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

OUTPUT = "/home/daytona/workspace/biochem-notes/MBBS_Biochemistry_Short_Notes.pdf"

# ── Colour palette ────────────────────────────────────────────────────────────
DARK_BLUE   = HexColor("#1a3a5c")
MID_BLUE    = HexColor("#2e6da4")
LIGHT_BLUE  = HexColor("#d6e8f7")
ACCENT_GOLD = HexColor("#e8a020")
LIGHT_GOLD  = HexColor("#fff5e0")
WHITE       = colors.white
BLACK       = colors.black
GREY_TEXT   = HexColor("#333333")
TABLE_HDR   = HexColor("#1a3a5c")
TABLE_ALT   = HexColor("#eef4fb")
BOX_BG      = HexColor("#f0f7ff")
BOX_BORDER  = HexColor("#2e6da4")
HIGHLIGHT   = HexColor("#fff3cd")

doc = SimpleDocTemplate(
    OUTPUT,
    pagesize=A4,
    leftMargin=1.8*cm, rightMargin=1.8*cm,
    topMargin=2.2*cm,  bottomMargin=2.2*cm,
    title="MBBS Biochemistry Short Notes",
    author="Orris Medical Education",
)

W = A4[0] - 3.6*cm   # usable width

# ── Styles ────────────────────────────────────────────────────────────────────
base = getSampleStyleSheet()

def S(name, parent='Normal', **kw):
    return ParagraphStyle(name, parent=base[parent], **kw)

styles = {
    'cover_title': S('cover_title', fontSize=30, textColor=WHITE,
                     fontName='Helvetica-Bold', alignment=TA_CENTER, leading=36),
    'cover_sub':   S('cover_sub',   fontSize=15, textColor=LIGHT_BLUE,
                     fontName='Helvetica', alignment=TA_CENTER, leading=20),
    'cover_note':  S('cover_note',  fontSize=10, textColor=LIGHT_BLUE,
                     fontName='Helvetica', alignment=TA_CENTER, leading=14),
    'topic_num':   S('topic_num',   fontSize=9,  textColor=WHITE,
                     fontName='Helvetica-Bold', alignment=TA_CENTER),
    'h1':          S('h1', fontSize=15, textColor=WHITE,
                     fontName='Helvetica-Bold', leading=18, spaceAfter=2),
    'h2':          S('h2', fontSize=11, textColor=DARK_BLUE,
                     fontName='Helvetica-Bold', leading=14, spaceBefore=8, spaceAfter=3),
    'h3':          S('h3', fontSize=10, textColor=MID_BLUE,
                     fontName='Helvetica-Bold', leading=13, spaceBefore=5, spaceAfter=2),
    'body':        S('body', fontSize=9, textColor=GREY_TEXT,
                     fontName='Helvetica', leading=13, spaceAfter=3, alignment=TA_JUSTIFY),
    'bullet':      S('bullet', fontSize=9, textColor=GREY_TEXT,
                     fontName='Helvetica', leading=12, leftIndent=12,
                     firstLineIndent=-8, spaceAfter=2),
    'code':        S('code', fontSize=8, textColor=HexColor("#1a1a2e"),
                     fontName='Courier', leading=11, leftIndent=8, spaceAfter=4,
                     backColor=HexColor("#f5f5f5")),
    'key_point':   S('key_point', fontSize=9, textColor=HexColor("#7a4000"),
                     fontName='Helvetica-Bold', leading=12, leftIndent=8, spaceAfter=2),
    'th':          S('th', fontSize=8, textColor=WHITE,
                     fontName='Helvetica-Bold', leading=10, alignment=TA_CENTER),
    'td':          S('td', fontSize=8, textColor=GREY_TEXT,
                     fontName='Helvetica', leading=10),
    'tdc':         S('tdc', fontSize=8, textColor=GREY_TEXT,
                     fontName='Helvetica', leading=10, alignment=TA_CENTER),
    'footer':      S('footer', fontSize=7.5, textColor=HexColor("#888888"),
                     fontName='Helvetica', alignment=TA_CENTER),
}

# ── Helper builders ───────────────────────────────────────────────────────────
def hr(color=MID_BLUE, thickness=0.8):
    return HRFlowable(width="100%", thickness=thickness, color=color, spaceAfter=4, spaceBefore=2)

def sp(h=4):
    return Spacer(1, h)

def P(text, style='body'):
    return Paragraph(text, styles[style])

def B(text):
    return Paragraph(f"• {text}", styles['bullet'])

def box_table(rows, col_widths, header=True):
    """Styled table with header row."""
    data = []
    for i, row in enumerate(rows):
        if i == 0 and header:
            data.append([Paragraph(c, styles['th']) for c in row])
        else:
            styled = []
            for j, c in enumerate(row):
                styled.append(Paragraph(c, styles['td']))
            data.append(styled)

    ts = TableStyle([
        ('BACKGROUND',   (0,0), (-1,0),  TABLE_HDR),
        ('ROWBACKGROUNDS',(0,1),(-1,-1), [WHITE, TABLE_ALT]),
        ('GRID',         (0,0), (-1,-1), 0.4, HexColor("#cccccc")),
        ('VALIGN',       (0,0), (-1,-1), 'TOP'),
        ('LEFTPADDING',  (0,0), (-1,-1), 4),
        ('RIGHTPADDING', (0,0), (-1,-1), 4),
        ('TOPPADDING',   (0,0), (-1,-1), 3),
        ('BOTTOMPADDING',(0,0), (-1,-1), 3),
        ('ROUNDEDCORNERS', [3]),
    ])
    t = Table(data, colWidths=col_widths, repeatRows=1 if header else 0)
    t.setStyle(ts)
    return t

def topic_header(num, title):
    """Blue banner with topic number badge."""
    num_cell  = Paragraph(str(num), styles['topic_num'])
    title_cell = Paragraph(title, styles['h1'])
    t = Table([[num_cell, title_cell]], colWidths=[1.1*cm, W - 1.1*cm])
    t.setStyle(TableStyle([
        ('BACKGROUND',   (0,0), (-1,-1), DARK_BLUE),
        ('BACKGROUND',   (0,0), (0,0),   ACCENT_GOLD),
        ('VALIGN',       (0,0), (-1,-1), 'MIDDLE'),
        ('LEFTPADDING',  (0,0), (-1,-1), 6),
        ('RIGHTPADDING', (0,0), (-1,-1), 6),
        ('TOPPADDING',   (0,0), (-1,-1), 7),
        ('BOTTOMPADDING',(0,0), (-1,-1), 7),
        ('ROUNDEDCORNERS', [4]),
    ]))
    return t

def highlight_box(text):
    t = Table([[Paragraph(text, styles['key_point'])]], colWidths=[W])
    t.setStyle(TableStyle([
        ('BACKGROUND',   (0,0), (-1,-1), HIGHLIGHT),
        ('BOX',          (0,0), (-1,-1), 1, ACCENT_GOLD),
        ('LEFTPADDING',  (0,0), (-1,-1), 8),
        ('TOPPADDING',   (0,0), (-1,-1), 5),
        ('BOTTOMPADDING',(0,0), (-1,-1), 5),
    ]))
    return t

def info_box(text):
    t = Table([[Paragraph(text, styles['body'])]], colWidths=[W])
    t.setStyle(TableStyle([
        ('BACKGROUND',   (0,0), (-1,-1), BOX_BG),
        ('BOX',          (0,0), (-1,-1), 1.2, BOX_BORDER),
        ('LEFTPADDING',  (0,0), (-1,-1), 10),
        ('RIGHTPADDING', (0,0), (-1,-1), 10),
        ('TOPPADDING',   (0,0), (-1,-1), 6),
        ('BOTTOMPADDING',(0,0), (-1,-1), 6),
    ]))
    return t

def flow_box(lines):
    """Monospace flowchart box."""
    text = "<br/>".join(lines)
    t = Table([[Paragraph(text, styles['code'])]], colWidths=[W])
    t.setStyle(TableStyle([
        ('BACKGROUND',   (0,0), (-1,-1), HexColor("#f8f9fa")),
        ('BOX',          (0,0), (-1,-1), 1, HexColor("#aaaaaa")),
        ('LEFTPADDING',  (0,0), (-1,-1), 8),
        ('TOPPADDING',   (0,0), (-1,-1), 6),
        ('BOTTOMPADDING',(0,0), (-1,-1), 6),
    ]))
    return t

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

# ─── COVER PAGE ───────────────────────────────────────────────────────────────
cover_bg = Table(
    [[
        Paragraph("MBBS Biochemistry", styles['cover_title']),
        Paragraph("Short Notes", styles['cover_title']),
    ]],
    colWidths=[W]
)
# Use a coloured background table as cover
cover = Table([
    [Paragraph("<br/><br/>", styles['cover_sub'])],
    [Paragraph("MBBS Biochemistry", styles['cover_title'])],
    [Paragraph("Short Notes", styles['cover_title'])],
    [Paragraph(" ", styles['cover_sub'])],
    [Paragraph("11 High-Yield Topics for MBBS Examinations", styles['cover_sub'])],
    [Paragraph(" ", styles['cover_note'])],
    [Paragraph("G6PD Deficiency  •  Metabolic Acidosis  •  Diabetes Complications", styles['cover_note'])],
    [Paragraph("Protein Misfolding  •  Electrolyte Disorders  •  Acute Phase Proteins", styles['cover_note'])],
    [Paragraph("Serum Electrophoresis  •  IRDS  •  Jaundice  •  GSD  •  Enzyme Inhibitors", styles['cover_note'])],
    [Paragraph(" ", styles['cover_note'])],
    [Paragraph("Based on: Lippincott's Biochemistry • Robbins Pathology • Harper's Biochemistry", styles['cover_note'])],
    [Paragraph("Goldman-Cecil Medicine • Basic Medical Biochemistry", styles['cover_note'])],
    [Paragraph("<br/>", styles['cover_note'])],
], colWidths=[W])
cover.setStyle(TableStyle([
    ('BACKGROUND',   (0,0), (-1,-1), DARK_BLUE),
    ('ALIGN',        (0,0), (-1,-1), 'CENTER'),
    ('TOPPADDING',   (0,0), (-1,-1), 8),
    ('BOTTOMPADDING',(0,0), (-1,-1), 8),
    ('ROUNDEDCORNERS', [6]),
]))
story += [cover, PageBreak()]

# ─── TABLE OF CONTENTS ────────────────────────────────────────────────────────
story += [
    P("Table of Contents", 'h2'),
    hr(),
    sp(4),
]
toc_data = [["#", "Topic", "Page"]]
toc_items = [
    ("1", "G-6-PD Deficiency"),
    ("2", "Metabolic Acidosis"),
    ("3", "Complications of Diabetes Mellitus"),
    ("4", "Protein Misfolding and Associated Disorders"),
    ("5", "Hyperkalemia and Hypokalemia"),
    ("6", "Acute Phase Plasma Proteins"),
    ("7", "Serum Electrophoresis – Normal vs Abnormal"),
    ("8", "Infant Respiratory Distress Syndrome (IRDS)"),
    ("9", "Jaundice"),
    ("10", "Glycogen Storage Disorders"),
    ("11", "Clinical Significance of Competitive Inhibitors"),
]
for num, title in toc_items:
    toc_data.append([num, title, "—"])
story.append(box_table(toc_data, [1*cm, W-3.2*cm, 2.2*cm]))
story += [PageBreak()]

# ══════════════════════════════════════════════════════════════════════════════
# TOPIC 1 — G6PD DEFICIENCY
# ══════════════════════════════════════════════════════════════════════════════
story += [topic_header(1, "G-6-PD Deficiency (Glucose-6-Phosphate Dehydrogenase Deficiency)"), sp(6)]
story += [P("G6PD deficiency is the most common red cell enzyme disorder worldwide (~500 million affected). "
            "It is an <b>X-linked recessive</b> condition causing deficiency of G6PD, the rate-limiting enzyme of the "
            "<b>Hexose Monophosphate (HMP) shunt</b>, leading to episodic hemolytic anemia on oxidative stress.")]

story += [P("Biochemical Basis", 'h2')]
story.append(flow_box([
    "HMP SHUNT:", 
    "Glucose-6-P + NADP+  --[G6PD]-->  6-Phosphogluconate + NADPH",
    "",
    "NADPH reduces Glutathione: GSSG + NADPH  -->  2 GSH + NADP+",
    "GSH neutralises H2O2 and free radicals  -->  protects RBC membrane",
    "",
    "IN G6PD DEFICIENCY:",
    "  low NADPH  -->  low GSH  -->  oxidative stress not neutralised",
    "  --> Hb oxidised --> Methemoglobin --> Heinz bodies (precipitates)",
    "  --> rigid RBCs trapped in spleen  --> HEMOLYTIC ANAEMIA",
]))
story += [sp(4)]

story += [P("Genetics", 'h2'), B("X-linked recessive; males affected, females are carriers"),
          B("Common variants: G6PD-A- (African, mild); G6PD-Mediterranean (severe)")]

story += [P("Precipitants — PRIMA", 'h2')]
story.append(highlight_box("P – Primaquine, dapsone  |  R – Infections (most common)  |  I – Ingestion of fava beans  |  M – Metabolic acidosis  |  A – Aspirin, sulfonamides, nitrofurantoin"))
story += [sp(4)]

story += [P("Laboratory Findings", 'h2')]
story.append(box_table([
    ["Test", "Finding", "Significance"],
    ["Blood film", "Heinz bodies, bite cells, blister cells", "Oxidised Hb precipitates"],
    ["Hb / Haematocrit", "Decreased", "Haemolytic anaemia"],
    ["Reticulocytes", "Increased", "Regenerative response"],
    ["LDH / Indirect bilirubin", "Increased", "Haemolysis markers"],
    ["Fluorescent spot test", "No fluorescence (NADPH absent)", "Screening test"],
    ["G6PD enzyme assay", "Markedly reduced activity", "Confirmatory test"],
], [3.5*cm, W-7.5*cm, 4*cm]))
story += [sp(4)]
story.append(highlight_box("Key: G6PD is the ONLY source of NADPH in RBCs (no mitochondria). "
                           "Do NOT test during acute haemolysis — reticulocytes have high enzyme levels giving false-normal results."))
story += [PageBreak()]

# ══════════════════════════════════════════════════════════════════════════════
# TOPIC 2 — METABOLIC ACIDOSIS
# ══════════════════════════════════════════════════════════════════════════════
story += [topic_header(2, "Metabolic Acidosis"), sp(6)]
story += [P("<b>Definition:</b> Primary acid-base disorder characterised by ↓ blood pH and ↓ HCO₃⁻, due to gain of fixed acid or loss of bicarbonate.")]

story += [P("Anion Gap Classification", 'h2')]
story.append(info_box("<b>Anion Gap (AG)</b> = Na⁺ − (Cl⁻ + HCO₃⁻)      Normal = 8–12 mEq/L"))
story += [sp(4)]

story.append(box_table([
    ["Type", "AG", "Mnemonic / Causes"],
    ["High Anion Gap (>12)", "↑", "MUDPILES: Methanol, Uraemia, DKA, Propylene glycol/Paracetamol, Isoniazid/Iron, Lactic acidosis, Ethylene glycol, Salicylates"],
    ["Normal AG (Hyperchloraemic)", "Normal", "HARD UP: Hyperalimentation, Acetazolamide/Addison's, Renal tubular acidosis, Diarrhoea, Ureteral diversion, Post-hypocapnia"],
], [3.5*cm, 1.5*cm, W-5*cm]))
story += [sp(4)]

story += [P("Compensation & ABG", 'h2')]
story.append(box_table([
    ["Parameter", "Change", "Detail"],
    ["pH", "↓ (<7.35)", "Primary disorder"],
    ["HCO₃⁻", "↓ (<22 mEq/L)", "Primary change"],
    ["PCO₂", "↓ (compensatory)", "Kussmaul breathing"],
    ["Expected PCO₂", "= 1.5 × [HCO₃⁻] + 8 ± 2", "Winter's formula"],
], [3*cm, 3*cm, W-6*cm]))
story += [sp(4)]

story += [P("Clinical Features", 'h2'),
          B("Kussmaul respiration (deep, rapid — fruity odour in DKA)"),
          B("Nausea, vomiting, abdominal pain"),
          B("Cardiac: arrhythmias, ↓ cardiac output, hypotension"),
          B("CNS: confusion → coma"),
          B("Hyperkalaemia (H⁺ enters cells, K⁺ exits)")]

story += [P("Treatment", 'h2'),
          B("Treat underlying cause (insulin in DKA, dialysis in renal failure)"),
          B("NaHCO₃ if pH < 7.1 or severe symptoms"),
          B("Dialysis for methanol, ethylene glycol poisoning")]
story += [PageBreak()]

