Adrenal (Suprarenal) Gland: Complete Overview

from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.lib.units import cm, mm
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    PageBreak, HRFlowable, KeepTogether
)
from reportlab.lib.enums import TA_LEFT, TA_CENTER, TA_JUSTIFY
from reportlab.platypus.flowables import Flowable
import io

# ── Colour palette ────────────────────────────────────────────────────────────
DARK_BLUE   = colors.HexColor("#1a3a5c")
MID_BLUE    = colors.HexColor("#2563a8")
LIGHT_BLUE  = colors.HexColor("#dbeafe")
TEAL        = colors.HexColor("#0f766e")
TEAL_LIGHT  = colors.HexColor("#ccfbf1")
ORANGE      = colors.HexColor("#c2410c")
ORANGE_LT   = colors.HexColor("#ffedd5")
PURPLE      = colors.HexColor("#6d28d9")
PURPLE_LT   = colors.HexColor("#ede9fe")
GREEN       = colors.HexColor("#15803d")
GREEN_LT    = colors.HexColor("#dcfce7")
RED         = colors.HexColor("#b91c1c")
YELLOW_LT   = colors.HexColor("#fef9c3")
GRAY_DARK   = colors.HexColor("#374151")
GRAY_MID    = colors.HexColor("#6b7280")
GRAY_LIGHT  = colors.HexColor("#f3f4f6")
WHITE       = colors.white

W, H = A4

# ── Document ──────────────────────────────────────────────────────────────────
doc = SimpleDocTemplate(
    "/tmp/workspace/adrenal-gland/Adrenal_Gland_Complete.pdf",
    pagesize=A4,
    leftMargin=2*cm, rightMargin=2*cm,
    topMargin=2.2*cm, bottomMargin=2.2*cm,
    title="Adrenal Gland – Complete Medical Reference",
    author="Orris Medical Education",
)

styles = getSampleStyleSheet()

# ── Custom styles ─────────────────────────────────────────────────────────────
def S(name, **kw):
    return ParagraphStyle(name, **kw)

cover_title = S("CoverTitle", fontSize=32, textColor=WHITE, fontName="Helvetica-Bold",
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cover_sub   = S("CoverSub",   fontSize=16, textColor=colors.HexColor("#bfdbfe"),
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cover_tag   = S("CoverTag",   fontSize=11, textColor=colors.HexColor("#93c5fd"),
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h_chapter   = S("HChapter",   fontSize=18, textColor=WHITE, fontName="Helvetica-Bold",
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body        = S("Body",       fontSize=10, textColor=GRAY_DARK, fontName="Helvetica",
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body_b      = S("BodyB",      fontSize=10, textColor=GRAY_DARK, fontName="Helvetica-Bold",
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small_it    = S("SmallIt",    fontSize=8.5, textColor=GRAY_MID, fontName="Helvetica-Oblique",
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key_point   = S("KeyPoint",   fontSize=10, textColor=DARK_BLUE, fontName="Helvetica-Bold",
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mnemonic    = S("Mnemonic",   fontSize=11, textColor=ORANGE, fontName="Helvetica-Bold",
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# ── Helper: coloured banner (chapter header) ──────────────────────────────────
class Banner(Flowable):
    def __init__(self, text, bg=DARK_BLUE, height=1.1*cm):
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        self.bh   = height
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class InfoBox(Flowable):
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        self.paragraphs = paragraphs
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def bul(text, style=bullet_s):
    return Paragraph(f"<bullet>&bull;</bullet> {text}", style)

def sp(h=6):
    return Spacer(1, h)

def hr(color=MID_BLUE, thickness=0.5):
    return HRFlowable(width="100%", thickness=thickness, color=color, spaceAfter=4, spaceBefore=4)

# ── TABLE helper ──────────────────────────────────────────────────────────────
def make_table(data, col_widths, header_bg=DARK_BLUE, row_bg1=GRAY_LIGHT, row_bg2=WHITE,
               header_color=WHITE, font_size=9):
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    t.setStyle(TableStyle(style))
    return t

# ══════════════════════════════════════════════════════════════════════════════
# CONTENT
# ══════════════════════════════════════════════════════════════════════════════
story = []

# ── COVER ─────────────────────────────────────────────────────────────────────
cover_data = [[
    Paragraph("ADRENAL GLAND", cover_title),
    Paragraph("Anatomy · Histology · Physiology · Applied", cover_sub),
    sp(8),
    Paragraph("A Comprehensive Medical Reference", cover_tag),
    sp(4),
    Paragraph("Based on Costanzo Physiology 7e · Medical Physiology (Barrett) ·<br/>"
              "Langman's Embryology · Schwartz's Principles of Surgery ·<br/>"
              "Fischer's Mastery of Surgery · Histology: A Text and Atlas", cover_tag),
]]
cover_tbl = Table(cover_data, colWidths=[W - 4*cm])
cover_tbl.setStyle(TableStyle([
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]))
story.append(cover_tbl)
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# CHAPTER 1 – ANATOMY
# ══════════════════════════════════════════════════════════════════════════════
story.append(Banner("CHAPTER 1  ·  GROSS ANATOMY", bg=DARK_BLUE))
story.append(sp(6))

story.append(Paragraph("1.1  Overview & Location", h1))
story.append(Paragraph(
    "The <b>adrenal (suprarenal) glands</b> are paired, retroperitoneal endocrine organs situated "
    "<b>superomedially on the upper poles of each kidney</b>, within Gerota's (perirenal) fascia. "
    "Each gland weighs approximately <b>4 g</b> in the adult but receives one of the highest blood flows "
    "per gram of any organ in the body — reflecting its intense secretory activity. "
    "Macroscopically, a bright-yellow outer cortex encloses a dark-brown/grey medulla.",
    body))

story.append(Paragraph("1.2  Shape & Side Differences", h1))
rel_data = [
    ["Feature", "Right Adrenal", "Left Adrenal"],
    ["Shape", "Pyramidal / triangular", "Semilunar / crescentic"],
    ["Anterior", "Bare area of liver; IVC", "Stomach; pancreatic tail; splenic vessels"],
    ["Posterior", "Right crus of diaphragm", "Left crus of diaphragm"],
    ["Medial", "IVC; right celiac ganglion", "Aorta; left celiac ganglion"],
    ["Inferior", "Upper pole of right kidney", "Upper pole of left kidney"],
    ["Adrenal vein drains into", "IVC directly (short, <1 cm)", "Left renal vein"],
]
story.append(make_table(rel_data,
    col_widths=[4.5*cm, 7*cm, 7*cm]))
story.append(sp(6))

story.append(Paragraph("1.3  Blood Supply", h1))
story.append(Paragraph(
    "The adrenal gland has a <b>triple arterial supply</b> — unlike most abdominal organs that have a single "
    "dominant vessel. All three sources anastomose in a subcapsular plexus before penetrating the cortex "
    "as sinusoids that flow centripetally toward the medulla.",
    body))

