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_CENTER, TA_LEFT, TA_JUSTIFY
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, PageBreak, ListFlowable, ListItem
)
from reportlab.pdfbase import pdfmetrics
from reportlab.pdfbase.ttfonts import TTFont
import os

OUTPUT = "/home/daytona/workspace/hyperammonemia-pdf/Hyperammonemia_Disorder.pdf"

# ── Colour palette ──────────────────────────────────────────────────────────
TEAL      = colors.HexColor("#0E7C7B")
TEAL_DARK = colors.HexColor("#065A59")
TEAL_LITE = colors.HexColor("#D4EDED")
AMBER     = colors.HexColor("#E07B00")
AMBER_LITE= colors.HexColor("#FFF3DC")
WHITE     = colors.white
GREY_TXT  = colors.HexColor("#333333")
GREY_LITE = colors.HexColor("#F5F5F5")
RED_LITE  = colors.HexColor("#FDE8E8")
RED_DARK  = colors.HexColor("#C0392B")
GREEN_LITE= colors.HexColor("#E8F8EF")
GREEN_DARK= colors.HexColor("#1A7A4A")

W, H = A4

doc = SimpleDocTemplate(
    OUTPUT, pagesize=A4,
    topMargin=1.8*cm, bottomMargin=1.8*cm,
    leftMargin=2*cm, rightMargin=2*cm
)

styles = getSampleStyleSheet()

def S(name, **kw):
    """Quick ParagraphStyle factory."""
    base = styles["Normal"]
    return ParagraphStyle(name, parent=base, **kw)

# ── Custom styles ────────────────────────────────────────────────────────────
TITLE   = S("title_slide", fontSize=30, textColor=WHITE,
            fontName="Helvetica-Bold", alignment=TA_CENTER, leading=38)
SUB     = S("subtitle", fontSize=14, textColor=TEAL_LITE,
            fontName="Helvetica-Oblique", alignment=TA_CENTER, leading=20)
TAG     = S("tag", fontSize=10, textColor=TEAL_LITE,
            fontName="Helvetica", alignment=TA_CENTER, leading=14)

SH      = S("section_h", fontSize=17, textColor=WHITE,
            fontName="Helvetica-Bold", alignment=TA_LEFT, leading=22,
            spaceAfter=4)
SH2     = S("subhead", fontSize=13, textColor=TEAL_DARK,
            fontName="Helvetica-Bold", spaceAfter=4, spaceBefore=6, leading=18)
BODY    = S("body", fontSize=10.5, textColor=GREY_TXT,
            leading=16, spaceAfter=4, alignment=TA_JUSTIFY)
BULLET  = S("bullet", fontSize=10.5, textColor=GREY_TXT,
            leading=16, leftIndent=14, spaceAfter=3,
            bulletIndent=4)
SMALL   = S("small", fontSize=9, textColor=colors.HexColor("#666666"),
            leading=13)
CITE    = S("cite", fontSize=8.5, textColor=colors.HexColor("#888888"),
            fontName="Helvetica-Oblique", leading=12)
CASE_H  = S("case_h", fontSize=11, textColor=AMBER,
            fontName="Helvetica-Bold", leading=16, spaceAfter=2)
CASE_B  = S("case_b", fontSize=10, textColor=GREY_TXT,
            leading=15, spaceAfter=3, alignment=TA_JUSTIFY)
EMPH    = S("emph", fontSize=10.5, textColor=RED_DARK,
            fontName="Helvetica-Bold", leading=16)

# ────────────────────────────────────────────────────────────────────────────
# Helper: section header bar
def sec_header(text):
    tbl = Table([[Paragraph(text, SH)]], colWidths=[W - 4*cm])
    tbl.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), TEAL_DARK),
        ("ROUNDEDCORNERS", [6,6,6,6]),
        ("TOPPADDING",  (0,0),(-1,-1), 8),
        ("BOTTOMPADDING",(0,0),(-1,-1), 8),
        ("LEFTPADDING", (0,0),(-1,-1), 14),
    ]))
    return tbl

# Helper: coloured info box
def info_box(text, bg=TEAL_LITE, border=TEAL):
    p = Paragraph(text, S("ib", parent=BODY, textColor=GREY_TXT, alignment=TA_JUSTIFY))
    t = Table([[p]], colWidths=[W - 4*cm])
    t.setStyle(TableStyle([
        ("BACKGROUND",(0,0),(-1,-1), bg),
        ("BOX",(0,0),(-1,-1), 1.2, border),
        ("TOPPADDING",(0,0),(-1,-1), 8),
        ("BOTTOMPADDING",(0,0),(-1,-1), 8),
        ("LEFTPADDING",(0,0),(-1,-1), 12),
        ("RIGHTPADDING",(0,0),(-1,-1), 8),
    ]))
    return t

# Helper: two-col table
def two_col(left_text, right_text, l_bg=TEAL_LITE, r_bg=AMBER_LITE,
            l_border=TEAL, r_border=AMBER):
    half = (W - 4*cm - 0.4*cm) / 2
    lp = Paragraph(left_text,  S("lp", parent=BODY))
    rp = Paragraph(right_text, S("rp", parent=BODY))
    t = Table([[lp, rp]], colWidths=[half, half], spaceBefore=0)
    t.setStyle(TableStyle([
        ("BACKGROUND",(0,0),(0,0), l_bg),
        ("BACKGROUND",(1,0),(1,0), r_bg),
        ("BOX",(0,0),(0,0), 1, l_border),
        ("BOX",(1,0),(1,0), 1, r_border),
        ("TOPPADDING",(0,0),(-1,-1), 8),
        ("BOTTOMPADDING",(0,0),(-1,-1), 8),
        ("LEFTPADDING",(0,0),(-1,-1), 10),
        ("RIGHTPADDING",(0,0),(-1,-1), 10),
        ("VALIGN",(0,0),(-1,-1),"TOP"),
    ]))
    return t

def b(txt): return f"<b>{txt}</b>"
def i(txt): return f"<i>{txt}</i>"
def br(): return Spacer(1, 8)
def hr(): return HRFlowable(width="100%", thickness=0.5, color=colors.HexColor("#CCCCCC"), spaceAfter=6, spaceBefore=6)

# ============================================================================
story = []

# ══════════════════════════════════════════════════════════════════
# PAGE 1 — TITLE SLIDE
# ══════════════════════════════════════════════════════════════════
# Full-width colour banner using a Table
title_tbl = Table(
    [[Paragraph("HYPERAMMONEMIA", TITLE)],
     [Paragraph("Urea Cycle Disorder — Biochemistry & Clinical Management", SUB)],
     [Spacer(1, 6)],
     [Paragraph("Biochemistry Presentation  •  Class Module", TAG)]],
    colWidths=[W - 4*cm]
)
title_tbl.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,-1), TEAL_DARK),
    ("TOPPADDING",(0,0),(-1,-1), 16),
    ("BOTTOMPADDING",(0,0),(-1,-1), 14),
    ("LEFTPADDING",(0,0),(-1,-1), 24),
    ("ROUNDEDCORNERS",[10,10,10,10]),
]))
story += [title_tbl, Spacer(1, 16)]

# Quick overview box
story += [
    info_box(
        "<b>What is Hyperammonemia?</b>  Ammonia (NH₃) is a by-product of amino acid "
        "breakdown. In health, the liver converts it to <b>urea</b> via the <b>Urea Cycle</b> and "
        "excretes it in urine. When this pathway fails — due to a genetic enzyme defect or liver "
        "disease — ammonia accumulates in blood, crosses the blood-brain barrier, and becomes "
        "<b>directly neurotoxic</b>. Normal blood NH₃ = <b>5–35 µmol/L</b>; toxic levels can exceed "
        "<b>1,000 µmol/L</b>."
    ),
    Spacer(1, 10),
]

