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.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, PageBreak, KeepTogether
)
from reportlab.lib.enums import TA_CENTER, TA_LEFT, TA_JUSTIFY
from reportlab.platypus import BaseDocTemplate, Frame, PageTemplate
from reportlab.lib.colors import HexColor

# ─── Colour palette ──────────────────────────────────────────────────────────
DARK_BLUE   = HexColor("#1a3a5c")
MED_BLUE    = HexColor("#2c6fad")
LIGHT_BLUE  = HexColor("#dce9f5")
ACCENT_RED  = HexColor("#c0392b")
ACCENT_GRN  = HexColor("#1e7e45")
ACCENT_ORG  = HexColor("#d35400")
ACCENT_PUR  = HexColor("#6c3483")
ACCENT_TEAL = HexColor("#117a8b")
LIGHT_GREY  = HexColor("#f4f4f4")
MID_GREY    = HexColor("#888888")
WHITE       = colors.white
BLACK       = colors.black

CASE_COLORS = [ACCENT_RED, ACCENT_ORG, ACCENT_GRN, ACCENT_PUR, ACCENT_TEAL]
CASE_LIGHT  = [
    HexColor("#fdecea"), HexColor("#fef0e6"), HexColor("#e8f5ee"),
    HexColor("#f3eaf8"), HexColor("#e6f4f7")
]

# ─── Document setup ───────────────────────────────────────────────────────────
OUTPUT = "/tmp/workspace/lipid-cases/Lipid_Metabolism_Quick_Reference.pdf"
PAGE_W, PAGE_H = A4
MARGIN = 1.5 * cm

doc = SimpleDocTemplate(
    OUTPUT,
    pagesize=A4,
    leftMargin=MARGIN, rightMargin=MARGIN,
    topMargin=2*cm, bottomMargin=2*cm,
    title="Lipid Metabolism - MBBS Quick Reference",
    author="Orris AI",
    subject="Biochemistry Case Studies"
)

styles = getSampleStyleSheet()

def S(name, **kw):
    """Build a ParagraphStyle from defaults + overrides."""
    return ParagraphStyle(name, **kw)

# ── shared styles ──────────────────────────────────────────────────────────────
body  = S("body",  fontName="Helvetica", fontSize=8.5, leading=12,
          textColor=BLACK, spaceAfter=4)
bodyJ = S("bodyJ", fontName="Helvetica", fontSize=8.5, leading=12,
          textColor=BLACK, spaceAfter=4, alignment=TA_JUSTIFY)
bold  = S("bold",  fontName="Helvetica-Bold", fontSize=8.5, leading=12,
          textColor=BLACK, spaceAfter=2)
small = S("small", fontName="Helvetica", fontSize=7.5, leading=10,
          textColor=MID_GREY)
code  = S("code",  fontName="Courier", fontSize=7.5, leading=11,
          textColor=DARK_BLUE, backColor=LIGHT_GREY, spaceAfter=4,
          leftIndent=6, rightIndent=6)

def header_style(color):
    return S(f"hdr_{id(color)}", fontName="Helvetica-Bold", fontSize=11,
             leading=14, textColor=WHITE, spaceAfter=0, spaceBefore=0,
             alignment=TA_LEFT)

def subhdr_style(color):
    return S(f"sub_{id(color)}", fontName="Helvetica-Bold", fontSize=9,
             leading=12, textColor=color, spaceAfter=3, spaceBefore=6)

# ─── Helper builders ──────────────────────────────────────────────────────────
def cover_table(story):
    """Full-width cover block."""
    cover_data = [[
        Paragraph(
            "<font color='white'><b>MBBS Biochemistry</b></font>",
            S("ct1", fontName="Helvetica-Bold", fontSize=22, leading=28,
              textColor=WHITE, alignment=TA_CENTER)
        )
    ], [
        Paragraph(
            "<font color='white'>Lipid Metabolism — Quick Reference Guide</font>",
            S("ct2", fontName="Helvetica", fontSize=14, leading=18,
              textColor=WHITE, alignment=TA_CENTER)
        )
    ], [
        Paragraph(
            "<font color='white'>5 Clinical Case Studies | Pathophysiology • Investigations • MCQs • Viva</font>",
            S("ct3", fontName="Helvetica", fontSize=9, leading=12,
              textColor=HexColor("#cce0f5"), alignment=TA_CENTER)
        )
    ]]
    t = Table(cover_data, colWidths=[PAGE_W - 2*MARGIN])
    t.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), DARK_BLUE),
        ("ALIGN",      (0,0), (-1,-1), "CENTER"),
        ("VALIGN",     (0,0), (-1,-1), "MIDDLE"),
        ("TOPPADDING", (0,0), (-1,-1), 14),
        ("BOTTOMPADDING", (0,-1), (-1,-1), 14),
        ("ROWBACKGROUNDS", (0,0), (-1,-1), [DARK_BLUE]),
        ("BOX", (0,0), (-1,-1), 0, DARK_BLUE),
    ]))
    story.append(t)

def case_header(story, num, title, subtitle, color):
    data = [[
        Paragraph(f"<b>CASE {num}</b>", header_style(color)),
        Paragraph(f"<b>{title}</b>", header_style(color)),
        Paragraph(subtitle, S("sh2", fontName="Helvetica", fontSize=8,
                               leading=10, textColor=HexColor("#ddeeff"),
                               alignment=TA_LEFT)),
    ]]
    t = Table(data, colWidths=[2.2*cm, 9*cm, None])
    t.setStyle(TableStyle([
        ("BACKGROUND",    (0,0), (-1,-1), color),
        ("VALIGN",        (0,0), (-1,-1), "MIDDLE"),
        ("TOPPADDING",    (0,0), (-1,-1), 8),
        ("BOTTOMPADDING", (0,0), (-1,-1), 8),
        ("LEFTPADDING",   (0,0), (-1,-1), 8),
        ("BOX",           (0,0), (-1,-1), 0, color),
    ]))
    story.append(t)

def section_title(story, text, color):
    story.append(Spacer(1, 4))
    t = Table([[Paragraph(f"  {text}", S("st", fontName="Helvetica-Bold",
               fontSize=8.5, textColor=WHITE, leading=12))]],
              colWidths=[PAGE_W - 2*MARGIN])
    t.setStyle(TableStyle([
        ("BACKGROUND",    (0,0), (-1,-1), color),
        ("TOPPADDING",    (0,0), (-1,-1), 4),
        ("BOTTOMPADDING", (0,0), (-1,-1), 4),
    ]))
    story.append(t)

def info_table(story, rows, col_widths, color, header_row=True):
    """Generic styled table."""
    t = Table(rows, colWidths=col_widths, repeatRows=1 if header_row else 0)
    ts = [
        ("GRID",         (0,0), (-1,-1), 0.4, HexColor("#cccccc")),
        ("FONTSIZE",     (0,0), (-1,-1), 7.5),
        ("LEADING",      (0,0), (-1,-1), 10),
        ("TOPPADDING",   (0,0), (-1,-1), 3),
        ("BOTTOMPADDING",(0,0), (-1,-1), 3),
        ("LEFTPADDING",  (0,0), (-1,-1), 5),
        ("ALIGN",        (0,0), (-1,-1), "LEFT"),
        ("VALIGN",       (0,0), (-1,-1), "TOP"),
    ]
    if header_row:
        ts += [
            ("BACKGROUND",  (0,0), (-1,0), color),
            ("TEXTCOLOR",   (0,0), (-1,0), WHITE),
            ("FONTNAME",    (0,0), (-1,0), "Helvetica-Bold"),
            ("ROWBACKGROUNDS", (0,1), (-1,-1), [WHITE, HexColor("#f7f7f7")]),
        ]
    t.setStyle(TableStyle(ts))
    story.append(t)

def mcq_block(story, questions, color):
    for i, (q, opts, ans_idx) in enumerate(questions):
        qp = Paragraph(f"<b>Q{i+1}.</b> {q}",
                       S("q", fontName="Helvetica-Bold", fontSize=8,
                         leading=11, textColor=DARK_BLUE, spaceAfter=1))
        story.append(qp)
        for j, opt in enumerate(opts):
            prefix = "✓" if j == ans_idx else "○"
            col = ACCENT_GRN if j == ans_idx else BLACK
            op = Paragraph(
                f"&nbsp;&nbsp;{prefix} {opt}",
                S(f"opt{i}{j}", fontName="Helvetica", fontSize=7.5,
                  leading=10, textColor=col, spaceAfter=1,
                  leftIndent=8)
            )
            story.append(op)
        story.append(Spacer(1, 3))

def viva_block(story, qas, color):
    for q, a in qas:
        story.append(Paragraph(
            f"<b>Q:</b> {q}",
            S("vq", fontName="Helvetica-Bold", fontSize=8, leading=11,
              textColor=color, spaceAfter=1, leftIndent=4)
        ))
        story.append(Paragraph(
            f"<b>A:</b> {a}",
            S("va", fontName="Helvetica", fontSize=8, leading=11,
              textColor=BLACK, spaceAfter=5, leftIndent=4)
        ))

def pathophys_box(story, steps, color, light):
    rows = [[Paragraph(s, S("pp", fontName="Courier", fontSize=7.5,
                             leading=11, textColor=DARK_BLUE))]
            for s in steps]
    t = Table(rows, colWidths=[PAGE_W - 2*MARGIN])
    t.setStyle(TableStyle([
        ("BACKGROUND",    (0,0), (-1,-1), light),
        ("LEFTPADDING",   (0,0), (-1,-1), 8),
        ("RIGHTPADDING",  (0,0), (-1,-1), 8),
        ("TOPPADDING",    (0,0), (-1,-1), 2),
        ("BOTTOMPADDING", (0,0), (-1,-1), 2),
        ("BOX",           (0,0), (-1,-1), 0.8, color),
    ]))
    story.append(t)

# =============================================================================
# BUILD STORY
# =============================================================================
story = []
W = PAGE_W - 2*MARGIN   # usable width

# ── COVER ─────────────────────────────────────────────────────────────────────
cover_table(story)
story.append(Spacer(1, 6))

# Index table
idx_data = [
    [Paragraph("<b>Case</b>", S("ih", fontName="Helvetica-Bold", fontSize=8.5,
               textColor=WHITE)),
     Paragraph("<b>Patient</b>", S("ih2", fontName="Helvetica-Bold", fontSize=8.5,
               textColor=WHITE)),
     Paragraph("<b>Diagnosis</b>", S("ih3", fontName="Helvetica-Bold", fontSize=8.5,
               textColor=WHITE)),
     Paragraph("<b>Key Enzyme/Defect</b>", S("ih4", fontName="Helvetica-Bold",
               fontSize=8.5, textColor=WHITE))],
    ["1", "Mr. Arjun, 35M", "Familial Hypercholesterolemia", "LDL Receptor (LDLR) mutation"],
    ["2", "Ravi, 22M",      "Diabetic Ketoacidosis",          "Insulin absence → ↑ ketogenesis"],
    ["3", "Mrs. Seema, 45F","NAFLD / NASH",                   "Insulin resistance → hepatic steatosis"],
    ["4", "Baby Mohan, 8M", "Gaucher Disease",                "Glucocerebrosidase deficiency"],
    ["5", "Mr. Dev, 52M",   "Alcoholic Fatty Liver",          "↑ NADH/NAD+ ratio"],
]
it = Table(idx_data, colWidths=[1.2*cm, 3.5*cm, 6*cm, None])
it.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,0), MED_BLUE),
    ("TEXTCOLOR",     (0,0), (-1,0), WHITE),
    ("FONTNAME",      (0,0), (-1,0), "Helvetica-Bold"),
    ("FONTSIZE",      (0,0), (-1,-1), 8.5),
    ("LEADING",       (0,0), (-1,-1), 11),
    ("ROWBACKGROUNDS",(0,1), (-1,-1),
     [CASE_LIGHT[i % 5] for i in range(5)]),
    ("GRID",          (0,0), (-1,-1), 0.4, HexColor("#bbbbbb")),
    ("ALIGN",         (0,0), (0,-1), "CENTER"),
    ("VALIGN",        (0,0), (-1,-1), "MIDDLE"),
    ("TOPPADDING",    (0,0), (-1,-1), 4),
    ("BOTTOMPADDING", (0,0), (-1,-1), 4),
    ("LEFTPADDING",   (0,0), (-1,-1), 6),
]))
story.append(Paragraph("Cases at a Glance",
    S("idx", fontName="Helvetica-Bold", fontSize=10, textColor=DARK_BLUE,
      spaceAfter=4, spaceBefore=8)))
story.append(it)
story.append(Spacer(1, 6))
story.append(HRFlowable(width=W, thickness=0.5, color=MID_GREY))
story.append(PageBreak())

# =============================================================================
# CASE 1 – Familial Hypercholesterolemia
# =============================================================================
C = 0
case_header(story, 1, "Familial Hypercholesterolemia (FH)",
            "LDLR mutation | Autosomal Semidominant | Premature CAD", CASE_COLORS[C])

# Vignette + key signs
section_title(story, "Clinical Vignette & Key Signs", CASE_COLORS[C])
story.append(Paragraph(
    "Mr. Arjun, 35-year-old male. Chest pain on exertion × 3 months. "
    "Father died of MI at 42. Non-smoker, non-diabetic, vegetarian diet.",
    bodyJ))

signs_data = [
    [Paragraph("<b>Sign</b>", bold), Paragraph("<b>Significance</b>", bold)],
    ["Tendon xanthomas (Achilles, extensors)", "Cholesterol deposits — pathognomonic of FH"],
    ["Xanthelasma (eyelids)",                  "Cholesterol in periorbital skin"],
    ["Premature arcus corneae",                 "Corneal cholesterol ring before age 45"],
    ["ST depression V4–V6 on ECG",              "Myocardial ischemia from early atherosclerosis"],
]
info_table(story, signs_data, [7*cm, None], CASE_COLORS[C])

# Investigations
section_title(story, "Key Investigations", CASE_COLORS[C])
inv_data = [
    [Paragraph("<b>Test</b>", bold), Paragraph("<b>Patient</b>", bold),
     Paragraph("<b>Normal</b>", bold)],
    ["Total cholesterol",  "620 mg/dL ↑↑",  "< 200 mg/dL"],
    ["LDL cholesterol",    "550 mg/dL ↑↑",  "< 100 mg/dL"],
    ["HDL cholesterol",    "42 mg/dL",       "> 40 mg/dL"],
    ["Triglycerides",      "160 mg/dL",      "< 150 mg/dL"],
    ["LDLR gene (genetic)","Heterozygous mutation", "Normal"],
]
info_table(story, inv_data, [5*cm, 4.5*cm, None], CASE_COLORS[C])