art_data = [
    ["Artery", "Origin", "Territory"],
    ["Superior suprarenal (multiple small branches)", "Inferior phrenic artery", "Upper cortex"],
    ["Middle suprarenal", "Abdominal aorta (directly)", "Midcortex"],
    ["Inferior suprarenal", "Renal artery", "Lower cortex / medulla"],
]
story.append(make_table(art_data, col_widths=[6*cm, 5*cm, 5.5*cm]))
story.append(sp(5))

story.append(Paragraph("<b>Venous drainage:</b> Each gland drains via a <b>single central adrenal vein.</b>", body))
story.append(bul("<b>Right adrenal vein:</b> Very short (&lt;1 cm); drains <b>directly into the IVC</b>. "
                 "Surgically hazardous — prone to avulsion during right adrenalectomy."))
story.append(bul("<b>Left adrenal vein:</b> Longer; drains into the <b>left renal vein</b>, which also "
                 "receives the left gonadal vein."))
story.append(sp(4))

story.append(Paragraph("1.4  Lymphatic Drainage & Nerve Supply", h1))
story.append(bul("<b>Lymphatics:</b> Drain to lateral aortic (para-aortic) lymph nodes."))
story.append(bul("<b>Nerve supply:</b> Preganglionic sympathetic fibres from the <b>greater, lesser, and least "
                 "splanchnic nerves</b> (T8–L1). These pass through the celiac plexus <i>without synapsing</i> "
                 "and synapse directly on chromaffin cells of the medulla — the chromaffin cells are therefore "
                 "functionally equivalent to post-ganglionic sympathetic neurons."))
story.append(sp(4))

story.append(InfoBox([
    Paragraph("<b>Key Anatomical Points (Exam Favourites)</b>", key_point),
    bul("Right adrenal vein is SHORT and drains directly to IVC — highest risk during surgery."),
    bul("Triple arterial supply means single-vessel ligation does NOT devascularise the gland."),
    bul("Both glands lie within Gerota's fascia — adrenalectomy approaches must respect this layer."),
    bul("Left adrenal vein receives the left inferior phrenic vein before entering left renal vein."),
], bg=LIGHT_BLUE, border=MID_BLUE))
story.append(sp(8))
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# CHAPTER 2 – EMBRYOLOGY
# ══════════════════════════════════════════════════════════════════════════════
story.append(Banner("CHAPTER 2  ·  EMBRYOLOGY & DEVELOPMENT", bg=TEAL))
story.append(sp(6))

story.append(Paragraph("2.1  Dual Embryological Origin", h1))
story.append(Paragraph(
    "The adrenal gland is unique among endocrine organs in being derived from <b>two completely separate "
    "embryological sources</b> — one mesodermal (cortex) and one ectodermal/neuroectodermal (medulla).",
    body))

emb_data = [
    ["Component", "Embryological Origin", "Week", "Key Events"],
    ["Cortex", "Coelomic mesothelium\n(mesodermal)", "Week 5",
     "Mesothelial cells between root of mesentery and gonadal ridge proliferate, "
     "penetrate mesenchyme → large acidophilic fetal cortex forms"],
    ["Medulla", "Neural crest cells\n(neuroectodermal)", "Week 6–7",
     "Neural crest cells migrate, guided by BMP signals from dorsal aorta, "
     "invade medial fetal cortex → differentiate into chromaffin cells"],
]
story.append(make_table(emb_data, col_widths=[3.2*cm, 3.8*cm, 2*cm, 7.5*cm]))
story.append(sp(6))

story.append(Paragraph("2.2  Fetal Cortex (Fetal Zone)", h1))
story.append(Paragraph(
    "The <b>first wave</b> of mesodermal cells forms the <b>fetal cortex (fetal zone)</b>, a large "
    "mass of eosinophilic cells constituting ~80% of the gland's mass by the fourth fetal month. "
    "The <b>second wave</b> of mesothelial cells surrounds the first and forms the thin "
    "<b>permanent (definitive) cortex</b>, which resembles the adult zona glomerulosa.",
    body))
story.append(bul("By 4th fetal month: adrenal gland is nearly as large as the adjacent kidney."))
story.append(bul("At term: adrenal glands weigh the same as adult glands (~4 g each) and produce "
                 "<b>100–200 mg of steroids/day</b> — about twice the adult rate."))
story.append(bul("Fetal cortex secretes <b>DHEA</b>, which is converted to <b>oestrogen</b> by the placenta "
                 "— essential for maintaining placental function and pregnancy."))
story.append(sp(4))

story.append(Paragraph("2.3  Postnatal Involution & Adult Zonation", h1))
story.append(Paragraph(
    "After birth, the fetal cortex <b>rapidly involutes</b> (stimulated by withdrawal of placental "
    "oestrogen and ACTH). Over 1–3 years, it is completely replaced by the three-layered adult cortex "
    "(zona glomerulosa, fasciculata, reticularis). Neural crest-derived chromaffin cells differentiate "
    "fully and become enclosed within the definitive cortex.",
    body))

story.append(InfoBox([
    Paragraph("<b>Clinical Correlate – Congenital Adrenal Hyperplasia (CAH)</b>", key_point),
    Paragraph(
        "Defects in steroidogenic enzymes (most commonly <b>21-hydroxylase / CYP21A2</b>) prevent normal "
        "cortisol synthesis even during fetal life. Excess ACTH drives the fetal adrenal to overproduce "
        "androgens, leading to virilisation of the female fetus. CAH can present at birth as ambiguous "
        "genitalia or as a life-threatening salt-wasting crisis in the neonatal period.",
        note_box),
], bg=ORANGE_LT, border=ORANGE))
story.append(sp(8))
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# CHAPTER 3 – HISTOLOGY
# ══════════════════════════════════════════════════════════════════════════════
story.append(Banner("CHAPTER 3  ·  HISTOLOGY", bg=PURPLE))
story.append(sp(6))

story.append(Paragraph("3.1  General Structure", h1))
story.append(Paragraph(
    "The adrenal gland is enclosed in a <b>fibrous capsule</b> from which septa extend inwards. "
    "Deep to the capsule is the <b>cortex</b> (80% of tissue, mesodermal origin) and centrally lies "
    "the <b>medulla</b> (20%, neuroectodermal origin). Blood flows <b>centripetally</b> — cortical "
    "sinusoids drain into medullary sinusoids, exposing the medulla to high concentrations of cortisol "
    "(which is required for the final step of epinephrine synthesis).",
    body))
story.append(sp(4))

story.append(Paragraph("3.2  The Three Zones of the Cortex", h1))
story.append(Paragraph(
    '<b>Mnemonic: "GFR" (outer → inner)</b> — Glomerulosa, Fasciculata, Reticularis',
    mnemonic))