# Key facts row
kf_data = [
    [Paragraph("<b>Normal NH₃</b>\n5–35 µmol/L", BODY),
     Paragraph("<b>Danger Level</b>\n> 100 µmol/L", S("kf2", parent=BODY, textColor=RED_DARK, fontName="Helvetica-Bold")),
     Paragraph("<b>Emergency</b>\n> 200 µmol/L coma risk", S("kf3", parent=BODY, textColor=RED_DARK, fontName="Helvetica-Bold")),
     Paragraph("<b>Incidence</b>\n~1 : 25,000 births", BODY)],
]
kf_tbl = Table(kf_data, colWidths=[(W-4*cm)/4]*4)
kf_tbl.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(0,0), TEAL_LITE),
    ("BACKGROUND",(1,0),(1,0), RED_LITE),
    ("BACKGROUND",(2,0),(2,0), RED_LITE),
    ("BACKGROUND",(3,0),(3,0), TEAL_LITE),
    ("BOX",(0,0),(-1,-1), 0.8, TEAL),
    ("INNERGRID",(0,0),(-1,-1), 0.5, colors.HexColor("#CCCCCC")),
    ("ALIGN",(0,0),(-1,-1),"CENTER"),
    ("VALIGN",(0,0),(-1,-1),"MIDDLE"),
    ("TOPPADDING",(0,0),(-1,-1), 10),
    ("BOTTOMPADDING",(0,0),(-1,-1), 10),
]))
story += [kf_tbl, PageBreak()]

# ══════════════════════════════════════════════════════════════════
# PAGE 2 — THE UREA CYCLE (Simple)
# ══════════════════════════════════════════════════════════════════
story += [sec_header("🔬  The Urea Cycle — How Ammonia Becomes Urea"), br()]

story += [
    Paragraph("Think of the Urea Cycle as a <b>5-step waste-processing factory</b> inside the liver. "
              "Its job: grab toxic NH₃ and package it as harmless urea (peed out in urine).", BODY),
    br(),
]

# Step-by-step cycle table
steps = [
    ["Step", "Location", "Enzyme", "What Happens", "Key Substrate → Product"],
    ["1", "Mitochondria", "CPS-I\n(needs NAGS as activator)", "NH₃ + CO₂ → Carbamoyl phosphate", "NH₃ → Carbamoyl-P"],
    ["2", "Mitochondria", "OTC\n(X-linked!)", "Carbamoyl-P + Ornithine → Citrulline", "Carbamoyl-P → Citrulline"],
    ["3", "Cytoplasm", "ASS", "Citrulline + Aspartate → Argininosuccinate", "Citrulline → Argininosuccinate"],
    ["4", "Cytoplasm", "ASL", "Argininosuccinate → Arginine + Fumarate", "Argininosuccinate → Arginine"],
    ["5", "Cytoplasm", "Arginase-I", "Arginine → Urea + Ornithine (cycle restarts!)", "Arginine → Urea"],
]
s_col = [1.2*cm, 2.2*cm, 3.5*cm, 5.5*cm, 4.5*cm]
s_tbl = Table(steps, colWidths=s_col)
s_tbl.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,0), TEAL_DARK),
    ("TEXTCOLOR",(0,0),(-1,0), WHITE),
    ("FONTNAME",(0,0),(-1,0),"Helvetica-Bold"),
    ("FONTSIZE",(0,0),(-1,-1), 8.5),
    ("ROWBACKGROUNDS",(0,1),(-1,-1), [WHITE, GREY_LITE]),
    ("ALIGN",(0,0),(-1,-1),"LEFT"),
    ("VALIGN",(0,0),(-1,-1),"MIDDLE"),
    ("TOPPADDING",(0,0),(-1,-1), 5),
    ("BOTTOMPADDING",(0,0),(-1,-1), 5),
    ("LEFTPADDING",(0,0),(-1,-1), 5),
    ("BOX",(0,0),(-1,-1), 1, TEAL),
    ("INNERGRID",(0,0),(-1,-1), 0.3, colors.HexColor("#CCCCCC")),
]))
story += [s_tbl, br()]

story += [
    info_box(
        "💡 <b>Key memory hook:</b>  <i>\"Ordinarily, Careless Cows Aren't Agitated\"</i> → "
        "Ornithine → Carbamoyl-P → Citrulline → Argininosuccinate → Arginine → (back to Ornithine). "
        "Two waste nitrogens enter per cycle (one from NH₃, one from Aspartate) → one urea exits.",
        bg=GREEN_LITE, border=GREEN_DARK
    ),
    PageBreak()
]

# ══════════════════════════════════════════════════════════════════
# PAGE 3 — BIOCHEMISTRY OF TOXICITY
# ══════════════════════════════════════════════════════════════════
story += [sec_header("⚠️  How Ammonia Damages the Brain"), br()]

story += [
    Paragraph(b("Mechanism of neurotoxicity — 3 key pathways:"), SH2), br(),
]

mech = [
    ["Mechanism", "What happens", "Clinical result"],
    ["α-Ketoglutarate\nDepletion",
     "NH₃ + α-KG → Glutamate (via GDH)\nGlutamate + NH₃ → Glutamine (via GS)\nDrains TCA cycle intermediates",
     "↓ ATP production\nBrain energy failure"],
    ["Glutamine\nAccumulation",
     "Glutamine builds up inside astrocytes.\nOsmotic swelling of glial cells",
     "Cerebral oedema\nRaised intracranial pressure"],
    ["Neurotransmitter\nDisruption",
     "Excess glutamate → excitotoxicity.\nAltered GABA signalling",
     "Seizures, altered consciousness"],
]
m_tbl = Table(mech, colWidths=[3*cm, 7.5*cm, 5.5*cm])
m_tbl.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,0), AMBER),
    ("TEXTCOLOR",(0,0),(-1,0), WHITE),
    ("FONTNAME",(0,0),(-1,0),"Helvetica-Bold"),
    ("FONTSIZE",(0,0),(-1,-1), 9),
    ("ROWBACKGROUNDS",(0,1),(-1,-1), [AMBER_LITE, WHITE]),
    ("VALIGN",(0,0),(-1,-1),"TOP"),
    ("ALIGN",(0,0),(-1,-1),"LEFT"),
    ("TOPPADDING",(0,0),(-1,-1), 6),
    ("BOTTOMPADDING",(0,0),(-1,-1), 6),
    ("LEFTPADDING",(0,0),(-1,-1), 6),
    ("BOX",(0,0),(-1,-1), 1, AMBER),
    ("INNERGRID",(0,0),(-1,-1), 0.3, colors.HexColor("#E0C080")),
]))
story += [m_tbl, br()]

story += [
    Paragraph(b("Ammonia transport in blood (non-toxic carriers):"), SH2),
    Paragraph(
        "Peripheral tissues cannot excrete NH₃ directly. They attach it to safe "
        "transport molecules:", BODY),
    br(),
]

transport = [
    [Paragraph(b("Glutamine") + " (main carrier)\n\nGlutamate + NH₃ → Glutamine\n(enzyme: Glutamine Synthetase)\n\n"
               "Glutamine travels to liver → Glutaminase releases NH₃ → fed into urea cycle.",
               S("tc", parent=BODY, fontSize=9.5)),
     Paragraph(b("Alanine") + " (glucose–alanine cycle)\n\nMuscle catabolises BCAAs → pyruvate + glutamate → "
               "Alanine (via ALT transaminase)\n\nAlanine → liver → transaminated back to pyruvate "
               "(used in gluconeogenesis) + glutamate → NH₃ → urea cycle.",
               S("tc2", parent=BODY, fontSize=9.5))],
]
tr_tbl = Table(transport, colWidths=[(W-4*cm)/2]*2)
tr_tbl.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(0,0), TEAL_LITE),
    ("BACKGROUND",(1,0),(1,0), GREEN_LITE),
    ("BOX",(0,0),(0,0), 1, TEAL),
    ("BOX",(1,0),(1,0), 1, GREEN_DARK),
    ("TOPPADDING",(0,0),(-1,-1), 8),
    ("BOTTOMPADDING",(0,0),(-1,-1), 8),
    ("LEFTPADDING",(0,0),(-1,-1), 10),
    ("RIGHTPADDING",(0,0),(-1,-1), 10),
    ("VALIGN",(0,0),(-1,-1),"TOP"),
]))
story += [tr_tbl, PageBreak()]