# ══════════════════════════════════════════════════════════════════════════════
# TOPIC 3 — COMPLICATIONS OF DIABETES MELLITUS
# ══════════════════════════════════════════════════════════════════════════════
story += [topic_header(3, "Complications of Diabetes Mellitus"), sp(6)]
story += [P("Chronic hyperglycaemia drives four major biochemical pathways of cellular damage, leading to microvascular and macrovascular complications.")]

story += [P("Four Pathways of Hyperglycaemic Damage", 'h2')]
story.append(box_table([
    ["Pathway", "Mechanism", "Outcome"],
    ["Polyol (Sorbitol)", "Glucose → Sorbitol (aldose reductase) → Fructose; sorbitol accumulates (impermeable)", "Osmotic damage: cataracts, neuropathy; ↓ NADPH → ↓ GSH"],
    ["AGEs", "Non-enzymatic glycation: glucose + protein → Schiff base → Amadori → AGE crosslinks collagen", "Basement membrane thickening, microangiopathy; HbA1c formed"],
    ["PKC Activation", "↑ Diacylglycerol → PKC → ↑ VEGF, TGF-β, fibronectin", "Retinal neovascularisation, glomerular hypertrophy, nephropathy"],
    ["Hexosamine Pathway", "Excess G6P → glucosamine-6-P → O-GlcNAc protein modification", "↑ TGF-β, PAI-1 → fibrosis and thrombosis"],
], [3*cm, W-6.5*cm, 3.5*cm]))
story += [sp(4)]

story += [P("Microvascular Complications", 'h2')]
story.append(box_table([
    ["Complication", "Key Features", "Biochemistry"],
    ["Retinopathy", "Non-proliferative → Proliferative; VEGF-driven neovascularisation; leading cause of blindness", "PKC activation; AGE crosslinks; VEGF ↑"],
    ["Nephropathy", "Microalbuminuria → Proteinuria → CKD; Kimmelstiel-Wilson nodules", "GBM thickening (AGEs); ↑ TGF-β; glomerular hypertrophy"],
    ["Neuropathy", "Glove-stocking sensory loss; autonomic (gastroparesis, impotence); mononeuritis", "Sorbitol accumulation; ↓ axonal myoinositol; ↓ Na/K-ATPase"],
], [2.5*cm, W-7*cm, 4.5*cm]))
story += [sp(4)]

story += [P("Acute Metabolic Complications", 'h2')]
story.append(box_table([
    ["Complication", "Type", "Biochemistry", "Key Feature"],
    ["DKA", "Type 1 (mainly)", "↑ Lipolysis → ↑ FFA → ↑ Ketone bodies (acetoacetate, β-hydroxybutyrate) → High AG acidosis", "pH <7.3, ketones ↑↑"],
    ["HHS", "Type 2", "Severe hyperglycaemia (>600 mg/dL); residual insulin prevents lipolysis — no ketosis", "Hyperosmolality, no ketosis"],
], [2*cm, 2*cm, W-7cm, 3*cm]))
story += [sp(4)]
story.append(highlight_box("HbA1c = glycated haemoglobin; reflects average blood glucose over 3 months. "
                           "Target HbA1c < 7% (53 mmol/mol) in most diabetic patients."))
story += [PageBreak()]

# ══════════════════════════════════════════════════════════════════════════════
# TOPIC 4 — PROTEIN MISFOLDING
# ══════════════════════════════════════════════════════════════════════════════
story += [topic_header(4, "Protein Misfolding and Associated Disorders"), sp(6)]
story += [P("Protein misfolding occurs when polypeptides fail to achieve their correct native conformation. "
            "Misfolded proteins expose hydrophobic regions, aggregate into β-sheet-rich fibrils, and cause cellular toxicity.")]

story += [P("Normal Folding vs. Misfolding", 'h2')]
story.append(flow_box([
    "NORMAL:  Polypeptide  -->  Native (alpha-helical, soluble) conformation",
    "          Assisted by CHAPERONES (Hsp70, Hsp90, GroEL)",
    "          Abnormal proteins degraded by UBIQUITIN-PROTEASOME system",
    "",
    "MISFOLDING (mutation / stress / ageing):",
    "  Exposes hydrophobic regions  -->  aggregation  -->  beta-sheet fibrils",
    "  Fibrils deposit as AMYLOID  -->  organ dysfunction"
]))
story += [sp(4)]

story += [P("Major Protein Misfolding Disorders", 'h2')]
story.append(box_table([
    ["Category", "Disease", "Protein", "Key Feature"],
    ["Amyloidoses", "AL amyloidosis", "Ig light chains", "Plasma cell dyscrasia"],
    ["", "AA amyloidosis", "Serum Amyloid A (SAA)", "Chronic inflammation"],
    ["", "Senile cardiac amyloidosis", "Transthyretin (TTR)", "Heart failure in elderly"],
    ["Neurodegenerative", "Alzheimer disease", "Aβ peptide + tau", "Plaques + tangles"],
    ["", "Parkinson disease", "α-synuclein", "Lewy bodies"],
    ["", "Huntington disease", "Huntingtin (polyQ)", "CAG expansion; chorea"],
    ["Prion diseases", "CJD / BSE / Scrapie", "PrP-Sc", "Infectious misfolding"],
    ["ER stress", "Cystic fibrosis (ΔF508)", "CFTR", "Retained in ER → degraded"],
], [2.8*cm, 3.5*cm, 3.5*cm, W-9.8*cm]))
story += [sp(4)]

story += [P("Amyloid — Key Biochemistry", 'h2'),
          B("All amyloid fibrils share a common <b>cross-β pleated sheet</b> structure"),
          B("Stain with <b>Congo red</b> → apple-green birefringence under polarised light"),
          B("Deposited extracellularly → organ dysfunction (heart, kidney, liver, nerves)")]

story += [P("Prion Disease — Unique Mechanism", 'h2')]
story.append(info_box(
    "<b>PrP-C</b> (normal, α-helical)  →  <b>PrP-Sc</b> (abnormal, β-sheet rich)<br/>"
    "PrP-Sc acts as a <b>template</b> to convert PrP-C → PrP-Sc (conformational propagation).<br/>"
    "Protein-only infectious agent — <b>no nucleic acid</b>. Resistant to protease, heat, UV radiation."
))
story += [sp(4)]
story.append(highlight_box("Unfolded Protein Response (UPR): Accumulation of misfolded proteins in ER triggers UPR. "
                           "Prolonged UPR → β-cell apoptosis (contributes to Type 2 DM)."))
story += [PageBreak()]

# ══════════════════════════════════════════════════════════════════════════════
# TOPIC 5 — HYPERKALEMIA AND HYPOKALEMIA
# ══════════════════════════════════════════════════════════════════════════════
story += [topic_header(5, "Hyperkalemia and Hypokalemia"), sp(6)]
story.append(info_box("<b>Normal serum K⁺ = 3.5–5.0 mEq/L.</b>  98% of total body K⁺ is intracellular; only 2% is extracellular."))
story += [sp(6)]

# Hypokalemia
story += [P("HYPOKALEMIA  (K⁺ < 3.5 mEq/L)", 'h2')]
story.append(box_table([
    ["Cause", "Examples"],
    ["↓ Intake", "Starvation, alcoholism"],
    ["GI losses", "Diarrhoea, vomiting, NG suction, laxative abuse"],
    ["Renal losses", "Loop/thiazide diuretics, hyperaldosteronism, RTA, hypomagnesaemia, Cushing's, Bartter syndrome"],
    ["Transcellular shift (K⁺ into cells)", "Insulin, catecholamines, alkalosis, β₂-agonists"],
], [3.5*cm, W-3.5*cm]))
story += [sp(4)]

story += [P("ECG Changes in Hypokalemia (in order):", 'h3'),
          B("1. Flat / inverted T waves"),
          B("2. Prominent U waves (after T wave, best seen V2–V3)  ← most characteristic"),
          B("3. ST depression"),
          B("4. Prolonged QU interval"),
          B("5. Severe: Ventricular fibrillation")]
story += [sp(4)]

story += [P("Clinical: muscle weakness, cramps, constipation, polyuria, cardiac arrhythmias, metabolic alkalosis."), sp(4)]
story.append(highlight_box("Treatment: Oral/IV KCl replacement; correct hypomagnesaemia (refractory hypokalaemia if Mg²⁺ not corrected)."))
story += [sp(8)]

# Hyperkalemia
story += [P("HYPERKALEMIA  (K⁺ > 5.0 mEq/L)", 'h2')]
story.append(box_table([
    ["Cause", "Examples"],
    ["↓ Excretion", "Renal failure (most common), ACE inhibitors/ARBs, K-sparing diuretics, Addison's disease"],
    ["Transcellular shift (K⁺ out of cells)", "Acidosis, insulin deficiency (DKA), cell lysis (haemolysis, rhabdomyolysis, TLS), succinylcholine, β-blockers"],
    ["Pseudohyperkalaemia", "Thrombocytosis, leukocytosis, haemolysed sample"],
], [3.5*cm, W-3.5*cm]))
story += [sp(4)]

story += [P("ECG Changes (in order of severity):", 'h3'),
          B("1. Tall peaked symmetric T waves  ← EARLIEST sign"),
          B("2. Prolonged PR interval"),
          B("3. Widened QRS"),
          B("4. Sine-wave pattern"),
          B("5. VF / Asystole")]
story += [sp(4)]

story += [P("Treatment — A-C-D-D-D-D:", 'h3')]
story.append(box_table([
    ["Drug / Intervention", "Mechanism", "Onset"],
    ["Calcium gluconate", "Membrane stabilisation (cardioprotective)", "Minutes — fastest"],
    ["Insulin + Dextrose", "Shifts K⁺ into cells via Na/K-ATPase", "20–30 min"],
    ["Sodium bicarbonate", "Shifts K⁺ into cells (if acidosis present)", "30–60 min"],
    ["Salbutamol (β₂-agonist)", "Shifts K⁺ into cells", "30 min"],
    ["Kayexalate / Patiromer", "Resin exchanges Na⁺/Ca²⁺ for K⁺ in gut", "Hours"],
    ["Dialysis", "Definitive K⁺ removal", "Definitive"],
], [4.5*cm, W-8.5*cm, 4*cm]))
story += [PageBreak()]

# ══════════════════════════════════════════════════════════════════════════════
# TOPIC 6 — ACUTE PHASE PLASMA PROTEINS
# ══════════════════════════════════════════════════════════════════════════════
story += [topic_header(6, "Acute Phase Plasma Proteins and Their Clinical Significance"), sp(6)]
story += [P("<b>Definition:</b> Proteins whose plasma concentration changes by ≥25% within hours to days "
            "in response to infection, inflammation, trauma, or malignancy.")]
story.append(info_box("Stimulus: IL-1β, IL-6, TNF-α from macrophages → Hepatocytes → Synthesis of acute phase proteins"))
story += [sp(6)]

story += [P("Positive Acute Phase Proteins (↑ in inflammation)", 'h2')]
story.append(box_table([
    ["Protein", "Function", "Clinical Use"],
    ["CRP (C-Reactive Protein)", "Opsonisation; activates complement; binds phosphocholine on bacteria", "Monitor infection/inflammation; cardiovascular risk (hs-CRP)"],
    ["Serum Amyloid A (SAA)", "Apolipoprotein; HDL remodelling", "Precursor of AA amyloid; monitor secondary amyloid risk"],
    ["Fibrinogen", "Forms fibrin clot (coagulation)", "↑ ESR; coats RBCs → rouleaux; procoagulant state"],
    ["Haptoglobin", "Binds free Hb → prevents haemoglobin loss in urine", "↓ in haemolysis (consumed); distinguishes intravascular haemolysis"],
    ["Ceruloplasmin", "Copper transport; ferroxidase activity", "↓ in Wilson's disease; ↑ in inflammation"],
    ["Alpha-1 antitrypsin (A1AT)", "Serine protease inhibitor (inhibits neutrophil elastase)", "↓ in A1AT deficiency → emphysema, liver cirrhosis"],
    ["Ferritin", "Iron storage protein", "↑ in inflammation, haemochromatosis, haemolysis"],
    ["Complement (C3, C4)", "Opsonisation, lysis (innate immunity)", "↑ acute inflammation; ↓ in SLE/complement consumption"],
], [3.5*cm, W-8.5*cm, 5*cm]))
story += [sp(4)]

story += [P("Negative Acute Phase Proteins (↓ in inflammation)", 'h2')]
story.append(box_table([
    ["Protein", "Reason for Fall", "Clinical Use"],
    ["Albumin", "↓ synthesis (resources diverted); ↑ vascular permeability", "Malnutrition, chronic disease, nephrotic syndrome"],
    ["Transferrin", "↓ synthesis during APR — sequesters iron from pathogens", "↑ in iron deficiency; ↓ in inflammation, malnutrition"],
    ["Prealbumin (Transthyretin)", "Short half-life (2 days); sensitive early marker", "Best acute nutritional status marker (ICU)"],
    ["Retinol-binding protein", "Rapidly ↓ in malnutrition and inflammation", "Vitamin A transport; nutritional assessment"],
], [3.5*cm, W-8.5*cm, 5*cm]))
story += [sp(4)]
story.append(highlight_box("CRP rises within 6 hours, peaks at 48 hrs. hs-CRP >3 mg/L = high cardiovascular risk. "
                           "Prealbumin (half-life 2 days) is the most sensitive early marker of nutritional status."))
story += [PageBreak()]

# ══════════════════════════════════════════════════════════════════════════════
# TOPIC 7 — SERUM ELECTROPHORESIS
# ══════════════════════════════════════════════════════════════════════════════
story += [topic_header(7, "Normal vs. Abnormal Serum Electrophoresis Patterns"), sp(6)]
story += [P("Serum proteins are separated by electrophoresis (movement in an electric field at alkaline pH) into "
            "<b>5 bands</b>: Albumin, α1, α2, β, and γ.")]

story += [P("Normal Serum Protein Fractions", 'h2')]
story.append(box_table([
    ["Band", "Proteins Included", "Normal %", "Normal (g/dL)"],
    ["Albumin", "Albumin", "~60%", "3.5–5.0"],
    ["α1 (alpha-1)", "A1AT (major), HDL, Orosomucoid", "2–4%", "0.2–0.4"],
    ["α2 (alpha-2)", "Haptoglobin, Ceruloplasmin, α2-Macroglobulin", "6–12%", "0.5–0.9"],
    ["β (beta)", "Transferrin, LDL, C3, Fibrinogen", "10–15%", "0.7–1.3"],
    ["γ (gamma)", "Immunoglobulins (IgG, IgA, IgM, IgD, IgE)", "15–20%", "0.7–1.6"],
], [2.5*cm, W-8.5*cm, 2*cm, 4*cm]))
story += [sp(4)]

story += [P("Abnormal Patterns", 'h2')]
story.append(box_table([
    ["Condition", "Albumin", "α1", "α2", "β", "γ", "Key Finding"],
    ["Multiple Myeloma", "↓", "↓", "↓", "↔", "M-spike ↑↑", "Narrow tall M-spike; monoclonal Ig; Bence-Jones proteins"],
    ["Polyclonal Gammopathy\n(cirrhosis/HIV)", "↓", "↓", "↓", "↑", "Broad ↑", "All Ig classes ↑; β-γ bridging in cirrhosis (IgA)"],
    ["Nephrotic Syndrome", "↓↓", "↓", "↑↑", "↑", "↓", "↑ α2-Macroglobulin (too large to lose); ↑ LDL"],
    ["Acute Inflammation", "↓", "↑", "↑", "↔", "↔", "↑ Acute phase proteins in α1/α2"],
    ["A1AT Deficiency", "↔", "↓↓", "↔", "↔", "↔", "Absent α1 band = A1AT deficiency"],
    ["Haemolysis", "↔", "↔", "↓", "↔", "↔", "↓ α2 = haptoglobin consumed"],
    ["Iron deficiency", "↔", "↔", "↔", "↑ (Transferrin)", "↔", "↑ β band (raised transferrin)"],
], [4*cm, 1.2*cm, 0.8*cm, 0.8*cm, 0.8*cm, 1.5*cm, W-9.1*cm]))
story += [sp(4)]
story.append(highlight_box("M-spike (monoclonal) = narrow sharp peak = same Ig class and same light chain (κ or λ). "
                           "Broad γ rise = polyclonal = many different Ig molecules (chronic inflammation/infection). "
                           "Beta-gamma bridging (β-γ fusion) = hallmark of liver cirrhosis (IgA)."))
story += [PageBreak()]