# Zone table
zone_data = [
    ["Zone", "% Cortex", "Cell Arrangement", "Cytoplasm", "Secretion", "Regulator"],
    ["Zona\nGlomerulosa\n(outer)", "~15%",
     "Rounded arches /\nclusters (glomerular\npattern)",
     "Small cells, scanty,\nsomewhat basophilic;\nclosely packed nuclei",
     "Aldosterone\n(mineralocorticoids)", "Angiotensin II,\nHyperkalemia\n(not ACTH)"],
    ["Zona\nFasciculata\n(middle)", "~75%",
     "Long radial cords\n(fascicles) separated\nby sinusoids",
     "Large spongiocytes:\npale, vacuolated,\nlipid-rich (foamy)",
     "Cortisol\n(glucocorticoids)\n+ some androgens", "ACTH"],
    ["Zona\nReticularis\n(inner)", "~10%",
     "Anastomosing cords\n(net/reticular pattern)",
     "Compact, acidophilic\n(eosinophilic),\nlipid-poor; darker nuclei",
     "DHEA, androstenedione\n(adrenal androgens)\n+ glucocorticoids", "ACTH"],
]
story.append(make_table(zone_data,
    col_widths=[3*cm, 1.8*cm, 3.5*cm, 3.5*cm, 3.5*cm, 3.2*cm],
    header_bg=PURPLE, font_size=8.5))
story.append(sp(6))

story.append(Paragraph("3.3  Zona Glomerulosa – Detailed Histology", h2))
story.append(bul("Cells arranged in <b>arched groups (glomeruli)</b> that extend into short cords."))
story.append(bul("Small cells with <b>closely packed nuclei and scanty cytoplasm</b>."))
story.append(bul("Slight basophilia of cytoplasm in H&E preparations."))
story.append(bul("Contains the enzyme <b>aldosterone synthase (CYP11B2)</b> — unique to this zone."))
story.append(bul("Lacks 17α-hydroxylase — cannot produce cortisol or sex steroids."))
story.append(sp(3))

story.append(Paragraph("3.4  Zona Fasciculata – Detailed Histology", h2))
story.append(bul("Widest zone; cells called <b>spongiocytes</b> due to foamy vacuolated cytoplasm."))
story.append(bul("Vacuoles represent dissolved <b>cholesterol ester lipid droplets</b> — the substrate for steroidogenesis."))
story.append(bul("Cells arranged in <b>long parallel cords (fascicles)</b> radiating from medulla outward."))
story.append(bul("Sinusoidal capillaries run between the cords, facilitating hormone secretion."))
story.append(bul("Large, pale-staining cells with round euchromatic nuclei."))
story.append(sp(3))

story.append(Paragraph("3.5  Zona Reticularis – Detailed Histology", h2))
story.append(bul("Cells form an <b>anastomosing network of cords</b> (reticular = net-like pattern)."))
story.append(bul("Cells are <b>compact with eosinophilic (acidophilic) cytoplasm</b> — lipid-poor."))
story.append(bul("Nuclei are slightly smaller and darker than in zona fasciculata."))
story.append(bul("Irregular, polygonal cells with prominent vascular sinusoids interspersed."))
story.append(bul("Contains <b>17,20-lyase (CYP17A1)</b> at high activity — produces DHEA and androstenedione."))
story.append(sp(3))

story.append(Paragraph("3.6  Adrenal Medulla – Detailed Histology", h2))
story.append(Paragraph(
    "The medulla is composed of <b>chromaffin cells (pheochromocytes)</b> of neural crest origin, "
    "arranged in cords, clusters, and nests supported by a rich sinusoidal vascular network.",
    body))
story.append(bul("Cells: large, polygonal, with <b>abundant granular eosinophilic cytoplasm</b>."))
story.append(bul("Cytoplasmic granules contain stored catecholamines (epinephrine and norepinephrine)."))
story.append(bul("<b>Chromaffin reaction</b>: Cells stain yellow-brown with chrome salts due to oxidation of catecholamines."))
story.append(bul("<b>Two cell populations:</b>"))
story.append(Paragraph("&nbsp;&nbsp;&nbsp;&nbsp;&bull; <b>Epinephrine-secreting cells</b> (~80%): "
                        "lighter staining, smaller granules; contain PNMT enzyme.", body))
story.append(Paragraph("&nbsp;&nbsp;&nbsp;&nbsp;&bull; <b>Norepinephrine-secreting cells</b> (~20%): "
                        "darker staining, denser, larger granules.", body))
story.append(bul("<b>Sustentacular (supporting) cells</b>: peripheral, spindle-shaped; S-100 positive."))
story.append(bul("Medullary sinusoids are large and fenestrated, enabling rapid catecholamine release."))
story.append(sp(4))

story.append(InfoBox([
    Paragraph("<b>Histological Mnemonics</b>", key_point),
    Paragraph(
        '<b>"Salt, Sugar, Sex"</b> (outer → inner): Glomerulosa (salt = aldosterone), '
        'Fasciculata (sugar = cortisol), Reticularis (sex = androgens).<br/>'
        '<b>"GFR"</b> matches kidney GFR — both involve filtration/regulation of electrolytes and fluids.<br/>'
        '<b>Spongiocytes</b> = Zona fasciculata (spongey = lipid-rich = cortisol factory).<br/>'
        '<b>Chromaffin cells</b> = medulla (chrome staining = catecholamines).',
        note_box),
], bg=YELLOW_LT, border=colors.HexColor("#ca8a04")))
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# CHAPTER 4 – PHYSIOLOGY: CORTEX
# ══════════════════════════════════════════════════════════════════════════════
story.append(Banner("CHAPTER 4  ·  PHYSIOLOGY — ADRENAL CORTEX", bg=TEAL))
story.append(sp(6))

story.append(Paragraph("4.1  Steroidogenesis – Shared Pathway", h1))
story.append(Paragraph(
    "All adrenocortical hormones are <b>steroid hormones</b> derived from cholesterol (a 27-carbon molecule). "
    "The rate-limiting step is the transfer of cholesterol into the inner mitochondrial membrane by "
    "<b>StAR protein (Steroidogenic Acute Regulatory protein)</b>, stimulated by ACTH. "
    "The shared precursor is <b>pregnenolone</b>.",
    body))
story.append(bul("<b>Glucocorticoids (cortisol)</b>: 21-carbon steroids; hydroxyl groups at C11, C17, C21."))
story.append(bul("<b>Mineralocorticoids (aldosterone)</b>: 21-carbon steroids; aldehyde at C18; lacks 17-OH."))
story.append(bul("<b>Androgens (DHEA)</b>: 19-carbon steroids; ketone at C17; lack C20–C21 side chain."))
story.append(sp(6))