# ══════════════════════════════════════════════════════════════════
# PAGE 4 — TYPES / ENZYME DEFECTS
# ══════════════════════════════════════════════════════════════════
story += [sec_header("🧬  Urea Cycle Enzyme Defects"), br()]

story += [
    Paragraph("Each enzyme in the cycle can be deficient. Below is a quick reference:", BODY), br(),
]

defects = [
    ["Enzyme Deficiency", "Also called", "Key Lab Finding", "Notes"],
    ["CPS-I deficiency", "—", "Low citrulline & arginine;\nNo orotic acid ↑", "Rare; neonatal crisis"],
    ["OTC deficiency\n(Most common!)", "OTC deficiency", "Low citrulline; orotic acid ↑↑ in urine", "X-linked; mainly males affected; female carriers can be symptomatic"],
    ["ASS deficiency", "Citrullinemia Type 1", "Citrulline ↑↑ in blood & urine", "Detected on newborn screen"],
    ["ASL deficiency", "Argininosuccinic aciduria", "Argininosuccinate ↑↑ in urine", "Neurological delays in severe forms"],
    ["Arginase-I deficiency", "Argininemia", "Arginine ↑↑; milder hyperammonemia", "Normal birth; symptoms after 1–3 yrs"],
    ["NAGS deficiency", "—", "Similar to CPS-I; responds to carglumic acid", "Very rare; treatable!"],
]
d_tbl = Table(defects, colWidths=[3.5*cm, 2.8*cm, 4.2*cm, 6.5*cm])
d_tbl.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,0), TEAL_DARK),
    ("TEXTCOLOR",(0,0),(-1,0), WHITE),
    ("FONTNAME",(0,0),(-1,0),"Helvetica-Bold"),
    ("FONTSIZE",(0,0),(-1,-1), 8.5),
    ("ROWBACKGROUNDS",(0,1),(-1,-1), [WHITE, GREY_LITE]),
    ("VALIGN",(0,0),(-1,-1),"TOP"),
    ("ALIGN",(0,0),(-1,-1),"LEFT"),
    ("TOPPADDING",(0,0),(-1,-1), 5),
    ("BOTTOMPADDING",(0,0),(-1,-1), 5),
    ("LEFTPADDING",(0,0),(-1,-1), 5),
    ("BOX",(0,0),(-1,-1), 1, TEAL),
    ("INNERGRID",(0,0),(-1,-1), 0.3, colors.HexColor("#CCCCCC")),
    ("BACKGROUND",(0,2),(-1,2), colors.HexColor("#FFF0D0")),  # Highlight OTC
    ("FONTNAME",(0,2),(0,2),"Helvetica-Bold"),
]))
story += [d_tbl, br()]

story += [
    info_box(
        "<b>OTC Deficiency — Remember:</b>  Only X-linked urea cycle disorder. "
        "Carbamoyl-P overflows into cytosol → used for pyrimidine synthesis → "
        "orotic acid ↑↑ in urine. This distinguishes OTC from CPS-I (no orotic acid rise).",
        bg=AMBER_LITE, border=AMBER
    ),
    PageBreak()
]

# ══════════════════════════════════════════════════════════════════
# PAGE 5 — SYMPTOMS & DIAGNOSIS
# ══════════════════════════════════════════════════════════════════
story += [sec_header("🩺  Clinical Features & Diagnosis"), br()]

story += [Paragraph(b("Symptoms — depend on severity and age of onset:"), SH2)]

sym_data = [
    ["Neonatal (Severe)", "Late-onset / Partial Defect"],
    ["• Refusal to feed (within 24–48 h of protein feeds)\n"
     "• Vomiting, lethargy\n"
     "• Rapid breathing (hyperventilation → respiratory alkalosis)\n"
     "• Hypotonia (floppy baby)\n"
     "• Seizures\n"
     "• Coma → death if untreated",
     "• Episodes triggered by illness, fasting, high protein meals, stress\n"
     "• Headache, confusion, irritability\n"
     "• Tremors, slurred speech\n"
     "• Intellectual disability over time\n"
     "• Developmental delay"],
]
sym_tbl = Table(sym_data, colWidths=[(W-4*cm)/2]*2)
sym_tbl.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(0,0), RED_LITE),
    ("BACKGROUND",(1,0),(1,0), AMBER_LITE),
    ("FONTNAME",(0,0),(-1,0),"Helvetica-Bold"),
    ("FONTSIZE",(0,0),(-1,-1), 9.5),
    ("VALIGN",(0,0),(-1,-1),"TOP"),
    ("BOX",(0,0),(0,0), 1, RED_DARK),
    ("BOX",(1,0),(1,0), 1, AMBER),
    ("TOPPADDING",(0,0),(-1,-1), 8),
    ("BOTTOMPADDING",(0,0),(-1,-1), 8),
    ("LEFTPADDING",(0,0),(-1,-1), 8),
]))
story += [sym_tbl, br()]

story += [Paragraph(b("Diagnostic Work-up:"), SH2)]

diag_data = [
    ["Test", "Finding", "Tells you"],
    ["Plasma ammonia", "> 100–200 µmol/L", "Confirms hyperammonemia"],
    ["Plasma amino acids", "↑ Glutamine, ↑ Alanine;\nSpecific AA changes per defect", "Pinpoints cycle block"],
    ["Urine orotic acid", "↑ in OTC deficiency", "Differentiates OTC from CPS-I"],
    ["Urine organic acids / amino acids", "Argininosuccinate ↑ → ASL\nCitrulline ↑ → ASS", "Specific enzyme defect"],
    ["ABG (blood gas)", "Respiratory alkalosis (↑ pH, ↓ pCO₂)", "NH₃ stimulates respiration"],
    ["Liver function tests", "Can be normal in congenital forms", "Rules out liver disease"],
    ["Genetic testing", "Confirms exact mutation", "Definitive diagnosis"],
]
diag_tbl = Table(diag_data, colWidths=[4*cm, 4.5*cm, 8.5*cm])
diag_tbl.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,0), TEAL_DARK),
    ("TEXTCOLOR",(0,0),(-1,0), WHITE),
    ("FONTNAME",(0,0),(-1,0),"Helvetica-Bold"),
    ("FONTSIZE",(0,0),(-1,-1), 8.5),
    ("ROWBACKGROUNDS",(0,1),(-1,-1), [WHITE, GREY_LITE]),
    ("VALIGN",(0,0),(-1,-1),"TOP"),
    ("TOPPADDING",(0,0),(-1,-1), 5),
    ("BOTTOMPADDING",(0,0),(-1,-1), 5),
    ("LEFTPADDING",(0,0),(-1,-1), 5),
    ("BOX",(0,0),(-1,-1), 1, TEAL),
    ("INNERGRID",(0,0),(-1,-1), 0.3, colors.HexColor("#CCCCCC")),
]))
story += [diag_tbl, PageBreak()]

# ══════════════════════════════════════════════════════════════════
# PAGE 6 — TREATMENT
# ══════════════════════════════════════════════════════════════════
story += [sec_header("💊  Treatment Plan"), br()]

story += [
    info_box(
        "<b>Goal:</b>  1️⃣ Reduce ammonia production  •  2️⃣ Enhance ammonia removal  "
        "•  3️⃣ Prevent brain damage  •  4️⃣ Long-term metabolic control",
        bg=TEAL_LITE, border=TEAL_DARK
    ), br(),
]

# Acute treatment
story += [Paragraph(b("ACUTE / Emergency Management (ICU):"), SH2)]
acute = [
    ["Intervention", "How it works"],
    ["Stop protein intake\n(48–72 h)", "Eliminates NH₃ source from amino acid catabolism"],
    ["High-calorie IV glucose\n(+/- lipids)", "Prevents body from breaking down own muscle (catabolism)"],
    ["IV Sodium Benzoate +\nSodium Phenylacetate\n(Ammonul®)", "Nitrogen scavengers:\n• Benzoate + Glycine → Hippurate (excreted in urine)\n• Phenylacetate + Glutamine → Phenylacetylglutamine (excreted)\n→ Each molecule excreted carries waste nitrogen out of body"],
    ["IV Arginine\n(or Citrulline)", "Replenishes urea cycle intermediates; promotes cycle activity;\nArginine → Urea + Ornithine (Arginase reaction)"],
    ["Dialysis\n(Haemodialysis preferred)", "Fastest method to clear ammonia when levels > 500 µmol/L or coma"],
    ["Carglumic acid\n(for NAGS deficiency)", "Synthetic NAG analogue → activates CPS-I → restores cycle"],
]
a_tbl = Table(acute, colWidths=[4.5*cm, 12.5*cm])
a_tbl.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,0), RED_DARK),
    ("TEXTCOLOR",(0,0),(-1,0), WHITE),
    ("FONTNAME",(0,0),(-1,0),"Helvetica-Bold"),
    ("FONTSIZE",(0,0),(-1,-1), 8.5),
    ("ROWBACKGROUNDS",(0,1),(-1,-1), [RED_LITE, WHITE]),
    ("VALIGN",(0,0),(-1,-1),"TOP"),
    ("TOPPADDING",(0,0),(-1,-1), 6),
    ("BOTTOMPADDING",(0,0),(-1,-1), 6),
    ("LEFTPADDING",(0,0),(-1,-1), 6),
    ("BOX",(0,0),(-1,-1), 1, RED_DARK),
    ("INNERGRID",(0,0),(-1,-1), 0.3, colors.HexColor("#CCCCCC")),
]))
story += [a_tbl, br()]