# Pathophys
section_title(story, "Pathophysiology", CASE_COLORS[C])
pathophys_box(story, [
    "NORMAL:  LDL → binds LDLR on hepatocyte → endocytosis → cholesterol extracted → LDLR recycled",
    "FH:      LDLR mutated/absent → LDL stays in blood → LDL ↑↑↑",
    "         → Macrophage uptake → Foam cells → Atherosclerotic plaques",
    "         → Cholesterol in tendons → Xanthomas",
    "         → Cholesterol in cornea → Arcus corneae",
    "PCSK9:   Protease that degrades LDLR — blocking it (evolocumab) = more receptors = ↓ LDL",
], CASE_COLORS[C], CASE_LIGHT[C])

# Gene dosage
section_title(story, "Gene Dosage Effect", CASE_COLORS[C])
gd_data = [
    [Paragraph("<b>Genotype</b>", bold), Paragraph("<b>LDL</b>", bold),
     Paragraph("<b>CAD Onset</b>", bold)],
    ["LDLR +/+ (Normal)",       "~130 mg/dL",   "6th–7th decade"],
    ["LDLR +/− (Heterozygote)", "~300 mg/dL (2×)", "4th–5th decade"],
    ["LDLR −/− (Homozygote)",   "700+ mg/dL (5×)", "Childhood (<20 yr); fatal by 3rd decade if untreated"],
]
info_table(story, gd_data, [4.5*cm, 4*cm, None], CASE_COLORS[C])

# Management
section_title(story, "Management", CASE_COLORS[C])
mgmt_data = [
    [Paragraph("<b>Drug/Intervention</b>", bold), Paragraph("<b>Mechanism</b>", bold)],
    ["Statins (atorvastatin, rosuvastatin)", "Inhibit HMG-CoA reductase → ↓ cholesterol synthesis → ↑ LDLR expression"],
    ["Ezetimibe",                            "Blocks intestinal cholesterol absorption (NPC1L1 inhibitor)"],
    ["PCSK9 inhibitors (evolocumab)",        "Prevent LDLR lysosomal degradation → more receptors available"],
    ["Bile acid sequestrants (cholestyramine)","Trap bile acids → liver uses cholesterol to make more → ↓ LDL"],
    ["LDL apheresis",                        "Mechanical LDL removal — for homozygous FH"],
]
info_table(story, mgmt_data, [5.5*cm, None], CASE_COLORS[C])

# MCQs
section_title(story, "MCQs", CASE_COLORS[C])
mcq_block(story, [
    ("Primary defect in FH is:",
     ["Excess dietary fat absorption", "Deficiency of LDL receptor",
      "Increased VLDL synthesis",      "Deficiency of HMG-CoA reductase"], 1),
    ("Xanthomas in FH are cholesterol deposits in:",
     ["Spleen macrophages", "Tendon sheath macrophages (foam cells)",
      "Hepatocytes",        "Corneal stroma"], 1),
    ("PCSK9 inhibitors lower LDL by:",
     ["Inhibiting cholesterol synthesis", "Reducing intestinal absorption",
      "Preventing lysosomal degradation of LDLR", "Increasing HDL production"], 2),
], CASE_COLORS[C])

# Viva
section_title(story, "Viva Q&A", CASE_COLORS[C])
viva_block(story, [
    ("Why do statins increase LDL receptor expression?",
     "Statins inhibit HMG-CoA reductase → ↓ intracellular cholesterol → hepatocyte senses low cholesterol "
     "→ SREBP activates LDLR gene transcription → more receptors pull LDL from blood."),
    ("Why is FH called autosomal semidominant?",
     "Both heterozygotes and homozygotes are clinically affected (unlike recessive), but with a clear "
     "gene-dosage effect — homozygotes are far more severely affected, unlike autosomal dominant."),
], CASE_COLORS[C])

story.append(PageBreak())

# =============================================================================
# CASE 2 – Diabetic Ketoacidosis
# =============================================================================
C = 1
case_header(story, 2, "Diabetic Ketoacidosis (DKA)",
            "Absolute insulin deficiency | Anion gap metabolic acidosis | Ketonemia", CASE_COLORS[C])

section_title(story, "Clinical Vignette & Key Signs", CASE_COLORS[C])
story.append(Paragraph(
    "Ravi, 22-year-old male, known T1DM. Missed insulin for 2 days. "
    "Vomiting + abdominal pain, progressive drowsiness. GCS 10/15.",
    bodyJ))

signs_data2 = [
    [Paragraph("<b>Sign</b>", bold), Paragraph("<b>Biochemical Basis</b>", bold)],
    ["Kussmaul breathing (deep, rapid sighing)", "Metabolic acidosis → central chemoreceptors → ↑ RR to blow off CO₂"],
    ["Fruity/sweet breath odor",                 "Acetone (volatile ketone) exhaled through lungs"],
    ["Dehydration (dry mucosa, ↓ skin turgor)",  "Osmotic diuresis from hyperglycemia → fluid loss"],
    ["Abdominal pain + vomiting",                "Ketone-induced gastric irritation, electrolyte disturbance"],
]
info_table(story, signs_data2, [7*cm, None], CASE_COLORS[C])

section_title(story, "Key Investigations", CASE_COLORS[C])
inv_data2 = [
    [Paragraph("<b>Test</b>", bold), Paragraph("<b>Patient</b>", bold),
     Paragraph("<b>Normal</b>", bold), Paragraph("<b>Significance</b>", bold)],
    ["Blood glucose",     "520 mg/dL ↑↑",    "70–100",    "Absolute insulin deficiency"],
    ["Arterial pH",       "7.12 ↓↓",         "7.35–7.45", "Severe metabolic acidosis"],
    ["HCO₃⁻",            "8 mEq/L ↓↓",      "22–26",     "Consumed buffering ketoacids"],
    ["pCO₂",             "20 mmHg ↓",        "35–45",     "Respiratory compensation"],
    ["Anion gap",         "28 ↑↑",           "8–12",      "Unmeasured ketoanions"],
    ["β-hydroxybutyrate", "8.5 mmol/L ↑↑",  "< 0.6",     "Major ketone body"],
    ["Serum K⁺",         "5.8 (initially ↑)","3.5–5.0",  "Acidosis shifts K⁺ out of cells"],
]
info_table(story, inv_data2, [4*cm, 3.2*cm, 2.5*cm, None], CASE_COLORS[C])

section_title(story, "Pathophysiology", CASE_COLORS[C])
pathophys_box(story, [
    "INSULIN ABSENT  →  Cells cannot use glucose  →  Glucagon ↑, Epinephrine ↑",
    "                →  Adipose lipolysis ↑↑  →  FFA flood liver",
    "                →  β-oxidation ↑↑  →  Excess Acetyl CoA overwhelms Krebs cycle",
    "KETOGENESIS (liver mitochondria):",
    "  2 Acetyl CoA → Acetoacetyl CoA → HMG-CoA → Acetoacetate",
    "                                           → β-Hydroxybutyrate (major, 75%)",
    "                                           → Acetone (exhaled → fruity breath)",
    "Ketoacids lower blood pH → Metabolic acidosis (anion gap type)",
    "NOTE: Liver produces ketones but CANNOT use them (lacks succinyl CoA transferase)",
], CASE_COLORS[C], CASE_LIGHT[C])

section_title(story, "The 3 Ketone Bodies", CASE_COLORS[C])
kb_data = [
    [Paragraph("<b>Ketone Body</b>", bold), Paragraph("<b>% in DKA</b>", bold),
     Paragraph("<b>Detection</b>", bold),   Paragraph("<b>Clinical Note</b>", bold)],
    ["Acetoacetate",      "~20%", "Nitroprusside test (positive)", "Direct acid"],
    ["β-Hydroxybutyrate", "~75%", "NOT detected by nitroprusside ⚠️", "Best blood marker (enzymatic assay)"],
    ["Acetone",           "~5%",  "Volatile — exhaled",              "Causes fruity breath; not an acid"],
]
info_table(story, kb_data, [4*cm, 2.5*cm, 4.5*cm, None], CASE_COLORS[C])

section_title(story, "Management (DKA Protocol)", CASE_COLORS[C])
mgmt_data2 = [
    [Paragraph("<b>Step</b>", bold), Paragraph("<b>Action</b>", bold),
     Paragraph("<b>Key Rationale</b>", bold)],
    ["1. IV Fluids",   "0.9% NaCl 1 L/hr",                "Correct dehydration, dilute glucose"],
    ["2. Insulin",     "IV regular insulin 0.1 U/kg/hr",   "Stop ketogenesis, allow glucose uptake"],
    ["3. Potassium",   "Add K⁺ once urine output confirmed","K⁺ will fall rapidly as insulin drives it into cells"],
    ["4. Monitor",     "Switch to D5W when glucose < 250", "Prevent hypoglycemia while insulin continues"],
    ["5. Treat cause", "Identify: missed dose? infection?", "DKA recurrence prevention"],
]
info_table(story, mgmt_data2, [2.5*cm, 5.5*cm, None], CASE_COLORS[C])

section_title(story, "MCQs", CASE_COLORS[C])
mcq_block(story, [
    ("Rate-limiting enzyme of ketogenesis:",
     ["Acetyl CoA carboxylase", "HMG-CoA synthase (mitochondrial)",
      "HMG-CoA reductase",     "Pyruvate dehydrogenase"], 1),
    ("Nitroprusside test does NOT detect:",
     ["Acetoacetate", "Acetone", "β-Hydroxybutyrate", "None of the above"], 2),
    ("The organ that produces but CANNOT use ketone bodies:",
     ["Brain", "Heart", "Liver", "Kidney"], 2),
    ("Initial hyperkalemia in DKA is because:",
     ["Excess dietary K⁺", "Acidosis shifts K⁺ out of cells",
      "Insulin pushes K⁺ into cells", "Renal failure"], 1),
], CASE_COLORS[C])

section_title(story, "Viva Q&A", CASE_COLORS[C])
viva_block(story, [
    ("Why does the liver produce ketones but not use them?",
     "The liver lacks succinyl CoA transferase (thiophorase) — the enzyme needed to reconvert "
     "acetoacetate to acetoacetyl CoA for Krebs cycle entry. Ketones are exported as fuel for brain, heart, and muscle."),
    ("What prevents ketogenesis in the fed state?",
     "Insulin activates acetyl CoA carboxylase → produces malonyl CoA → inhibits CPT-1 "
     "(carnitine palmitoyl transferase I) → fatty acids cannot enter mitochondria → no β-oxidation → no ketogenesis."),
], CASE_COLORS[C])

story.append(PageBreak())

# =============================================================================
# CASE 3 – NAFLD / NASH
# =============================================================================
C = 2
case_header(story, 3, "Non-Alcoholic Fatty Liver Disease (NAFLD / NASH)",
            "Insulin resistance | Hepatic steatosis → steatohepatitis → cirrhosis", CASE_COLORS[C])

section_title(story, "Clinical Vignette & Key Signs", CASE_COLORS[C])
story.append(Paragraph(
    "Mrs. Seema, 45F. BMI 36 (obese). T2DM on metformin. Fatigue, RUQ discomfort × 3 years. "
    "NO alcohol. Hepatomegaly. No stigmata of chronic liver disease.",
    bodyJ))

section_title(story, "Key Investigations", CASE_COLORS[C])
inv_data3 = [
    [Paragraph("<b>Test</b>", bold), Paragraph("<b>Patient</b>", bold),
     Paragraph("<b>Normal</b>", bold), Paragraph("<b>Significance</b>", bold)],
    ["ALT",             "115 U/L ↑",   "< 40",       "Hepatocellular injury (ALT > AST in NAFLD)"],
    ["AST",             "80 U/L ↑",    "< 40",       "AST:ALT < 1 — favors NAFLD over alcohol"],
    ["AST:ALT ratio",   "0.7 (<1) ✓",  "< 1 = NAFLD","Key differentiator from alcoholic liver disease"],
    ["GGT",             "110 U/L ↑",   "< 50",       "Mild elevation; markedly elevated in alcohol"],
    ["Fasting glucose", "145 mg/dL ↑", "< 100",      "Insulin resistance / T2DM"],
    ["Triglycerides",   "280 mg/dL ↑", "< 150",      "Hypertriglyceridemia from excess FFA flux"],
    ["HDL",             "32 mg/dL ↓",  "> 50 (F)",   "Metabolic syndrome component"],
    ["USG abdomen",     "Bright echogenic liver", "Normal", "Fatty infiltration — first-line imaging"],
    ["Liver biopsy",    "Macrovesicular steatosis + hepatocyte ballooning + neutrophils", "—", "Confirms NASH"],
]
info_table(story, inv_data3, [4*cm, 3.8*cm, 2.5*cm, None], CASE_COLORS[C])

section_title(story, "NAFLD Spectrum", CASE_COLORS[C])
pathophys_box(story, [
    "Normal Liver  →  NAFL (steatosis ≥5%, no inflammation)  →  NASH (steatosis + inflammation + ballooning)",
    "             →  Fibrosis  →  Cirrhosis (micronodular)  →  Hepatocellular Carcinoma (HCC)",
    "",
    "TWO-HIT HYPOTHESIS:",
    "  1st Hit: Insulin resistance → ↑ FFA to liver + ↑ de novo lipogenesis → STEATOSIS",
    "  2nd Hit: Oxidative stress + mitochondrial dysfunction + gut dysbiosis → NASH / FIBROSIS",
], CASE_COLORS[C], CASE_LIGHT[C])

section_title(story, "Liver Biopsy Findings (Robbins)", CASE_COLORS[C])
bx_data = [
    [Paragraph("<b>Finding</b>", bold), Paragraph("<b>Description</b>", bold),
     Paragraph("<b>Significance</b>", bold)],
    ["Macrovesicular steatosis", "Large lipid droplets displace nucleus — begins centrilobular (zone 3)", "Earliest, most reversible change"],
    ["Hepatocyte ballooning",    "Swelling + necrosis of centrilobular hepatocytes", "Marker of lipotoxic injury"],
    ["Mallory hyaline bodies",   "Ubiquitinated keratins 8 & 18 — eosinophilic inclusions", "Degeneration marker"],
    ["Neutrophil infiltration",  "Surrounds ballooned hepatocytes (lobular inflammation)", "Distinguishes NASH from simple steatosis"],
    ["Perisinusoidal fibrosis",  "\"Chicken-wire fence\" collagen in space of Disse (zone 3)", "Progressive → cirrhosis"],
    ["Micronodular cirrhosis",   "Nodules < 0.3 cm — end stage burned-out NAFLD", "Irreversible end stage"],
]
info_table(story, bx_data, [4.5*cm, 6*cm, None], CASE_COLORS[C])