story.append(Paragraph("4.2  Cortisol (Glucocorticoid)", h1))
story.append(Paragraph("4.2.1  Regulation – HPA Axis", h2))
story.append(bul("<b>CRH</b> (41 amino acids) secreted by paraventricular nuclei of hypothalamus → "
                 "travels in hypothalamic-hypophysial portal blood → acts on corticotrophs via "
                 "adenylyl cyclase/cAMP."))
story.append(bul("<b>ACTH</b> from anterior pituitary corticotrophs → acts on zona fasciculata/reticularis:"))
story.append(Paragraph("&nbsp;&nbsp;&nbsp;&nbsp;&bull; <b>Immediate:</b> Activates cholesterol desmolase; "
                        "transfers cholesterol to mitochondria; stimulates StAR.", body))
story.append(Paragraph("&nbsp;&nbsp;&nbsp;&nbsp;&bull; <b>Long-term:</b> Upregulates CYP450 genes, "
                        "adrenodoxin, and ACTH receptors.", body))
story.append(Paragraph("&nbsp;&nbsp;&nbsp;&nbsp;&bull; <b>Chronic elevated ACTH:</b> Hypertrophy and "
                        "hyperplasia of cortical cells (via IGF-2).", body))
story.append(bul("<b>Negative feedback:</b> Cortisol inhibits (1) CRH from hypothalamus, "
                 "(2) ACTH synthesis and secretion from pituitary, (3) ACTH gene transcription."))
story.append(bul("<b>Diurnal rhythm:</b> Peak ~8 AM (just before awakening); nadir ~midnight. "
                 "~10 pulsatile secretory bursts per 24 hours. Abolished by coma, blindness, or constant light/dark."))
story.append(sp(4))

story.append(Paragraph("4.2.2  Transport in Blood", h2))
story.append(bul("75–80%: bound to <b>corticosteroid-binding globulin (CBG / transcortin)</b>"))
story.append(bul("~15%: loosely bound to albumin"))
story.append(bul("~5%: <b>free (biologically active)</b> form"))
story.append(bul("Half-life in plasma: ~60–90 minutes"))
story.append(sp(4))

story.append(Paragraph("4.2.3  Actions of Cortisol", h2))
act_data = [
    ["System / Tissue", "Effect of Cortisol", "Net Result"],
    ["Carbohydrate\nmetabolism", "↑ Gluconeogenesis (liver)\n↓ Peripheral glucose uptake\n↑ Glycogen synthesis", "Hyperglycaemia (diabetogenic)"],
    ["Protein\nmetabolism", "↑ Protein catabolism in muscle/skin/bone\n↑ Amino acid mobilisation → liver", "Muscle wasting, thin skin, poor wound healing"],
    ["Fat metabolism", "↑ Lipolysis in extremities\nRedistributes fat centrally", "Thin arms/legs; central obesity, moon face, buffalo hump"],
    ["Immune system", "↓ Cytokines (IL-1, IL-2, TNF-α)\n↓ Lymphocytes, eosinophils\nStabilises lysosomal membranes", "Anti-inflammatory, immunosuppressive"],
    ["Bone", "↓ Osteoblast activity\n↓ Intestinal Ca²⁺ absorption\n↑ Renal Ca²⁺ excretion", "Osteoporosis with chronic excess"],
    ["Cardiovascular", "↑ Vascular reactivity (upregulates α1 adrenoceptors)\nWeak mineralocorticoid effect", "Hypertension in excess"],
    ["Kidney", "Weak mineralocorticoid activity\n(inactivated by 11β-HSD2 in collecting duct)", "Mild Na⁺ retention, K⁺ loss"],
    ["CNS", "Affects mood, cognition, sleep", "Euphoria/psychosis in excess; depression in deficiency"],
    ["Fetal lung", "↑ Surfactant synthesis by type II pneumocytes", "Lung maturation before birth"],
    ["GI tract", "↑ Gastric acid secretion\n↓ Mucosal cell turnover", "Peptic ulcer risk"],
    ["Haematology", "↑ RBC, platelets, neutrophils\n↓ Lymphocytes, eosinophils, basophils", "Leukocytosis on blood count"],
]
story.append(make_table(act_data, col_widths=[3.5*cm, 7*cm, 5.5*cm], header_bg=TEAL, font_size=8.5))
story.append(sp(8))
story.append(PageBreak())

# ── Aldosterone ───────────────────────────────────────────────────────────────
story.append(Paragraph("4.3  Aldosterone (Mineralocorticoid)", h1))
story.append(Paragraph("4.3.1  Regulation – RAAS", h2))
story.append(Paragraph(
    "Aldosterone secretion is primarily regulated by the <b>Renin-Angiotensin-Aldosterone System (RAAS)</b> "
    "and by plasma <b>potassium (K⁺) levels</b>. ACTH plays only a minor role.",
    body))

raas_data = [
    ["Step", "Location", "Event"],
    ["1", "Kidney juxtaglomerular (JG) cells", "↓ BP / ↓ Na⁺ / β1 stimulation → release Renin"],
    ["2", "Liver", "Renin cleaves angiotensinogen → Angiotensin I (10 AA)"],
    ["3", "Pulmonary endothelium", "ACE converts Angiotensin I → Angiotensin II (8 AA)"],
    ["4", "Adrenal zona glomerulosa", "Angiotensin II (+ hyperkalaemia) → Aldosterone secretion"],
    ["5", "Kidney (late DCT, collecting duct)", "Aldosterone binds intracellular MR → ↑ ENaC & Na⁺/K⁺-ATPase"],
    ["6", "Systemic", "↑ Na⁺ & water retention → ↑ BP → ↓ Renin (negative feedback)"],
]
story.append(make_table(raas_data, col_widths=[1.2*cm, 5.5*cm, 9.8*cm], header_bg=TEAL, font_size=9))
story.append(sp(5))

story.append(Paragraph("4.3.2  Actions of Aldosterone", h2))
story.append(bul("<b>Principal cells of late distal tubule and collecting duct:</b>"))
story.append(Paragraph("&nbsp;&nbsp;&nbsp;&nbsp;&bull; ↑ Na⁺ reabsorption via ENaC (epithelial Na⁺ channels) → "
                        "water retention → volume expansion → hypertension.", body))
story.append(Paragraph("&nbsp;&nbsp;&nbsp;&nbsp;&bull; ↑ K⁺ secretion via ROMK channels → "
                        "hypokalaemia in excess.", body))
story.append(Paragraph("&nbsp;&nbsp;&nbsp;&nbsp;&bull; ↑ H⁺ secretion via H⁺-ATPase → "
                        "metabolic alkalosis in excess.", body))
story.append(bul("<b>Secondary sites:</b> Salivary glands, sweat glands, colon (reduces Na⁺ losses)."))
story.append(sp(4))

story.append(Paragraph("4.3.3  Why Cortisol Does NOT Act as a Mineralocorticoid (Normally)", h2))
story.append(InfoBox([
    Paragraph("<b>The 11β-HSD2 'Protection' Mechanism</b>", key_point),
    Paragraph(
        "Mineralocorticoid receptors (MR) bind cortisol with equal affinity as aldosterone. Since circulating "
        "cortisol levels are ~100-1000× higher than aldosterone, cortisol would otherwise dominate MRs. "
        "Renal tubular cells solve this by expressing <b>11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2)</b>, "
        "which converts cortisol → cortisone (inactive at MR). This 'protects' MRs for aldosterone. "
        "<b>Clinical consequence:</b> Inhibition of 11β-HSD2 (e.g. by liquorice/carbenoxolone or "
        "in apparent mineralocorticoid excess syndrome) allows cortisol to activate MRs → "
        "hypertension + hypokalaemia even though aldosterone levels are low.",
        note_box),
], bg=TEAL_LIGHT, border=TEAL))
story.append(sp(6))