# Chronic treatment
story += [Paragraph(b("CHRONIC / Long-term Management:"), SH2)]
chronic = [
    ["Strategy", "Detail"],
    ["Low-protein diet", "Tailored to age/weight; enough protein for growth, minimal excess"],
    ["Special medical formula", "Essential amino acids without excess nitrogen load"],
    ["Oral sodium phenylbutyrate\n(Buphenyl®) / Glycerol\nphenylbutyrate (Ravicti®)", "Oral nitrogen scavenger — daily long-term use"],
    ["Arginine / Citrulline\nsupplementation", "Replenishes depleted cycle intermediates"],
    ["Liver transplantation", "Curative — replaces defective enzyme in hepatocytes.\nAmmonia normalises, but neurological damage already present is not reversed"],
    ["Gene therapy\n(investigational)", "Emerging — AAV-mediated OTC/ASS gene correction in trials"],
]
c_tbl = Table(chronic, colWidths=[4.5*cm, 12.5*cm])
c_tbl.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,0), GREEN_DARK),
    ("TEXTCOLOR",(0,0),(-1,0), WHITE),
    ("FONTNAME",(0,0),(-1,0),"Helvetica-Bold"),
    ("FONTSIZE",(0,0),(-1,-1), 8.5),
    ("ROWBACKGROUNDS",(0,1),(-1,-1), [GREEN_LITE, WHITE]),
    ("VALIGN",(0,0),(-1,-1),"TOP"),
    ("TOPPADDING",(0,0),(-1,-1), 6),
    ("BOTTOMPADDING",(0,0),(-1,-1), 6),
    ("LEFTPADDING",(0,0),(-1,-1), 6),
    ("BOX",(0,0),(-1,-1), 1, GREEN_DARK),
    ("INNERGRID",(0,0),(-1,-1), 0.3, colors.HexColor("#AADDBB")),
]))
story += [c_tbl, PageBreak()]

# ══════════════════════════════════════════════════════════════════
# PAGE 7 — CLINICAL CASE
# ══════════════════════════════════════════════════════════════════
story += [sec_header("📋  Clinical Case — OTC Deficiency"), br()]

case_box_data = [[
    Paragraph(
        "<b>PRESENTING COMPLAINT</b>\n\n"
        "Baby <i>Hamza</i>, a 5-day-old male infant, born at term via normal delivery. "
        "Birth weight 3.2 kg. Breastfeeding started on day 1.\n\n"
        "On day 4, mother notices baby is <b>feeding poorly, vomiting</b>, and becoming "
        "<b>increasingly lethargic</b>. By day 5 he is <b>hypotonic, unresponsive</b>, "
        "and breathing very fast. Rushed to emergency.",
        CASE_B
    )
]]
case_tbl_1 = Table(case_box_data, colWidths=[W-4*cm])
case_tbl_1.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,-1), AMBER_LITE),
    ("BOX",(0,0),(-1,-1), 1.5, AMBER),
    ("TOPPADDING",(0,0),(-1,-1), 10),
    ("BOTTOMPADDING",(0,0),(-1,-1), 10),
    ("LEFTPADDING",(0,0),(-1,-1), 14),
    ("RIGHTPADDING",(0,0),(-1,-1), 14),
]))
story += [case_tbl_1, br()]

# Investigations
story += [Paragraph(b("Investigations:"), SH2)]
inv_data = [
    ["Investigation", "Result", "Interpretation"],
    ["Plasma Ammonia", "780 µmol/L (N: 5–35)", "Severely elevated → hyperammonemia"],
    ["Blood Gas (ABG)", "pH 7.55, pCO₂ 28 mmHg", "Respiratory alkalosis (NH₃ drives hyperventilation)"],
    ["Plasma Amino Acids", "Glutamine ↑↑, Alanine ↑↑\nCitrulline very low", "Consistent with early urea cycle block"],
    ["Urine Orotic Acid", "Markedly elevated", "KEY finding → OTC deficiency (not CPS-I)"],
    ["Plasma Arginine", "Low", "Confirms downstream cycle product depleted"],
    ["Liver enzymes / LFTs", "Normal", "Excludes liver disease as cause"],
    ["Genetic testing", "Hemizygous OTC mutation confirmed", "Definitive: OTC deficiency"],
]
inv_tbl = Table(inv_data, colWidths=[4*cm, 4.5*cm, 8.5*cm])
inv_tbl.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,0), TEAL_DARK),
    ("TEXTCOLOR",(0,0),(-1,0), WHITE),
    ("FONTNAME",(0,0),(-1,0),"Helvetica-Bold"),
    ("FONTSIZE",(0,0),(-1,-1), 8.5),
    ("ROWBACKGROUNDS",(0,1),(-1,-1), [WHITE, GREY_LITE]),
    ("VALIGN",(0,0),(-1,-1),"TOP"),
    ("TOPPADDING",(0,0),(-1,-1), 5),
    ("BOTTOMPADDING",(0,0),(-1,-1), 5),
    ("LEFTPADDING",(0,0),(-1,-1), 5),
    ("BOX",(0,0),(-1,-1), 1, TEAL),
    ("INNERGRID",(0,0),(-1,-1), 0.3, colors.HexColor("#CCCCCC")),
    ("BACKGROUND",(0,4),(-1,4), colors.HexColor("#FFF0D0")),
]))
story += [inv_tbl, br()]

# Diagnosis box
diag_final = Table([[
    Paragraph(
        "<b>DIAGNOSIS:  OTC Deficiency</b>\n\n"
        "Ornithine Transcarbamylase (OTC) is step 2 of the urea cycle. "
        "Without it, carbamoyl phosphate overflows into the cytoplasm, enters "
        "the pyrimidine synthesis pathway, and produces excess <b>orotic acid</b>. "
        "This is the diagnostic hallmark distinguishing OTC from CPS-I deficiency.",
        CASE_B
    )
]], colWidths=[W-4*cm])
diag_final.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,-1), RED_LITE),
    ("BOX",(0,0),(-1,-1), 2, RED_DARK),
    ("TOPPADDING",(0,0),(-1,-1), 10),
    ("BOTTOMPADDING",(0,0),(-1,-1), 10),
    ("LEFTPADDING",(0,0),(-1,-1), 14),
    ("RIGHTPADDING",(0,0),(-1,-1), 14),
]))
story += [diag_final, PageBreak()]

# ══════════════════════════════════════════════════════════════════
# PAGE 8 — CASE MANAGEMENT & KEY TAKEAWAYS
# ══════════════════════════════════════════════════════════════════
story += [sec_header("💉  Case Management & Key Takeaways"), br()]

story += [Paragraph(b("Management of Baby Hamza (OTC Deficiency):"), SH2)]

mgmt = [
    ["Phase", "Action", "Rationale"],
    ["Immediate", "Stop breastfeeding (stop protein)",
     "Remove NH₃ source immediately"],
    ["Immediate", "IV 10% Dextrose + Intralipid",
     "High calorie → suppress catabolism"],
    ["Acute", "IV Ammonul® (Na Benzoate + Na Phenylacetate)",
     "Nitrogen scavengers → excrete NH₃ as hippurate & phenylacetylglutamine"],
    ["Acute", "IV Arginine infusion",
     "Replenish depleted cycle intermediates"],
    ["Acute", "Haemodialysis",
     "Ammonia 780 µmol/L → dialysis needed urgently"],
    ["Once stable", "Reintroduce protein gradually with formula",
     "Minimum protein for growth; monitor NH₃"],
    ["Long-term", "Oral sodium phenylbutyrate daily",
     "Chronic nitrogen scavenging"],
    ["Long-term", "Liver transplant evaluation",
     "Curative option for severe OTC deficiency"],
]
mgmt_tbl = Table(mgmt, colWidths=[2.5*cm, 5.5*cm, 9*cm])
mgmt_tbl.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,0), TEAL_DARK),
    ("TEXTCOLOR",(0,0),(-1,0), WHITE),
    ("FONTNAME",(0,0),(-1,0),"Helvetica-Bold"),
    ("FONTSIZE",(0,0),(-1,-1), 8.5),
    ("ROWBACKGROUNDS",(0,1),(-1,-1), [WHITE, GREY_LITE]),
    ("VALIGN",(0,0),(-1,-1),"TOP"),
    ("TOPPADDING",(0,0),(-1,-1), 5),
    ("BOTTOMPADDING",(0,0),(-1,-1), 5),
    ("LEFTPADDING",(0,0),(-1,-1), 5),
    ("BOX",(0,0),(-1,-1), 1, TEAL),
    ("INNERGRID",(0,0),(-1,-1), 0.3, colors.HexColor("#CCCCCC")),
]))
story += [mgmt_tbl, br()]