section_title(story, "Management", CASE_COLORS[C])
mgmt_data3 = [
    [Paragraph("<b>Intervention</b>", bold), Paragraph("<b>Effect</b>", bold)],
    ["Weight loss ≥7–10% body weight (most effective)", "Reduces steatosis, inflammation, fibrosis stage"],
    ["Aerobic exercise (150 min/week)",                  "↑ Insulin sensitivity, ↓ hepatic FFA flux"],
    ["Vitamin E (800 IU/day)",                           "Antioxidant — reduces oxidative 2nd hit in NASH"],
    ["GLP-1 agonists (semaglutide)",                     "↓ Liver fat, ↓ inflammation, ↓ fibrosis — emerging"],
    ["Avoid alcohol, NSAIDs, hepatotoxic drugs",         "Prevent additional hepatic injury"],
]
info_table(story, mgmt_data3, [8*cm, None], CASE_COLORS[C])

section_title(story, "MCQs", CASE_COLORS[C])
mcq_block(story, [
    ("Earliest and most reversible change in fatty liver disease:",
     ["Fibrosis", "Steatohepatitis", "Macrovesicular steatosis", "Cirrhosis"], 2),
    ("Mallory hyaline bodies are composed of:",
     ["Amyloid", "Ubiquitinated keratins 8 and 18", "Fibronectin", "Collagen IV"], 1),
    ("Fat accumulation in NAFLD begins in:",
     ["Zone 1 (periportal)", "Zone 2 (midzonal)", "Zone 3 (centrilobular)", "Uniform"], 2),
    ("AST:ALT ratio in NAFLD vs. alcoholic liver disease:",
     ["Both > 2:1", "NAFLD < 1; alcoholic > 2:1", "NAFLD > 2:1; alcoholic < 1", "Equal in both"], 1),
], CASE_COLORS[C])

section_title(story, "Viva Q&A", CASE_COLORS[C])
viva_block(story, [
    ("How does insulin resistance cause fatty liver?",
     "Insulin resistance: (1) fails to suppress adipose lipolysis → ↑ FFA to liver; "
     "(2) still activates SREBP-1c in liver → ↑ de novo lipogenesis; "
     "(3) impairs VLDL export. Net: triglyceride accumulation in hepatocytes."),
    ("What is the significance of perisinusoidal 'chicken-wire' fibrosis?",
     "Collagen deposition in the space of Disse in zone 3 — characteristic of NAFLD/ALD. "
     "Reflects stellate cell activation by lipotoxic injury. Differs from portal fibrosis in viral hepatitis."),
], CASE_COLORS[C])

story.append(PageBreak())

# =============================================================================
# CASE 4 – Gaucher Disease
# =============================================================================
C = 3
case_header(story, 4, "Gaucher Disease (Sphingolipidosis)",
            "Glucocerebrosidase deficiency | AR | Hepatosplenomegaly + Pancytopenia", CASE_COLORS[C])

section_title(story, "Clinical Vignette", CASE_COLORS[C])
story.append(Paragraph(
    "Baby Mohan, 8-month-old male. Ashkenazi Jewish parents (consanguineous). "
    "Progressive abdominal distension, failure to thrive, pallor. "
    "Massive splenomegaly (8 cm), hepatomegaly (5 cm). Neurologically normal (Type 1).",
    bodyJ))

section_title(story, "Key Investigations", CASE_COLORS[C])
inv_data4 = [
    [Paragraph("<b>Test</b>", bold), Paragraph("<b>Patient</b>", bold),
     Paragraph("<b>Significance</b>", bold)],
    ["Haemoglobin",       "7.2 g/dL ↓",         "Marrow infiltration → anemia"],
    ["Platelets",         "65,000/µL ↓",         "Hypersplenism + marrow infiltration"],
    ["Bone marrow biopsy","Gaucher cells (crumpled tissue paper cytoplasm)", "Pathognomonic"],
    ["Glucocerebrosidase activity (leukocytes)", "< 15% of normal ↓↓", "Confirmatory enzymatic diagnosis"],
    ["Plasma chitotriosidase","Markedly elevated", "Disease activity biomarker for monitoring"],
    ["GBA1 gene",         "Homozygous mutation",  "Confirms genetic diagnosis"],
    ["X-ray femur",       "Erlenmeyer flask deformity", "Marrow infiltration → failed remodeling"],
]
info_table(story, inv_data4, [5.5*cm, 4*cm, None], CASE_COLORS[C])

section_title(story, "Pathophysiology", CASE_COLORS[C])
pathophys_box(story, [
    "Normal: Cell membranes (RBC, WBC) broken down → sphingolipids enter lysosomes",
    "        Glucocerebroside  →[glucocerebrosidase]→  Ceramide + Glucose",
    "",
    "Gaucher: Glucocerebrosidase ABSENT (GBA1 mutation)",
    "         Glucocerebroside ACCUMULATES in macrophage lysosomes → GAUCHER CELLS",
    "         Gaucher cells in SPLEEN → Splenomegaly",
    "                         LIVER  → Hepatomegaly",
    "                         BONE MARROW → Pancytopenia (anemia, thrombocytopenia)",
    "                         BONE       → Avascular necrosis, Erlenmeyer flask deformity",
], CASE_COLORS[C], CASE_LIGHT[C])

section_title(story, "Three Types of Gaucher Disease", CASE_COLORS[C])
types_data = [
    [Paragraph("<b>Type</b>", bold), Paragraph("<b>Neuro involvement</b>", bold),
     Paragraph("<b>Severity</b>", bold), Paragraph("<b>Notes</b>", bold)],
    ["Type 1 (most common)", "None",         "Variable — can live normally with ERT", "Ashkenazi Jews (1:850); N370S mutation"],
    ["Type 2 (acute neuro)", "Severe, early","Fatal by age 2–3",                      "All populations; no ERT benefit for CNS"],
    ["Type 3 (subacute)",    "Mild-moderate","Variable",                               "Swedish Norrbottnian population"],
]
info_table(story, types_data, [3.5*cm, 3.5*cm, 4*cm, None], CASE_COLORS[C])

section_title(story, "Sphingolipidosis Comparison", CASE_COLORS[C])
slipid_data = [
    [Paragraph("<b>Disease</b>", bold), Paragraph("<b>Enzyme deficient</b>", bold),
     Paragraph("<b>Substrate stored</b>", bold), Paragraph("<b>Inheritance</b>", bold)],
    ["Gaucher",     "Glucocerebrosidase",     "Glucocerebroside",    "AR"],
    ["Tay-Sachs",   "Hexosaminidase A",       "GM2 ganglioside",     "AR"],
    ["Niemann-Pick","Sphingomyelinase",        "Sphingomyelin",       "AR"],
    ["Fabry",       "α-Galactosidase A",      "Globotriaosylceramide","X-linked ⚠️"],
    ["Krabbe",      "Galactocerebrosidase",   "Galactocerebroside",  "AR"],
]
info_table(story, slipid_data, [3.5*cm, 4.5*cm, 4*cm, None], CASE_COLORS[C])

section_title(story, "Management", CASE_COLORS[C])
mgmt_data4 = [
    [Paragraph("<b>Treatment</b>", bold), Paragraph("<b>Mechanism</b>", bold)],
    ["Enzyme Replacement Therapy (ERT) — imiglucerase (Cerezyme), IV infusion",
     "Recombinant glucocerebrosidase → clears glucocerebroside from macrophages"],
    ["Substrate Reduction Therapy (SRT) — miglustat, eliglustat",
     "Inhibit glucosylceramide synthase → ↓ substrate production"],
    ["HSCT",                     "Curative but high risk — limited to severe cases"],
]
info_table(story, mgmt_data4, [6.5*cm, None], CASE_COLORS[C])

section_title(story, "MCQs", CASE_COLORS[C])
mcq_block(story, [
    ("Enzyme deficient in Gaucher disease:",
     ["Sphingomyelinase", "Hexosaminidase A", "Glucocerebrosidase", "α-Galactosidase A"], 2),
    ("Gaucher cells show:",
     ["Foam cell vacuolated cytoplasm", "Crumpled tissue paper cytoplasm",
      "Cherry-red spot", "PAS-negative granules"], 1),
    ("Only X-linked sphingolipidosis:",
     ["Gaucher", "Tay-Sachs", "Niemann-Pick A", "Fabry disease"], 3),
    ("Biomarker for monitoring Gaucher disease activity:",
     ["Serum LDH", "Plasma chitotriosidase", "Ceruloplasmin", "Urine homogentisic acid"], 1),
], CASE_COLORS[C])

section_title(story, "Viva Q&A", CASE_COLORS[C])
viva_block(story, [
    ("Why does Gaucher disease cause bone disease?",
     "Gaucher cells infiltrate bone marrow → (1) displace hematopoiesis → pancytopenia; "
     "(2) ↑ intramedullary pressure → ischemia → avascular necrosis of femoral head; "
     "(3) disrupt bone remodeling → Erlenmeyer flask deformity."),
    ("Why does ERT not work for CNS disease in Type 2?",
     "Imiglucerase is a large protein and cannot cross the blood-brain barrier. "
     "Therefore, neuronal glucocerebroside accumulation is not reversed, and Type 2 (acute neuropathic) "
     "Gaucher disease remains fatal despite ERT."),
], CASE_COLORS[C])

story.append(PageBreak())

# =============================================================================
# CASE 5 – Alcoholic Fatty Liver Disease
# =============================================================================
C = 4
case_header(story, 5, "Alcoholic Fatty Liver Disease",
            "↑ NADH/NAD⁺ ratio | Steatosis → Steatohepatitis → Cirrhosis", CASE_COLORS[C])

section_title(story, "Clinical Vignette & Key Signs", CASE_COLORS[C])
story.append(Paragraph(
    "Mr. Dev, 52M. Chronic alcoholic (500 mL whisky/day × 15 years). "
    "Jaundice, ascites, confusion. Hepatomegaly (tender, firm). Spider naevi, palmar erythema, asterixis.",
    bodyJ))

section_title(story, "Key Investigations", CASE_COLORS[C])
inv_data5 = [
    [Paragraph("<b>Test</b>", bold), Paragraph("<b>Patient</b>", bold),
     Paragraph("<b>Normal</b>", bold), Paragraph("<b>Significance</b>", bold)],
    ["AST",          "280 U/L ↑↑",   "< 40",      "Mitochondrial enzyme — released by alcohol damage"],
    ["ALT",          "110 U/L ↑",    "< 40",      "Cytoplasmic enzyme"],
    ["AST:ALT ratio","2.5:1 ↑ (>2)", "< 1",       "KEY: >2:1 strongly suggests alcoholic etiology"],
    ["GGT",          "520 U/L ↑↑↑",  "< 50",      "Alcohol induction marker — most sensitive for alcohol use"],
    ["Total bilirubin","8.5 mg/dL ↑", "< 1.2",    "Impaired hepatic excretion"],
    ["Albumin",      "2.4 g/dL ↓",   "3.5–5.0",  "Impaired synthetic function"],
    ["PT/INR",       "2.1 ↑",        "< 1.2",    "Impaired clotting factor synthesis"],
    ["Triglycerides","380 mg/dL ↑",  "< 150",    "↑ NADH → ↓ β-oxidation → fat accumulates → ↑ TG"],
]
info_table(story, inv_data5, [3.8*cm, 3.2*cm, 2*cm, None], CASE_COLORS[C])

section_title(story, "Pathophysiology — The NADH/NAD⁺ Story", CASE_COLORS[C])
pathophys_box(story, [
    "Ethanol  →[ADH]→  Acetaldehyde + NADH",
    "Acetaldehyde  →[ALDH]→  Acetate + NADH",
    "BOTH STEPS produce NADH → NADH/NAD⁺ ratio ↑↑↑",
    "",
    "Consequences of high NADH:",
    "  1. β-oxidation ↓ (needs NAD⁺) → FFA accumulate → STEATOSIS",
    "  2. Krebs cycle ↓ (NAD⁺ depleted) → Acetyl CoA diverted to FA synthesis",
    "  3. Gluconeogenesis ↓ (pyruvate → lactate instead of glucose) → HYPOGLYCEMIA",
    "  4. Lactate ↑ → LACTIC ACIDOSIS",
    "  5. Uric acid excretion ↓ (competes with lactate) → GOUT",
    "  6. CYP2E1 induction → ROS → lipid peroxidation → STEATOHEPATITIS",
], CASE_COLORS[C], CASE_LIGHT[C])

section_title(story, "NAFLD vs. Alcoholic Liver Disease — Key Differences", CASE_COLORS[C])
diff_data = [
    [Paragraph("<b>Feature</b>", bold), Paragraph("<b>NAFLD</b>", bold),
     Paragraph("<b>Alcoholic LD</b>", bold)],
    ["History",           "Obesity, T2DM, no alcohol",       "Significant alcohol use (>21 units/week)"],
    ["AST:ALT ratio",     "< 1:1 ✓",                        "> 2:1 ✓"],
    ["GGT",               "Mildly elevated",                 "Markedly elevated (enzyme induction)"],
    ["Mallory bodies",    "Less common",                     "Prominent"],
    ["Neutrophil infiltration","Moderate",                   "Prominent, perihepatocytic"],
    ["Fibrosis pattern",  "Zone 3 perisinusoidal",           "Zone 3 perisinusoidal (same)"],
    ["Treatment",         "Weight loss, GLP-1 agonists",     "Alcohol abstinence, corticosteroids (severe)"],
]
info_table(story, diff_data, [4*cm, 5*cm, None], CASE_COLORS[C])

section_title(story, "MCQs", CASE_COLORS[C])
mcq_block(story, [
    ("AST:ALT ratio in alcoholic liver disease is typically:",
     ["< 1:1", "Exactly 1:1", "> 2:1", "> 5:1"], 2),
    ("Key metabolic change from alcohol driving fatty liver:",
     ["Increased gluconeogenesis", "Increased NADH/NAD⁺ ratio",
      "Decreased acetyl CoA", "Increased urea cycle activity"], 1),
    ("Why are alcoholics prone to hypoglycemia?",
     ["Increased insulin secretion", "High NADH inhibits gluconeogenesis (pyruvate → lactate)",
      "Decreased glycogen breakdown", "Increased peripheral glucose uptake"], 1),
    ("Most sensitive marker for alcohol use/abuse:",
     ["ALT", "AST", "GGT", "Alkaline phosphatase"], 2),
], CASE_COLORS[C])

section_title(story, "Viva Q&A", CASE_COLORS[C])
viva_block(story, [
    ("Why does elevated NADH/NAD⁺ cause hypertriglyceridemia?",
     "High NADH suppresses β-oxidation (NAD⁺ needed as electron acceptor) → FFA not oxidized → "
     "esterified into triglycerides. Plus, ↑ acetyl CoA from ethanol → ↑ de novo FA synthesis. "
     "TG stored in hepatocytes + secreted as VLDL → hypertriglyceridemia."),
    ("Why does GGT rise in alcoholics even without liver damage?",
     "Alcohol induces hepatic CYP2E1 and GGT enzyme synthesis via enzyme induction (microsomal induction). "
     "GGT rises even with modest alcohol use and normalizes with abstinence — making it a useful compliance marker."),
], CASE_COLORS[C])

story.append(PageBreak())