story.append(Paragraph("4.4  Adrenal Androgens", h1))
story.append(Paragraph(
    "The adrenal zona reticularis produces <b>DHEA (dehydroepiandrosterone)</b>, "
    "<b>DHEAS (sulphated form)</b>, and <b>androstenedione</b> — all weak androgens that are "
    "converted peripherally to testosterone and oestrogens.",
    body))
story.append(bul("Regulated by ACTH (parallel diurnal variation to cortisol)."))
story.append(bul("DHEAS circulates at much higher concentrations than DHEA (half-life ~10 hours vs ~20 min) "
                 "and shows no diurnal variation."))
story.append(bul("<b>In males:</b> Minor role — testicular testosterone synthesis far exceeds adrenal contribution."))
story.append(bul("<b>In females:</b> Adrenal androgens are the <b>primary androgen source</b> — responsible for "
                 "pubic/axillary hair development and libido."))
story.append(bul("<b>Excess:</b> Virilisation in females; early pubic/axillary hair; suppresses gonadal function. "
                 "↑ Urinary 17-ketosteroids."))
story.append(sp(4))

story.append(Paragraph("4.5  Steroid Hormone Receptor Mechanism", h1))
story.append(Paragraph(
    "Steroid hormones are <b>lipid-soluble</b> — they diffuse across the cell membrane and bind to "
    "<b>intracellular (cytoplasmic or nuclear) receptors</b>. The hormone-receptor complex then acts as a "
    "transcription factor, binding hormone-response elements (HREs) in DNA to modulate gene expression. "
    "This mechanism has a <b>delayed onset (hours)</b> but <b>prolonged duration</b> compared with peptide hormones.",
    body))
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# CHAPTER 5 – PHYSIOLOGY: MEDULLA
# ══════════════════════════════════════════════════════════════════════════════
story.append(Banner("CHAPTER 5  ·  PHYSIOLOGY — ADRENAL MEDULLA", bg=colors.HexColor("#92400e")))
story.append(sp(6))

story.append(Paragraph("5.1  Catecholamine Synthesis Pathway", h1))
story.append(Paragraph(
    "Catecholamines are synthesised from the amino acid <b>tyrosine</b> in a four-step pathway within "
    "chromaffin cell cytoplasm and vesicles. <b>PNMT (phenylethanolamine-N-methyltransferase)</b>, "
    "the enzyme converting norepinephrine → epinephrine, requires <b>high local cortisol concentrations</b> — "
    "delivered via the portal blood from the adrenal cortex. This explains why the medulla is surrounded "
    "by cortex: cortisol is needed to maintain full epinephrine synthesis.",
    body))

syn_data = [
    ["Step", "Substrate", "Enzyme", "Product", "Location"],
    ["1", "Tyrosine", "Tyrosine hydroxylase (rate-limiting)", "DOPA (L-DOPA)", "Cytoplasm"],
    ["2", "DOPA", "DOPA decarboxylase (AAAD)", "Dopamine", "Cytoplasm"],
    ["3", "Dopamine", "Dopamine β-hydroxylase (DBH)", "Norepinephrine", "Secretory vesicle"],
    ["4 (medulla only)", "Norepinephrine", "PNMT (requires cortisol)", "Epinephrine", "Cytoplasm"],
]
story.append(make_table(syn_data, col_widths=[3*cm, 3*cm, 5*cm, 3.5*cm, 2.5*cm],
    header_bg=colors.HexColor("#92400e"), font_size=9))
story.append(sp(5))

story.append(Paragraph("5.2  Secretion & Storage", h1))
story.append(bul("Catecholamines are stored in <b>chromaffin granules</b> complexed with ATP and chromogranins."))
story.append(bul("Released by <b>exocytosis</b> triggered by preganglionic ACh acting on nicotinic receptors."))
story.append(bul("Medulla secretes: ~<b>80% epinephrine, ~20% norepinephrine</b>."))
story.append(bul("Plasma half-life: ~2 minutes (rapidly inactivated)."))
story.append(sp(4))

story.append(Paragraph("5.3  Catecholamine Receptors & Actions", h1))
cat_data = [
    ["Receptor", "Location", "Mediator", "Effect"],
    ["α1", "Skin, viscera, arterioles", "Both (NE>Epi)", "Vasoconstriction, ↑ peripheral resistance"],
    ["α2", "Presynaptic nerve terminals, GI", "NE", "↓ NE release (feedback), ↓ GI motility"],
    ["β1", "Heart, JG cells (kidney)", "Both (Epi=NE)", "↑ Heart rate, ↑ contractility, ↑ renin"],
    ["β2", "Bronchi, skeletal muscle vessels", "Epi > NE", "Bronchodilation, vasodilation, glycogenolysis"],
    ["β3", "Adipose tissue, bladder", "NE > Epi", "Lipolysis, bladder relaxation"],
]
story.append(make_table(cat_data, col_widths=[2.5*cm, 4.5*cm, 3.5*cm, 7*cm],
    header_bg=colors.HexColor("#92400e"), font_size=9))
story.append(sp(5))

story.append(Paragraph("5.4  Physiological Role (Fight-or-Flight Response)", h1))
ff_data = [
    ["System", "Response", "Purpose"],
    ["Heart", "↑ Rate, ↑ force (β1)", "↑ Cardiac output"],
    ["Vasculature", "Vasoconstriction skin/viscera (α1); vasodilation muscle (β2)", "Blood redirected to muscle"],
    ["Lungs", "Bronchodilation (β2)", "↑ O₂ delivery"],
    ["Liver/muscle", "Glycogenolysis (β2/β1)", "↑ Blood glucose for energy"],
    ["Adipose", "Lipolysis (β3/β1)", "↑ Free fatty acids for energy"],
    ["Pupils", "Dilation (α1 radial muscle)", "↑ Visual field"],
    ["GI tract", "↓ Motility, sphincter contraction (α)", "Redirect blood flow"],
    ["Bladder", "Sphincter contraction (α1), detrusor relaxation (β2)", "Retain urine"],
    ["Sweat glands", "↑ Sweating (cholinergic despite sympathetic)", "Thermoregulation"],
]
story.append(make_table(ff_data, col_widths=[3.5*cm, 8*cm, 5*cm],
    header_bg=colors.HexColor("#92400e"), font_size=9))
story.append(sp(5))

