T1.5DM,
• Addison,
• Hypoparathyroidism (low PTH, hypocalcemia)

• TB adrenals:
• Important cause in India

Secondary Addison

• Sheehan syndrome:
• Postpartum hemorrhage → Pituitary damage → Secondary Addison

• Pituitary defect:
• ↓ ACTH → Hypopigmentation (Pale)

Q. A 42-year-old man presents with hypoglycemia. He is a known patient of tuberculosis with poor adherence to treatment. He was treated with dextrose and before discharge he wanted a dermatological opinion for hyperpigmentation of gums, dorsum of the tongue and joints. The dermatologist suspected Addison's. The cause of hyperpigmentation in Addison's disease is:

• A. Glucocorticoid stimulates MSH.

• B. ACTH has MSH activity.

• C. ACTH and MSH are synthesised from proopiomelanocortin.

• D. Autoimmune process stimulates pigmentation.

Other Disorders

Glucocorticoid remediable hyperaldosteronism

• Fusion of Aldosterone synthase and 11 β-hydroxylase genes
• results in Hybrid enzyme.
• regulated by ACTH (typically cortisol production).
• → sustained release of aldosterone regulated by ACTH,
• [instead of angiotensin II/K⁺ ]

• A/w Intracranial aneurysms → hemorrhagic stroke.

• TOC: Low-dose Dexamethasone.

SAME (Syndrome of Apparent Mineralocorticoid Excess)

Feature	Normal Physiology	SAME
11 β-HSD type 2 enzyme	Active	⛔ by Glycyrrhetinic acid  (from Licorice consumption)
Cortisol Conversion	Cortisol → Inactive cortisol	not converted → remains active
Cortisol binding to mR	Prevented	Unopposed binding (due to enzyme inhibition)
Resulting Mineralocorticoid Action	Normal	Increased (apparent excess)

Liddle Syndrome

• Cause of low-renin hypertension

• Autosomal dominant

• Gain of function: ENaC
• HTN + Hypokalemic alkalosis

Mechanism

• Aldosterone ↓ (negative feedback)

• Excess salt & water reabsorption:
• Excess ENaC activity

• ↑ urinary loss of H and K+

• RAAS: Aldosterone ↓, Renin ↓

• Imaging: Normal adrenals

Treatment:

• Amiloride (DOC)

Differential diagnosis

• Conn's: ↑ hormone (aldosterone)

• Liddle: ↑ ENaC (↓ aldosterone)

Cushing's Syndrome

Important

• Neutrophil: ↑↑ → because of ⛔ of chemotaxis

• Eosinophil: ↓↓

• Lymphocytes: ↓↓

• BP ↑↑, Diabetes, Myopathy

Features

• Normal:
• Cortisol fluctuates, lowest 4 - 6 am, rises in morning

• Cushing's:
• Loss of diurnal variation, overall ↑
• Earliest feature

• MC cause:
• Iatrogenic steroids (exogenous, ↑ cortisol, ↓ ACTH)

• Endogenous:
• Pituitary adenoma (Cushing's disease; ↑ cortisol, ↑ ACTH)

• Adrenal adenoma:
• ↑ cortisol, ↓ ACTH

• Oat cell cancer lung:
• ↑ cortisol, ↑ ACTH

Clinical features

• Centripetal obesity ("lemon on sticks")

• Moon facies and buffalo hump is rare

• Hirsutism

• Short stature

• Hypertension

• Bone pains

• Muscle weakness

• Cataract

• Hyperglycemia

• Neuropsychiatric changes

• Behavioral problems

• ↑ cortisol: ↑blood sugar, impaired glucose tolerance

• FBS & 2 hr value ↑: Secondary diabetes

Screening

• 24h urine cortisol ↑

• MRI pituitary:
• Differentiate cushing's disease vs adrenal adenoma

• IOC:
• Low dose (1 mg) dexamethasone test
• In cushing’s → Cortisol remains high

• To differentiate Pituitary and ectopic source
• High dose (2 mg) dexamethasone test

Nelson syndrome:

• Microadenoma of Pituitary may be missed → and misdiagnosed as Adrenal adenoma/hyperplasia → H/o B/L adrenalectomy for Cushing syndrome

• Then Pt present with
• Hyperpigmentation + Headache/visual symptoms
• D/t unopposed/↓ inhibition from Adrenal → ↑↑↑ ACTH → ↑↑ Symptoms

Pheochromocytoma

Thyroid

Multiple Endocrine Neoplasia (MEN)