# ══════════════════════════════════════════════════════════════════════════════
# TOPIC 8 — IRDS
# ══════════════════════════════════════════════════════════════════════════════
story += [topic_header(8, "Infant Respiratory Distress Syndrome (IRDS / Neonatal RDS)"), sp(6)]
story += [P("IRDS is a life-threatening condition in <b>premature neonates</b> (<37 weeks gestation) caused by "
            "<b>deficiency of pulmonary surfactant</b>, leading to alveolar collapse, hypoxia, and hyaline membrane formation.")]

story += [P("Surfactant — Biochemistry", 'h2')]
story.append(box_table([
    ["Component", "Detail", "Function"],
    ["DPPC (Dipalmitoylphosphatidylcholine)", "Major lipid (~40% of surfactant)", "↓ Surface tension at air-liquid interface; prevents alveolar collapse"],
    ["Phosphatidylglycerol (PG)", "Aids spreading of surfactant film", "Marker of lung maturity in amniotic fluid"],
    ["Sphingomyelin", "NOT a surfactant component; constant in amniotic fluid", "Reference denominator for L:S ratio"],
    ["SP-A, SP-D", "Hydrophilic proteins; immune function", "Collectins; innate immunity in lung"],
    ["SP-B, SP-C", "Hydrophobic proteins", "Aid surfactant spreading and adsorption"],
], [4.5*cm, 4*cm, W-8.5*cm]))
story += [sp(4)]

story.append(info_box(
    "<b>Synthesis:</b> Made by Type II pneumocytes (alveolar cells) — matures after 34–36 weeks gestation.<br/>"
    "<b>Pathway:</b> CDP-choline (Kennedy) pathway: Choline → Phosphocholine → CDP-choline → Lecithin (PC).<br/>"
    "<b>Storage:</b> In lamellar bodies → secreted into alveolar space."
))
story += [sp(4)]

story += [P("L:S Ratio (Lecithin:Sphingomyelin Ratio)", 'h2')]
story.append(box_table([
    ["L:S Ratio", "Interpretation"],
    ["< 2.0", "Lung IMMATURE → High risk of IRDS"],
    ["≥ 2.0", "Lung MATURE → Low risk of IRDS"],
    ["PG present", "Additional marker of lung maturity"],
], [3*cm, W-3*cm]))
story += [sp(4)]

story += [P("Pathophysiology", 'h2')]
story.append(flow_box([
    "PREMATURITY (<34 weeks)",
    "  --> Immature Type II pneumocytes --> low DPPC synthesis",
    "  --> High alveolar surface tension (LaPlace: P = 2T/r)",
    "  --> Alveolar COLLAPSE (atelectasis) at end-expiration",
    "  --> Hypoxia + Acidosis --> Pulmonary vasoconstriction",
    "  --> R-->L shunting --> further hypoxia",
    "  --> Protein-rich exudate + fibrin --> HYALINE MEMBRANES",
]))
story += [sp(4)]

story += [P("Treatment", 'h2')]
story.append(box_table([
    ["Intervention", "Detail"],
    ["Antenatal corticosteroids", "Betamethasone/dexamethasone to mother ≥24 hrs before birth; ↑ surfactant synthesis; ↑ lung maturity"],
    ["Exogenous surfactant (intratracheal)", "Beractant (Survanta), Poractant alfa (Curosurf); given at birth or shortly after"],
    ["CPAP / Mechanical ventilation", "Maintains positive end-expiratory pressure; prevents alveolar collapse"],
], [4*cm, W-4*cm]))
story += [PageBreak()]

# ══════════════════════════════════════════════════════════════════════════════
# TOPIC 9 — JAUNDICE
# ══════════════════════════════════════════════════════════════════════════════
story += [topic_header(9, "Jaundice"), sp(6)]
story += [P("Jaundice is yellow discolouration of skin, sclerae, and mucous membranes due to ↑ serum bilirubin. "
            "Clinical jaundice appears at serum bilirubin <b>>2 mg/dL</b>; laboratory detection at >1 mg/dL (latent jaundice).")]

story += [P("Bilirubin Metabolism — Biochemical Pathway", 'h2')]
story.append(flow_box([
    "HEME (from destroyed RBCs, 80%)",
    "  --[Heme oxygenase, RES]-->  Biliverdin + CO + Fe2+",
    "  --[Biliverdin reductase]-->  BILIRUBIN (unconjugated/indirect)",
    "  (fat-soluble; insoluble in water; TOXIC to brain; bound to albumin in blood)",
    "",
    "  --[Hepatocyte uptake via OATP transporters]-->  Hepatocyte",
    "  --[UDP-glucuronosyltransferase UGT1A1, in SER]-->",
    "  BILIRUBIN DIGLUCURONIDE (conjugated/direct)",
    "  (water-soluble; NON-toxic; excreted in bile via MRP2)",
    "",
    "  Intestine: [Bacterial beta-glucuronidase]-->  UROBILINOGEN",
    "  20% reabsorbed --> portal vein --> liver/kidney --> URINE urobilinogen",
    "  80% --> oxidised --> STERCOBILIN (brown colour of faeces)",
]))
story += [sp(4)]

story += [P("Classification of Jaundice", 'h2')]
story.append(box_table([
    ["Type", "Cause", "Bilirubin", "Urine", "Stool", "Other"],
    ["Pre-hepatic\n(Haemolytic)", "↑ RBC destruction", "↑ Unconjugated", "↑ Urobilinogen; NO bilirubin", "Normal/dark", "↑ LDH, ↓ haptoglobin, anaemia"],
    ["Hepatic\n(Hepatocellular)", "Liver damage\n(hepatitis, cirrhosis)", "↑ Both (mixed)", "Bilirubin + ↑ urobilinogen", "Pale", "↑ AST, ALT, ↑ PT"],
    ["Post-hepatic\n(Obstructive)", "Bile duct obstruction\n(stones, carcinoma)", "↑ Conjugated", "Bilirubin ++ ; NO urobilinogen", "Pale/clay", "↑ ALP, GGT; pruritus; dark urine"],
], [2.5*cm, 3*cm, 2.5*cm, 3.5*cm, 2*cm, W-13.5*cm]))
story += [sp(4)]

story += [P("Specific Bilirubin Metabolism Disorders", 'h2')]
story.append(box_table([
    ["Syndrome", "Defect", "Bilirubin", "Key Feature"],
    ["Gilbert's syndrome", "↓ UGT1A1 (mild, 30%)", "↑ Unconjugated", "Benign; fasting/stress precipitates; no treatment"],
    ["Crigler-Najjar Type I", "Absent UGT1A1", "↑↑↑ Unconjugated", "Kernicterus; fatal without phototherapy/transplant"],
    ["Crigler-Najjar Type II", "Partial UGT1A1 deficiency", "↑ Unconjugated", "Responds to phenobarbitone (↑ UGT1A1 induction)"],
    ["Dubin-Johnson syndrome", "Defective MRP2 (canalicular transporter)", "↑ Conjugated", "Black liver (melanin-like pigment); benign"],
    ["Rotor syndrome", "Defective hepatic bilirubin storage", "↑ Conjugated", "Benign; no black liver; normal life expectancy"],
], [3.5*cm, 3.5*cm, 3*cm, W-10*cm]))
story += [sp(4)]
story.append(highlight_box("Neonatal Physiological Jaundice: Day 2–3 to Day 10–14. Cause: immature UGT1A1 + ↑ fetal Hb breakdown. "
                           "Unconjugated bilirubin crosses BBB → KERNICTERUS if severe. Treatment: Phototherapy (converts bilirubin to water-soluble photoisomers)."))
story += [PageBreak()]

# ══════════════════════════════════════════════════════════════════════════════
# TOPIC 10 — GLYCOGEN STORAGE DISORDERS
# ══════════════════════════════════════════════════════════════════════════════
story += [topic_header(10, "Glycogen Storage Disorders (Glycogenoses)"), sp(6)]
story += [P("Glycogen storage diseases (GSDs) are a group of <b>inherited (autosomal recessive)</b> disorders caused by deficiency of enzymes in "
            "glycogen synthesis or degradation, resulting in abnormal accumulation of glycogen in various tissues.")]

story += [P("Normal Glycogen Metabolism", 'h2')]
story.append(flow_box([
    "SYNTHESIS:",
    "  Glucose --> G-6-P --> G-1-P --> UDP-Glucose --> GLYCOGEN",
    "  [Glycogen synthase] + [Branching enzyme (IV)] build the polymer",
    "",
    "DEGRADATION:",
    "  GLYCOGEN --[Phosphorylase (V,VI)]--> G-1-P --[Phosphoglucomutase]--> G-6-P",
    "  [Debranching enzyme (III)] needed at branch points",
    "  G-6-P --[G-6-Phosphatase (I)]--> FREE GLUCOSE (liver only)",
    "  [Lysosomal acid maltase (II)] degrades glycogen in lysosomes",
]))
story += [sp(4)]

story += [P("Classification of Glycogen Storage Diseases", 'h2')]
story.append(box_table([
    ["Type", "Name", "Enzyme Deficient", "Organ(s)", "Key Features"],
    ["Ia", "Von Gierke", "Glucose-6-phosphatase (G6PC)", "Liver, Kidney", "Hepatomegaly, fasting hypoglycaemia, lactic acidosis, hyperuricaemia, hyperlipidaemia; 'doll-like' facies"],
    ["Ib", "Von Gierke variant", "G6P translocase (SLC37A4)", "Liver, Kidney, WBCs", "Same as Ia + NEUTROPENIA + IBD"],
    ["II", "Pompe", "Lysosomal acid α-glucosidase (GAA)", "All organs (heart dominant)", "Massive cardiomegaly; hypotonia; death <2 yrs; ONLY GSD with enzyme replacement (alglucosidase alfa)"],
    ["III", "Cori / Forbes", "Debranching enzyme (AGL)", "Liver, heart, muscle", "Mild hepatomegaly; hypoglycaemia; progressive myopathy"],
    ["IV", "Andersen", "Branching enzyme (GBE1)", "Liver, all tissues", "Abnormal glycogen → cirrhosis, liver failure"],
    ["V", "McArdle", "Muscle phosphorylase (PYGM)", "Skeletal muscle", "Exercise cramps; no blood lactate rise on exercise; myoglobinuria"],
    ["VII", "Tarui", "Muscle phosphofructokinase", "Muscle, RBCs", "McArdle-like + haemolytic anaemia"],
], [1.2*cm, 2.5*cm, 4*cm, 3*cm, W-10.7*cm]))
story += [sp(4)]

story += [P("Type I (Von Gierke) — Biochemistry in Detail", 'h2')]
story.append(flow_box([
    "G6Pase ABSENT  -->  Glucose-6-P ACCUMULATES",
    "   |",
    "   +--[Glycolysis]-->  Pyruvate --> LACTATE  --> LACTIC ACIDOSIS",
    "   |",
    "   +--[HMP shunt]--> Ribose-5-P --> Purines --> URIC ACID -->  HYPERURICAEMIA / GOUT",
    "   |",
    "   +--[Lipogenesis]--> Acetyl-CoA --> FFA -->  HYPERTRIGLYCERIDAEMIA",
    "   |",
    "   +--Cannot dephosphorylate --> No free glucose -->  HYPOGLYCAEMIA",
    "      Both GLYCOGENOLYSIS and GLUCONEOGENESIS blocked (both feed G6P)",
]))
story += [sp(4)]

story.append(highlight_box("Most common GSD = Type I (Von Gierke).  "
                           "Only lysosomal GSD = Type II (Pompe) — has enzyme replacement.  "
                           "Exercise cramps + no lactate rise = Types V and VII (myopathic).  "
                           "Treatment cornerstone for Type I: Uncooked Cornstarch (UCCS) every 4–6 hours; avoid fructose and galactose."))
story += [PageBreak()]

# ══════════════════════════════════════════════════════════════════════════════
# TOPIC 11 — COMPETITIVE INHIBITORS
# ══════════════════════════════════════════════════════════════════════════════
story += [topic_header(11, "Clinical Significance of Competitive Inhibitors as Drugs"), sp(6)]
story += [P("A <b>competitive inhibitor</b> structurally resembles the substrate and competes for binding at the enzyme <b>active site</b>. "
            "Inhibition is <b>reversible</b> and overcome by increasing substrate concentration.")]

story += [P("Kinetics (Michaelis-Menten)", 'h2')]
story.append(box_table([
    ["Parameter", "Effect of Competitive Inhibition", "Explanation"],
    ["Vmax", "UNCHANGED", "Can still be achieved with excess substrate"],
    ["Apparent Km", "INCREASED (↑)", "More substrate needed to achieve half-Vmax"],
    ["Lineweaver-Burk", "Lines intersect on Y-axis", "Same Vmax, different x-intercept"],
], [3*cm, 3*cm, W-6*cm]))
story += [sp(4)]

story += [P("Clinically Important Competitive Inhibitor Drugs", 'h2')]
story.append(box_table([
    ["Drug", "Target Enzyme", "Structural Analog Of", "Clinical Use"],
    ["Statins\n(Atorvastatin, etc.)", "HMG-CoA reductase (rate-limiting step in cholesterol synthesis)", "HMG-CoA", "Hypercholesterolaemia; CVD prevention; ↑ LDL receptors"],
    ["Methotrexate", "Dihydrofolate reductase (DHFR)", "Dihydrofolate", "Cancer, rheumatoid arthritis, psoriasis; ↓ THF → ↓ purine/thymidylate synthesis"],
    ["Trimethoprim", "Bacterial DHFR (selectivity)", "Dihydrofolate", "UTI, PCP; 50,000× selectivity for bacterial vs human DHFR"],
    ["Allopurinol", "Xanthine oxidase", "Hypoxanthine/xanthine", "Gout; hyperuricaemia in GSD Type I; tumour lysis syndrome"],
    ["ACE Inhibitors\n(Captopril, Enalapril)", "Angiotensin-converting enzyme (ACE)", "Angiotensin I (C-terminus)", "Hypertension, heart failure, diabetic nephropathy"],
    ["Sildenafil", "Phosphodiesterase-5 (PDE-5)", "cGMP", "Erectile dysfunction; pulmonary arterial hypertension"],
    ["Carbidopa", "DOPA decarboxylase (peripheral)", "L-DOPA", "Parkinson's disease (with L-DOPA); ↑ L-DOPA in CNS; ↓ peripheral side-effects"],
    ["Pyrimethamine", "Parasite DHFR", "Dihydrofolate", "Malaria, toxoplasmosis"],
    ["Eflornithine", "Ornithine decarboxylase (ODC)", "Ornithine", "African sleeping sickness; facial hirsutism"],
], [3.2*cm, 4*cm, 2.8*cm, W-10*cm]))
story += [sp(4)]

story += [P("Why Competitive Inhibitors Make Ideal Drugs", 'h2')]
story.append(box_table([
    ["Advantage", "Explanation"],
    ["1. Selectivity", "Drug mimics substrate → targets specific enzyme active site → fewer off-target effects"],
    ["2. Reversibility", "Inhibition reversed by ↑ substrate or removing drug → safer, titratable"],
    ["3. Dose-response", "Doubling dose doubles inhibition (unlike irreversible inhibitors)"],
    ["4. Rescue possible", "Substrate supplement can overcome inhibition (e.g. folinic acid rescue after methotrexate overdose)"],
    ["5. Species selectivity", "Selectivity for pathogen enzyme vs. human enzyme possible (e.g. Trimethoprim for bacterial DHFR)"],
], [3.5*cm, W-3.5*cm]))
story += [sp(6)]
story.append(highlight_box(
    "Note: Aspirin is a SPECIAL CASE — it irreversibly acetylates the active-site serine of COX-1/COX-2 "
    "(irreversible competitive inhibition). Platelets cannot synthesise new COX → antiplatelet effect lasts platelet lifespan (7–10 days)."
))
story += [sp(8)]