story.append(Paragraph("5.5  Catecholamine Metabolism", h1))
story.append(bul("<b>MAO (monoamine oxidase)</b>: Intraneuronal; degrades free cytoplasmic catecholamines."))
story.append(bul("<b>COMT (catechol-O-methyltransferase)</b>: Extraneuronal; methylates catecholamines."))
story.append(bul("<b>End metabolites:</b>"))
story.append(Paragraph("&nbsp;&nbsp;&nbsp;&nbsp;&bull; Epinephrine → <b>Metanephrine</b> (COMT) → VMA", body))
story.append(Paragraph("&nbsp;&nbsp;&nbsp;&nbsp;&bull; Norepinephrine → <b>Normetanephrine</b> (COMT) → VMA", body))
story.append(Paragraph("&nbsp;&nbsp;&nbsp;&nbsp;&bull; Both → <b>VMA (Vanillylmandelic acid)</b> (final urine metabolite)", body))
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# CHAPTER 6 – APPLIED ANATOMY & PHYSIOLOGY
# ══════════════════════════════════════════════════════════════════════════════
story.append(Banner("CHAPTER 6  ·  APPLIED ANATOMY & CLINICAL PHYSIOLOGY", bg=RED))
story.append(sp(6))

story.append(Paragraph("6.1  Cushing's Syndrome vs Cushing's Disease", h1))
cush_data = [
    ["Feature", "Cushing's SYNDROME (Primary)", "Cushing's DISEASE (Pituitary)"],
    ["Cause", "Autonomous cortisol-secreting adrenal adenoma/carcinoma or ectopic ACTH", "ACTH-secreting pituitary microadenoma"],
    ["Primary defect", "Adrenal cortex", "Anterior pituitary"],
    ["ACTH levels", "↓ LOW (suppressed by high cortisol)", "↑ HIGH"],
    ["Clinical features", "Shared: central obesity, moon face, buffalo hump, striae, muscle wasting, osteoporosis, hypertension, hyperglycaemia, poor wound healing", "Same + hyperpigmentation if ACTH very high"],
    ["Dexamethasone\nsuppression test", "NOT suppressed by either low- or\nhigh-dose dexamethasone (autonomous)", "Suppressed by HIGH-dose; not by low-dose"],
    ["Treatment", "Ketoconazole / metyrapone (block synthesis);\nif failed: bilateral adrenalectomy + replacement", "Transsphenoidal pituitary adenoma resection"],
]
story.append(make_table(cush_data, col_widths=[4*cm, 6.5*cm, 6*cm], header_bg=RED, font_size=8.5))
story.append(sp(6))

story.append(Paragraph("6.2  Conn's Syndrome (Primary Hyperaldosteronism)", h1))
story.append(bul("<b>Cause:</b> Aldosterone-secreting adrenal adenoma (or bilateral adrenal hyperplasia)."))
story.append(bul("<b>Hallmarks (explain by physiology):</b>"))
story.append(Paragraph("&nbsp;&nbsp;&nbsp;&nbsp;&bull; <b>Hypertension</b> — ↑ Na⁺ retention → ↑ ECF volume.", body))
story.append(Paragraph("&nbsp;&nbsp;&nbsp;&nbsp;&bull; <b>Hypokalaemia</b> — ↑ K⁺ secretion at collecting duct.", body))
story.append(Paragraph("&nbsp;&nbsp;&nbsp;&nbsp;&bull; <b>Metabolic alkalosis</b> — ↑ H⁺ secretion.", body))
story.append(Paragraph("&nbsp;&nbsp;&nbsp;&nbsp;&bull; <b>Low plasma renin</b> — volume expansion suppresses JG cell renin release.", body))
story.append(bul("<b>Diagnosis:</b> Elevated aldosterone : renin ratio (ARR). Confirmed by CT adrenals ± adrenal vein sampling."))
story.append(bul("<b>Treatment:</b> Spironolactone (MR antagonist) or eplerenone; unilateral adrenalectomy for adenoma."))
story.append(sp(5))

story.append(Paragraph("6.3  Addison's Disease (Primary Adrenal Insufficiency)", h1))
add_data = [
    ["Feature", "Details"],
    ["Cause", "Autoimmune adrenalitis (most common in developed world); TB (most common globally); haemorrhage; metastasis; fungal infection"],
    ["Deficiencies", "Cortisol + Aldosterone + Androgens (all three cortical zones affected)"],
    ["Symptoms", "Fatigue, weakness, weight loss, anorexia, nausea, vomiting, diarrhoea, abdominal pain, postural dizziness"],
    ["Signs", "Hypotension, hyperpigmentation (buccal mucosa, palmar creases, scars — due to ↑ ACTH/MSH), dehydration"],
    ["Electrolytes", "↓ Na⁺ (hyponatraemia), ↑ K⁺ (hyperkalaemia), ↓ glucose (hypoglycaemia), metabolic acidosis"],
    ["Diagnosis", "8 AM serum cortisol; ACTH stimulation test (cosyntropin); ↑ plasma ACTH; anti-21-hydroxylase antibodies"],
    ["Addisonian crisis", "Precipitated by illness/surgery/trauma; severe hypotension, shock, fever, vomiting; treat with IV hydrocortisone + saline + dextrose IMMEDIATELY"],
    ["Treatment", "Hydrocortisone (glucocorticoid replacement) + fludrocortisone (mineralocorticoid replacement); double dose during illness ('sick day rules')"],
]
story.append(make_table(add_data, col_widths=[4.5*cm, 12*cm], header_bg=RED, font_size=9))
story.append(sp(6))

story.append(Paragraph("6.4  Congenital Adrenal Hyperplasia (CAH)", h1))
story.append(Paragraph(
    "<b>Most common cause (>90%):</b> 21-hydroxylase (CYP21A2) deficiency. "
    "Without this enzyme, the pathway to cortisol and aldosterone is blocked; "
    "precursors (17-hydroxyprogesterone) are shunted into the androgen synthesis pathway. "
    "Low cortisol causes chronic ACTH elevation → bilateral adrenal hyperplasia.",
    body))

cah_data = [
    ["Form", "Enzyme", "Aldosterone", "Cortisol", "Androgens", "Clinical Presentation"],
    ["Salt-wasting CAH\n(most severe)", "21-hydroxylase\n(CYP21A2)", "↓↓", "↓↓", "↑↑", "Neonatal crisis: vomiting, dehydration, shock, hyperkalaemia, hyponatraemia. Ambiguous genitalia (46XX females)."],
    ["Simple virilising CAH", "21-hydroxylase\n(CYP21A2)", "Normal/low", "↓", "↑↑", "Virilisation in females; precocious puberty in males. No salt-wasting crisis."],
    ["11β-Hydroxylase\ndeficiency", "CYP11B1", "Low\n(but 11-DOC↑)", "↓", "↑", "Virilisation + HYPERTENSION (↑ deoxycorticosterone has mineralocorticoid activity)."],
    ["17α-Hydroxylase\ndeficiency", "CYP17A1", "↑", "↓", "↓↓", "Hypertension, hypokalaemia; sexual infantilism (↓ sex steroids); primary amenorrhoea in females."],
]
story.append(make_table(cah_data, col_widths=[2.8*cm, 2.8*cm, 2*cm, 2*cm, 2*cm, 6.9*cm],
    header_bg=RED, font_size=8.5))
story.append(sp(6))
story.append(PageBreak())