# Key takeaways
story += [Paragraph(b("Key Takeaways — Remember These for the Exam:"), SH2)]

takeaways = [
    ["✅  Urea cycle is the ONLY way liver clears NH₃ → 5 enzymes, 6 steps (including NAGS activation)"],
    ["✅  OTC deficiency = most common, X-linked, OROTIC ACID ↑ in urine (distinguishes from CPS-I)"],
    ["✅  NH₃ neurotoxicity: depletes α-KG → TCA failure; glutamine in astrocytes → cerebral oedema"],
    ["✅  Neonates present 24–72 h after protein feeds: feeding refusal, vomiting, coma"],
    ["✅  Diagnosis: plasma NH₃, plasma amino acids, URINE OROTIC ACID, genetic testing"],
    ["✅  Treatment: STOP protein → high-cal IV → nitrogen scavengers (benzoate/phenylacetate) → arginine → dialysis if severe"],
    ["✅  Liver transplant = curative (but does NOT reverse existing brain damage)"],
]
for row in takeaways:
    tk_tbl = Table(row, colWidths=[W-4*cm])
    tk_tbl.setStyle(TableStyle([
        ("BACKGROUND",(0,0),(-1,-1), GREEN_LITE),
        ("BOX",(0,0),(-1,-1), 0.8, GREEN_DARK),
        ("TOPPADDING",(0,0),(-1,-1), 5),
        ("BOTTOMPADDING",(0,0),(-1,-1), 5),
        ("LEFTPADDING",(0,0),(-1,-1), 10),
        ("FONTSIZE",(0,0),(-1,-1), 9.5),
    ]))
    story += [tk_tbl, Spacer(1, 4)]

story += [
    br(),
    hr(),
    Paragraph(
        "Source: Biochemistry, 8th ed — Lippincott Illustrated Reviews (Ferrier, 2019), pp. 722–728  "
        "•  Bradley & Daroff's Neurology in Clinical Practice  •  Basic Medical Biochemistry 6e",
        CITE
    ),
]

# ── Build ────────────────────────────────────────────────────────────────────
doc.build(story)
print("PDF created:", OUTPUT)

Successfully replaced 1 instance(s) of the string in '/home/daytona/workspace/hyperammonemia-pdf/build_pdf.py'

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

OUTPUT = "/home/daytona/workspace/hyperammonemia-pdf/Hyperammonemia_Disorder.pdf"

# Colour palette
TEAL      = colors.HexColor("#0E7C7B")
TEAL_DARK = colors.HexColor("#065A59")
TEAL_LITE = colors.HexColor("#D4EDED")
AMBER     = colors.HexColor("#E07B00")
AMBER_LITE= colors.HexColor("#FFF3DC")
WHITE     = colors.white
GREY_TXT  = colors.HexColor("#333333")
GREY_LITE = colors.HexColor("#F5F5F5")
RED_LITE  = colors.HexColor("#FDE8E8")
RED_DARK  = colors.HexColor("#C0392B")
GREEN_LITE= colors.HexColor("#E8F8EF")
GREEN_DARK= colors.HexColor("#1A7A4A")

W, H = A4

doc = SimpleDocTemplate(
    OUTPUT, pagesize=A4,
    topMargin=1.8*cm, bottomMargin=1.8*cm,
    leftMargin=2*cm, rightMargin=2*cm
)

styles = getSampleStyleSheet()

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

TITLE = S("title_slide", fontSize=30, textColor=WHITE,
          fontName="Helvetica-Bold", alignment=TA_CENTER, leading=38)
SUB   = S("subtitle", fontSize=14, textColor=TEAL_LITE,
          fontName="Helvetica-Oblique", alignment=TA_CENTER, leading=20)
TAG   = S("tag", fontSize=10, textColor=TEAL_LITE,
          fontName="Helvetica", alignment=TA_CENTER, leading=14)
SH    = S("section_h", fontSize=17, textColor=WHITE,
          fontName="Helvetica-Bold", alignment=TA_LEFT, leading=22)
SH2   = S("subhead", fontSize=13, textColor=TEAL_DARK,
          fontName="Helvetica-Bold", spaceAfter=4, spaceBefore=6, leading=18)
BODY  = S("body", fontSize=10.5, textColor=GREY_TXT,
          leading=16, spaceAfter=4, alignment=TA_JUSTIFY)
CITE  = S("cite", fontSize=8.5, textColor=colors.HexColor("#888888"),
          fontName="Helvetica-Oblique", leading=12)
CASE_B= S("case_b", fontSize=10, textColor=GREY_TXT,
          leading=15, spaceAfter=3, alignment=TA_JUSTIFY)

def sec_header(text):
    tbl = Table([[Paragraph(text, SH)]], colWidths=[W - 4*cm])
    tbl.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), TEAL_DARK),
        ("TOPPADDING",  (0,0), (-1,-1), 8),
        ("BOTTOMPADDING",(0,0),(-1,-1), 8),
        ("LEFTPADDING", (0,0), (-1,-1), 14),
    ]))
    return tbl

def info_box(text, bg=TEAL_LITE, border=TEAL):
    p = Paragraph(text, S("ib", parent=BODY))
    t = Table([[p]], colWidths=[W - 4*cm])
    t.setStyle(TableStyle([
        ("BACKGROUND",(0,0),(-1,-1), bg),
        ("BOX",(0,0),(-1,-1), 1.2, border),
        ("TOPPADDING",(0,0),(-1,-1), 8),
        ("BOTTOMPADDING",(0,0),(-1,-1), 8),
        ("LEFTPADDING",(0,0),(-1,-1), 12),
        ("RIGHTPADDING",(0,0),(-1,-1), 8),
    ]))
    return t

def make_table(data, col_widths, header_bg=TEAL_DARK, row_colors=None):
    if row_colors is None:
        row_colors = [WHITE, GREY_LITE]
    tbl = Table(data, colWidths=col_widths)
    tbl.setStyle(TableStyle([
        ("BACKGROUND",(0,0),(-1,0), header_bg),
        ("TEXTCOLOR",(0,0),(-1,0), WHITE),
        ("FONTNAME",(0,0),(-1,0),"Helvetica-Bold"),
        ("FONTSIZE",(0,0),(-1,-1), 8.5),
        ("ROWBACKGROUNDS",(0,1),(-1,-1), row_colors),
        ("VALIGN",(0,0),(-1,-1),"TOP"),
        ("ALIGN",(0,0),(-1,-1),"LEFT"),
        ("TOPPADDING",(0,0),(-1,-1), 5),
        ("BOTTOMPADDING",(0,0),(-1,-1), 5),
        ("LEFTPADDING",(0,0),(-1,-1), 5),
        ("BOX",(0,0),(-1,-1), 1, TEAL),
        ("INNERGRID",(0,0),(-1,-1), 0.3, colors.HexColor("#CCCCCC")),
    ]))
    return tbl

def br(n=8): return Spacer(1, n)
def hr(): return HRFlowable(width="100%", thickness=0.5,
                            color=colors.HexColor("#CCCCCC"),
                            spaceAfter=6, spaceBefore=6)
def b(t): return f"<b>{t}</b>"

story = []