# ── FOOTER PAGE ───────────────────────────────────────────────────────────────
story += [hr(DARK_BLUE, 1.2), sp(6),
          P("MBBS Biochemistry Short Notes", 'footer'),
          P("Based on: Lippincott's Illustrated Reviews: Biochemistry 8th ed. | Robbins & Kumar Basic Pathology | "
            "Robbins Cotran & Kumar Pathologic Basis of Disease | Goldman-Cecil Medicine | "
            "Basic Medical Biochemistry (Lieberman & Peet) | Tietz Textbook of Laboratory Medicine | "
            "Goodman & Gilman's Pharmacological Basis of Therapeutics", 'footer'),
          P("For educational purposes only. Clinical decisions must be based on current guidelines and clinical judgement.", 'footer')]

# ── BUILD ─────────────────────────────────────────────────────────────────────
def on_page(canvas, doc):
    canvas.saveState()
    canvas.setFont('Helvetica', 7)
    canvas.setFillColor(HexColor("#aaaaaa"))
    canvas.drawString(1.8*cm, 1.2*cm, "MBBS Biochemistry Short Notes")
    canvas.drawRightString(A4[0]-1.8*cm, 1.2*cm, f"Page {doc.page}")
    canvas.restoreState()

doc.build(story, onFirstPage=on_page, onLaterPages=on_page)
print("PDF generated successfully:", OUTPUT)

Successfully replaced 1 instance(s) of the string in '/home/daytona/workspace/biochem-notes/generate_pdf.py'

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<!-- COVER -->
<div class="cover">
  <h1>MBBS Biochemistry</h1>
  <h2>Short Notes</h2>
  <p style="font-size:11pt; color:#fff; margin-bottom:14px;">11 High-Yield Topics for MBBS Examinations</p>
  <p>G6PD Deficiency &nbsp;•&nbsp; Metabolic Acidosis &nbsp;•&nbsp; Diabetes Complications</p>
  <p>Protein Misfolding &nbsp;•&nbsp; Electrolyte Disorders &nbsp;•&nbsp; Acute Phase Proteins</p>
  <p>Serum Electrophoresis &nbsp;•&nbsp; IRDS &nbsp;•&nbsp; Jaundice &nbsp;•&nbsp; GSD &nbsp;•&nbsp; Enzyme Inhibitors</p>
  <p style="margin-top:18px;">Based on: Lippincott's Biochemistry • Robbins Pathology • Harper's Biochemistry<br/>Goldman-Cecil Medicine • Basic Medical Biochemistry</p>
</div>

<!-- TOC -->
<h3 style="page-break-before:avoid;">Table of Contents</h3>
<hr/>
<div class="toc-item"><span class="toc-num">1.</span><span class="toc-title">G-6-PD Deficiency</span></div>
<div class="toc-item"><span class="toc-num">2.</span><span class="toc-title">Metabolic Acidosis</span></div>
<div class="toc-item"><span class="toc-num">3.</span><span class="toc-title">Complications of Diabetes Mellitus</span></div>
<div class="toc-item"><span class="toc-num">4.</span><span class="toc-title">Protein Misfolding and Associated Disorders</span></div>
<div class="toc-item"><span class="toc-num">5.</span><span class="toc-title">Hyperkalemia and Hypokalemia</span></div>
<div class="toc-item"><span class="toc-num">6.</span><span class="toc-title">Acute Phase Plasma Proteins and Their Clinical Significance</span></div>
<div class="toc-item"><span class="toc-num">7.</span><span class="toc-title">Normal vs. Abnormal Serum Electrophoresis Patterns</span></div>
<div class="toc-item"><span class="toc-num">8.</span><span class="toc-title">Infant Respiratory Distress Syndrome (IRDS)</span></div>
<div class="toc-item"><span class="toc-num">9.</span><span class="toc-title">Jaundice</span></div>
<div class="toc-item"><span class="toc-num">10.</span><span class="toc-title">Glycogen Storage Disorders</span></div>
<div class="toc-item"><span class="toc-num">11.</span><span class="toc-title">Clinical Significance of Competitive Inhibitors as Drugs</span></div>

<!-- ═══════════════════════════════════════════════════ TOPIC 1 ══ -->
<div class="topic-header"><span class="topic-num">1</span><span class="topic-title">G-6-PD Deficiency (Glucose-6-Phosphate Dehydrogenase Deficiency)</span></div>

<p><b>Definition:</b> X-linked recessive deficiency of G6PD, the rate-limiting enzyme of the <b>Hexose Monophosphate (HMP) shunt</b>, causing episodic hemolytic anemia on oxidative stress. Affects ~500 million people worldwide.</p>

<h3>Biochemical Basis</h3>
<div class="flow">HMP SHUNT:
Glucose-6-P + NADP+  --[G6PD]-->  6-Phosphogluconate + NADPH

NADPH reduces Glutathione:
  GSSG + NADPH  -->  2 GSH + NADP+
  GSH neutralises H2O2 and free radicals --> protects RBC membrane

IN G6PD DEFICIENCY:
  ↓ NADPH  -->  ↓ GSH  -->  oxidative stress NOT neutralised
  --> Hb oxidised --> Methemoglobin --> Heinz bodies (precipitates)
  --> Rigid RBCs trapped in spleen  -->  HEMOLYTIC ANAEMIA</div>

<h3>Genetics &amp; Variants</h3>
<ul>
  <li><b>X-linked recessive</b> — males affected, females are carriers</li>
  <li><b>G6PD-A-</b> (African variant): mild, episodic; <b>G6PD-Mediterranean</b>: severe, chronic</li>
</ul>

<h3>Precipitants — "PRIMA"</h3>
<div class="highlight">P – Primaquine, dapsone &nbsp;|&nbsp; R – Infections (most common trigger) &nbsp;|&nbsp; I – Ingestion of fava beans (favism) &nbsp;|&nbsp; M – Metabolic acidosis &nbsp;|&nbsp; A – Aspirin, sulfonamides, nitrofurantoin</div>

<h3>Laboratory Findings</h3>
<table>
  <thead><tr><th>Test</th><th>Finding</th><th>Significance</th></tr></thead>
  <tbody>
    <tr><td>Blood film</td><td>Heinz bodies, bite cells, blister cells</td><td>Oxidised Hb precipitates</td></tr>
    <tr><td>Hb / Haematocrit</td><td>Decreased</td><td>Haemolytic anaemia</td></tr>
    <tr><td>Reticulocytes</td><td>Increased</td><td>Regenerative response</td></tr>
    <tr><td>LDH / Indirect bilirubin</td><td>Increased</td><td>Haemolysis markers</td></tr>
    <tr><td>Fluorescent spot test</td><td>No fluorescence (NADPH absent)</td><td>Screening test</td></tr>
    <tr><td>G6PD enzyme assay</td><td>Markedly reduced activity</td><td>Confirmatory test</td></tr>
  </tbody>
</table>

<div class="highlight">⚠ Key: G6PD is the ONLY source of NADPH in RBCs (no mitochondria). Do NOT test during acute haemolysis — reticulocytes give false-normal results.</div>

<!-- ═══════════════════════════════════════════════════ TOPIC 2 ══ -->
<div class="topic-header"><span class="topic-num">2</span><span class="topic-title">Metabolic Acidosis</span></div>

<p><b>Definition:</b> Primary acid-base disorder characterised by ↓ blood pH and ↓ HCO₃⁻, caused by gain of fixed acid or loss of bicarbonate.</p>

<h3>Anion Gap Classification</h3>
<div class="info-box"><b>Anion Gap (AG) = Na⁺ − (Cl⁻ + HCO₃⁻)</b> &nbsp;&nbsp; Normal = 8–12 mEq/L</div>

<table>
  <thead><tr><th>Type</th><th>AG</th><th>Mnemonic / Causes</th></tr></thead>
  <tbody>
    <tr><td><b>High Anion Gap (&gt;12)</b></td><td>↑</td><td><b>MUDPILES:</b> Methanol, Uraemia, DKA, Propylene glycol/Paracetamol, Isoniazid/Iron, Lactic acidosis, Ethylene glycol, Salicylates</td></tr>
    <tr><td><b>Normal AG (Hyperchloraemic)</b></td><td>Normal</td><td><b>HARD UP:</b> Hyperalimentation, Acetazolamide/Addison's, Renal tubular acidosis, Diarrhoea, Ureteral diversion, Post-hypocapnia</td></tr>
  </tbody>
</table>

<h3>ABG &amp; Compensation</h3>
<table>
  <thead><tr><th>Parameter</th><th>Change</th><th>Detail</th></tr></thead>
  <tbody>
    <tr><td>pH</td><td>↓ (&lt;7.35)</td><td>Primary disorder</td></tr>
    <tr><td>HCO₃⁻</td><td>↓ (&lt;22 mEq/L)</td><td>Primary change</td></tr>
    <tr><td>PCO₂</td><td>↓ (compensatory)</td><td>Kussmaul breathing (deep, rapid)</td></tr>
    <tr><td>Expected PCO₂</td><td>= 1.5 × [HCO₃⁻] + 8 ± 2</td><td><b>Winter's formula</b></td></tr>
  </tbody>
</table>

<h3>Clinical Features</h3>
<ul>
  <li>Kussmaul respiration (fruity odour in DKA)</li>
  <li>Nausea, vomiting, abdominal pain</li>
  <li>Cardiac: arrhythmias, ↓ cardiac output, hypotension</li>
  <li>CNS: confusion → coma</li>
  <li><b>Hyperkalaemia</b> (H⁺ enters cells, K⁺ exits in exchange)</li>
</ul>
<h3>Treatment</h3>
<ul>
  <li>Treat underlying cause (insulin in DKA; dialysis in renal failure)</li>
  <li>NaHCO₃ if pH &lt; 7.1 or severe symptoms</li>
  <li>Dialysis for methanol, ethylene glycol poisoning</li>
</ul>

<!-- ═══════════════════════════════════════════════════ TOPIC 3 ══ -->
<div class="topic-header"><span class="topic-num">3</span><span class="topic-title">Complications of Diabetes Mellitus</span></div>

<p>Chronic hyperglycaemia drives <b>four major biochemical pathways</b> of cellular damage:</p>

<table>
  <thead><tr><th>Pathway</th><th>Mechanism</th><th>Outcome</th></tr></thead>
  <tbody>
    <tr><td><b>Polyol (Sorbitol)</b></td><td>Glucose → Sorbitol (aldose reductase) → Fructose; sorbitol accumulates (impermeable to membranes)</td><td>Osmotic damage: cataracts, neuropathy; ↓ NADPH → ↓ GSH (oxidative stress)</td></tr>
    <tr><td><b>AGEs</b></td><td>Non-enzymatic glycation: Glucose + protein → Schiff base → Amadori → AGE crosslinks collagen</td><td>Basement membrane thickening; microangiopathy; HbA1c formed</td></tr>
    <tr><td><b>PKC Activation</b></td><td>↑ Diacylglycerol → PKC → ↑ VEGF, TGF-β, fibronectin</td><td>Retinal neovascularisation; glomerular hypertrophy; nephropathy</td></tr>
    <tr><td><b>Hexosamine Pathway</b></td><td>Excess G6P → glucosamine-6-P → O-GlcNAc protein modification</td><td>↑ TGF-β, PAI-1 → fibrosis and thrombosis</td></tr>
  </tbody>
</table>

<h3>Microvascular Complications</h3>
<table>
  <thead><tr><th>Complication</th><th>Key Features</th><th>Biochemistry</th></tr></thead>
  <tbody>
    <tr><td><b>Retinopathy</b></td><td>Non-proliferative → Proliferative; VEGF-driven neovascularisation; leading cause of blindness</td><td>PKC activation; ↑ VEGF; AGE crosslinks</td></tr>
    <tr><td><b>Nephropathy</b></td><td>Microalbuminuria → Proteinuria → CKD; Kimmelstiel-Wilson nodules</td><td>GBM thickening (AGEs); ↑ TGF-β; glomerular hypertrophy</td></tr>
    <tr><td><b>Neuropathy</b></td><td>Glove-stocking sensory loss; autonomic (gastroparesis, impotence)</td><td>Sorbitol accumulation; ↓ axonal myoinositol; ↓ Na/K-ATPase</td></tr>
  </tbody>
</table>

<h3>Acute Metabolic Complications</h3>
<table>
  <thead><tr><th>Complication</th><th>Type</th><th>Biochemistry</th><th>Key</th></tr></thead>
  <tbody>
    <tr><td><b>DKA</b></td><td>Type 1</td><td>↑ Lipolysis → ↑ FFA → ↑ Ketone bodies (acetoacetate, β-hydroxybutyrate) → High AG acidosis</td><td>pH &lt;7.3; ketones ↑↑</td></tr>
    <tr><td><b>HHS</b></td><td>Type 2</td><td>Severe hyperglycaemia (&gt;600 mg/dL); residual insulin prevents lipolysis — no ketosis</td><td>Hyperosmolality; no ketosis</td></tr>
  </tbody>
</table>
<div class="highlight">HbA1c = glycated haemoglobin — reflects average blood glucose over 3 months. Target HbA1c &lt; 7% (53 mmol/mol) in most patients.</div>

<!-- ═══════════════════════════════════════════════════ TOPIC 4 ══ -->
<div class="topic-header"><span class="topic-num">4</span><span class="topic-title">Protein Misfolding and Associated Disorders</span></div>

<p>Protein misfolding occurs when polypeptides fail to achieve their correct native conformation. Misfolded proteins expose hydrophobic regions, aggregate into <b>β-sheet-rich fibrils</b>, and cause cellular toxicity.</p>

<div class="flow">NORMAL:  Polypeptide  -->  Native (alpha-helical, soluble) conformation
         Assisted by CHAPERONES (Hsp70, Hsp90, GroEL)
         Abnormal proteins degraded by UBIQUITIN-PROTEASOME system

MISFOLDING (mutation / oxidative stress / ageing):
  Exposes hydrophobic residues  -->  protein AGGREGATION
  -->  beta-sheet rich FIBRILS  -->  AMYLOID deposits  -->  organ dysfunction</div>

<h3>Major Protein Misfolding Disorders</h3>
<table>
  <thead><tr><th>Category</th><th>Disease</th><th>Protein</th><th>Key Feature</th></tr></thead>
  <tbody>
    <tr><td rowspan="3"><b>Amyloidoses</b></td><td>AL amyloidosis</td><td>Ig light chains</td><td>Plasma cell dyscrasia (myeloma)</td></tr>
    <tr><td>AA amyloidosis</td><td>Serum Amyloid A (SAA)</td><td>Secondary to chronic inflammation (RA, TB)</td></tr>
    <tr><td>Senile cardiac amyloidosis</td><td>Transthyretin (TTR)</td><td>Heart failure in elderly</td></tr>
    <tr><td rowspan="3"><b>Neurodegenerative</b></td><td>Alzheimer disease</td><td>Aβ peptide + tau</td><td>Amyloid plaques + neurofibrillary tangles</td></tr>
    <tr><td>Parkinson disease</td><td>α-synuclein</td><td>Lewy bodies in dopaminergic neurons</td></tr>
    <tr><td>Huntington disease</td><td>Huntingtin (polyQ expansion)</td><td>CAG repeat expansion; chorea</td></tr>
    <tr><td><b>Prion diseases</b></td><td>CJD / BSE / Scrapie</td><td>PrP-Sc</td><td>Infectious misfolding; protein-only pathogen</td></tr>
    <tr><td><b>ER stress disease</b></td><td>Cystic fibrosis (ΔF508)</td><td>CFTR protein</td><td>Misfolded CFTR retained in ER and degraded</td></tr>
  </tbody>
</table>