story.append(Paragraph("6.5  Phaeochromocytoma", h1))
story.append(InfoBox([
    Paragraph('<b>Rule of 10s for Phaeochromocytoma</b>', key_point),
    bul("10% bilateral"),
    bul("10% malignant"),
    bul("10% extraadrenal (paraganglioma — most commonly organ of Zuckerkandl near aortic bifurcation)"),
    bul("10% paediatric"),
    bul("10% familial (MEN 2A, MEN 2B, von Hippel-Lindau, NF-1, SDH mutations)"),
], bg=ORANGE_LT, border=ORANGE))
story.append(sp(4))

pheo_data = [
    ["Feature", "Details"],
    ["Symptoms", "Classic triad: episodic headache + palpitations + diaphoresis. Paroxysmal or sustained hypertension, pallor, anxiety, tremor"],
    ["Biochemical\ndiagnosis", "Plasma/urine metanephrines (most sensitive + specific). Urine VMA and catecholamines. 24-hour urine collection."],
    ["Imaging", "CT/MRI abdomen (adrenals + paraganglia). ¹²³I-MIBG scan for localisation of metastatic/extraadrenal disease. ⁶⁸Ga-DOTATATE PET for SDH-related tumours."],
    ["Histology", "Chromaffin cells in Zellballen (nest/alveolar) pattern with sustentacular cells at periphery (S-100+). Pleomorphism does not = malignancy; only metastasis confirms malignancy."],
    ["Surgical\npreparation", "α-blocker (phenoxybenzamine 10–14 days pre-op) FIRST → then β-blocker if needed. NEVER start β-blocker first (unopposed α → hypertensive crisis). IV fluids to expand volume post-α blockade."],
    ["Anaesthetic risks", "Hypertensive crisis on induction/tumour manipulation; hypotension after tumour removal (volume depletion). Treat crisis with phentolamine or nitroprusside IV."],
    ["Treatment", "Laparoscopic adrenalectomy (gold standard). Bilateral: cortex-sparing surgery to avoid lifelong steroid replacement."],
]
story.append(make_table(pheo_data, col_widths=[4*cm, 12.5*cm], header_bg=RED, font_size=9))
story.append(sp(6))

story.append(Paragraph("6.6  Waterhouse-Friderichsen Syndrome", h1))
story.append(bul("<b>Definition:</b> Bilateral adrenal haemorrhage causing acute adrenal crisis."))
story.append(bul("<b>Classic cause:</b> Meningococcal septicaemia (<i>Neisseria meningitidis</i>). Also: Pseudomonas, pneumococcus, DIC."))
story.append(bul("<b>Pathology:</b> Massive bilateral adrenal infarction/haemorrhage → acute loss of all cortical and medullary hormones."))
story.append(bul("<b>Clinical features:</b> High fever, purpuric/petechial rash, shock, DIC, rapid deterioration."))
story.append(bul("<b>Treatment:</b> Immediate IV hydrocortisone + fluid resuscitation + antibiotics. High mortality."))
story.append(sp(5))

story.append(Paragraph("6.7  Adrenal Incidentaloma", h1))
story.append(Paragraph(
    "An adrenal incidentaloma is an adrenal mass ≥1 cm discovered incidentally on imaging "
    "performed for a non-adrenal indication. Prevalence increases with age (~5% of CT scans in adults >50).",
    body))
story.append(bul("<b>Workup:</b> Hormonal screening (overnight 1 mg dexamethasone suppression test; "
                 "plasma/urine metanephrines; plasma aldosterone:renin ratio if hypertensive; DHEAS)."))
story.append(bul("<b>Radiology clues:</b> Lipid-rich adenoma: &lt;10 HU on non-contrast CT. "
                 "Lipid-poor / indeterminate: >10 HU; washout characteristics used."))
story.append(bul("<b>Surgical indications:</b> Functional tumours; size >4 cm; growth on follow-up."))
story.append(sp(5))

story.append(Paragraph("6.8  Neuroblastoma", h1))
story.append(bul("<b>Definition:</b> Malignant tumour of neural crest origin arising from adrenal medulla or sympathetic chain."))
story.append(bul("<b>Epidemiology:</b> Most common extracranial solid tumour of childhood; median age 17–19 months."))
story.append(bul("<b>Biochemical markers:</b> ↑ urine VMA (vanillylmandelic acid) and HVA (homovanillic acid)."))
story.append(bul("<b>Histology:</b> Small round blue cells; Homer-Wright pseudorosettes; differentiating forms show ganglion cells."))
story.append(bul("<b>MYCN amplification:</b> Poor prognostic marker."))
story.append(bul("<b>Presentation:</b> Abdominal mass crossing midline, raccoon eyes (periorbital ecchymosis), proptosis, bone pain, Horner's syndrome."))
story.append(sp(5))

story.append(Paragraph("6.9  Critical Illness-Related Corticosteroid Insufficiency (CIRCI)", h1))
story.append(Paragraph(
    "CIRCI describes disruption of the HPA axis during critical illness (sepsis, major trauma, burns, "
    "pancreatitis, hepatic failure) resulting in relative glucocorticoid deficiency and exaggerated "
    "systemic inflammation.",
    body))
story.append(bul("Presents as vasopressor-dependent hypotension in ICU patients."))
story.append(bul("Classic Addisonian markers (hyperpigmentation, hyperkalaemia) typically absent."))
story.append(bul("Cosyntropin (ACTH) stimulation test: utility in ICU is controversial."))
story.append(bul("Current Surviving Sepsis Guidelines (2021): do NOT recommend stimulation testing to guide steroid use; "
                 "recommend hydrocortisone 200 mg/day IV if vasopressors not weaned within first days."))
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# CHAPTER 7 – SUMMARY TABLES & QUICK REVIEW
# ══════════════════════════════════════════════════════════════════════════════
story.append(Banner("CHAPTER 7  ·  SUMMARY TABLES & QUICK REVIEW", bg=colors.HexColor("#475569")))
story.append(sp(6))

story.append(Paragraph("7.1  Hormones at a Glance", h1))
hor_data = [
    ["Hormone", "Zone/Source", "Regulator", "Receptor", "Key Actions", "Excess Syndrome", "Deficiency Syndrome"],
    ["Cortisol", "Zona fasciculata", "ACTH (HPA axis); diurnal", "Intracellular GR", "Gluconeogenesis; anti-inflammatory; lipolysis; protein catabolism", "Cushing's syndrome/disease", "Addison's disease; adrenal crisis"],
    ["Aldosterone", "Zona glomerulosa", "Angiotensin II; K⁺; minor ACTH", "Intracellular MR", "↑ Na⁺ reabsorption; ↑ K⁺ & H⁺ secretion", "Conn's syndrome (1° hyperaldosteronism)", "Addison's disease; hyperkalaemia, hyponatraemia"],
    ["DHEA / DHEAS", "Zona reticularis", "ACTH", "Intracellular AR (peripheral)", "Weak androgen; pubic/axillary hair; libido (female)", "CAH; adrenogenital syndrome (virilisation)", "Loss of pubic/axillary hair; ↓ libido (female)"],
    ["Epinephrine (~80%)", "Adrenal medulla", "Preganglionic ACh; stress", "α & β adrenoceptors", "↑ HR/CO; bronchodilation; glycogenolysis; vasodilation muscle", "Phaeochromocytoma", "Impaired stress response"],
    ["Norepinephrine (~20%)", "Adrenal medulla", "Preganglionic ACh; stress", "α > β adrenoceptors", "Vasoconstriction; ↑ BP (mainly diastolic); little HR effect alone", "Phaeochromocytoma", "—"],
]
story.append(make_table(hor_data, col_widths=[2.5*cm, 2.5*cm, 2.5*cm, 2.3*cm, 4*cm, 2.8*cm, 2.9*cm],
    header_bg=colors.HexColor("#475569"), font_size=7.5))
story.append(sp(6))