# =============================================================================
# MASTER SUMMARY TABLE
# =============================================================================
story.append(Paragraph("MASTER SUMMARY — All 5 Lipid Metabolism Cases",
    S("mst", fontName="Helvetica-Bold", fontSize=13, textColor=WHITE,
      spaceBefore=0, spaceAfter=0, alignment=TA_CENTER)))

# Cover
summary_hdr = Table([[Paragraph(
    "<b>MASTER SUMMARY — All 5 Lipid Metabolism Cases</b>",
    S("msthdr", fontName="Helvetica-Bold", fontSize=12, textColor=WHITE,
      alignment=TA_CENTER))]],
    colWidths=[W])
summary_hdr.setStyle(TableStyle([
    ("BACKGROUND", (0,0), (-1,-1), DARK_BLUE),
    ("TOPPADDING", (0,0), (-1,-1), 8),
    ("BOTTOMPADDING", (0,0), (-1,-1), 8),
]))
story.append(summary_hdr)

summary_data = [
    [Paragraph("<b>Feature</b>", bold),
     Paragraph("<b>Case 1: FH</b>", S("shfh", fontName="Helvetica-Bold", fontSize=7.5,
               textColor=WHITE)),
     Paragraph("<b>Case 2: DKA</b>", S("shdka", fontName="Helvetica-Bold", fontSize=7.5,
               textColor=WHITE)),
     Paragraph("<b>Case 3: NAFLD</b>", S("shnafl", fontName="Helvetica-Bold", fontSize=7.5,
               textColor=WHITE)),
     Paragraph("<b>Case 4: Gaucher</b>", S("shg", fontName="Helvetica-Bold", fontSize=7.5,
               textColor=WHITE)),
     Paragraph("<b>Case 5: ALD</b>", S("shald", fontName="Helvetica-Bold", fontSize=7.5,
               textColor=WHITE))],
    ["Enzyme/Defect",
     "LDLR mutation", "Insulin absence → ↑ ketogenesis",
     "Insulin resistance → steatosis", "Glucocerebrosidase ↓",
     "↑ NADH/NAD⁺ ratio"],
    ["Key lipid",
     "LDL cholesterol", "Ketone bodies",
     "Triglycerides in liver", "Glucocerebroside", "Triglycerides / FFA"],
    ["Key sign",
     "Tendon xanthomas, arcus", "Kussmaul breathing, fruity breath",
     "Hepatomegaly, obesity", "Hepatosplenomegaly, pancytopenia",
     "AST:ALT > 2, GGT ↑↑"],
    ["Lab hallmark",
     "LDL > 300 mg/dL", "Anion gap acidosis, β-OHB ↑",
     "AST:ALT < 1, bright liver USG", "Gaucher cells, ↓ glucocerebrosidase",
     "AST:ALT > 2, GGT ↑↑"],
    ["Inheritance",
     "Autosomal semidominant", "Not inherited (T1DM)",
     "Polygenic + lifestyle", "Autosomal recessive",
     "Not inherited"],
    ["Gene / Chromosome",
     "LDLR gene, Chr 19", "—",
     "—", "GBA1 gene, Chr 1",
     "—"],
    ["Treatment",
     "Statins, PCSK9 inhibitors, LDL apheresis",
     "IV insulin, fluids, K⁺ replacement",
     "Weight loss, GLP-1 agonists, Vit E",
     "ERT (imiglucerase), SRT",
     "Alcohol abstinence, corticosteroids (severe)"],
]

col_w = [3*cm, 2.8*cm, 2.8*cm, 2.8*cm, 2.8*cm, 2.8*cm]
sum_t = Table(summary_data, colWidths=col_w, repeatRows=1)
sum_t.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,0),
     [DARK_BLUE, CASE_COLORS[0], CASE_COLORS[1], CASE_COLORS[2],
      CASE_COLORS[3], CASE_COLORS[4]]),
    ("BACKGROUND",    (1,0), (1,0), CASE_COLORS[0]),
    ("BACKGROUND",    (2,0), (2,0), CASE_COLORS[1]),
    ("BACKGROUND",    (3,0), (3,0), CASE_COLORS[2]),
    ("BACKGROUND",    (4,0), (4,0), CASE_COLORS[3]),
    ("BACKGROUND",    (5,0), (5,0), CASE_COLORS[4]),
    ("TEXTCOLOR",     (0,0), (-1,0), WHITE),
    ("FONTNAME",      (0,0), (-1,0), "Helvetica-Bold"),
    ("FONTNAME",      (0,0), (0,-1), "Helvetica-Bold"),
    ("FONTSIZE",      (0,0), (-1,-1), 7.5),
    ("LEADING",       (0,0), (-1,-1), 10),
    ("ROWBACKGROUNDS",(0,1), (-1,-1), [WHITE, LIGHT_GREY]),
    ("GRID",          (0,0), (-1,-1), 0.4, HexColor("#aaaaaa")),
    ("TOPPADDING",    (0,0), (-1,-1), 4),
    ("BOTTOMPADDING", (0,0), (-1,-1), 4),
    ("LEFTPADDING",   (0,0), (-1,-1), 4),
    ("VALIGN",        (0,0), (-1,-1), "TOP"),
]))
story.append(sum_t)

story.append(Spacer(1, 10))
story.append(HRFlowable(width=W, thickness=0.5, color=MID_GREY))
story.append(Spacer(1, 4))
story.append(Paragraph(
    "Sources: Robbins & Kumar Basic Pathology | Thompson & Thompson Genetics, 9e | "
    "Mulholland & Greenfield's Surgery, 7e | Tietz Textbook of Laboratory Medicine, 7e | "
    "Ganong's Review of Medical Physiology, 26e | Harrison's Principles of Internal Medicine, 22e",
    S("src", fontName="Helvetica-Oblique", fontSize=6.5, leading=9,
      textColor=MID_GREY, alignment=TA_CENTER)
))
story.append(Spacer(1, 2))
story.append(Paragraph(
    "Generated by Orris AI · For educational use only · Not a substitute for clinical judgment",
    S("disc", fontName="Helvetica", fontSize=6, leading=8,
      textColor=MID_GREY, alignment=TA_CENTER)
))

# ─── Build PDF ────────────────────────────────────────────────────────────────
def add_page_number(canvas, doc):
    canvas.saveState()
    canvas.setFont("Helvetica", 7)
    canvas.setFillColor(MID_GREY)
    page_num = canvas.getPageNumber()
    canvas.drawCentredString(PAGE_W / 2, 1.2*cm,
                             f"Lipid Metabolism Quick Reference  |  Page {page_num}")
    canvas.restoreState()

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

Successfully replaced 1 instance(s) of the string in '/tmp/workspace/lipid-cases/generate_pdf.py'

"""
MBBS Biochemistry – Complete Metabolism Case Studies PDF
All 7 categories: Carbohydrates, Proteins, Lipids, Nucleic Acids,
                  Vitamins, Minerals, Water & Electrolytes
"""
from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.units import cm
from reportlab.lib.styles import ParagraphStyle
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, PageBreak
)
from reportlab.lib.enums import TA_CENTER, TA_LEFT, TA_JUSTIFY
from reportlab.lib.colors import HexColor

# ── Palette ──────────────────────────────────────────────────────────────────
DARK_NAVY  = HexColor("#0d2137")
CAT_COLORS = {
    "CARB":  HexColor("#1565c0"),   # deep blue
    "PROT":  HexColor("#6a1b9a"),   # purple
    "LIPID": HexColor("#b71c1c"),   # red
    "NUC":   HexColor("#004d40"),   # teal
    "VIT":   HexColor("#e65100"),   # orange
    "MIN":   HexColor("#558b2f"),   # green
    "WE":    HexColor("#37474f"),   # blue-grey
}
CAT_LIGHT = {
    "CARB":  HexColor("#e3f2fd"),
    "PROT":  HexColor("#f3e5f5"),
    "LIPID": HexColor("#ffebee"),
    "NUC":   HexColor("#e0f2f1"),
    "VIT":   HexColor("#fff3e0"),
    "MIN":   HexColor("#f1f8e9"),
    "WE":    HexColor("#eceff1"),
}
LGREY = HexColor("#f5f5f5")
MGREY = HexColor("#9e9e9e")
WHITE = colors.white
BLACK = colors.black

# ── Document ─────────────────────────────────────────────────────────────────
OUT = "/tmp/workspace/lipid-cases/MBBS_All_Metabolism_Cases.pdf"
W, H = A4
MAR = 1.4*cm

doc = SimpleDocTemplate(
    OUT, pagesize=A4,
    leftMargin=MAR, rightMargin=MAR,
    topMargin=1.8*cm, bottomMargin=1.8*cm,
    title="MBBS Biochemistry – All Metabolism Case Studies",
    author="Orris AI", subject="Biochemistry Case Studies"
)
UW = W - 2*MAR   # usable width

# ── Style helpers ─────────────────────────────────────────────────────────────
def S(n, **k):
    return ParagraphStyle(n, **k)

BODY  = S("body",  fontName="Helvetica",      fontSize=8,   leading=11, spaceAfter=3)
BODYJ = S("bodyJ", fontName="Helvetica",      fontSize=8,   leading=11, spaceAfter=3, alignment=TA_JUSTIFY)
BOLD  = S("bold",  fontName="Helvetica-Bold", fontSize=8,   leading=11, spaceAfter=2)
SMALL = S("small", fontName="Helvetica",      fontSize=7,   leading=9,  textColor=MGREY)
CODE  = S("code",  fontName="Courier",        fontSize=7.5, leading=10, textColor=HexColor("#1a237e"))

# ── Reusable builders ─────────────────────────────────────────────────────────
def cat_banner(story, cat_key, cat_name, icon=""):
    c = CAT_COLORS[cat_key]
    t = Table([[Paragraph(
        f"<b>{icon}  {cat_name}</b>",
        S("cb", fontName="Helvetica-Bold", fontSize=14, textColor=WHITE,
          alignment=TA_CENTER)
    )]], colWidths=[UW])
    t.setStyle(TableStyle([
        ("BACKGROUND", (0,0),(-1,-1), c),
        ("TOPPADDING", (0,0),(-1,-1), 10),
        ("BOTTOMPADDING",(0,0),(-1,-1), 10),
    ]))
    story.append(t)

def case_hdr(story, num, title, subtitle, ck):
    c = CAT_COLORS[ck]
    row = [[
        Paragraph(f"<b>CASE {num}</b>",
                  S("cn", fontName="Helvetica-Bold", fontSize=10,
                    textColor=WHITE)),
        Paragraph(f"<b>{title}</b>",
                  S("ct", fontName="Helvetica-Bold", fontSize=9.5,
                    textColor=WHITE)),
        Paragraph(subtitle,
                  S("cs", fontName="Helvetica", fontSize=7.5,
                    textColor=HexColor("#ddddff"))),
    ]]
    t = Table(row, colWidths=[2*cm, 8.5*cm, None])
    t.setStyle(TableStyle([
        ("BACKGROUND",    (0,0),(-1,-1), c),
        ("VALIGN",        (0,0),(-1,-1), "MIDDLE"),
        ("TOPPADDING",    (0,0),(-1,-1), 7),
        ("BOTTOMPADDING", (0,0),(-1,-1), 7),
        ("LEFTPADDING",   (0,0),(-1,-1), 7),
    ]))
    story.append(t)

def sec(story, text, ck):
    c = CAT_COLORS[ck]
    t = Table([[Paragraph(f"  {text}",
        S("st", fontName="Helvetica-Bold", fontSize=8, textColor=WHITE,
          leading=11))]], colWidths=[UW])
    t.setStyle(TableStyle([
        ("BACKGROUND",    (0,0),(-1,-1), c),
        ("TOPPADDING",    (0,0),(-1,-1), 3),
        ("BOTTOMPADDING", (0,0),(-1,-1), 3),
    ]))
    story.append(Spacer(1,3))
    story.append(t)

def grid(story, rows, widths, ck, hdr=True):
    t = Table(rows, colWidths=widths, repeatRows=1 if hdr else 0)
    c = CAT_COLORS[ck]
    ts = [
        ("GRID",          (0,0),(-1,-1), 0.4, HexColor("#cccccc")),
        ("FONTSIZE",      (0,0),(-1,-1), 7.5),
        ("LEADING",       (0,0),(-1,-1), 10),
        ("TOPPADDING",    (0,0),(-1,-1), 3),
        ("BOTTOMPADDING", (0,0),(-1,-1), 3),
        ("LEFTPADDING",   (0,0),(-1,-1), 5),
        ("VALIGN",        (0,0),(-1,-1), "TOP"),
    ]
    if hdr:
        ts += [
            ("BACKGROUND",  (0,0),(-1,0), c),
            ("TEXTCOLOR",   (0,0),(-1,0), WHITE),
            ("FONTNAME",    (0,0),(-1,0), "Helvetica-Bold"),
            ("ROWBACKGROUNDS",(0,1),(-1,-1),[WHITE, LGREY]),
        ]
    t.setStyle(TableStyle(ts))
    story.append(t)

def pathbox(story, lines, ck):
    c   = CAT_COLORS[ck]
    cl  = CAT_LIGHT[ck]
    rows = [[Paragraph(l, CODE)] for l in lines]
    t = Table(rows, colWidths=[UW])
    t.setStyle(TableStyle([
        ("BACKGROUND",    (0,0),(-1,-1), cl),
        ("BOX",           (0,0),(-1,-1), 0.8, c),
        ("LEFTPADDING",   (0,0),(-1,-1), 7),
        ("TOPPADDING",    (0,0),(-1,-1), 2),
        ("BOTTOMPADDING", (0,0),(-1,-1), 2),
    ]))
    story.append(t)

def mcqs(story, qs, ck):
    for i,(q,opts,ai) in enumerate(qs):
        story.append(Paragraph(f"<b>Q{i+1}.</b> {q}",
            S(f"mq{i}", fontName="Helvetica-Bold", fontSize=7.5, leading=10,
              textColor=HexColor("#1a237e"), spaceAfter=1, leftIndent=4)))
        for j,o in enumerate(opts):
            col = HexColor("#1b5e20") if j==ai else BLACK
            mk  = "✓" if j==ai else "○"
            story.append(Paragraph(f"    {mk} {o}",
                S(f"mo{i}{j}", fontName="Helvetica", fontSize=7.5,
                  leading=10, textColor=col, spaceAfter=1, leftIndent=12)))
        story.append(Spacer(1,3))

def viva(story, qas, ck):
    c = CAT_COLORS[ck]
    for q,a in qas:
        story.append(Paragraph(f"<b>Q:</b> {q}",
            S("vq", fontName="Helvetica-Bold", fontSize=7.5, leading=10,
              textColor=c, spaceAfter=1, leftIndent=4)))
        story.append(Paragraph(f"<b>A:</b> {a}",
            S("va", fontName="Helvetica", fontSize=7.5, leading=10,
              textColor=BLACK, spaceAfter=5, leftIndent=4)))

def add_pg(canvas, doc):
    canvas.saveState()
    canvas.setFont("Helvetica", 6.5)
    canvas.setFillColor(MGREY)
    pg = canvas.getPageNumber()
    canvas.drawCentredString(W/2, 1.1*cm,
        f"MBBS Biochemistry – All Metabolism Case Studies  |  Page {pg}")
    canvas.restoreState()