<h3>Amyloid — Key Biochemistry</h3>
<ul>
  <li>All amyloid fibrils share a common <b>cross-β pleated sheet</b> structure</li>
  <li>Stain with <b>Congo red</b> → <b>apple-green birefringence</b> under polarised light</li>
  <li>Deposited extracellularly → organ dysfunction (heart, kidney, liver, nerves)</li>
</ul>

<h3>Prion Disease — Unique Mechanism</h3>
<div class="info-box"><b>PrP-C</b> (normal, α-helical) → <b>PrP-Sc</b> (abnormal, β-sheet rich)<br/>
PrP-Sc acts as a <b>template</b> to convert PrP-C → PrP-Sc (conformational propagation).<br/>
Protein-only infectious agent — <b>no nucleic acid</b>. Resistant to protease, heat, UV radiation.</div>

<div class="highlight">Unfolded Protein Response (UPR): Accumulation of misfolded proteins in ER triggers UPR. Prolonged UPR → β-cell apoptosis (contributes to Type 2 DM).</div>

<!-- ═══════════════════════════════════════════════════ TOPIC 5 ══ -->
<div class="topic-header"><span class="topic-num">5</span><span class="topic-title">Hyperkalemia and Hypokalemia</span></div>

<div class="info-box"><b>Normal serum K⁺ = 3.5–5.0 mEq/L.</b> 98% of total body K⁺ is intracellular; only 2% extracellular. Small changes in plasma K⁺ have major effects on cardiac and neuromuscular function.</div>

<h3>HYPOKALEMIA (K⁺ &lt; 3.5 mEq/L)</h3>
<table>
  <thead><tr><th>Cause</th><th>Examples</th></tr></thead>
  <tbody>
    <tr><td>↓ Intake</td><td>Starvation, alcoholism</td></tr>
    <tr><td>GI losses</td><td>Diarrhoea, vomiting, NG suction, laxative abuse</td></tr>
    <tr><td>Renal losses</td><td>Loop/thiazide diuretics, hyperaldosteronism, RTA, hypomagnesaemia, Cushing's, Bartter syndrome</td></tr>
    <tr><td>Transcellular shift (K⁺ into cells)</td><td>Insulin, catecholamines, alkalosis, β₂-agonists</td></tr>
  </tbody>
</table>

<h4>ECG Changes (in order):</h4>
<ul>
  <li>1. Flat / inverted T waves</li>
  <li>2. <b>Prominent U waves</b> (after T wave, best seen V2–V3) ← most characteristic</li>
  <li>3. ST depression &nbsp; 4. Prolonged QU interval &nbsp; 5. Ventricular fibrillation</li>
</ul>
<p><b>Clinical:</b> Muscle weakness, cramps, constipation, polyuria, cardiac arrhythmias, metabolic alkalosis.</p>
<div class="highlight">Treatment: Oral/IV KCl. Always correct hypomagnesaemia (refractory hypokalaemia if Mg²⁺ low).</div>

<h3>HYPERKALEMIA (K⁺ &gt; 5.0 mEq/L)</h3>
<table>
  <thead><tr><th>Cause</th><th>Examples</th></tr></thead>
  <tbody>
    <tr><td>↓ Excretion</td><td>Renal failure (most common), ACE inhibitors/ARBs, K-sparing diuretics, Addison's disease</td></tr>
    <tr><td>Transcellular shift (K⁺ out of cells)</td><td>Acidosis, insulin deficiency (DKA), cell lysis (haemolysis, rhabdomyolysis, TLS), succinylcholine, β-blockers</td></tr>
    <tr><td>Pseudohyperkalaemia</td><td>Thrombocytosis, leukocytosis, haemolysed sample</td></tr>
  </tbody>
</table>

<h4>ECG Changes (in order of severity):</h4>
<ul>
  <li>1. <b>Tall peaked symmetric T waves</b> ← EARLIEST sign</li>
  <li>2. Prolonged PR interval &nbsp; 3. Widened QRS &nbsp; 4. Sine-wave pattern &nbsp; 5. VF / Asystole</li>
</ul>

<h4>Treatment — A-C-D-D-D-D:</h4>
<table>
  <thead><tr><th>Drug / Intervention</th><th>Mechanism</th><th>Onset</th></tr></thead>
  <tbody>
    <tr><td><b>Calcium gluconate</b></td><td>Membrane stabilisation (cardioprotective)</td><td>Minutes — FASTEST</td></tr>
    <tr><td>Insulin + Dextrose</td><td>Shifts K⁺ into cells via Na/K-ATPase</td><td>20–30 min</td></tr>
    <tr><td>Sodium bicarbonate</td><td>Shifts K⁺ into cells (if acidosis)</td><td>30–60 min</td></tr>
    <tr><td>Salbutamol (β₂-agonist)</td><td>Shifts K⁺ into cells</td><td>30 min</td></tr>
    <tr><td>Kayexalate / Patiromer</td><td>Resin: exchanges Na⁺/Ca²⁺ for K⁺ in gut</td><td>Hours</td></tr>
    <tr><td>Dialysis</td><td>Definitive K⁺ removal</td><td>Definitive</td></tr>
  </tbody>
</table>

<!-- ═══════════════════════════════════════════════════ TOPIC 6 ══ -->
<div class="topic-header"><span class="topic-num">6</span><span class="topic-title">Acute Phase Plasma Proteins and Their Clinical Significance</span></div>

<p><b>Definition:</b> Proteins whose plasma concentration changes by ≥25% within hours to days in response to infection, inflammation, trauma, or malignancy.</p>
<div class="info-box">Stimulus: IL-1β, IL-6, TNF-α from macrophages → Hepatocytes → Synthesis of acute phase proteins</div>

<h3>Positive Acute Phase Proteins (↑ in inflammation)</h3>
<table>
  <thead><tr><th>Protein</th><th>Function</th><th>Clinical Significance</th></tr></thead>
  <tbody>
    <tr><td><b>CRP</b></td><td>Opsonisation; activates complement; binds phosphocholine on bacteria</td><td>Monitor infection/inflammation; hs-CRP for cardiovascular risk (&gt;3 mg/L = high risk)</td></tr>
    <tr><td><b>Serum Amyloid A (SAA)</b></td><td>Apolipoprotein; HDL remodelling</td><td>Precursor of AA amyloid; monitor secondary amyloid risk in chronic inflammation</td></tr>
    <tr><td><b>Fibrinogen</b></td><td>Forms fibrin clot; coagulation factor</td><td>↑ ESR (coats RBCs → rouleaux); procoagulant state</td></tr>
    <tr><td><b>Haptoglobin</b></td><td>Binds free Hb → prevents renal loss of Hb</td><td>↓ or absent in haemolysis (consumed); distinguishes intravascular haemolysis</td></tr>
    <tr><td><b>Ceruloplasmin</b></td><td>Copper transport; ferroxidase activity</td><td>↓ in Wilson's disease; ↑ in inflammation</td></tr>
    <tr><td><b>Alpha-1 Antitrypsin (A1AT)</b></td><td>Serine protease inhibitor (inhibits neutrophil elastase)</td><td>↓ in A1AT deficiency → emphysema, liver cirrhosis; absent α1 band on SPEP</td></tr>
    <tr><td><b>Ferritin</b></td><td>Iron storage</td><td>↑ in inflammation, haemochromatosis, haemolysis; ↓ in iron deficiency</td></tr>
    <tr><td><b>Complement (C3, C4)</b></td><td>Opsonisation, lysis (innate immunity)</td><td>↑ in acute inflammation; ↓ in SLE (complement consumption)</td></tr>
  </tbody>
</table>

<h3>Negative Acute Phase Proteins (↓ in inflammation)</h3>
<table>
  <thead><tr><th>Protein</th><th>Reason for Fall</th><th>Clinical Use</th></tr></thead>
  <tbody>
    <tr><td><b>Albumin</b></td><td>↓ synthesis (resources diverted); ↑ vascular permeability</td><td>Malnutrition, chronic disease marker; ↓ in nephrotic syndrome</td></tr>
    <tr><td><b>Transferrin</b></td><td>↓ synthesis during APR — sequesters iron from pathogens</td><td>↑ in iron deficiency; ↓ in inflammation, malnutrition</td></tr>
    <tr><td><b>Prealbumin (Transthyretin)</b></td><td>Short half-life (2 days); very sensitive to ↓ synthesis</td><td>Best acute nutritional status marker (ICU/malnutrition)</td></tr>
  </tbody>
</table>
<div class="highlight">CRP rises within 6 hours, peaks at 48 hrs, normalises in 3–7 days (excellent kinetic marker). Prealbumin (t½ = 2 days) is the most sensitive early nutritional marker — better than albumin (t½ = 20 days).</div>

<!-- ═══════════════════════════════════════════════════ TOPIC 7 ══ -->
<div class="topic-header"><span class="topic-num">7</span><span class="topic-title">Normal vs. Abnormal Serum Electrophoresis Patterns</span></div>

<p>Serum proteins are separated by electrophoresis at alkaline pH into <b>5 bands</b>: Albumin, α1, α2, β, and γ.</p>

<h3>Normal Serum Protein Fractions</h3>
<table>
  <thead><tr><th>Band</th><th>Proteins Included</th><th>Normal %</th><th>Normal (g/dL)</th></tr></thead>
  <tbody>
    <tr><td><b>Albumin</b></td><td>Albumin</td><td>~60%</td><td>3.5–5.0</td></tr>
    <tr><td><b>α1</b></td><td>A1AT (major), HDL, Orosomucoid</td><td>2–4%</td><td>0.2–0.4</td></tr>
    <tr><td><b>α2</b></td><td>Haptoglobin, Ceruloplasmin, α2-Macroglobulin</td><td>6–12%</td><td>0.5–0.9</td></tr>
    <tr><td><b>β</b></td><td>Transferrin, LDL, C3, Fibrinogen</td><td>10–15%</td><td>0.7–1.3</td></tr>
    <tr><td><b>γ</b></td><td>Immunoglobulins (IgG, IgA, IgM, IgD, IgE)</td><td>15–20%</td><td>0.7–1.6</td></tr>
  </tbody>
</table>

<h3>Abnormal Patterns</h3>
<table>
  <thead><tr><th>Condition</th><th>Albumin</th><th>α1</th><th>α2</th><th>β</th><th>γ</th><th>Key Finding</th></tr></thead>
  <tbody>
    <tr><td><b>Multiple Myeloma</b></td><td>↓</td><td>↓</td><td>↓</td><td>↔</td><td>M-spike ↑↑</td><td>Narrow tall sharp peak; monoclonal Ig; Bence-Jones proteins in urine</td></tr>
    <tr><td><b>Polyclonal Gammopathy</b> (cirrhosis, SLE, HIV)</td><td>↓</td><td>↓</td><td>↓</td><td>↑</td><td>Broad diffuse ↑</td><td>All Ig classes ↑; β-γ bridging in cirrhosis (IgA)</td></tr>
    <tr><td><b>Nephrotic Syndrome</b></td><td>↓↓</td><td>↓</td><td>↑↑</td><td>↑</td><td>↓</td><td>↑ α2-Macroglobulin (too large to lose in urine); ↑ LDL</td></tr>
    <tr><td><b>Acute Inflammation</b></td><td>↓</td><td>↑</td><td>↑</td><td>↔</td><td>↔</td><td>↑ Acute phase proteins in α1/α2 bands</td></tr>
    <tr><td><b>A1AT Deficiency</b></td><td>↔</td><td>↓↓</td><td>↔</td><td>↔</td><td>↔</td><td><b>Absent α1 band</b> — pathognomonic</td></tr>
    <tr><td><b>Haemolysis</b></td><td>↔</td><td>↔</td><td>↓</td><td>↔</td><td>↔</td><td>↓ α2 = haptoglobin consumed by free Hb</td></tr>
    <tr><td><b>Iron deficiency</b></td><td>↔</td><td>↔</td><td>↔</td><td>↑</td><td>↔</td><td>↑ β band = raised transferrin</td></tr>
  </tbody>
</table>
<div class="highlight">M-spike (monoclonal) = narrow sharp peak = all identical Ig (same class + same light chain κ or λ).<br/>
Broad γ = polyclonal = many different Ig molecules (chronic infection/inflammation).<br/>
Beta-gamma (β-γ) bridging = hallmark of liver cirrhosis (IgA spans β and γ bands).</div>

<!-- ═══════════════════════════════════════════════════ TOPIC 8 ══ -->
<div class="topic-header"><span class="topic-num">8</span><span class="topic-title">Infant Respiratory Distress Syndrome (IRDS / Neonatal RDS)</span></div>

<p><b>Definition:</b> Life-threatening respiratory disorder in premature neonates (&lt;37 weeks, especially &lt;28 weeks) caused by <b>deficiency of pulmonary surfactant</b>, leading to alveolar collapse, hypoxia, and hyaline membrane formation.</p>

<h3>Surfactant — Biochemistry</h3>
<table>
  <thead><tr><th>Component</th><th>Detail</th><th>Function</th></tr></thead>
  <tbody>
    <tr><td><b>DPPC</b> (Dipalmitoylphosphatidylcholine / Lecithin)</td><td>Major lipid (~40% of surfactant)</td><td>↓ Surface tension at air-liquid interface; prevents alveolar collapse</td></tr>
    <tr><td>Phosphatidylglycerol (PG)</td><td>Aids spreading of surfactant film</td><td>Marker of lung maturity in amniotic fluid</td></tr>
    <tr><td>Sphingomyelin</td><td>NOT a surfactant; constant in amniotic fluid</td><td>Reference denominator for L:S ratio</td></tr>
    <tr><td>SP-B, SP-C</td><td>Hydrophobic surfactant proteins</td><td>Aid surfactant spreading and adsorption</td></tr>
    <tr><td>SP-A, SP-D</td><td>Hydrophilic surfactant proteins</td><td>Innate immunity in the lung (collectins)</td></tr>
  </tbody>
</table>

<div class="info-box"><b>Synthesis:</b> Type II pneumocytes (matures after 34–36 weeks). Pathway: CDP-choline (Kennedy pathway): Choline → Phosphocholine → CDP-choline → Lecithin (DPPC). Stored in lamellar bodies → secreted into alveolar space.</div>

<h3>L:S Ratio (Lecithin:Sphingomyelin Ratio) — Amniotic Fluid</h3>
<table>
  <thead><tr><th>L:S Ratio</th><th>Interpretation</th></tr></thead>
  <tbody>
    <tr><td><b>&lt; 2.0</b></td><td>Lung IMMATURE → High risk of IRDS</td></tr>
    <tr><td><b>≥ 2.0</b></td><td>Lung MATURE → Low risk of IRDS</td></tr>
    <tr><td>PG present</td><td>Additional marker of lung maturity</td></tr>
  </tbody>
</table>

<h3>Pathophysiology</h3>
<div class="flow">PREMATURITY (&lt;34 weeks)
  -->  Immature Type II pneumocytes  -->  ↓ DPPC synthesis
  -->  ↑ Alveolar surface tension (LaPlace's law: P = 2T/r)
  -->  Alveolar COLLAPSE (atelectasis) at end-expiration
  -->  Hypoxia + Acidosis  -->  Pulmonary vasoconstriction
  -->  Right-to-Left shunting  -->  further hypoxia
  -->  Protein-rich exudate + fibrin  -->  HYALINE MEMBRANES</div>

<h3>Treatment</h3>
<table>
  <thead><tr><th>Intervention</th><th>Detail</th></tr></thead>
  <tbody>
    <tr><td><b>Antenatal corticosteroids</b></td><td>Betamethasone/dexamethasone to mother ≥24 hrs before birth; ↑ surfactant synthesis via ↑ Type II pneumocyte maturation</td></tr>
    <tr><td><b>Exogenous surfactant (intratracheal)</b></td><td>Beractant (Survanta), Poractant alfa (Curosurf); given at birth; dramatically reduces mortality</td></tr>
    <tr><td><b>CPAP / Mechanical ventilation</b></td><td>Maintains positive end-expiratory pressure; prevents alveolar collapse</td></tr>
  </tbody>
</table>