story.append(Paragraph("7.2  Clinical Electrolyte Patterns in Adrenal Disorders", h1))
elec_data = [
    ["Disorder", "Na⁺", "K⁺", "HCO₃⁻ (acid-base)", "Glucose", "BP"],
    ["Conn's syndrome", "↑ (normal–high)", "↓↓", "↑ (alkalosis)", "Normal", "↑↑ Hypertension"],
    ["Addison's disease", "↓↓", "↑↑", "↓ (acidosis)", "↓ (fasting)", "↓ Hypotension"],
    ["Cushing's syndrome", "↑ (mild)", "↓ (mild)", "↑ (mild alkalosis)", "↑↑ Hyperglycaemia", "↑ Hypertension"],
    ["CAH – 21-OH def (salt-wasting)", "↓↓", "↑↑", "↓ (acidosis)", "↓", "↓ Hypotension/shock"],
    ["CAH – 11β-OH def", "↑", "↓", "↑ (alkalosis)", "↓", "↑↑ Hypertension"],
    ["Phaeochromocytoma", "Normal", "Normal", "Normal", "↑ (catecholamine)", "↑↑ Paroxysmal hypertension"],
]
story.append(make_table(elec_data, col_widths=[4*cm, 2*cm, 2*cm, 3.5*cm, 2.8*cm, 3.2*cm],
    header_bg=colors.HexColor("#475569"), font_size=9))
story.append(sp(6))

story.append(Paragraph("7.3  High-Yield Mnemonics", h1))
mn_data = [
    [Paragraph("<b>Mnemonic</b>", body_b), Paragraph("<b>Meaning</b>", body_b)],
    ["GFR (outer→inner cortex)", "Glomerulosa (salt/aldosterone) → Fasciculata (sugar/cortisol) → Reticularis (sex/androgens)"],
    ["Salt, Sugar, Sex", "Same as above — aldosterone, cortisol, androgens"],
    ["Spongiocytes", "Zona Fasciculata — foamy lipid-rich cytoplasm = cortisol factory"],
    ["Rule of 10s", "Phaeochromocytoma: 10% bilateral / malignant / extraadrenal / paediatric / familial"],
    ["α before β", "Phaeochromocytoma surgery: give α-blocker FIRST, then β-blocker"],
    ["ACTH-independent aldosterone", "Zona glomerulosa is NOT regulated by ACTH (regulated by Ang II + K⁺)"],
    ["Waterhouse-Friderichsen", "Bilateral adrenal haemorrhage → meningococcaemia → purpura + shock + adrenal crisis"],
    ["StAR = rate limiting", "Steroidogenic Acute Regulatory protein = rate-limiting step in steroidogenesis"],
    ["Cortisol diurnal peak", "Peak 8 AM, nadir midnight (like cortisol peaks before a 'morning rush')"],
    ["11β-HSD2 protects kidney MR", "Converts cortisol → cortisone in kidney → aldosterone can work without interference"],
    ["PNMT needs cortisol", "Medulla needs high cortisol (from cortical portal blood) to convert NE → Epi"],
]
story.append(make_table(mn_data, col_widths=[5.5*cm, 11*cm],
    header_bg=colors.HexColor("#475569"), font_size=9))
story.append(sp(6))

story.append(Paragraph("7.4  Key Laboratory Investigations", h1))
lab_data = [
    ["Test", "What it Measures", "Used For"],
    ["8 AM serum cortisol", "Baseline cortisol at diurnal peak", "Screen for adrenal insufficiency; if &lt;3 µg/dL = Addison's"],
    ["Overnight 1 mg DST (dexamethasone suppression test)", "Post-dex cortisol <1.8 µg/dL = normal suppression", "Screen for Cushing's syndrome"],
    ["High-dose DST (8 mg)", "Cortisol suppressed in Cushing's disease but not adrenal Cushing's", "Distinguish pituitary vs adrenal Cushing's"],
    ["24-h urine free cortisol", "Total daily cortisol production", "Confirm Cushing's syndrome"],
    ["Plasma ACTH", "Pituitary ACTH level", "↓ in primary adrenal disease; ↑ in Cushing's disease / Addison's"],
    ["ACTH stimulation test\n(cosyntropin/synacthen)", "Cortisol response at 30 & 60 min (normal >18 µg/dL)", "Diagnose primary/secondary adrenal insufficiency"],
    ["Aldosterone : Renin ratio (ARR)", "Autonomous aldosterone production", "Screen for Conn's syndrome"],
    ["Plasma/urine metanephrines", "Catecholamine metabolites", "Screen for phaeochromocytoma (high sensitivity)"],
    ["Urine VMA + HVA", "Catecholamine metabolites", "Screen for neuroblastoma in children"],
    ["17-hydroxyprogesterone (17-OHP)", "Precursor to cortisol (accumulates in 21-OH deficiency)", "Diagnose CAH (21-hydroxylase deficiency)"],
    ["24-h urine 17-ketosteroids", "Adrenal androgen metabolites", "↑ in CAH, adrenogenital syndrome, adrenal carcinoma"],
]
story.append(make_table(lab_data, col_widths=[5*cm, 5.5*cm, 6*cm],
    header_bg=colors.HexColor("#475569"), font_size=8.5))
story.append(sp(8))

# Footer references
story.append(hr(color=GRAY_MID))
story.append(Paragraph(
    "<b>Sources:</b> Costanzo Physiology 7e | Medical Physiology – Barrett | Langman's Medical Embryology | "
    "Histology: A Text and Atlas – Ross & Pawlina | Schwartz's Principles of Surgery 11e | "
    "Fischer's Mastery of Surgery 8e | Sabiston Textbook of Surgery | Morgan & Mikhail's Clinical Anaesthesiology 7e",
    small_it))

# ── BUILD ─────────────────────────────────────────────────────────────────────
def add_page_number(canvas, doc):
    canvas.saveState()
    canvas.setFont("Helvetica", 8)
    canvas.setFillColor(colors.HexColor("#9ca3af"))
    page_num = canvas.getPageNumber()
    canvas.drawRightString(A4[0] - 2*cm, 1.2*cm, f"Page {page_num}")
    canvas.drawString(2*cm, 1.2*cm, "Adrenal Gland — Complete Medical Reference  |  Orris")
    canvas.restoreState()

doc.build(story, onFirstPage=add_page_number, onLaterPages=add_page_number)
print("PDF created successfully!")