# ── PAGE 1: TITLE ──────────────────────────────────────────────────────────
title_tbl = Table(
    [[Paragraph("HYPERAMMONEMIA", TITLE)],
     [Paragraph("Urea Cycle Disorder — Biochemistry & Clinical Management", SUB)],
     [Spacer(1, 6)],
     [Paragraph("Biochemistry Presentation  •  Class Module", TAG)]],
    colWidths=[W - 4*cm]
)
title_tbl.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,-1), TEAL_DARK),
    ("TOPPADDING",(0,0),(-1,-1), 16),
    ("BOTTOMPADDING",(0,0),(-1,-1), 14),
    ("LEFTPADDING",(0,0),(-1,-1), 24),
]))
story += [title_tbl, br(16)]

story += [
    info_box(
        b("What is Hyperammonemia?") + "  Ammonia (NH3) is a by-product of amino acid "
        "breakdown. In health, the liver converts it to <b>urea</b> via the <b>Urea Cycle</b> and "
        "excretes it in urine. When this pathway fails — due to a genetic enzyme defect or liver "
        "disease — ammonia accumulates in blood, crosses the blood-brain barrier, and becomes "
        "<b>directly neurotoxic</b>. Normal blood NH3 = <b>5-35 umol/L</b>; toxic levels can exceed "
        "<b>1,000 umol/L</b>."
    ),
    br(10),
]

kf_data = [[
    Paragraph(b("Normal NH3") + "\n5-35 umol/L", BODY),
    Paragraph(b("Danger Level") + "\n> 100 umol/L",
              S("kf2", parent=BODY, textColor=RED_DARK, fontName="Helvetica-Bold")),
    Paragraph(b("Emergency") + "\n> 200 umol/L\ncoma risk",
              S("kf3", parent=BODY, textColor=RED_DARK, fontName="Helvetica-Bold")),
    Paragraph(b("Incidence") + "\n~1 : 25,000 births", BODY),
]]
kf_tbl = Table(kf_data, colWidths=[(W-4*cm)/4]*4)
kf_tbl.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(0,0), TEAL_LITE),
    ("BACKGROUND",(1,0),(1,0), RED_LITE),
    ("BACKGROUND",(2,0),(2,0), RED_LITE),
    ("BACKGROUND",(3,0),(3,0), TEAL_LITE),
    ("BOX",(0,0),(-1,-1), 0.8, TEAL),
    ("INNERGRID",(0,0),(-1,-1), 0.5, colors.HexColor("#CCCCCC")),
    ("ALIGN",(0,0),(-1,-1),"CENTER"),
    ("VALIGN",(0,0),(-1,-1),"MIDDLE"),
    ("TOPPADDING",(0,0),(-1,-1), 10),
    ("BOTTOMPADDING",(0,0),(-1,-1), 10),
]))
story += [kf_tbl, PageBreak()]

# ── PAGE 2: UREA CYCLE ────────────────────────────────────────────────────
story += [sec_header("The Urea Cycle — How Ammonia Becomes Urea"), br()]
story += [
    Paragraph(
        "Think of the Urea Cycle as a <b>5-step waste-processing factory</b> inside the liver. "
        "Its job: grab toxic NH3 and package it as harmless urea (peed out in urine).", BODY),
    br(),
]

steps = [
    ["Step", "Location", "Enzyme", "What Happens", "Key Change"],
    ["1", "Mitochondria", "CPS-I\n(needs NAGS)", "NH3 + CO2 form Carbamoyl phosphate", "NH3 captured"],
    ["2", "Mitochondria", "OTC\n(X-linked!)", "Carbamoyl-P + Ornithine form Citrulline", "Citrulline made"],
    ["3", "Cytoplasm", "ASS", "Citrulline + Aspartate form Argininosuccinate", "2nd N enters"],
    ["4", "Cytoplasm", "ASL", "Argininosuccinate splits to Arginine + Fumarate", "Arginine released"],
    ["5", "Cytoplasm", "Arginase-I", "Arginine splits to Urea + Ornithine (cycle restarts)", "Urea out!"],
]
story += [make_table(steps, [1.2*cm, 2.2*cm, 3.5*cm, 5.8*cm, 4.3*cm]), br()]

story += [
    info_box(
        b("Memory trick:") + " <i>\"Ordinarily, Careless Cows Aren't Agitated\"</i> "
        "= Ornithine > Carbamoyl-P > Citrulline > Argininosuccinate > Arginine > back to Ornithine. "
        "Two waste nitrogens enter per turn (one from NH3, one from Aspartate) and one urea exits.",
        bg=GREEN_LITE, border=GREEN_DARK
    ),
    PageBreak()
]

# ── PAGE 3: HOW AMMONIA DAMAGES THE BRAIN ────────────────────────────────
story += [sec_header("How Ammonia Damages the Brain"), br()]

story += [Paragraph(b("3 Key Mechanisms of Neurotoxicity:"), SH2), br()]

mech = [
    ["Mechanism", "What happens inside", "Clinical result"],
    ["Alpha-KG Depletion",
     "NH3 + alpha-KG form Glutamate (enzyme: GDH)\n"
     "Glutamate + NH3 form Glutamine (enzyme: GS)\n"
     "This drains the TCA cycle of alpha-KG",
     "Less ATP produced\nBrain energy failure"],
    ["Glutamine Accumulation",
     "Glutamine builds up inside astrocytes\n"
     "Osmotic water follows into glial cells",
     "Cerebral oedema\nRaised intracranial pressure"],
    ["Neurotransmitter Disruption",
     "Excess glutamate causes excitotoxicity\n"
     "Altered GABA signalling",
     "Seizures\nAltered consciousness"],
]
mech_tbl = Table(mech, colWidths=[3.5*cm, 8*cm, 5.5*cm])
mech_tbl.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,0), AMBER),
    ("TEXTCOLOR",(0,0),(-1,0), WHITE),
    ("FONTNAME",(0,0),(-1,0),"Helvetica-Bold"),
    ("FONTSIZE",(0,0),(-1,-1), 9),
    ("ROWBACKGROUNDS",(0,1),(-1,-1), [AMBER_LITE, WHITE]),
    ("VALIGN",(0,0),(-1,-1),"TOP"),
    ("TOPPADDING",(0,0),(-1,-1), 6),
    ("BOTTOMPADDING",(0,0),(-1,-1), 6),
    ("LEFTPADDING",(0,0),(-1,-1), 6),
    ("BOX",(0,0),(-1,-1), 1, AMBER),
    ("INNERGRID",(0,0),(-1,-1), 0.3, colors.HexColor("#E0C080")),
]))
story += [mech_tbl, br()]

story += [Paragraph(b("How Ammonia Travels Safely in Blood:"), SH2)]

half = (W - 4*cm - 0.4*cm) / 2
tr_data = [[
    Paragraph(
        b("Glutamine (main carrier)") + "\n\n"
        "Glutamate + NH3 > Glutamine\n(enzyme: Glutamine Synthetase)\n\n"
        "Glutamine travels safely to liver.\nIn liver: Glutaminase releases NH3 "
        "which enters urea cycle.",
        S("tc", parent=BODY, fontSize=9.5)
    ),
    Paragraph(
        b("Alanine (Glucose-Alanine Cycle)") + "\n\n"
        "Muscle breaks down amino acids > pyruvate + glutamate > Alanine\n(via ALT)\n\n"
        "Alanine > liver > transaminated back to pyruvate (for gluconeogenesis) "
        "+ glutamate > NH3 > urea cycle.",
        S("tc2", parent=BODY, fontSize=9.5)
    ),
]]
tr_tbl = Table(tr_data, colWidths=[half, half])
tr_tbl.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(0,0), TEAL_LITE),
    ("BACKGROUND",(1,0),(1,0), GREEN_LITE),
    ("BOX",(0,0),(0,0), 1, TEAL),
    ("BOX",(1,0),(1,0), 1, GREEN_DARK),
    ("TOPPADDING",(0,0),(-1,-1), 8),
    ("BOTTOMPADDING",(0,0),(-1,-1), 8),
    ("LEFTPADDING",(0,0),(-1,-1), 10),
    ("RIGHTPADDING",(0,0),(-1,-1), 10),
    ("VALIGN",(0,0),(-1,-1),"TOP"),
]))
story += [tr_tbl, PageBreak()]