<!-- ═══════════════════════════════════════════════════ TOPIC 9 ══ -->
<div class="topic-header"><span class="topic-num">9</span><span class="topic-title">Jaundice</span></div>

<p>Yellow discolouration of skin, sclerae, and mucous membranes due to ↑ serum bilirubin. Clinical jaundice appears at <b>&gt;2 mg/dL</b>; detectable in lab at &gt;1 mg/dL (latent jaundice).</p>

<h3>Bilirubin Metabolism — Biochemical Pathway</h3>
<div class="flow">HEME (from destroyed RBCs ~80%)
  --[Heme oxygenase, RES]-->  Biliverdin + CO + Fe2+
  --[Biliverdin reductase]-->  BILIRUBIN (unconjugated/indirect)
  (fat-soluble; water-insoluble; TOXIC to brain; bound to albumin in blood)

  --[Hepatocyte uptake via OATP transporters]-->  Hepatocyte
  --[UDP-glucuronosyltransferase UGT1A1, in SER]-->
  BILIRUBIN DIGLUCURONIDE (conjugated/direct)
  (water-soluble; NON-toxic; excreted in bile via MRP2 canalicular transporter)

  Intestine: [Bacterial beta-glucuronidase]-->  UROBILINOGEN
  20% reabsorbed --> portal vein --> liver & kidney --> URINE urobilinogen (normal)
  80% --> oxidised in gut --> STERCOBILIN (brown colour of faeces)</div>

<h3>Classification of Jaundice</h3>
<table>
  <thead><tr><th>Type</th><th>Cause</th><th>Bilirubin</th><th>Urine</th><th>Stool</th><th>Other</th></tr></thead>
  <tbody>
    <tr><td><b>Pre-hepatic (Haemolytic)</b></td><td>↑ RBC destruction</td><td>↑ Unconjugated</td><td>↑ Urobilinogen; NO bilirubin</td><td>Normal/dark</td><td>↑ LDH, ↓ haptoglobin, anaemia</td></tr>
    <tr><td><b>Hepatic (Hepatocellular)</b></td><td>Liver damage (hepatitis, cirrhosis)</td><td>↑ Both (mixed)</td><td>Bilirubin + ↑ urobilinogen</td><td>Pale</td><td>↑ AST, ALT, ↑ PT</td></tr>
    <tr><td><b>Post-hepatic (Obstructive)</b></td><td>Bile duct obstruction (stones, carcinoma)</td><td>↑ Conjugated</td><td>Bilirubin ++ ; NO urobilinogen</td><td>Pale/clay</td><td>↑ ALP, GGT; pruritus; dark urine</td></tr>
  </tbody>
</table>

<h3>Specific Bilirubin Metabolism Disorders</h3>
<table>
  <thead><tr><th>Syndrome</th><th>Defect</th><th>Bilirubin</th><th>Key Feature</th></tr></thead>
  <tbody>
    <tr><td><b>Gilbert's syndrome</b></td><td>↓ UGT1A1 (mild, ~30%)</td><td>↑ Unconjugated</td><td>Benign; fasting/stress triggers; no treatment needed</td></tr>
    <tr><td><b>Crigler-Najjar Type I</b></td><td>Absent UGT1A1</td><td>↑↑↑ Unconjugated</td><td>Kernicterus; fatal without phototherapy/transplant</td></tr>
    <tr><td><b>Crigler-Najjar Type II</b></td><td>Partial UGT1A1 deficiency</td><td>↑ Unconjugated</td><td>Responds to phenobarbitone (↑ UGT1A1 induction)</td></tr>
    <tr><td><b>Dubin-Johnson</b></td><td>Defective MRP2 (canalicular transporter)</td><td>↑ Conjugated</td><td>Black liver (melanin-like pigment); benign</td></tr>
    <tr><td><b>Rotor syndrome</b></td><td>Defective hepatic bilirubin storage</td><td>↑ Conjugated</td><td>Benign; no black liver; normal life expectancy</td></tr>
  </tbody>
</table>
<div class="highlight">Neonatal Physiological Jaundice: Day 2–3 to Day 10–14. Cause: Immature UGT1A1 + ↑ fetal Hb breakdown. Unconjugated bilirubin crosses BBB → KERNICTERUS if severe. Treatment: Phototherapy converts bilirubin to water-soluble lumirubin photoisomers.</div>

<!-- ═══════════════════════════════════════════════════ TOPIC 10 ══ -->
<div class="topic-header"><span class="topic-num">10</span><span class="topic-title">Glycogen Storage Disorders (Glycogenoses)</span></div>

<p>Group of <b>autosomal recessive</b> inherited disorders caused by deficiency of enzymes in glycogen synthesis or degradation, resulting in abnormal accumulation of glycogen in various tissues.</p>

<h3>Normal Glycogen Metabolism</h3>
<div class="flow">SYNTHESIS:
  Glucose --> G-6-P --> G-1-P --> UDP-Glucose --> GLYCOGEN
  [Glycogen synthase] + [Branching enzyme (IV)]

DEGRADATION:
  GLYCOGEN --[Phosphorylase (V, VI)]--> G-1-P --[Phosphoglucomutase]--> G-6-P
  [Debranching enzyme (III)] needed at branch points
  G-6-P --[Glucose-6-Phosphatase (I)]--> FREE GLUCOSE (liver only)
  [Lysosomal acid maltase (II)] degrades glycogen in lysosomes</div>

<h3>Classification of Glycogen Storage Diseases</h3>
<table>
  <thead><tr><th>Type</th><th>Name</th><th>Enzyme Deficient</th><th>Organ(s)</th><th>Key Features</th></tr></thead>
  <tbody>
    <tr><td><b>Ia</b></td><td><b>Von Gierke</b></td><td>Glucose-6-phosphatase (G6PC)</td><td>Liver, Kidney</td><td>Hepatomegaly, fasting hypoglycaemia, lactic acidosis, hyperuricaemia, hyperlipidaemia; "doll-like" facies</td></tr>
    <tr><td><b>Ib</b></td><td>Von Gierke variant</td><td>G6P translocase (SLC37A4)</td><td>Liver, Kidney, WBCs</td><td>Same as Ia + <b>NEUTROPENIA + IBD</b></td></tr>
    <tr><td><b>II</b></td><td><b>Pompe</b></td><td>Lysosomal acid α-glucosidase (GAA)</td><td>All organs (heart dominant)</td><td>Massive cardiomegaly; hypotonia; death &lt;2 yrs; <b>ONLY GSD with enzyme replacement</b> (alglucosidase alfa)</td></tr>
    <tr><td><b>III</b></td><td>Cori / Forbes</td><td>Debranching enzyme (AGL)</td><td>Liver, heart, muscle</td><td>Mild hepatomegaly; hypoglycaemia; progressive myopathy</td></tr>
    <tr><td><b>IV</b></td><td>Andersen</td><td>Branching enzyme (GBE1)</td><td>Liver, all tissues</td><td>Abnormal glycogen → cirrhosis, liver failure</td></tr>
    <tr><td><b>V</b></td><td><b>McArdle</b></td><td>Muscle phosphorylase (PYGM)</td><td>Skeletal muscle</td><td>Exercise cramps; <b>no blood lactate rise on exercise</b>; myoglobinuria</td></tr>
    <tr><td><b>VII</b></td><td>Tarui</td><td>Muscle phosphofructokinase</td><td>Muscle, RBCs</td><td>McArdle-like + haemolytic anaemia</td></tr>
  </tbody>
</table>

<h3>Type I (Von Gierke) — Biochemistry</h3>
<div class="flow">G6Pase ABSENT  -->  Glucose-6-P ACCUMULATES
  |
  +--[Glycolysis]-->  Pyruvate --> LACTATE  -->  LACTIC ACIDOSIS
  |
  +--[HMP shunt]--> Ribose-5-P --> Purines --> URIC ACID --> HYPERURICAEMIA / GOUT
  |
  +--[Lipogenesis]--> Acetyl-CoA --> FFA -->  HYPERTRIGLYCERIDAEMIA
  |
  +--Cannot dephosphorylate --> No free glucose -->  HYPOGLYCAEMIA
     (Both GLYCOGENOLYSIS and GLUCONEOGENESIS blocked — both feed into G6P)</div>

<div class="highlight">Most common GSD = Type I (Von Gierke). Only lysosomal GSD = Type II (Pompe) — has enzyme replacement therapy. Exercise cramps + no lactate rise = Types V and VII (myopathic). Treatment of Type I: Uncooked Cornstarch (UCCS) every 4–6 hours; avoid fructose and galactose.</div>

<!-- ═══════════════════════════════════════════════════ TOPIC 11 ══ -->
<div class="topic-header"><span class="topic-num">11</span><span class="topic-title">Clinical Significance of Competitive Inhibitors as Drugs</span></div>

<p>A <b>competitive inhibitor</b> structurally resembles the substrate and competes for binding at the enzyme <b>active site</b>. Inhibition is <b>reversible</b> and overcome by increasing substrate concentration.</p>

<h3>Enzyme Kinetics</h3>
<table>
  <thead><tr><th>Parameter</th><th>Effect of Competitive Inhibition</th><th>Explanation</th></tr></thead>
  <tbody>
    <tr><td><b>Vmax</b></td><td>UNCHANGED</td><td>Can still be achieved with excess substrate</td></tr>
    <tr><td><b>Apparent Km</b></td><td>INCREASED (↑)</td><td>More substrate needed to achieve half-Vmax</td></tr>
    <tr><td>Lineweaver-Burk plot</td><td>Lines intersect on Y-axis</td><td>Same Vmax, different x-intercept (−1/Km)</td></tr>
  </tbody>
</table>

<h3>Clinically Important Competitive Inhibitor Drugs</h3>
<table>
  <thead><tr><th>Drug</th><th>Target Enzyme</th><th>Analog Of</th><th>Clinical Use</th></tr></thead>
  <tbody>
    <tr><td><b>Statins</b> (Atorvastatin, Simvastatin)</td><td>HMG-CoA reductase (rate-limiting step in cholesterol synthesis)</td><td>HMG-CoA</td><td>Hypercholesterolaemia; CVD prevention; ↑ LDL receptors in liver</td></tr>
    <tr><td><b>Methotrexate</b></td><td>Dihydrofolate reductase (DHFR)</td><td>Dihydrofolate</td><td>Cancer, rheumatoid arthritis, psoriasis; ↓ THF → ↓ purine/thymidylate synthesis</td></tr>
    <tr><td><b>Trimethoprim</b></td><td>Bacterial DHFR (50,000× selectivity over human DHFR)</td><td>Dihydrofolate</td><td>UTI, PCP; combined with sulfamethoxazole (co-trimoxazole)</td></tr>
    <tr><td><b>Allopurinol</b></td><td>Xanthine oxidase</td><td>Hypoxanthine / Xanthine</td><td>Gout; hyperuricaemia in GSD Type I; tumour lysis syndrome</td></tr>
    <tr><td><b>ACE Inhibitors</b> (Captopril, Enalapril)</td><td>Angiotensin-converting enzyme (ACE)</td><td>C-terminus of Angiotensin I</td><td>Hypertension, heart failure, diabetic nephropathy; ↑ bradykinin (cough)</td></tr>
    <tr><td><b>Sildenafil</b></td><td>Phosphodiesterase-5 (PDE-5)</td><td>cGMP</td><td>Erectile dysfunction; pulmonary arterial hypertension; ↑ cGMP → vasodilation</td></tr>
    <tr><td><b>Carbidopa</b></td><td>DOPA decarboxylase (peripheral, does not cross BBB)</td><td>L-DOPA</td><td>Parkinson's disease (with L-DOPA); ↑ CNS L-DOPA; ↓ nausea, vomiting</td></tr>
    <tr><td><b>Pyrimethamine</b></td><td>Parasite DHFR</td><td>Dihydrofolate</td><td>Malaria prophylaxis; toxoplasmosis</td></tr>
    <tr><td><b>Eflornithine</b></td><td>Ornithine decarboxylase (ODC)</td><td>Ornithine</td><td>African sleeping sickness; facial hirsutism</td></tr>
  </tbody>
</table>

<h3>Why Competitive Inhibitors Make Ideal Drugs</h3>
<table>
  <thead><tr><th>Advantage</th><th>Explanation</th></tr></thead>
  <tbody>
    <tr><td>1. Selectivity</td><td>Drug mimics substrate → targets specific enzyme active site → fewer off-target effects</td></tr>
    <tr><td>2. Reversibility</td><td>Inhibition reversed by ↑ substrate or removing drug → safer, titratable dose-response</td></tr>
    <tr><td>3. Dose-response</td><td>Doubling dose doubles inhibition (unlike irreversible inhibitors)</td></tr>
    <tr><td>4. Rescue possible</td><td>Substrate supplement can overcome inhibition (folinic acid rescue after methotrexate overdose)</td></tr>
    <tr><td>5. Species selectivity</td><td>Pathogen enzyme vs. human enzyme differences exploitable (e.g. Trimethoprim for bacterial DHFR)</td></tr>
  </tbody>
</table>

<div class="highlight">⚠ Special case — Aspirin: Irreversibly acetylates the active-site serine of COX-1/COX-2 (irreversible competitive inhibition). Platelets cannot synthesise new COX → antiplatelet effect lasts platelet lifespan (7–10 days).</div>

<!-- FOOTER -->
<div class="footer">
  MBBS Biochemistry Short Notes &nbsp;|&nbsp; For educational purposes only<br/>
  Sources: Lippincott's Illustrated Reviews: Biochemistry 8e &nbsp;•&nbsp; Robbins &amp; Kumar Basic Pathology &nbsp;•&nbsp; Robbins Cotran &amp; Kumar Pathologic Basis of Disease &nbsp;•&nbsp; Goldman-Cecil Medicine &nbsp;•&nbsp; Basic Medical Biochemistry (Lieberman &amp; Peet)
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    pdf.cell(0, 7, title, ln=True)
    pdf.set_draw_color(220, 220, 220)
    pdf.set_line_width(0.2)
    pdf.line(18, pdf.get_y(), 192, pdf.get_y())

# ══════════════════════════════════════════════════════════════════════════════
# TOPIC 1 — G6PD
# ══════════════════════════════════════════════════════════════════════════════
pdf.add_page()
pdf.set_y(12)
pdf.topic_banner(1, "G-6-PD Deficiency")
pdf.body("X-linked recessive deficiency of G6PD, the rate-limiting enzyme of the HMP shunt, causing episodic hemolytic anemia on oxidative stress. Affects ~500 million people worldwide.")
pdf.h2("Biochemical Basis")
pdf.flow([
    "HMP SHUNT:",
    "  Glucose-6-P + NADP+  --[G6PD]-->  6-Phosphogluconate + NADPH",
    "",
    "NADPH reduces Glutathione:",
    "  GSSG + NADPH  -->  2 GSH + NADP+",
    "  GSH neutralises H2O2 and free radicals --> protects RBC membrane",
    "",
    "IN G6PD DEFICIENCY:",
    "  low NADPH --> low GSH --> oxidative stress NOT neutralised",
    "  --> Hb oxidised --> Methemoglobin --> Heinz bodies",
    "  --> rigid RBCs trapped in spleen --> HEMOLYTIC ANAEMIA",
])
pdf.h2("Genetics & Variants")
pdf.bullet("X-linked recessive — males affected, females are carriers")
pdf.bullet("G6PD-A- (African, mild episodic); G6PD-Mediterranean (severe, chronic)")
pdf.h2("Precipitants — PRIMA")
pdf.highlight("P - Primaquine, dapsone  |  R - Infections (most common)  |  I - Fava beans (favism)  |  M - Metabolic acidosis  |  A - Aspirin, sulfonamides, nitrofurantoin")
pdf.h2("Laboratory Findings")
pdf.table(
    ["Test", "Finding", "Significance"],
    [
        ["Blood film", "Heinz bodies, bite cells, blister cells", "Oxidised Hb precipitates"],
        ["Hb / Haematocrit", "Decreased", "Haemolytic anaemia"],
        ["LDH / Indirect bilirubin", "Increased", "Haemolysis markers"],
        ["Fluorescent spot test", "No fluorescence (NADPH absent)", "Screening test"],
        ["G6PD enzyme assay", "Markedly reduced activity", "Confirmatory test"],
    ],
    [50, 70, 54]
)
pdf.highlight("KEY: G6PD is the ONLY source of NADPH in RBCs (no mitochondria). Do NOT test during acute haemolysis - reticulocytes give false-normal results.")