# =============================================================================
# BUILD STORY
# =============================================================================
S_ = story = []

# ── MASTER COVER ──────────────────────────────────────────────────────────────
cover = Table([[
    Paragraph("<font color='white'><b>MBBS Biochemistry</b></font>",
              S("cov1", fontName="Helvetica-Bold", fontSize=24,
                textColor=WHITE, alignment=TA_CENTER)),
]], colWidths=[UW])
cover.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,-1), DARK_NAVY),
    ("TOPPADDING",(0,0),(-1,-1), 16),
    ("BOTTOMPADDING",(0,0),(-1,-1), 4),
]))
story.append(cover)

sub = Table([[
    Paragraph("Complete Metabolism Case Studies",
              S("cov2", fontName="Helvetica-Bold", fontSize=15,
                textColor=HexColor("#b0c8e8"), alignment=TA_CENTER)),
]], colWidths=[UW])
sub.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,-1), DARK_NAVY),
    ("TOPPADDING",(0,0),(-1,-1), 2),
    ("BOTTOMPADDING",(0,0),(-1,-1), 10),
]))
story.append(sub)
story.append(Spacer(1,6))

cats = [
    ("CARB",  "A", "Carbohydrate Metabolism", "Von Gierke Disease • Galactosemia • Diabetes Mellitus Type 1"),
    ("PROT",  "B", "Protein Metabolism",       "PKU • Urea Cycle Defect (OTC) • Kwashiorkor"),
    ("LIPID", "C", "Lipid Metabolism",          "Familial Hypercholesterolemia • DKA • NAFLD • Gaucher • Alcoholic Liver"),
    ("NUC",   "D", "Nucleic Acid Metabolism",   "Gout • Lesch-Nyhan Syndrome • Orotic Aciduria"),
    ("VIT",   "E", "Vitamin Deficiencies",      "Scurvy (C) • Rickets (D) • Pellagra (B3) • Beriberi (B1) • Night Blindness (A)"),
    ("MIN",   "F", "Mineral Disorders",         "Iron Deficiency Anaemia • Wilson Disease • Iodine Deficiency (Goitre)"),
    ("WE",    "G", "Water & Electrolyte",       "SIADH / Hyponatremia • DKA Hyperkalemia • Dehydration"),
]

idx_rows = [[
    Paragraph("<b>Section</b>", S("ih", fontName="Helvetica-Bold", fontSize=8, textColor=WHITE)),
    Paragraph("<b>Category</b>", S("ih2", fontName="Helvetica-Bold", fontSize=8, textColor=WHITE)),
    Paragraph("<b>Cases Covered</b>", S("ih3", fontName="Helvetica-Bold", fontSize=8, textColor=WHITE)),
]]
for ck, ltr, cname, cases in cats:
    idx_rows.append([
        Paragraph(f"<b>{ltr}</b>", S(f"il{ck}", fontName="Helvetica-Bold",
                  fontSize=8, textColor=CAT_COLORS[ck], alignment=TA_CENTER)),
        Paragraph(cname, S(f"ic{ck}", fontName="Helvetica-Bold", fontSize=8)),
        Paragraph(cases, S(f"ics{ck}", fontName="Helvetica", fontSize=7.5)),
    ])

it = Table(idx_rows, colWidths=[1.5*cm, 5*cm, None])
it.setStyle(TableStyle([
    ("BACKGROUND",    (0,0),(-1,0), DARK_NAVY),
    ("TEXTCOLOR",     (0,0),(-1,0), WHITE),
    ("FONTNAME",      (0,0),(-1,0), "Helvetica-Bold"),
    ("FONTSIZE",      (0,0),(-1,-1), 8),
    ("ROWBACKGROUNDS",(0,1),(-1,-1),
     [CAT_LIGHT[c] for c,_,_,_ in cats]),
    ("GRID",          (0,0),(-1,-1), 0.4, HexColor("#bbbbbb")),
    ("ALIGN",         (0,0),(0,-1), "CENTER"),
    ("VALIGN",        (0,0),(-1,-1), "MIDDLE"),
    ("TOPPADDING",    (0,0),(-1,-1), 4),
    ("BOTTOMPADDING", (0,0),(-1,-1), 4),
    ("LEFTPADDING",   (0,0),(-1,-1), 6),
]))
story.append(Paragraph("Contents",
    S("ctitle", fontName="Helvetica-Bold", fontSize=10,
      textColor=DARK_NAVY, spaceAfter=4, spaceBefore=4)))
story.append(it)
story.append(Spacer(1,6))
story.append(HRFlowable(width=UW, thickness=0.5, color=MGREY))
story.append(PageBreak())

# =============================================================================
# SECTION A – CARBOHYDRATE METABOLISM
# =============================================================================
CK = "CARB"
cat_banner(story, CK, "SECTION A — CARBOHYDRATE METABOLISM")
story.append(Spacer(1,5))

# ── Case A1: Von Gierke Disease ───────────────────────────────────────────────
case_hdr(story, "A1", "Von Gierke Disease (GSD Type I)",
         "Glucose-6-phosphatase deficiency | AR | Severe fasting hypoglycemia", CK)
sec(story, "Clinical Vignette", CK)
story.append(Paragraph(
    "Baby Priya, 6-month-old female. Parents noticed she becomes limp, pale and unresponsive if "
    "feeds are delayed > 3 hours. Abdomen is protuberant. Developmental milestones slightly delayed. "
    "Doll-like facies with fat cheeks.", BODYJ))
sec(story, "Key Investigations", CK)
grid(story,[
    [Paragraph("<b>Test</b>",BOLD), Paragraph("<b>Patient</b>",BOLD), Paragraph("<b>Normal</b>",BOLD), Paragraph("<b>Significance</b>",BOLD)],
    ["Fasting blood glucose","28 mg/dL ↓↓","70–100","Severe hypoglycemia — cannot release glucose from liver glycogen"],
    ["Blood lactate","8 mmol/L ↑↑","0.5–2.2","G-6-P → lactic acid instead of glucose"],
    ["Serum uric acid","9.8 mg/dL ↑","2–7","G-6-P → ribose-5-P → purine synthesis ↑ → uric acid ↑"],
    ["Serum triglycerides","680 mg/dL ↑↑","< 150","Acetyl CoA diverted to FA synthesis (can't release glucose)"],
    ["Liver biopsy","Massive glycogen + fat in hepatocytes","Normal","Pathognomonic"],
    ["Liver glucose-6-phosphatase activity","Absent","Normal","Confirmatory enzymatic test"],
],[3.5*cm,3.5*cm,2*cm,None],CK)
sec(story, "Pathophysiology", CK)
pathbox(story,[
    "Normal:  Glycogen → Glucose-1-P → Glucose-6-P →[G-6-Pase]→ FREE GLUCOSE → blood",
    "         Gluconeogenesis → Glucose-6-P →[G-6-Pase]→ FREE GLUCOSE → blood",
    "",
    "Von Gierke: G-6-Pase ABSENT",
    "  Glucose-6-P cannot be cleaved → ACCUMULATES in liver",
    "  → Glycogen piles up (cannot release glucose) → HEPATOMEGALY",
    "  → Hypoglycemia (no glucose release during fasting)",
    "  → G-6-P shunted to lactate → LACTIC ACIDOSIS",
    "  → G-6-P → pentose phosphate pathway → PURINE synthesis ↑ → HYPERURICEMIA",
    "  → Acetyl CoA → fatty acids → HYPERTRIGLYCERIDEMIA",
    "ALSO: Kidneys store glycogen → enlarged kidneys (nephromegaly)",
],CK)
sec(story,"Management",CK)
grid(story,[
    [Paragraph("<b>Treatment</b>",BOLD), Paragraph("<b>Mechanism</b>",BOLD)],
    ["Frequent feeds / continuous night-time nasogastric feeds","Prevent fasting hypoglycemia — never allow more than 3–4 hr fast"],
    ["Uncooked cornstarch (UCCS)","Slow-release glucose — mainstay of management in older children"],
    ["Allopurinol","Inhibit xanthine oxidase → ↓ uric acid (treat hyperuricemia)"],
    ["Liver transplant","Curative in severe cases — restores G-6-Pase activity"],
],[6*cm,None],CK)
sec(story,"MCQs",CK)
mcqs(story,[
    ("Enzyme deficient in Von Gierke disease:",
     ["Glycogen phosphorylase","Glucose-6-phosphatase","Acid maltase","Branching enzyme"],1),
    ("In Von Gierke disease, the triad of hypoglycemia + lactic acidosis + hyperuricemia is due to:",
     ["Insulin excess","Glucose-6-phosphate accumulation","Glycogen phosphorylase defect","Lysosomal enzyme deficiency"],1),
    ("Safest carbohydrate source for Von Gierke patients:",
     ["Fructose","Galactose","Uncooked cornstarch","Sucrose"],2),
],CK)
sec(story,"Viva Q&A",CK)
viva(story,[
    ("Why is fructose/galactose harmful in Von Gierke disease?",
     "Both fructose and galactose are metabolized via glucose-6-phosphate in the liver. "
     "In Von Gierke disease, G-6-Pase is absent, so they cannot be converted to free glucose, "
     "worsening the accumulation of G-6-P, lactate, and fat."),
    ("Why does Von Gierke cause hyperuricemia?",
     "Accumulated glucose-6-phosphate is shunted through the pentose phosphate pathway, "
     "producing excess ribose-5-phosphate → de novo purine synthesis ↑ → uric acid ↑. "
     "Lactic acidosis also competes with uric acid for renal tubular excretion."),
],CK)
story.append(Spacer(1,8))

# ── Case A2: Galactosemia ─────────────────────────────────────────────────────
case_hdr(story,"A2","Classic Galactosemia",
         "GALT deficiency | AR | Jaundice + cataracts + E. coli sepsis in neonate",CK)
sec(story,"Clinical Vignette",CK)
story.append(Paragraph(
    "Baby Aryan, 5-day-old male. Exclusively breastfed. Jaundice since day 2, vomiting, "
    "poor weight gain. Day 5: developed E. coli sepsis. Eye exam: bilateral cataracts noted on "
    "slit lamp. Liver: enlarged and tender. Newborn screen: elevated galactose.",BODYJ))
sec(story,"Pathophysiology",CK)
pathbox(story,[
    "Normal: Galactose →[GALK]→ Galactose-1-P →[GALT]→ UDP-Glucose → Glucose",
    "",
    "Galactosemia: GALT (galactose-1-phosphate uridylyltransferase) ABSENT",
    "  Galactose-1-phosphate ACCUMULATES in liver, brain, kidneys, lens",
    "  → LIVER: hepatocellular damage → jaundice, cirrhosis",
    "  → LENS: galactose → galactitol (aldose reductase) → osmotic swelling → CATARACTS",
    "  → BRAIN: galactitol accumulation → intellectual disability",
    "  → KIDNEY: tubular dysfunction (Fanconi syndrome)",
    "  → IMMUNE: galactose-1-P impairs neutrophil killing → E. coli sepsis susceptibility",
],CK)
sec(story,"Key Investigations & Management",CK)
grid(story,[
    [Paragraph("<b>Investigation/Feature</b>",BOLD), Paragraph("<b>Finding</b>",BOLD), Paragraph("<b>Management</b>",BOLD)],
    ["Urine reducing substances","Positive (galactose) — but NOT detected by glucose oxidase strip","Galactose-free diet (no breast milk, use soya formula)"],
    ["Serum GALT enzyme activity","Absent (<1% normal)","Lifelong lactose restriction"],
    ["Urine galactitol","Markedly elevated","Calcium + Vitamin D supplementation (bone health)"],
    ["Newborn screen (tandem MS/MS)","Elevated galactose-1-P","Ovarian dysfunction in females — follow-up required"],
],[5*cm,4.5*cm,None],CK)
mcqs(story,[
    ("Classic galactosemia is caused by deficiency of:",
     ["Galactokinase (GALK)","GALT (galactose-1-phosphate uridylyltransferase)","Galactose epimerase","UDP-glucose-4-epimerase"],1),
    ("Cataracts in galactosemia are due to accumulation of:",
     ["Galactose-1-phosphate","Galactitol (via aldose reductase)","UDP-galactose","Glycogen"],1),
],CK)
viva(story,[
    ("Why do galactosemia patients get E. coli sepsis?",
     "Galactose-1-phosphate accumulation impairs the bactericidal activity of neutrophils — "
     "specifically reducing their ability to kill gram-negative organisms. "
     "The gut is also affected, allowing E. coli translocation. "
     "This is a classic and life-threatening neonatal presentation."),
],CK)
story.append(Spacer(1,8))