# ── PAGE 4: ENZYME DEFECTS ───────────────────────────────────────────────
story += [sec_header("Urea Cycle Enzyme Defects"), br()]
story += [Paragraph("Each enzyme in the cycle can be deficient. Quick reference:", BODY), br()]

defects = [
    ["Deficiency", "Other Name", "Key Lab Finding", "Notes"],
    ["CPS-I", "—", "Low citrulline & arginine\nNo orotic acid rise", "Rare; severe neonatal crisis"],
    ["OTC\n(MOST COMMON)", "OTC deficiency", "Low citrulline\nOrotic acid HIGH in urine", "X-linked; mainly males; female carriers can be symptomatic"],
    ["ASS", "Citrullinemia Type 1", "Citrulline very HIGH in blood & urine", "Detected on newborn screening"],
    ["ASL", "Argininosuccinic aciduria", "Argininosuccinate HIGH in urine", "Neuro delays in severe forms"],
    ["Arginase-I", "Argininemia / Hyperargininemia", "Arginine HIGH; milder hyperammonemia", "Normal birth; symptoms after 1-3 yrs"],
    ["NAGS", "—", "Same as CPS-I; responds to carglumic acid", "Very rare; specifically treatable!"],
]
def_tbl = make_table(defects, [2.5*cm, 3*cm, 4.5*cm, 7*cm])
# Highlight OTC row
def_tbl.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,0), TEAL_DARK),
    ("TEXTCOLOR",(0,0),(-1,0), WHITE),
    ("FONTNAME",(0,0),(-1,0),"Helvetica-Bold"),
    ("FONTSIZE",(0,0),(-1,-1), 8.5),
    ("ROWBACKGROUNDS",(0,1),(-1,-1), [WHITE, GREY_LITE]),
    ("BACKGROUND",(0,2),(-1,2), colors.HexColor("#FFF0D0")),
    ("FONTNAME",(0,2),(0,2),"Helvetica-Bold"),
    ("VALIGN",(0,0),(-1,-1),"TOP"),
    ("TOPPADDING",(0,0),(-1,-1), 5),
    ("BOTTOMPADDING",(0,0),(-1,-1), 5),
    ("LEFTPADDING",(0,0),(-1,-1), 5),
    ("BOX",(0,0),(-1,-1), 1, TEAL),
    ("INNERGRID",(0,0),(-1,-1), 0.3, colors.HexColor("#CCCCCC")),
]))
story += [def_tbl, br()]

story += [
    info_box(
        b("OTC vs CPS-I — How to tell them apart:") +
        "  Both give low citrulline and arginine, BUT only OTC deficiency raises "
        "urinary orotic acid. Why? When OTC is blocked, carbamoyl phosphate overflows "
        "into the cytoplasm and gets used to make pyrimidines, producing excess orotic acid.",
        bg=AMBER_LITE, border=AMBER
    ),
    PageBreak()
]

# ── PAGE 5: SYMPTOMS & DIAGNOSIS ──────────────────────────────────────────
story += [sec_header("Clinical Features and Diagnosis"), br()]
story += [Paragraph(b("Symptoms — depend on severity and age:"), SH2)]

sym_data = [[
    Paragraph(
        b("Neonatal (Severe)\n\n") +
        "- Refusal to feed (24-48 h after protein)\n"
        "- Vomiting, lethargy\n"
        "- Rapid breathing (hyperventilation)\n"
        "- Floppy baby (hypotonia)\n"
        "- Seizures\n"
        "- Coma and death if untreated",
        S("sl", parent=BODY, fontSize=9.5)
    ),
    Paragraph(
        b("Late-onset / Partial Defect\n\n") +
        "- Episodes triggered by illness, fasting,\n  high protein meals, or stress\n"
        "- Headache, confusion, irritability\n"
        "- Tremors, slurred speech\n"
        "- Intellectual disability over time\n"
        "- Developmental delay",
        S("sr", parent=BODY, fontSize=9.5)
    ),
]]
sym_tbl = Table(sym_data, colWidths=[(W-4*cm)/2]*2)
sym_tbl.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(0,0), RED_LITE),
    ("BACKGROUND",(1,0),(1,0), AMBER_LITE),
    ("FONTNAME",(0,0),(-1,0),"Helvetica-Bold"),
    ("FONTSIZE",(0,0),(-1,-1), 9.5),
    ("VALIGN",(0,0),(-1,-1),"TOP"),
    ("BOX",(0,0),(0,0), 1, RED_DARK),
    ("BOX",(1,0),(1,0), 1, AMBER),
    ("TOPPADDING",(0,0),(-1,-1), 8),
    ("BOTTOMPADDING",(0,0),(-1,-1), 8),
    ("LEFTPADDING",(0,0),(-1,-1), 8),
]))
story += [sym_tbl, br()]

story += [Paragraph(b("Diagnostic Tests:"), SH2)]

diag_rows = [
    ["Test", "Finding", "Tells You"],
    ["Plasma Ammonia", "> 100-200 umol/L", "Confirms hyperammonemia"],
    ["Plasma Amino Acids", "Glutamine up, Alanine up;\nSpecific AAs per defect", "Locates cycle block"],
    ["Urine Orotic Acid", "HIGH in OTC deficiency", "Tells OTC from CPS-I"],
    ["Urine Amino Acids", "Argininosuccinate up > ASL\nCitrulline up > ASS", "Specific enzyme defect"],
    ["Blood Gas (ABG)", "Respiratory alkalosis\n(high pH, low pCO2)", "NH3 drives hyperventilation"],
    ["LFTs", "Often normal in congenital forms", "Excludes liver disease"],
    ["Genetic Testing", "Confirms exact mutation", "Definitive diagnosis"],
]
story += [make_table(diag_rows, [4*cm, 4.5*cm, 8.5*cm]), PageBreak()]

# ── PAGE 6: TREATMENT ──────────────────────────────────────────────────────
story += [sec_header("Treatment Plan"), br()]
story += [
    info_box(
        b("4 Goals of Treatment:  ") +
        "1) Reduce NH3 production  "
        "2) Enhance NH3 removal  "
        "3) Prevent brain damage  "
        "4) Long-term metabolic control"
    ), br(),
]

story += [Paragraph(b("ACUTE Emergency Management (ICU):"), SH2)]
acute = [
    ["Intervention", "How it works"],
    ["Stop protein intake (48-72 h)", "Removes NH3 source immediately"],
    ["IV 10% Glucose + Lipid infusion", "High-calorie — stops body breaking down own muscle"],
    ["IV Sodium Benzoate +\nSodium Phenylacetate (Ammonul)", "Nitrogen scavengers:\nBenzoate + Glycine > Hippurate (urine)\nPhenylacetate + Glutamine > Phenylacetylglutamine (urine)\nEach molecule excreted carries waste nitrogen out"],
    ["IV Arginine (or Citrulline)", "Replenishes urea cycle intermediates; drives cycle forward"],
    ["Haemodialysis", "Fastest NH3 clearance; needed when NH3 > 500 umol/L or coma"],
    ["Carglumic acid\n(NAGS deficiency only)", "Synthetic NAG analogue > activates CPS-I > restores cycle"],
]
a_tbl = Table(acute, colWidths=[4.5*cm, 12.5*cm])
a_tbl.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,0), RED_DARK),
    ("TEXTCOLOR",(0,0),(-1,0), WHITE),
    ("FONTNAME",(0,0),(-1,0),"Helvetica-Bold"),
    ("FONTSIZE",(0,0),(-1,-1), 8.5),
    ("ROWBACKGROUNDS",(0,1),(-1,-1), [RED_LITE, WHITE]),
    ("VALIGN",(0,0),(-1,-1),"TOP"),
    ("TOPPADDING",(0,0),(-1,-1), 6),
    ("BOTTOMPADDING",(0,0),(-1,-1), 6),
    ("LEFTPADDING",(0,0),(-1,-1), 6),
    ("BOX",(0,0),(-1,-1), 1, RED_DARK),
    ("INNERGRID",(0,0),(-1,-1), 0.3, colors.HexColor("#CCCCCC")),
]))
story += [a_tbl, br()]

story += [Paragraph(b("LONG-TERM Chronic Management:"), SH2)]
chronic = [
    ["Strategy", "Detail"],
    ["Low-protein diet", "Tailored to age and weight; enough for growth, minimal excess"],
    ["Medical formula / special foods", "Essential amino acids without excess nitrogen load"],
    ["Oral sodium phenylbutyrate\n(Buphenyl / Ravicti)", "Daily nitrogen scavenger — taken long-term"],
    ["Arginine / Citrulline supplementation", "Replenishes depleted urea cycle intermediates"],
    ["Liver transplantation", "CURATIVE — replaces the defective enzyme.\nNote: brain damage already present is NOT reversed"],
    ["Gene therapy (investigational)", "AAV-mediated OTC/ASS gene correction — in clinical trials"],
]
c_tbl = Table(chronic, colWidths=[4.5*cm, 12.5*cm])
c_tbl.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,0), GREEN_DARK),
    ("TEXTCOLOR",(0,0),(-1,0), WHITE),
    ("FONTNAME",(0,0),(-1,0),"Helvetica-Bold"),
    ("FONTSIZE",(0,0),(-1,-1), 8.5),
    ("ROWBACKGROUNDS",(0,1),(-1,-1), [GREEN_LITE, WHITE]),
    ("VALIGN",(0,0),(-1,-1),"TOP"),
    ("TOPPADDING",(0,0),(-1,-1), 6),
    ("BOTTOMPADDING",(0,0),(-1,-1), 6),
    ("LEFTPADDING",(0,0),(-1,-1), 6),
    ("BOX",(0,0),(-1,-1), 1, GREEN_DARK),
    ("INNERGRID",(0,0),(-1,-1), 0.3, colors.HexColor("#AADDBB")),
]))
story += [c_tbl, PageBreak()]