# ══════════════════════════════════════════════════════════════════════════════
# TOPIC 2 — METABOLIC ACIDOSIS
# ══════════════════════════════════════════════════════════════════════════════
pdf.add_page()
pdf.set_y(12)
pdf.topic_banner(2, "Metabolic Acidosis")
pdf.body("Primary acid-base disorder characterised by decreased blood pH and decreased HCO3-, caused by gain of fixed acid or loss of bicarbonate.")
pdf.info_box("Anion Gap (AG) = Na+ - (Cl- + HCO3-)     Normal = 8-12 mEq/L")
pdf.h2("Classification")
pdf.table(
    ["Type", "AG", "Mnemonic / Causes"],
    [
        ["High Anion Gap (>12)", "Increased", "MUDPILES: Methanol, Uraemia, DKA, Propylene glycol/Paracetamol, Isoniazid/Iron, Lactic acidosis, Ethylene glycol, Salicylates"],
        ["Normal AG (Hyperchloraemic)", "Normal", "HARD UP: Hyperalimentation, Acetazolamide/Addison's, Renal tubular acidosis, Diarrhoea, Ureteral diversion, Post-hypocapnia"],
    ],
    [46, 22, 106]
)
pdf.h2("ABG & Compensation")
pdf.table(
    ["Parameter", "Change", "Detail"],
    [
        ["pH", "Decreased (<7.35)", "Primary disorder"],
        ["HCO3-", "Decreased (<22 mEq/L)", "Primary change"],
        ["PCO2", "Decreased (compensatory)", "Kussmaul breathing (deep, rapid)"],
        ["Expected PCO2", "= 1.5 x [HCO3-] + 8 +/- 2", "Winter's formula"],
    ],
    [40, 50, 84]
)
pdf.h2("Clinical Features")
pdf.bullet("Kussmaul respiration - deep, rapid breathing (fruity odour in DKA)")
pdf.bullet("Nausea, vomiting, abdominal pain")
pdf.bullet("Cardiac: arrhythmias, decreased cardiac output, hypotension")
pdf.bullet("CNS: confusion progressing to coma")
pdf.bullet("Hyperkalaemia (H+ enters cells, K+ exits in exchange)")
pdf.h2("Treatment")
pdf.bullet("Treat underlying cause (insulin in DKA; dialysis in renal failure)")
pdf.bullet("NaHCO3 if pH < 7.1 or severe symptoms")
pdf.bullet("Dialysis for methanol, ethylene glycol poisoning")

# ══════════════════════════════════════════════════════════════════════════════
# TOPIC 3 — DIABETES COMPLICATIONS
# ══════════════════════════════════════════════════════════════════════════════
pdf.add_page()
pdf.set_y(12)
pdf.topic_banner(3, "Complications of Diabetes Mellitus")
pdf.body("Chronic hyperglycaemia drives four major biochemical pathways of cellular damage:")
pdf.table(
    ["Pathway", "Mechanism", "Outcome"],
    [
        ["Polyol (Sorbitol)", "Glucose -> Sorbitol (aldose reductase); sorbitol accumulates (impermeable)", "Osmotic damage: cataracts, neuropathy; decreased NADPH -> decreased GSH"],
        ["AGEs", "Non-enzymatic glycation: Glucose + protein -> Schiff base -> Amadori -> AGE crosslinks", "Basement membrane thickening; microangiopathy; HbA1c formed"],
        ["PKC Activation", "Increased DAG -> PKC -> increased VEGF, TGF-beta, fibronectin", "Retinal neovascularisation; glomerular hypertrophy; nephropathy"],
        ["Hexosamine Pathway", "Excess G6P -> glucosamine-6-P -> O-GlcNAc protein modification", "Increased TGF-beta, PAI-1 -> fibrosis and thrombosis"],
    ],
    [34, 76, 64]
)
pdf.h2("Microvascular Complications")
pdf.table(
    ["Complication", "Key Features", "Biochemistry"],
    [
        ["Retinopathy", "Non-proliferative -> Proliferative; VEGF-driven neovascularisation; leading cause of blindness", "PKC activation; increased VEGF; AGE crosslinks"],
        ["Nephropathy", "Microalbuminuria -> Proteinuria -> CKD; Kimmelstiel-Wilson nodules", "GBM thickening (AGEs); increased TGF-beta"],
        ["Neuropathy", "Glove-stocking sensory loss; autonomic (gastroparesis, impotence)", "Sorbitol accumulation; decreased myoinositol; decreased Na/K-ATPase"],
    ],
    [30, 84, 60]
)
pdf.h2("Acute Metabolic Complications")
pdf.table(
    ["Complication", "Type", "Biochemistry", "Key Feature"],
    [
        ["DKA", "Type 1", "Increased lipolysis -> increased FFA -> ketone bodies (acetoacetate, beta-hydroxybutyrate) -> High AG acidosis", "pH <7.3; ketones ++"],
        ["HHS", "Type 2", "Severe hyperglycaemia (>600 mg/dL); residual insulin prevents lipolysis - no ketosis", "Hyperosmolality; no ketosis"],
    ],
    [22, 18, 96, 38]
)
pdf.highlight("HbA1c = glycated haemoglobin; reflects average blood glucose over 3 months. Target HbA1c < 7% (53 mmol/mol) in most patients.")

# ══════════════════════════════════════════════════════════════════════════════
# TOPIC 4 — PROTEIN MISFOLDING
# ══════════════════════════════════════════════════════════════════════════════
pdf.add_page()
pdf.set_y(12)
pdf.topic_banner(4, "Protein Misfolding and Associated Disorders")
pdf.body("Misfolding occurs when polypeptides fail to achieve their correct native conformation, expose hydrophobic regions, aggregate into beta-sheet-rich fibrils, and cause cellular toxicity.")
pdf.flow([
    "NORMAL:  Polypeptide  -->  Native (alpha-helical, soluble) conformation",
    "          Assisted by CHAPERONES (Hsp70, Hsp90, GroEL)",
    "          Abnormal proteins degraded by UBIQUITIN-PROTEASOME system",
    "",
    "MISFOLDING (mutation / oxidative stress / ageing):",
    "  Exposes hydrophobic residues  -->  protein AGGREGATION",
    "  -->  beta-sheet rich FIBRILS  -->  AMYLOID deposits  -->  organ dysfunction",
])
pdf.h2("Major Protein Misfolding Disorders")
pdf.table(
    ["Category", "Disease", "Protein", "Key Feature"],
    [
        ["Amyloidoses", "AL amyloidosis", "Ig light chains", "Plasma cell dyscrasia (myeloma)"],
        ["", "AA amyloidosis", "Serum Amyloid A (SAA)", "Chronic inflammation (RA, TB)"],
        ["", "Senile cardiac amyloidosis", "Transthyretin (TTR)", "Heart failure in elderly"],
        ["Neurodegenerative", "Alzheimer disease", "Amyloid-beta + tau", "Amyloid plaques + neurofibrillary tangles"],
        ["", "Parkinson disease", "alpha-synuclein", "Lewy bodies in dopaminergic neurons"],
        ["", "Huntington disease", "Huntingtin (polyQ)", "CAG repeat expansion; chorea"],
        ["Prion diseases", "CJD / BSE / Scrapie", "PrP-Sc", "Protein-only infectious agent; no nucleic acid"],
        ["ER stress disease", "Cystic fibrosis (dF508)", "CFTR", "Misfolded CFTR retained in ER and degraded"],
    ],
    [36, 42, 44, 52]
)
pdf.h2("Key Points")
pdf.bullet("All amyloid fibrils share a common CROSS-BETA PLEATED SHEET structure")
pdf.bullet("Congo red stain -> apple-green birefringence under polarised light")
pdf.info_box("Prion mechanism: PrP-C (normal, alpha-helical) -> PrP-Sc (abnormal, beta-sheet). PrP-Sc acts as template to convert more PrP-C. Protein-only infectious agent. Resistant to protease, heat, UV.")
pdf.highlight("Unfolded Protein Response (UPR): Accumulation of misfolded proteins in ER triggers UPR. Prolonged UPR -> beta-cell apoptosis (contributes to Type 2 DM).")

# ══════════════════════════════════════════════════════════════════════════════
# TOPIC 5 — POTASSIUM DISORDERS
# ══════════════════════════════════════════════════════════════════════════════
pdf.add_page()
pdf.set_y(12)
pdf.topic_banner(5, "Hyperkalemia and Hypokalemia")
pdf.info_box("Normal serum K+ = 3.5-5.0 mEq/L. 98% of total body K+ is intracellular; only 2% extracellular.")
pdf.h2("HYPOKALEMIA (K+ < 3.5 mEq/L)")
pdf.table(
    ["Cause", "Examples"],
    [
        ["Decreased Intake", "Starvation, alcoholism"],
        ["GI losses", "Diarrhoea, vomiting, NG suction, laxative abuse"],
        ["Renal losses", "Loop/thiazide diuretics, hyperaldosteronism, RTA, hypomagnesaemia, Cushing's, Bartter syndrome"],
        ["Transcellular shift (K+ into cells)", "Insulin, catecholamines, alkalosis, beta2-agonists"],
    ],
    [60, 114]
)
pdf.h2("ECG Changes in Hypokalemia (in order)")
pdf.bullet("1. Flat / inverted T waves")
pdf.bullet("2. Prominent U waves (after T wave, best seen V2-V3) <- most characteristic")
pdf.bullet("3. ST depression    4. Prolonged QU interval    5. Ventricular fibrillation")
pdf.body("Clinical: Muscle weakness, cramps, constipation, polyuria, cardiac arrhythmias, metabolic alkalosis.")
pdf.highlight("Treatment: Oral/IV KCl. Always correct hypomagnesaemia (refractory hypokalaemia if Mg2+ not corrected).")
pdf.h2("HYPERKALEMIA (K+ > 5.0 mEq/L)")
pdf.table(
    ["Cause", "Examples"],
    [
        ["Decreased Excretion", "Renal failure (most common), ACE inhibitors/ARBs, K-sparing diuretics, Addison's disease"],
        ["Transcellular shift (K+ out of cells)", "Acidosis, insulin deficiency (DKA), cell lysis (haemolysis, rhabdomyolysis, TLS), succinylcholine, beta-blockers"],
        ["Pseudohyperkalaemia", "Thrombocytosis, leukocytosis, haemolysed sample"],
    ],
    [60, 114]
)
pdf.h2("ECG Changes (in order of severity)")
pdf.bullet("1. Tall peaked symmetric T waves <- EARLIEST sign")
pdf.bullet("2. Prolonged PR interval    3. Widened QRS    4. Sine-wave pattern    5. VF / Asystole")
pdf.h2("Treatment - A-C-D-D-D-D")
pdf.table(
    ["Drug / Intervention", "Mechanism", "Onset"],
    [
        ["Calcium gluconate", "Membrane stabilisation (cardioprotective)", "Minutes - FASTEST"],
        ["Insulin + Dextrose", "Shifts K+ into cells via Na/K-ATPase", "20-30 min"],
        ["Sodium bicarbonate", "Shifts K+ into cells (if acidosis present)", "30-60 min"],
        ["Salbutamol (beta2-agonist)", "Shifts K+ into cells", "30 min"],
        ["Kayexalate / Patiromer", "Resin: exchanges Na+/Ca2+ for K+ in gut", "Hours"],
        ["Dialysis", "Definitive K+ removal", "Definitive"],
    ],
    [55, 82, 37]
)

# ══════════════════════════════════════════════════════════════════════════════
# TOPIC 6 — ACUTE PHASE PROTEINS
# ══════════════════════════════════════════════════════════════════════════════
pdf.add_page()
pdf.set_y(12)
pdf.topic_banner(6, "Acute Phase Plasma Proteins")
pdf.body("Proteins whose plasma concentration changes by >=25% within hours to days in response to infection, inflammation, trauma, or malignancy.")
pdf.info_box("Stimulus: IL-1b, IL-6, TNF-alpha from macrophages --> Hepatocytes --> Synthesis of acute phase proteins")
pdf.h2("Positive Acute Phase Proteins (Increased in inflammation)")
pdf.table(
    ["Protein", "Function", "Clinical Significance"],
    [
        ["CRP (C-Reactive Protein)", "Opsonisation; activates complement; binds phosphocholine on bacteria", "Monitor infection/inflammation; hs-CRP >3 mg/L = high cardiovascular risk"],
        ["Serum Amyloid A (SAA)", "Apolipoprotein; HDL remodelling", "Precursor of AA amyloid; monitor secondary amyloid risk"],
        ["Fibrinogen", "Forms fibrin clot (coagulation)", "Increased ESR (coats RBCs -> rouleaux); procoagulant state"],
        ["Haptoglobin", "Binds free Hb -> prevents renal Hb loss", "Absent/decreased in haemolysis (consumed); distinguishes intravascular haemolysis"],
        ["Ceruloplasmin", "Copper transport; ferroxidase activity", "Decreased in Wilson's disease; increased in inflammation"],
        ["Alpha-1 Antitrypsin (A1AT)", "Serine protease inhibitor (inhibits elastase)", "Decreased in A1AT deficiency -> emphysema, liver cirrhosis; absent alpha1 band on SPEP"],
        ["Ferritin", "Iron storage protein", "Increased in inflammation, haemochromatosis; decreased in iron deficiency"],
        ["Complement (C3, C4)", "Opsonisation, lysis (innate immunity)", "Increased in acute inflammation; decreased in SLE (complement consumption)"],
    ],
    [42, 64, 68]
)
pdf.h2("Negative Acute Phase Proteins (Decreased in inflammation)")
pdf.table(
    ["Protein", "Reason for Fall", "Clinical Use"],
    [
        ["Albumin", "Decreased synthesis; increased vascular permeability", "Malnutrition, chronic disease; decreased in nephrotic syndrome"],
        ["Transferrin", "Decreased synthesis during APR; sequesters iron from pathogens", "Increased in iron deficiency; decreased in inflammation"],
        ["Prealbumin (Transthyretin)", "Short half-life (2 days); very sensitive to decreased synthesis", "Best acute nutritional status marker (ICU/malnutrition)"],
    ],
    [42, 72, 60]
)
pdf.highlight("CRP rises within 6 hours, peaks at 48 hrs. Prealbumin (half-life 2 days) is more sensitive than albumin (half-life 20 days) for nutritional status.")

# ══════════════════════════════════════════════════════════════════════════════
# TOPIC 7 — SERUM ELECTROPHORESIS
# ══════════════════════════════════════════════════════════════════════════════
pdf.add_page()
pdf.set_y(12)
pdf.topic_banner(7, "Normal vs. Abnormal Serum Electrophoresis Patterns")
pdf.body("Serum proteins are separated by electrophoresis at alkaline pH into 5 bands: Albumin, alpha1, alpha2, beta, and gamma.")
pdf.h2("Normal Serum Protein Fractions")
pdf.table(
    ["Band", "Proteins Included", "Normal %", "Normal (g/dL)"],
    [
        ["Albumin", "Albumin", "~60%", "3.5-5.0"],
        ["alpha1", "A1AT (major), HDL, Orosomucoid", "2-4%", "0.2-0.4"],
        ["alpha2", "Haptoglobin, Ceruloplasmin, alpha2-Macroglobulin", "6-12%", "0.5-0.9"],
        ["beta", "Transferrin, LDL, C3, Fibrinogen", "10-15%", "0.7-1.3"],
        ["gamma", "Immunoglobulins (IgG, IgA, IgM, IgD, IgE)", "15-20%", "0.7-1.6"],
    ],
    [24, 88, 24, 38]
)
pdf.h2("Abnormal Patterns")
pdf.table(
    ["Condition", "Albumin", "alpha1", "alpha2", "beta", "gamma", "Key Finding"],
    [
        ["Multiple Myeloma", "Low", "Low", "Low", "Normal", "M-spike++", "Narrow tall sharp peak; monoclonal Ig; Bence-Jones proteins in urine"],
        ["Polyclonal Gammopathy (cirrhosis/SLE/HIV)", "Low", "Low", "Low", "High", "Broad high", "All Ig classes increased; beta-gamma bridging in cirrhosis (IgA)"],
        ["Nephrotic Syndrome", "Very low", "Low", "Very high", "High", "Low", "alpha2-Macroglobulin too large to lose in urine; increased LDL"],
        ["Acute Inflammation", "Low", "High", "High", "Normal", "Normal", "Increased acute phase proteins in alpha1/alpha2 bands"],
        ["A1AT Deficiency", "Normal", "Absent", "Normal", "Normal", "Normal", "Absent alpha1 band - pathognomonic"],
        ["Haemolysis", "Normal", "Normal", "Low", "Normal", "Normal", "Decreased alpha2 = haptoglobin consumed by free Hb"],
    ],
    [36, 16, 16, 18, 16, 20, 52]
)
pdf.highlight("M-spike (monoclonal) = narrow sharp peak = identical Ig (same class + same light chain kappa or lambda). Broad gamma = polyclonal = many different Ig molecules. Beta-gamma bridging = hallmark of liver cirrhosis (IgA).")