# ── Case A3: Type 1 Diabetes / DKA (brief — detailed in Lipid section) ────────
case_hdr(story,"A3","Type 1 Diabetes Mellitus — Metabolic Overview",
         "Absolute insulin deficiency | Hyperglycemia + glycosuria + osmotic diuresis",CK)
sec(story,"Carbohydrate Metabolism Disruptions in T1DM",CK)
pathbox(story,[
    "INSULIN ABSENT  →  GLUT-4 not translocated → Glucose CANNOT enter muscle/fat cells",
    "                →  Liver glycogen breakdown ↑ (glycogenolysis) → glucose ↑",
    "                →  Gluconeogenesis ↑ (from AA + glycerol) → glucose ↑ further",
    "                →  Hexokinase/glucokinase activity ↓ → glucose not phosphorylated",
    "Hyperglycemia   →  Glucose filtered > Tm (~180 mg/dL) → GLYCOSURIA",
    "                →  Osmotic diuresis → polyuria → polydipsia → dehydration",
    "HbA1c           =  Glycated Hb; reflects average glucose over 2–3 months",
    "                   Normal < 5.7%; Pre-DM 5.7–6.4%; DM ≥ 6.5%",
],CK)
grid(story,[
    [Paragraph("<b>Test</b>",BOLD), Paragraph("<b>T1DM Value</b>",BOLD), Paragraph("<b>Diagnostic Threshold</b>",BOLD)],
    ["Fasting plasma glucose","≥ 240 mg/dL","≥ 126 mg/dL"],
    ["2h post-OGTT glucose","≥ 280 mg/dL","≥ 200 mg/dL"],
    ["HbA1c","9.2%","≥ 6.5%"],
    ["C-peptide","Very low / absent","Present in T2DM"],
    ["Anti-GAD antibodies","Positive (autoimmune)","Confirms T1DM"],
],[4.5*cm,4*cm,None],CK)
story.append(PageBreak())

# =============================================================================
# SECTION B – PROTEIN METABOLISM
# =============================================================================
CK = "PROT"
cat_banner(story, CK, "SECTION B — PROTEIN METABOLISM")
story.append(Spacer(1,5))

# ── Case B1: PKU ──────────────────────────────────────────────────────────────
case_hdr(story,"B1","Phenylketonuria (PKU)",
         "Phenylalanine hydroxylase deficiency | AR | Intellectual disability + mousy odor",CK)
sec(story,"Clinical Vignette",CK)
story.append(Paragraph(
    "Baby Riya, 6-week-old female. Hypopigmented skin and hair despite dark-skinned parents. "
    "Irritability, eczema, mousy/musty odor in urine/sweat. "
    "Parents are first cousins. Older sibling died with brain damage.",BODYJ))
sec(story,"Pathophysiology",CK)
pathbox(story,[
    "Normal: Phenylalanine →[PAH + BH4]→ Tyrosine → Melanin / Catecholamines / Thyroxine",
    "",
    "PKU: Phenylalanine hydroxylase (PAH) ABSENT",
    "  Phenylalanine ACCUMULATES → inhibits LNAA transport across blood-brain barrier",
    "  → Impairs myelin synthesis + neurotransmitter synthesis → Intellectual disability",
    "  Shunted pathways:",
    "    Phe → Phenylpyruvic acid (urine — FeCl3 test blue-green)",
    "    Phe → Phenylacetic acid (mousy/musty odor in urine + sweat)",
    "    Phe → Phenyllactic acid",
    "  Tyrosine DEFICIENT → Melanin ↓ → Hypopigmentation (fair skin, blue eyes, light hair)",
],CK)
sec(story,"Investigations & Diagnosis",CK)
grid(story,[
    [Paragraph("<b>Test</b>",BOLD), Paragraph("<b>Result</b>",BOLD), Paragraph("<b>Principle</b>",BOLD)],
    ["Guthrie test (heel-prick, day 2–3)","Positive (bacterial growth)","B. subtilis inhibition assay — phenylalanine reverses inhibition"],
    ["Serum phenylalanine","28 mg/dL (normal < 2)","Diagnostic — Phe/Tyr ratio > 3 on MS/MS"],
    ["Urine FeCl3 test","Blue-green color","Phenylpyruvic acid + ferric chloride → blue-green"],
    ["Phenistix urine strip","Grey-green (positive)","Ferric ammonium sulfate detects phenylpyruvate"],
    ["Urine pterin profile + DHPR","Normal (both)","Rules out BH4 deficiency variant"],
],[4.5*cm,3*cm,None],CK)
sec(story,"Management",CK)
grid(story,[
    [Paragraph("<b>Treatment</b>",BOLD), Paragraph("<b>Details</b>",BOLD)],
    ["Phenylalanine-restricted diet (lifelong)","Low-Phe formula (Lofenalac). Keep blood Phe < 6 mg/dL. Phe is essential — cannot eliminate entirely"],
    ["Sapropterin (BH4)","BH4-responsive PKU only — acts as chaperone for residual PAH activity"],
    ["LNAA supplementation","Competes with Phe at BBB — reduces brain Phe uptake"],
    ["Maternal PKU protocol","Women must control Phe before/during pregnancy — prevents fetal damage (microcephaly, CHD)"],
],[5.5*cm,None],CK)
mcqs(story,[
    ("Mousy/musty odor in PKU is due to:","Phenylpyruvic acid Phenylacetic acid Phenyllactic acid Phenylethylamine".split(),1),
    ("Hypopigmentation in PKU is because:","Melanin precursor tyrosine is deficient Melanocytes are destroyed Phenylalanine inhibits melanin directly Tyrosinase is absent".split("  "),0),
],CK)
story.append(Spacer(1,6))

# ── Case B2: Urea Cycle Defect (OTC Deficiency) ───────────────────────────────
case_hdr(story,"B2","OTC Deficiency — Urea Cycle Defect",
         "Ornithine transcarbamylase deficiency | X-linked | Hyperammonemia + encephalopathy",CK)
sec(story,"Clinical Vignette",CK)
story.append(Paragraph(
    "Baby Kiran, 3-day-old male. Vigorous feeder at birth. Day 3: refuses feeds, lethargic, "
    "tachypneic, progresses to coma. Mother has history of 'protein intolerance' and migraines. "
    "Plasma ammonia: 850 µmol/L (normal < 50). Urine orotic acid: markedly elevated.",BODYJ))
sec(story,"Pathophysiology — The Urea Cycle",CK)
pathbox(story,[
    "UREA CYCLE (liver mitochondria + cytoplasm):",
    "  NH4+ + CO2 →[CPS-1]→ Carbamoyl phosphate",
    "  + Ornithine →[OTC]→ Citrulline (exits to cytoplasm)",
    "  + Aspartate →[ASS]→ Argininosuccinate →[ASL]→ Arginine + Fumarate",
    "  Arginine →[Arginase]→ Urea + Ornithine (recycled)",
    "",
    "OTC DEFICIENT (X-linked — most common urea cycle defect):",
    "  Carbamoyl phosphate ACCUMULATES → spills to cytoplasm",
    "  → Enters pyrimidine synthesis → OROTIC ACID ↑ in urine (diagnostic!)",
    "  → NH4+ cannot be incorporated into urea → HYPERAMMONEMIA",
    "  Ammonia crosses BBB → inhibits Krebs cycle → cerebral edema → COMA",
    "  Citrulline: LOW or absent (proximal defect)",
    "  Glutamine: HIGH (ammonia detox mechanism overloaded)",
],CK)
sec(story,"Investigations",CK)
grid(story,[
    [Paragraph("<b>Test</b>",BOLD), Paragraph("<b>OTC Deficiency</b>",BOLD), Paragraph("<b>Diagnostic Significance</b>",BOLD)],
    ["Plasma ammonia","850 µmol/L ↑↑ (critical)","> 150 = encephalopathy risk; > 400 = life-threatening"],
    ["Plasma citrulline","LOW / absent","Proximal block (before citrulline synthesis step)"],
    ["Urine orotic acid","MARKEDLY ELEVATED ✓","Pathognomonic for OTC deficiency vs. CPS-1/NAGS deficiency"],
    ["Plasma glutamine","Elevated","NH3 detox → glutamine rises in all urea cycle defects"],
    ["Plasma amino acids","Elevated glutamine, low citrulline","Pattern helps localize the defect"],
    ["Inheritance (gene)","X-linked (OTC gene, Xp21)","Most common urea cycle defect. Females are carriers — may be symptomatic"],
],[4.5*cm,4*cm,None],CK)
sec(story,"Management",CK)
grid(story,[
    [Paragraph("<b>Treatment</b>",BOLD), Paragraph("<b>Mechanism</b>",BOLD)],
    ["IV glucose (stop catabolism)","Protein catabolism releases NH3 — glucose stops this immediately"],
    ["Nitrogen scavengers: sodium benzoate + sodium phenylbutyrate","Conjugate with glycine/glutamine → excreted as hippurate/phenylacetylglutamine (bypass urea cycle)"],
    ["Arginine supplementation","Arginine is essential in urea cycle defects (cannot synthesize)"],
    ["Dietary protein restriction","Reduce nitrogen load — individualized low-protein diet"],
    ["Liver transplant","Curative — restores hepatic OTC activity"],
],[5.5*cm,None],CK)
mcqs(story,[
    ("OTC deficiency is unique among urea cycle defects because it is:",
     ["Autosomal recessive","X-linked","Autosomal dominant","Mitochondrial"],1),
    ("Markedly elevated urine orotic acid is seen in OTC deficiency because:",
     ["Orotic acid is a metabolite of urea","Carbamoyl phosphate accumulates and enters pyrimidine synthesis pathway",
      "OTC directly inhibits orotate phosphoribosyltransferase","Liver failure causes orotic aciduria"],1),
    ("Nitrogen scavengers (sodium benzoate) work by:",
     ["Inhibiting protein catabolism","Conjugating with glycine → hippurate → excreted renally",
      "Activating CPS-1","Increasing urea synthesis"],1),
],CK)
viva(story,[
    ("How does hyperammonemia cause brain damage?",
     "Ammonia crosses the BBB and is taken up by astrocytes. Glutamine synthase converts "
     "glutamate + NH3 → glutamine, depleting glutamate (a neurotransmitter). "
     "Excess glutamine accumulates in astrocytes causing osmotic swelling → cerebral edema. "
     "Ammonia also directly inhibits the alpha-ketoglutarate dehydrogenase step of the Krebs cycle, "
     "impairing neuronal energy production. - Harrison's, 2025"),
],CK)
story.append(Spacer(1,6))

# ── Case B3: Kwashiorkor ──────────────────────────────────────────────────────
case_hdr(story,"B3","Kwashiorkor — Protein-Energy Malnutrition",
         "Severe protein deficiency with adequate calories | Edema + hypoalbuminemia",CK)
sec(story,"Clinical Vignette",CK)
story.append(Paragraph(
    "Tunde, 2-year-old male, sub-Saharan Africa. Weaned abruptly at 12 months onto maize porridge "
    "(high carb, very low protein). Presents with: bilateral pitting edema of legs, "
    "pot-belly (ascites), 'flaky paint' skin rash, sparse reddish hair. Alert but apathetic. "
    "Weight-for-height: -3 SD. No wasting (muscle bulk preserved due to adequate calories).",BODYJ))
sec(story,"Biochemistry",CK)
pathbox(story,[
    "PROTEIN DEFICIENT (calories adequate from carbohydrate):",
    "  Plasma amino acids ↓ → Liver cannot synthesize albumin → Albumin ↓↓ (< 2.5 g/dL)",
    "  Low albumin → Oncotic pressure ↓ → Fluid leaks into interstitium → EDEMA / ASCITES",
    "  Insulin ↑ (from carbohydrate diet) → Inhibits lipolysis → Fat stays in liver",
    "  VLDL synthesis ↓ (apoprotein B-100 synthesis requires amino acids) → FATTY LIVER",
    "  Zinc deficiency → Poor wound healing, immune deficiency, skin lesions",
    "  Insulin-like effect on muscles → Protein catabolism ↓ (UNLIKE marasmus)",
    "  KEY DIFFERENCE from Marasmus: EDEMA present; caused by LOW PROTEIN not total starvation",
],CK)
grid(story,[
    [Paragraph("<b>Feature</b>",BOLD), Paragraph("<b>Kwashiorkor</b>",BOLD), Paragraph("<b>Marasmus</b>",BOLD)],
    ["Cause","Protein deficiency (calories adequate)","Total calorie deficiency"],
    ["Edema","Present ✓","Absent"],
    ["Appearance","'Moon face', pot belly, skin rash","Wasted, 'old man' appearance, skin and bones"],
    ["Serum albumin","Very low (< 2.5 g/dL)","Low-normal (preserved longer)"],
    ["Fatty liver","Yes","No"],
    ["Muscle wasting","Mild","Severe"],
],[5*cm,5*cm,None],CK)
story.append(PageBreak())

# =============================================================================
# SECTION C – LIPID METABOLISM (Summary reference)
# =============================================================================
CK = "LIPID"
cat_banner(story, CK, "SECTION C — LIPID METABOLISM  (See separate detailed guide)")
story.append(Spacer(1,5))
story.append(Paragraph(
    "Five detailed lipid metabolism cases are covered in the companion PDF. "
    "Below is the quick-reference summary.",BODY))
sum_rows=[
    [Paragraph("<b>Case</b>",BOLD), Paragraph("<b>Diagnosis</b>",BOLD),
     Paragraph("<b>Enzyme/Defect</b>",BOLD), Paragraph("<b>Key Sign</b>",BOLD),
     Paragraph("<b>Treatment</b>",BOLD)],
    ["C1","Familial Hypercholesterolemia","LDLR mutation","Xanthomas, premature CAD","Statins, PCSK9 inhibitors"],
    ["C2","Diabetic Ketoacidosis","Insulin absence → ↑ ketogenesis","Kussmaul breathing, fruity breath","IV insulin, fluids, K⁺"],
    ["C3","NAFLD / NASH","Insulin resistance","Hepatomegaly, obesity","Weight loss, GLP-1 agonists"],
    ["C4","Gaucher Disease","Glucocerebrosidase ↓","Hepatosplenomegaly","ERT (imiglucerase)"],
    ["C5","Alcoholic Fatty Liver","↑ NADH/NAD⁺","AST:ALT > 2, ↑ GGT","Abstinence, corticosteroids"],
]
grid(story,sum_rows,[1.5*cm,5*cm,5*cm,4*cm,None],CK)
story.append(PageBreak())

# =============================================================================
# SECTION D – NUCLEIC ACID METABOLISM
# =============================================================================
CK = "NUC"
cat_banner(story, CK, "SECTION D — NUCLEIC ACID METABOLISM")
story.append(Spacer(1,5))