# ── PAGE 7: CLINICAL CASE ─────────────────────────────────────────────────
story += [sec_header("Clinical Case — OTC Deficiency"), br()]

case1 = Table([[
    Paragraph(
        b("PRESENTING COMPLAINT") + "\n\n"
        "Baby Hamza, a 5-day-old male, born at full term. Birth weight 3.2 kg. "
        "Breastfeeding started on day 1.\n\n"
        "On day 4, mother notices he is <b>feeding poorly and vomiting</b>. "
        "By day 5 he is <b>hypotonic, unresponsive</b>, and breathing very fast. "
        "Rushed to emergency department.",
        CASE_B
    )
]], colWidths=[W-4*cm])
case1.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,-1), AMBER_LITE),
    ("BOX",(0,0),(-1,-1), 1.5, AMBER),
    ("TOPPADDING",(0,0),(-1,-1), 10),
    ("BOTTOMPADDING",(0,0),(-1,-1), 10),
    ("LEFTPADDING",(0,0),(-1,-1), 14),
    ("RIGHTPADDING",(0,0),(-1,-1), 14),
]))
story += [case1, br()]

story += [Paragraph(b("Investigations:"), SH2)]
inv = [
    ["Test", "Result", "Interpretation"],
    ["Plasma Ammonia", "780 umol/L (N: 5-35)", "SEVERELY elevated"],
    ["Blood Gas (ABG)", "pH 7.55, pCO2 28 mmHg", "Respiratory alkalosis (NH3 drives hyperventilation)"],
    ["Plasma Amino Acids", "Glutamine HIGH, Alanine HIGH\nCitrulline very LOW", "Block early in urea cycle"],
    ["Urine Orotic Acid", "MARKEDLY elevated", "KEY finding > OTC deficiency (not CPS-I)"],
    ["Plasma Arginine", "Low", "Downstream product depleted"],
    ["LFTs", "Normal", "Excludes liver disease"],
    ["Genetic Testing", "Hemizygous OTC mutation", "DEFINITIVE: OTC deficiency"],
]
inv_tbl = make_table(inv, [4*cm, 4.5*cm, 8.5*cm])
inv_tbl.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,0), TEAL_DARK),
    ("TEXTCOLOR",(0,0),(-1,0), WHITE),
    ("FONTNAME",(0,0),(-1,0),"Helvetica-Bold"),
    ("FONTSIZE",(0,0),(-1,-1), 8.5),
    ("ROWBACKGROUNDS",(0,1),(-1,-1), [WHITE, GREY_LITE]),
    ("BACKGROUND",(0,4),(-1,4), colors.HexColor("#FFF0D0")),
    ("VALIGN",(0,0),(-1,-1),"TOP"),
    ("TOPPADDING",(0,0),(-1,-1), 5),
    ("BOTTOMPADDING",(0,0),(-1,-1), 5),
    ("LEFTPADDING",(0,0),(-1,-1), 5),
    ("BOX",(0,0),(-1,-1), 1, TEAL),
    ("INNERGRID",(0,0),(-1,-1), 0.3, colors.HexColor("#CCCCCC")),
]))
story += [inv_tbl, br()]

diag_box = Table([[
    Paragraph(
        b("DIAGNOSIS: OTC Deficiency") + "\n\n"
        "OTC (step 2 of urea cycle) is blocked. Carbamoyl phosphate cannot proceed and "
        "overflows into the cytoplasm > enters pyrimidine synthesis > produces excess orotic acid. "
        "This is the DIAGNOSTIC HALLMARK that differentiates OTC from CPS-I deficiency.",
        CASE_B
    )
]], colWidths=[W-4*cm])
diag_box.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,-1), RED_LITE),
    ("BOX",(0,0),(-1,-1), 2, RED_DARK),
    ("TOPPADDING",(0,0),(-1,-1), 10),
    ("BOTTOMPADDING",(0,0),(-1,-1), 10),
    ("LEFTPADDING",(0,0),(-1,-1), 14),
    ("RIGHTPADDING",(0,0),(-1,-1), 14),
]))
story += [diag_box, PageBreak()]

# ── PAGE 8: CASE MANAGEMENT & TAKEAWAYS ──────────────────────────────────
story += [sec_header("Case Management and Key Takeaways"), br()]

story += [Paragraph(b("Management of Baby Hamza (OTC Deficiency):"), SH2)]

mgmt = [
    ["Phase", "Action", "Rationale"],
    ["Immediate", "Stop breastfeeding (stop protein)", "Removes NH3 source immediately"],
    ["Immediate", "IV 10% Dextrose + Intralipid", "High calorie input suppresses catabolism"],
    ["Acute", "IV Ammonul (Na Benzoate + Na Phenylacetate)", "Nitrogen scavengers; excrete NH3 as hippurate and phenylacetylglutamine"],
    ["Acute", "IV Arginine infusion", "Replenish depleted urea cycle intermediates"],
    ["Acute", "Haemodialysis", "NH3 at 780 umol/L — urgent dialysis required"],
    ["Stabilised", "Reintroduce protein gradually with formula", "Minimum protein for growth; monitor NH3 closely"],
    ["Long-term", "Oral sodium phenylbutyrate daily", "Chronic nitrogen scavenging"],
    ["Long-term", "Liver transplant evaluation", "Curative option for severe OTC deficiency"],
]
mgmt_tbl = Table(mgmt, colWidths=[2.5*cm, 5.5*cm, 9*cm])
mgmt_tbl.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,0), TEAL_DARK),
    ("TEXTCOLOR",(0,0),(-1,0), WHITE),
    ("FONTNAME",(0,0),(-1,0),"Helvetica-Bold"),
    ("FONTSIZE",(0,0),(-1,-1), 8.5),
    ("ROWBACKGROUNDS",(0,1),(-1,-1), [WHITE, GREY_LITE]),
    ("VALIGN",(0,0),(-1,-1),"TOP"),
    ("TOPPADDING",(0,0),(-1,-1), 5),
    ("BOTTOMPADDING",(0,0),(-1,-1), 5),
    ("LEFTPADDING",(0,0),(-1,-1), 5),
    ("BOX",(0,0),(-1,-1), 1, TEAL),
    ("INNERGRID",(0,0),(-1,-1), 0.3, colors.HexColor("#CCCCCC")),
]))
story += [mgmt_tbl, br()]

story += [Paragraph(b("Key Takeaways to Remember:"), SH2)]

points = [
    "Urea cycle is the ONLY pathway to clear NH3 from blood — 5 enzymes, 6 steps (NAGS activates CPS-I)",
    "OTC deficiency = most common urea cycle disorder; X-linked; OROTIC ACID rises in urine (unlike CPS-I)",
    "NH3 toxicity: depletes alpha-KG from TCA cycle; glutamine swells astrocytes causing cerebral oedema",
    "Neonates present 24-72 h after protein feeds: feeding refusal, vomiting, rapid breathing, coma",
    "Diagnosis: plasma NH3 + plasma amino acids + URINE OROTIC ACID + genetic testing",
    "Treatment: STOP protein > IV glucose/lipid > nitrogen scavengers (benzoate/phenylacetate) > arginine > dialysis if severe",
    "Liver transplant = curative — BUT does NOT reverse existing neurological damage",
]
for pt in points:
    row = Table([[Paragraph("  " + pt, S("pt", parent=BODY, fontSize=9.5))]], colWidths=[W-4*cm])
    row.setStyle(TableStyle([
        ("BACKGROUND",(0,0),(-1,-1), GREEN_LITE),
        ("BOX",(0,0),(-1,-1), 0.8, GREEN_DARK),
        ("TOPPADDING",(0,0),(-1,-1), 5),
        ("BOTTOMPADDING",(0,0),(-1,-1), 5),
        ("LEFTPADDING",(0,0),(-1,-1), 10),
    ]))
    story += [row, Spacer(1, 4)]

story += [
    br(),
    hr(),
    Paragraph(
        "Sources: Biochemistry 8th ed — Lippincott Illustrated Reviews (Ferrier, 2019) pp. 722-728  "
        "|  Bradley & Daroff's Neurology in Clinical Practice  "
        "|  Basic Medical Biochemistry 6e",
        CITE
    ),
]

doc.build(story)
print("PDF created:", OUTPUT)