# ══════════════════════════════════════════════════════════════════════════════
# TOPIC 8 — IRDS
# ══════════════════════════════════════════════════════════════════════════════
pdf.add_page()
pdf.set_y(12)
pdf.topic_banner(8, "Infant Respiratory Distress Syndrome (IRDS / Neonatal RDS)")
pdf.body("Life-threatening respiratory disorder in premature neonates (<37 weeks, especially <28 weeks) caused by DEFICIENCY OF PULMONARY SURFACTANT, leading to alveolar collapse, hypoxia, and hyaline membrane formation.")
pdf.h2("Surfactant - Biochemistry")
pdf.table(
    ["Component", "Detail", "Function"],
    [
        ["DPPC (Lecithin)", "Major lipid (~40% of surfactant)", "Reduces surface tension at air-liquid interface; prevents alveolar collapse"],
        ["Phosphatidylglycerol (PG)", "Aids spreading of surfactant film", "Marker of lung maturity in amniotic fluid"],
        ["Sphingomyelin", "NOT a surfactant; constant in amniotic fluid", "Reference denominator for L:S ratio"],
        ["SP-B, SP-C", "Hydrophobic surfactant proteins", "Aid surfactant spreading and adsorption"],
        ["SP-A, SP-D", "Hydrophilic surfactant proteins", "Innate immunity in the lung (collectins)"],
    ],
    [40, 56, 78]
)
pdf.info_box("Synthesis: Type II pneumocytes (mature after 34-36 weeks). Pathway: CDP-choline (Kennedy) pathway: Choline -> Phosphocholine -> CDP-choline -> DPPC (Lecithin). Stored in lamellar bodies -> secreted into alveolar space.")
pdf.h2("L:S Ratio (Lecithin:Sphingomyelin) - Amniotic Fluid")
pdf.table(
    ["L:S Ratio", "Interpretation"],
    [
        ["< 2.0", "Lung IMMATURE -> High risk of IRDS"],
        [">= 2.0", "Lung MATURE -> Low risk of IRDS"],
        ["PG present", "Additional marker of lung maturity"],
    ],
    [40, 134]
)
pdf.h2("Pathophysiology")
pdf.flow([
    "PREMATURITY (<34 weeks)",
    "  --> Immature Type II pneumocytes --> decreased DPPC synthesis",
    "  --> Increased alveolar surface tension (LaPlace's law: P = 2T/r)",
    "  --> Alveolar COLLAPSE at end-expiration (atelectasis)",
    "  --> Hypoxia + Acidosis --> Pulmonary vasoconstriction",
    "  --> Right-to-Left shunting --> further hypoxia",
    "  --> Protein-rich exudate + fibrin --> HYALINE MEMBRANES",
])
pdf.h2("Treatment")
pdf.table(
    ["Intervention", "Detail"],
    [
        ["Antenatal corticosteroids", "Betamethasone/dexamethasone to mother >=24 hrs before birth; increases surfactant synthesis via Type II pneumocyte maturation"],
        ["Exogenous surfactant (intratracheal)", "Beractant (Survanta), Poractant alfa (Curosurf); given at birth; dramatically reduces mortality"],
        ["CPAP / Mechanical ventilation", "Maintains positive end-expiratory pressure; prevents alveolar collapse"],
    ],
    [50, 124]
)

# ══════════════════════════════════════════════════════════════════════════════
# TOPIC 9 — JAUNDICE
# ══════════════════════════════════════════════════════════════════════════════
pdf.add_page()
pdf.set_y(12)
pdf.topic_banner(9, "Jaundice")
pdf.body("Yellow discolouration of skin, sclerae, and mucous membranes due to increased serum bilirubin. Clinical jaundice appears at >2 mg/dL; detectable in lab at >1 mg/dL (latent jaundice).")
pdf.h2("Bilirubin Metabolism - Biochemical Pathway")
pdf.flow([
    "HEME (from destroyed RBCs, ~80%)",
    "  --[Heme oxygenase, RES]-->  Biliverdin + CO + Fe2+",
    "  --[Biliverdin reductase]-->  BILIRUBIN (unconjugated / indirect)",
    "  (fat-soluble; water-insoluble; TOXIC to brain; bound to albumin in blood)",
    "",
    "  --[Hepatocyte uptake via OATP transporters]-->  Hepatocyte",
    "  --[UDP-glucuronosyltransferase UGT1A1, in SER]-->",
    "  BILIRUBIN DIGLUCURONIDE (conjugated / direct)",
    "  (water-soluble; NON-toxic; excreted in bile via MRP2 transporter)",
    "",
    "  Intestine: [Bacterial beta-glucuronidase] --> UROBILINOGEN",
    "  20% reabsorbed -> portal vein -> liver & kidney -> URINE urobilinogen",
    "  80% -> oxidised in gut -> STERCOBILIN (brown colour of faeces)",
])
pdf.h2("Classification of Jaundice")
pdf.table(
    ["Type", "Cause", "Bilirubin", "Urine", "Stool", "Other"],
    [
        ["Pre-hepatic\n(Haemolytic)", "Increased RBC destruction", "Increased Unconjugated", "Increased urobilinogen; NO bilirubin", "Normal/dark", "Increased LDH, decreased haptoglobin, anaemia"],
        ["Hepatic\n(Hepatocellular)", "Liver damage (hepatitis, cirrhosis)", "Both increased (mixed)", "Bilirubin + increased urobilinogen", "Pale", "Increased AST, ALT, prolonged PT"],
        ["Post-hepatic\n(Obstructive)", "Bile duct obstruction (stones, carcinoma)", "Increased Conjugated", "Bilirubin++; NO urobilinogen", "Pale/clay", "Increased ALP, GGT; pruritus; dark urine"],
    ],
    [26, 34, 34, 36, 16, 28]
)
pdf.h2("Specific Bilirubin Metabolism Disorders")
pdf.table(
    ["Syndrome", "Defect", "Bilirubin", "Key Feature"],
    [
        ["Gilbert's syndrome", "Decreased UGT1A1 (mild, ~30%)", "Increased Unconjugated", "Benign; fasting/stress triggers; no treatment"],
        ["Crigler-Najjar Type I", "Absent UGT1A1", "Very high Unconjugated", "Kernicterus; fatal without phototherapy/transplant"],
        ["Crigler-Najjar Type II", "Partial UGT1A1 deficiency", "Increased Unconjugated", "Responds to phenobarbitone (induces UGT1A1)"],
        ["Dubin-Johnson", "Defective MRP2 canalicular transporter", "Increased Conjugated", "Black liver (melanin-like pigment); benign"],
        ["Rotor syndrome", "Defective hepatic bilirubin storage", "Increased Conjugated", "Benign; no black liver; normal lifespan"],
    ],
    [40, 52, 34, 48]
)
pdf.highlight("Neonatal Physiological Jaundice: Day 2-3 to Day 10-14. Cause: Immature UGT1A1 + increased fetal Hb breakdown. Unconjugated bilirubin crosses BBB -> KERNICTERUS if severe. Treatment: Phototherapy converts bilirubin to water-soluble lumirubin photoisomers.")

# ══════════════════════════════════════════════════════════════════════════════
# TOPIC 10 — GLYCOGEN STORAGE DISORDERS
# ══════════════════════════════════════════════════════════════════════════════
pdf.add_page()
pdf.set_y(12)
pdf.topic_banner(10, "Glycogen Storage Disorders (Glycogenoses)")
pdf.body("Autosomal recessive inherited disorders caused by deficiency of enzymes in glycogen synthesis or degradation, resulting in abnormal glycogen accumulation in various tissues.")
pdf.h2("Normal Glycogen Metabolism")
pdf.flow([
    "SYNTHESIS:",
    "  Glucose --> G-6-P --> G-1-P --> UDP-Glucose --> GLYCOGEN",
    "  [Glycogen synthase] + [Branching enzyme (IV)]",
    "",
    "DEGRADATION:",
    "  GLYCOGEN --[Phosphorylase (V, VI)]--> G-1-P --> G-6-P",
    "  [Debranching enzyme (III)] needed at branch points",
    "  G-6-P --[Glucose-6-Phosphatase (I)]--> FREE GLUCOSE (liver only)",
    "  [Lysosomal acid maltase (II)] degrades glycogen in lysosomes",
])
pdf.h2("Classification of Glycogen Storage Diseases")
pdf.table(
    ["Type", "Name", "Enzyme Deficient", "Organ(s)", "Key Features"],
    [
        ["Ia", "Von Gierke", "Glucose-6-phosphatase (G6PC)", "Liver, Kidney", "Hepatomegaly, fasting hypoglycaemia, lactic acidosis, hyperuricaemia, hyperlipidaemia; doll-like facies"],
        ["Ib", "Von Gierke variant", "G6P translocase (SLC37A4)", "Liver, Kidney, WBCs", "Same as Ia + NEUTROPENIA + IBD"],
        ["II", "Pompe", "Lysosomal acid glucosidase (GAA)", "All organs (heart dominant)", "Massive cardiomegaly; hypotonia; death <2 yrs; ONLY GSD with enzyme replacement (alglucosidase alfa)"],
        ["III", "Cori / Forbes", "Debranching enzyme (AGL)", "Liver, heart, muscle", "Mild hepatomegaly; hypoglycaemia; progressive myopathy"],
        ["IV", "Andersen", "Branching enzyme (GBE1)", "Liver, all tissues", "Abnormal glycogen -> cirrhosis, liver failure"],
        ["V", "McArdle", "Muscle phosphorylase (PYGM)", "Skeletal muscle", "Exercise cramps; NO blood lactate rise on exercise; myoglobinuria"],
        ["VII", "Tarui", "Muscle phosphofructokinase", "Muscle, RBCs", "McArdle-like + haemolytic anaemia"],
    ],
    [12, 24, 42, 32, 64]
)
pdf.h2("Type I (Von Gierke) - Biochemistry")
pdf.flow([
    "G6Pase ABSENT  -->  Glucose-6-P ACCUMULATES",
    "  |",
    "  +--[Glycolysis]--> Pyruvate --> LACTATE --> LACTIC ACIDOSIS",
    "  |",
    "  +--[HMP shunt]--> Ribose-5-P --> Purines --> URIC ACID --> GOUT",
    "  |",
    "  +--[Lipogenesis]--> Acetyl-CoA --> FFA --> HYPERTRIGLYCERIDAEMIA",
    "  |",
    "  +-- No free glucose --> HYPOGLYCAEMIA",
    "      (Both GLYCOGENOLYSIS and GLUCONEOGENESIS blocked)",
])
pdf.highlight("Most common GSD = Type I (Von Gierke). Only lysosomal GSD = Type II (Pompe) - has enzyme replacement therapy. Exercise cramps + no lactate rise = Types V and VII. Treatment of Type I: Uncooked Cornstarch (UCCS) every 4-6 hours; avoid fructose and galactose.")

# ══════════════════════════════════════════════════════════════════════════════
# TOPIC 11 — COMPETITIVE INHIBITORS
# ══════════════════════════════════════════════════════════════════════════════
pdf.add_page()
pdf.set_y(12)
pdf.topic_banner(11, "Clinical Significance of Competitive Inhibitors as Drugs")
pdf.body("A competitive inhibitor structurally resembles the substrate and competes for binding at the enzyme ACTIVE SITE. Inhibition is REVERSIBLE and overcome by increasing substrate concentration.")
pdf.h2("Enzyme Kinetics")
pdf.table(
    ["Parameter", "Effect", "Explanation"],
    [
        ["Vmax", "UNCHANGED", "Can still be achieved with excess substrate"],
        ["Apparent Km", "INCREASED", "More substrate needed to achieve half-Vmax"],
        ["Lineweaver-Burk plot", "Lines intersect on Y-axis", "Same Vmax, different x-intercept (-1/Km)"],
    ],
    [42, 40, 92]
)
pdf.h2("Clinically Important Competitive Inhibitor Drugs")
pdf.table(
    ["Drug", "Target Enzyme", "Analog Of", "Clinical Use"],
    [
        ["Statins (Atorvastatin, etc.)", "HMG-CoA reductase (rate-limiting step in cholesterol synthesis)", "HMG-CoA", "Hypercholesterolaemia; CVD prevention; increases LDL receptors in liver"],
        ["Methotrexate", "Dihydrofolate reductase (DHFR)", "Dihydrofolate", "Cancer, RA, psoriasis; decreased THF -> decreased purine/thymidylate synthesis"],
        ["Trimethoprim", "Bacterial DHFR (50,000x selectivity over human DHFR)", "Dihydrofolate", "UTI, PCP; combined with sulfamethoxazole (co-trimoxazole)"],
        ["Allopurinol", "Xanthine oxidase", "Hypoxanthine / Xanthine", "Gout; hyperuricaemia in GSD Type I; tumour lysis syndrome"],
        ["ACE Inhibitors (Captopril, Enalapril)", "Angiotensin-converting enzyme", "C-terminus of Angiotensin I", "Hypertension, heart failure, diabetic nephropathy; increased bradykinin causes cough"],
        ["Sildenafil", "Phosphodiesterase-5 (PDE-5)", "cGMP", "Erectile dysfunction; pulmonary arterial hypertension"],
        ["Carbidopa", "DOPA decarboxylase (peripheral, does not cross BBB)", "L-DOPA", "Parkinson's disease (with L-DOPA); increases CNS L-DOPA; decreases nausea"],
        ["Pyrimethamine", "Parasite DHFR", "Dihydrofolate", "Malaria prophylaxis; toxoplasmosis"],
        ["Eflornithine", "Ornithine decarboxylase (ODC)", "Ornithine", "African sleeping sickness; facial hirsutism"],
    ],
    [40, 52, 32, 50]
)
pdf.h2("Why Competitive Inhibitors Make Ideal Drugs")
pdf.table(
    ["Advantage", "Explanation"],
    [
        ["1. Selectivity", "Drug mimics substrate -> targets specific enzyme active site -> fewer off-target effects"],
        ["2. Reversibility", "Inhibition reversed by increased substrate or removing drug -> safer, titratable"],
        ["3. Dose-response", "Doubling dose doubles inhibition (unlike irreversible inhibitors)"],
        ["4. Rescue possible", "Substrate supplement can overcome inhibition (folinic acid rescue after methotrexate overdose)"],
        ["5. Species selectivity", "Pathogen enzyme vs. human enzyme differences exploitable (e.g. Trimethoprim for bacterial DHFR)"],
    ],
    [50, 124]
)
pdf.highlight("Special case - Aspirin: Irreversibly acetylates active-site serine of COX-1/COX-2. Platelets cannot synthesise new COX -> antiplatelet effect lasts platelet lifespan (7-10 days). This is IRREVERSIBLE competitive inhibition.")

# ── OUTPUT ────────────────────────────────────────────────────────────────────
pdf.output(OUT)
print(f"Done: {OUT}")
import os
print(f"Size: {os.path.getsize(OUT)//1024} KB")