# ── Case D1: Gout ─────────────────────────────────────────────────────────────
case_hdr(story,"D1","Gout — Primary Hyperuricemia",
         "Uric acid overproduction/underexcretion | Monosodium urate crystal deposition",CK)
sec(story,"Clinical Vignette",CK)
story.append(Paragraph(
    "Mr. Suresh, 48-year-old male. Overweight, heavy beer drinker. 2 AM woke up with "
    "SEVERE pain, redness and swelling of right big toe (1st MTP joint). "
    "Recurrent episodes x 3 years. Now has hard, painless nodules over earlobes and Achilles tendon (tophi). "
    "Passed a kidney stone last year.",BODYJ))
sec(story,"Investigations",CK)
grid(story,[
    [Paragraph("<b>Test</b>",BOLD), Paragraph("<b>Patient</b>",BOLD), Paragraph("<b>Significance</b>",BOLD)],
    ["Serum uric acid","9.8 mg/dL (normal M < 7.0)","Hyperuricemia — not always elevated during attack"],
    ["Joint fluid microscopy","Needle-shaped, NEGATIVELY birefringent crystals","MSU crystals — PATHOGNOMONIC for gout"],
    ["X-ray joint","Punched-out erosions with overhanging edge ('rat-bite')","Tophaceous gout — chronic"],
    ["24-hr urine uric acid","650 mg/day","< 600 = underexcretor; > 800 = overproducer"],
    ["Serum creatinine","1.4 mg/dL (mildly elevated)","Urate nephropathy / uric acid stones"],
],[4.5*cm,4.5*cm,None],CK)
sec(story,"Pathophysiology — Purine Metabolism",CK)
pathbox(story,[
    "PURINE CATABOLISM:",
    "  Adenine → Hypoxanthine →[XO]→ Xanthine →[XO]→ URIC ACID (excreted in urine)",
    "  Guanine → Xanthine →[XO]→ URIC ACID",
    "",
    "SALVAGE PATHWAY (normal, recycles purines):",
    "  Hypoxanthine + PRPP →[HGPRT]→ IMP (reused)",
    "  Guanine + PRPP →[HGPRT]→ GMP (reused)",
    "",
    "GOUT: Uric acid overproduced OR underexcreted:",
    "  Overproduction: ↑ purine turnover (myeloproliferative), HGPRT deficiency, PRPP synthetase overactivity",
    "  Underexcretion (90% of cases): renal tubular defect, diuretics, low-dose aspirin",
    "  Uric acid in blood → supersaturation → MSU crystals deposit in joints, soft tissue, kidney",
    "  MSU crystals phagocytosed by neutrophils → NLRP3 inflammasome → IL-1β → ACUTE ARTHRITIS",
],CK)
sec(story,"Management",CK)
grid(story,[
    [Paragraph("<b>Drug</b>",BOLD), Paragraph("<b>Mechanism</b>",BOLD), Paragraph("<b>Use</b>",BOLD)],
    ["Colchicine","Inhibits microtubule polymerization → blocks neutrophil migration","Acute attack (first 24–48h)"],
    ["NSAIDs (indomethacin)","Inhibit prostaglandin synthesis → ↓ inflammation","Acute attack"],
    ["Allopurinol","Inhibits xanthine oxidase → ↓ uric acid production","Chronic prophylaxis (urate-lowering)"],
    ["Febuxostat","Non-purine XO inhibitor","Allopurinol-intolerant patients"],
    ["Probenecid","Inhibits URAT1 → ↑ renal uric acid excretion (uricosuric)","Underexcretors"],
    ["Rasburicase","Recombinant uricase → converts uric acid to allantoin","Tumour lysis syndrome"],
],[3.5*cm,6*cm,None],CK)
mcqs(story,[
    ("Joint fluid in gout shows crystals that are:",
     ["Positively birefringent rhomboid (pseudogout)","Negatively birefringent needle-shaped (gout)",
      "No crystals","Positively birefringent needle-shaped"],1),
    ("Allopurinol works by inhibiting:",
     ["HGPRT","Xanthine oxidase","PRPP synthetase","Adenosine deaminase"],1),
    ("The rate-limiting enzyme of de novo purine synthesis is:",
     ["PRPP synthetase","HGPRT","Adenylosuccinate lyase","Glutamine PRPP amidotransferase"],3),
],CK)
story.append(Spacer(1,6))

# ── Case D2: Lesch-Nyhan Syndrome ─────────────────────────────────────────────
case_hdr(story,"D2","Lesch-Nyhan Syndrome",
         "HGPRT complete deficiency | X-linked recessive | Self-mutilation + hyperuricemia",CK)
sec(story,"Clinical Vignette",CK)
story.append(Paragraph(
    "Rohan, 3-year-old male. Normal at birth. At 6 months: orange crystal (uric acid) in nappy. "
    "By age 2: choreoathetosis, spasticity, intellectual disability. "
    "Now biting own fingers and lips compulsively (self-mutilation). "
    "Serum uric acid: 12 mg/dL. Urine uric acid: markedly elevated.",BODYJ))
pathbox(story,[
    "HGPRT (hypoxanthine-guanine phosphoribosyltransferase) COMPLETELY ABSENT (X-linked)",
    "  Salvage pathway BLOCKED:",
    "    Hypoxanthine + PRPP CANNOT → IMP  ← hypoxanthine accumulates",
    "    Guanine + PRPP CANNOT → GMP  ← guanine accumulates",
    "  PRPP accumulates (not consumed) → De novo purine synthesis ↑↑",
    "  → Massive uric acid overproduction:",
    "    - Orange crystals in diapers (uric acid)",
    "    - Gout (tophi, arthritis)",
    "    - Uric acid nephrolithiasis / obstructive uropathy",
    "  Dopaminergic neurotransmitter deficiency in basal ganglia → self-mutilation (neurological)",
    "NOTE: Partial HGPRT deficiency (Kelley-Seegmiller) = gout only, NO neurological features",
],CK)
grid(story,[
    [Paragraph("<b>Feature</b>",BOLD), Paragraph("<b>Lesch-Nyhan (HGPRT absent)</b>",BOLD), Paragraph("<b>Gout (partial/other)</b>",BOLD)],
    ["HGPRT activity","Absent (< 1%)","Normal or partial"],
    ["Uric acid","Massively elevated","Elevated"],
    ["Neurological features","Self-mutilation, chorea, spasticity, ID","Absent"],
    ["Inheritance","X-linked recessive","Polygenic / AR"],
    ["Treatment","Allopurinol (uric acid) + supportive (no cure for neuro)","Allopurinol / uricosuric"],
],[4.5*cm,5.5*cm,None],CK)
story.append(PageBreak())

# =============================================================================
# SECTION E – VITAMIN DEFICIENCIES
# =============================================================================
CK = "VIT"
cat_banner(story, CK, "SECTION E — VITAMIN DEFICIENCIES")
story.append(Spacer(1,5))

# ── Case E1: Scurvy ────────────────────────────────────────────────────────────
case_hdr(story,"E1","Scurvy — Vitamin C (Ascorbic Acid) Deficiency",
         "Impaired collagen hydroxylation | Hemorrhages + poor wound healing",CK)
sec(story,"Clinical Vignette",CK)
story.append(Paragraph(
    "Mr. John, 70-year-old widower. Lives alone, eats mostly canned food and tea. "
    "3-month history of fatigue, leg pain, bleeding gums that bleed on gentle touch. "
    "Examination: perifollicular hemorrhages on thighs, corkscrew hairs, "
    "swollen bleeding gums (scorbutic gums), poor healing of old surgical scar. "
    "X-ray: ground-glass osteoporosis, Trümmerfeld zone (zone of destruction at metaphysis).",BODYJ))
sec(story,"Pathophysiology (from Robbins Basic Pathology)",CK)
pathbox(story,[
    "Vitamin C (ascorbic acid) activates prolyl hydroxylase and lysyl hydroxylase",
    "→ These enzymes hydroxylate proline and lysine residues in procollagen",
    "→ Hydroxyproline/hydroxylysine allow collagen to form stable TRIPLE HELIX",
    "→ Crosslinking of collagen fibers (tensile strength)",
    "",
    "SCURVY: Vitamin C absent → Proline/lysine NOT hydroxylated",
    "  → Procollagen cannot form triple helix → secreted as abnormal, weak collagen",
    "  → Collagen most affected (highest hydroxyproline content):",
    "     Blood vessel walls: weak → PERIVASCULAR HEMORRHAGES",
    "     Gums: fragile → BLEEDING GUMS (scorbutic gums)",
    "     Bone: osteoid not mineralized properly → BONE PAIN",
    "     Wounds: poor healing (collagen needed for repair)",
    "     Skin appendages: CORKSCREW HAIRS, PERIFOLLICULAR PETECHIAE",
    "  Vitamin C also: regenerates Vitamin E, iron absorption ↑, antioxidant, norepinephrine synthesis",
],CK)
sec(story,"Key Features & Management",CK)
grid(story,[
    [Paragraph("<b>Clinical Feature</b>",BOLD), Paragraph("<b>Biochemical Basis</b>",BOLD)],
    ["Bleeding gums (scorbutic gums)","Capillary fragility — weak collagen in vessel walls"],
    ["Perifollicular hemorrhages","Perivascular collagen weak → bleeds around hair follicles"],
    ["Corkscrew/swan-neck hairs","Abnormal keratin structure (vitamin C-dependent)"],
    ["Impaired wound healing","Collagen synthesis needed for scar formation — absent"],
    ["Bone pain / subperiosteal haemorrhage","Osteoid matrix weak; periosteal collagen torn by minor trauma"],
    ["Iron deficiency anaemia","Vitamin C normally aids non-haem iron absorption (reduces Fe3+ to Fe2+)"],
    ["Treatment","500 mg Vitamin C orally daily × 1 month; increase fresh fruits/vegetables in diet"],
],[6*cm,None],CK)
mcqs(story,[
    ("Vitamin C deficiency causes scurvy by impairing:",
     ["HMG-CoA reductase","Prolyl and lysyl hydroxylase (collagen hydroxylation)",
      "Thymidylate synthase","Homocysteine methylation"],1),
    ("Corkscrew hairs are characteristic of:",
     ["Pellagra","Vitamin A deficiency","Scurvy","Biotin deficiency"],2),
    ("Vitamin C assists iron absorption by:",
     ["Acting as a chelating agent","Reducing Fe³⁺ to Fe²⁺ (ferric to ferrous) in the gut",
      "Increasing transferrin production","Inhibiting hepcidin"],1),
],CK)
story.append(Spacer(1,6))

# ── Case E2: Rickets ──────────────────────────────────────────────────────────
case_hdr(story,"E2","Rickets — Vitamin D Deficiency",
         "Impaired calcium/phosphate absorption | Defective bone mineralization",CK)
sec(story,"Clinical Vignette",CK)
story.append(Paragraph(
    "Raj, 18-month-old male. Exclusively breastfed. Lives in northern UK (low sunlight). "
    "Presenting with: waddling gait, delayed walking. "
    "Examination: frontal bossing, craniotabes, Harrison sulcus (groove along lower ribs), "
    "rachitic rosary (beading of costochondral junctions), bow legs (genu varum). "
    "X-ray: widened, frayed, cupped metaphyses (champagne glass appearance).",BODYJ))
sec(story,"Vitamin D Metabolism & Pathophysiology",CK)
pathbox(story,[
    "SUN: 7-dehydrocholesterol (skin) →[UV-B]→ Cholecalciferol (Vit D3)",
    "DIET: D2 (ergocalciferol) from plants; D3 (cholecalciferol) from fish/eggs",
    "",
    "Vit D3 →[25-hydroxylase, LIVER]→ 25-OH-D3 (storage form, measured in serum)",
    "      →[1α-hydroxylase, KIDNEY]→ 1,25-(OH)₂-D3 (CALCITRIOL — active form)",
    "        (1α-hydroxylase stimulated by PTH and low phosphate)",
    "",
    "Active calcitriol actions:",
    "  INTESTINE: ↑ Calcium absorption (induces calbindin D) + ↑ Phosphate absorption",
    "  BONE: ↑ Osteoclast activity (bone resorption) to mobilize Ca²⁺",
    "  KIDNEY: ↑ Ca²⁺ reabsorption",
    "",
    "DEFICIENCY: Ca²⁺ ↓ + PO4³⁻ ↓ → osteoid cannot mineralize → SOFT BONES",
    "  Rickets (growing children) / Osteomalacia (adults)",
    "  PTH ↑ (secondary hyperparathyroidism) → Ca²⁺ pulled from bones → deformities",
],CK)
sec(story,"Investigations",CK)
grid(story,[
    [Paragraph("<b>Test</b>",BOLD), Paragraph("<b>Rickets</b>",BOLD), Paragraph("<b>Significance</b>",BOLD)],
    ["Serum 25-OH-D3","< 12 ng/mL (deficient)","Gold standard for vitamin D status"],
    ["Serum calcium","Low / low-normal","Reduced intestinal absorption"],
    ["Serum phosphate","Low","Reduced absorption + PTH-mediated urinary loss"],
    ["Alkaline phosphatase (ALP)","Markedly elevated","Osteoblast activity ↑ (compensatory bone repair)"],
    ["PTH","Elevated (secondary)","Compensates for low calcium"],
    ["X-ray","Widened, frayed, cupped metaphyses","Pathognomonic — 'champagne glass' appearance"],
],[4.5*cm,4*cm,None],CK)
mcqs(story,[
    ("The active form of vitamin D is:",
     ["Cholecalciferol (Vit D3)","25-hydroxycholecalciferol","1,25-dihydroxycholecalciferol (calcitriol)","Ergocalciferol"],2),
    ("1α-hydroxylase that activates vitamin D is located in:",
     ["Liver","Skin","Kidney","Intestine"],2),
    ("Rachitic rosary is due to:",
     ["Calcium deposits at costochondral junctions","Subperiosteal hemorrhage",
      "Excess osteoid at costochondral junctions from unmineralized bone","Inflammatory arthritis"],2),
],CK)
story.append(Spacer(1,6))

# ── Case E3: Pellagra & Beriberi (condensed) ──────────────────────────────────
case_hdr(story,"E3","Pellagra (B3) & Beriberi (B1) — B-Vitamin Deficiencies",
         "NAD⁺ deficiency (pellagra) | Thiamine deficiency (beriberi) | Both affect energy metabolism",CK)
sec(story,"Quick Comparison",CK)
grid(story,[
    [Paragraph("<b>Feature</b>",BOLD), Paragraph("<b>Pellagra (Niacin/B3 ↓)</b>",BOLD), Paragraph("<b>Beriberi (Thiamine/B1 ↓)</b>",BOLD)],
    ["Vitamin","Niacin (B3) — precursor of NAD⁺/NADP⁺","Thiamine (B1) — cofactor for pyruvate dehydrogenase, α-KGD, transketolase"],
    ["Classic triad","4 Ds: Dermatitis, Diarrhoea, Dementia, Death","Wet: high-output cardiac failure. Dry: peripheral neuropathy"],
    ["Skin sign","Casal necklace (photosensitive dermatitis on sun-exposed areas)","No specific skin sign"],
    ["Neurological","Dementia, confusion (late)","Peripheral neuropathy (dry), Wernicke-Korsakoff (alcoholics)"],
    ["Cardiac","Absent","Wet beriberi: dilated cardiomyopathy, high-output failure, oedema"],
    ["Cause","Maize-based diet (low niacin + tryptophan); Hartnup disease; carcinoid","Polished white rice diet; alcoholism; prolonged IV glucose without thiamine"],
    ["Biochemistry","NAD⁺/NADP⁺ ↓ → impairs oxidative phosphorylation (Krebs cycle)","Pyruvate dehydrogenase needs thiamine-PP → pyruvate accumulates → lactic acidosis"],
    ["Lab finding","Low urinary N-methylnicotinamide","↑ Pyruvate + ↑ lactate; ↑ erythrocyte transketolase activity (functional test)"],
    ["Treatment","Nicotinamide (niacin) 300 mg/day","Thiamine 100 mg IV (Wernicke must be treated BEFORE glucose infusion)"],
],[4*cm,6*cm,None],CK)
mcqs(story,[
    ("Casal necklace (photosensitive rash around the neck) is seen in:",
     ["Scurvy","Pellagra","Beriberi","Riboflavin deficiency"],1),
    ("In Wernicke's encephalopathy, thiamine must be given BEFORE glucose because:",
     ["Glucose is toxic to neurons","Glucose infusion precipitates acute thiamine depletion → worsens encephalopathy",
      "Thiamine inhibits glucose absorption","Glucose increases thiamine clearance"],1),
    ("Hartnup disease predisposes to pellagra because:",
     ["Excess niacin consumed","Defective intestinal/renal transport of tryptophan (niacin precursor)",
      "Niacin excreted in urine","Carcinoid consumes NAD⁺"],1),
],CK)
story.append(PageBreak())

# =============================================================================
# SECTION F – MINERAL DISORDERS
# =============================================================================
CK = "MIN"
cat_banner(story, CK, "SECTION F — MINERAL DISORDERS")
story.append(Spacer(1,5))

# ── Case F1: Iron Deficiency Anaemia ─────────────────────────────────────────
case_hdr(story,"F1","Iron Deficiency Anaemia",
         "Most common nutritional deficiency worldwide | Microcytic hypochromic anaemia",CK)
sec(story,"Clinical Vignette",CK)
story.append(Paragraph(
    "Mrs. Kavya, 28-year-old female. Fatigue, exertional breathlessness for 6 months. "
    "Heavy menstrual periods (menorrhagia). Diet: vegetarian. "
    "Pallor, koilonychia (spoon-shaped nails), angular stomatitis, glossitis. "
    "Pica: craving for ice (pagophagia).",BODYJ))
sec(story,"Iron Metabolism & Pathophysiology",CK)
pathbox(story,[
    "IRON ABSORPTION (duodenum):",
    "  Dietary Fe³⁺ →[Dcytb (duodenal cytochrome b)]→ Fe²⁺ (ferrous)",
    "  Fe²⁺ enters enterocyte via DMT-1 → exported by FERROPORTIN to blood",
    "  In blood: Fe²⁺ →[ceruloplasmin]→ Fe³⁺ → binds TRANSFERRIN (transport)",
    "  Stored as FERRITIN (liver, spleen, bone marrow, macrophages)",
    "  HEPCIDIN (liver hormone): inhibits ferroportin → ↓ iron release (in inflammation)",
    "",
    "IRON DEFICIENCY stages:",
    "  Stage 1: Storage iron depleted → ↓ ferritin (first to fall)",
    "  Stage 2: Transport iron ↓ → ↑ TIBC, ↓ serum iron, ↓ transferrin saturation",
    "  Stage 3: Erythropoiesis affected → microcytic hypochromic RBCs, ↓ Hb",
],CK)
sec(story,"Investigations",CK)
grid(story,[
    [Paragraph("<b>Test</b>",BOLD), Paragraph("<b>IDA</b>",BOLD), Paragraph("<b>ACD</b>",BOLD), Paragraph("<b>Thalassaemia</b>",BOLD)],
    ["Hb","↓","↓","↓"],
    ["MCV/MCH","↓↓ (microcytic)","Normal/↓","↓↓"],
    ["Serum iron","↓","↓","Normal/↑"],
    ["TIBC","↑↑ (high)","↓ or Normal","Normal"],
    ["Ferritin","↓↓ (best indicator IDA)","↑ (acute phase)","Normal/↑"],
    ["Transferrin sat.","< 15%","< 15%","Normal/↑"],
    ["Reticulocyte Hb","↓ (early sensitive marker)","↓","Normal"],
    ["Serum hepcidin","↓","↑ (↑ in inflammation)","↓"],
],[4*cm,2.5*cm,2.5*cm,None],CK)
mcqs(story,[
    ("The FIRST parameter to fall in early iron deficiency is:",
     ["Haemoglobin","Serum iron","Serum ferritin","MCV"],2),
    ("Koilonychia is a sign of:",
     ["Vitamin B12 deficiency","Iron deficiency","Zinc deficiency","Folate deficiency"],1),
    ("Hepcidin inhibits iron absorption by:",
     ["Blocking Dcytb","Promoting lysosomal degradation of ferroportin",
      "Inhibiting DMT-1","Increasing transferrin binding"],1),
],CK)
story.append(Spacer(1,6))

# ── Case F2: Wilson Disease ──────────────────────────────────────────────────
case_hdr(story,"F2","Wilson Disease — Copper Metabolism Disorder",
         "ATP7B mutation | AR | Hepatic + neuropsychiatric + Kayser-Fleischer rings",CK)
sec(story,"Clinical Vignette",CK)
story.append(Paragraph(
    "Amit, 19-year-old male. Presents with tremor, dysarthria, and personality change over 6 months. "
    "Liver function tests mildly abnormal. "
    "On slit-lamp exam: golden-brown Kayser-Fleischer rings at corneal periphery. "
    "Urine copper: markedly elevated. Serum ceruloplasmin: low.",BODYJ))
sec(story,"Copper Metabolism & Pathophysiology",CK)
pathbox(story,[
    "Normal: Dietary copper → absorbed in gut → binds albumin → liver",
    "  In liver: copper incorporated into CERULOPLASMIN (ATP7B / ATP7A)",
    "            excess copper excreted into bile via ATP7B",
    "",
    "Wilson Disease: ATP7B gene mutation (AR, Chr 13)",
    "  ATP7B function impaired:",
    "  1. Copper NOT incorporated into ceruloplasmin → Ceruloplasmin ↓ (apoprotein only)",
    "  2. Copper NOT excreted into bile → copper ACCUMULATES in liver",
    "     → Hepatitis → Cirrhosis",
    "  Excess copper spills into blood → deposited in:",
    "     EYES:   Kayser-Fleischer rings (Descemet membrane, corneal periphery)",
    "     BRAIN:  Basal ganglia, cerebellum → tremor, dysarthria, psychiatric symptoms",
    "     KIDNEY: Fanconi syndrome (tubular dysfunction)",
    "     BLOOD:  Haemolytic anaemia (Coombs-negative)",
],CK)
grid(story,[
    [Paragraph("<b>Test</b>",BOLD), Paragraph("<b>Wilson Disease</b>",BOLD), Paragraph("<b>Normal</b>",BOLD)],
    ["Serum ceruloplasmin","< 20 mg/dL ↓↓","20–40 mg/dL"],
    ["Serum copper","Variable (may be low if ceruloplasmin ↓)","70–140 µg/dL"],
    ["24-hr urine copper","↑↑ (> 100 µg/day)","< 40 µg/day"],
    ["Liver copper (biopsy)","↑↑ (> 250 µg/g dry wt)","< 50 µg/g dry wt"],
    ["Kayser-Fleischer rings (slit lamp)","Present in neurological Wilson","Absent"],
    ["Penicillamine challenge test","Urine copper ↑↑ after penicillamine","Used for confirmation in children"],
],[4.5*cm,4.5*cm,None],CK)
grid(story,[
    [Paragraph("<b>Treatment</b>",BOLD), Paragraph("<b>Mechanism</b>",BOLD)],
    ["D-Penicillamine (first-line)","Chelates copper → urinary excretion ↑"],
    ["Trientine","Alternative chelator (less toxic than penicillamine)"],
    ["Zinc acetate","Blocks gut copper absorption (induces metallothionein in enterocytes)"],
    ["Liver transplant","Curative — restores hepatic ATP7B function"],
],[5.5*cm,None],CK)
story.append(PageBreak())

# =============================================================================
# SECTION G – WATER & ELECTROLYTE DISORDERS
# =============================================================================
CK = "WE"
cat_banner(story, CK, "SECTION G — WATER & ELECTROLYTE DISORDERS")
story.append(Spacer(1,5))

# ── Case G1: SIADH / Hyponatremia ─────────────────────────────────────────────
case_hdr(story,"G1","SIADH — Euvolaemic Hyponatremia",
         "Inappropriate ADH secretion | Water retention | Cerebral oedema",CK)
sec(story,"Clinical Vignette",CK)
story.append(Paragraph(
    "Mrs. Radha, 65-year-old female. Started on carbamazepine for trigeminal neuralgia 3 weeks ago. "
    "Now presents with headache, nausea, confusion. No oedema, no dehydration signs. "
    "Na⁺: 118 mEq/L. Urine Na⁺: 45 mEq/L. Urine osmolality: 550 mOsm/kg. "
    "Serum osmolality: 248 mOsm/kg.",BODYJ))
sec(story,"Pathophysiology",CK)
pathbox(story,[
    "Normal: ADH (vasopressin) released from posterior pituitary in response to:",
    "         - ↑ serum osmolality (primary trigger: osmoreceptors, hypothalamus)",
    "         - ↓ blood volume / pressure (baroreceptors)",
    "ADH → V2 receptors on renal collecting duct → ↑ aquaporin-2 insertion → water reabsorption",
    "",
    "SIADH: ADH secreted DESPITE normal/low serum osmolality (INAPPROPRIATE)",
    "  Causes: CNS disease, pulmonary disease, drugs (carbamazepine, SSRIs, cyclophosphamide,",
    "          thiazides, vincristine, desmopressin), ectopic ADH (SCLC — small cell lung cancer)",
    "",
    "  Consequences: Free water retained → dilutional HYPONATREMIA",
    "    Serum osmolality ↓ → brain cells swell (osmotic water entry) → CEREBRAL OEDEMA",
    "    → Headache → Confusion → Seizures → Herniation (if severe)",
    "    Urine: inappropriately concentrated (osmolality > serum) and Na⁺-rich (> 20 mEq/L)",
],CK)
sec(story,"SIADH Diagnostic Criteria",CK)
grid(story,[
    [Paragraph("<b>Criterion</b>",BOLD), Paragraph("<b>Finding</b>",BOLD), Paragraph("<b>This case</b>",BOLD)],
    ["Serum Na⁺","< 135 mEq/L","118 mEq/L ✓"],
    ["Serum osmolality","< 280 mOsm/kg","248 mOsm/kg ✓"],
    ["Urine osmolality","> 100 mOsm/kg (inappropriately concentrated)","550 mOsm/kg ✓"],
    ["Urine Na⁺","> 20–40 mEq/L (natriuresis persists)","45 mEq/L ✓"],
    ["Volume status","Euvolaemic (no oedema, no dehydration)","Euvolaemic ✓"],
    ["Adrenal/thyroid function","Normal (excludes addison's, hypothyroidism)","Normal ✓"],
],[5*cm,5*cm,None],CK)
sec(story,"Management — Hyponatremia",CK)
pathbox(story,[
    "RATE OF CORRECTION IS CRITICAL:",
    "  Correct Na⁺ NO FASTER than 8–10 mEq/L per 24 hours",
    "  Too rapid correction → OSMOTIC DEMYELINATION SYNDROME (central pontine myelinolysis)",
    "  → Locked-in syndrome, quadriplegia",
    "",
    "Mild-moderate SIADH: FLUID RESTRICTION (800–1000 mL/day) — first-line",
    "Severe/symptomatic (seizures, coma):",
    "  3% hypertonic saline IV — raise Na⁺ by 1–2 mEq/L/hr for first 3–4 hours only",
    "  Target: Na⁺ > 125 mEq/L, symptoms resolve",
    "Chronic SIADH: Vaptans (tolvaptan, conivaptan) — V2 receptor antagonists → aquaresis",
    "Treat underlying cause (stop carbamazepine here)",
],CK)
mcqs(story,[
    ("SIADH is characterized by urine osmolality that is:",
     ["Low (dilute)","Inappropriately high/concentrated relative to serum","Equal to serum","Unmeasurable"],1),
    ("Rapid correction of hyponatremia causes:",
     ["Cerebral oedema","Osmotic demyelination syndrome (central pontine myelinolysis)",
      "Renal failure","Hyperkalaemia"],1),
    ("The first-line treatment for mild SIADH is:",
     ["IV hypertonic saline","Furosemide","Fluid restriction","Tolvaptan"],2),
],CK)
viva(story,[
    ("Why does too-rapid correction of hyponatremia cause brain damage?",
     "In chronic hyponatremia, brain cells adapt by exporting organic osmoles (amino acids, taurine, "
     "myoinositol) to prevent swelling. If sodium is corrected too quickly, plasma osmolality rises "
     "faster than brain cells can re-accumulate osmoles. Water leaves brain cells rapidly → "
     "myelin sheath dehydration → osmotic demyelination (central pontine myelinolysis). "
     "Neurons in the pons are most susceptible. This causes spastic quadriplegia, locked-in syndrome, death."),
],CK)
story.append(Spacer(1,6))

# ── Case G2: Hyperkalemia / DKA Potassium ─────────────────────────────────────
case_hdr(story,"G2","Potassium Disorders — Hyper and Hypokalemia",
         "K⁺ regulation | Acidosis/alkalosis shifts | Life-threatening cardiac effects",CK)
sec(story,"Potassium Physiology & Disorders",CK)
pathbox(story,[
    "INTERNAL K⁺ DISTRIBUTION (98% intracellular):",
    "  Na/K-ATPase pumps K⁺ in, Na⁺ out — maintains [K⁺]i ~150 mEq/L vs [K⁺]e ~4 mEq/L",
    "  Resting membrane potential depends on K⁺ gradient",
    "",
    "FACTORS SHIFTING K⁺ INTO CELLS (→ hypokalaemia):",
    "  Insulin → activates Na/K-ATPase",
    "  Alkalosis → H⁺ exits cells (buffer), K⁺ enters in exchange",
    "  Beta-2 agonists → activate Na/K-ATPase",
    "",
    "FACTORS SHIFTING K⁺ OUT OF CELLS (→ hyperkalaemia):",
    "  Acidosis → H⁺ enters cells, K⁺ exits (as in DKA)",
    "  Insulin deficiency → Na/K-ATPase activity ↓",
    "  Cell destruction (haemolysis, rhabdomyolysis, tumour lysis)",
    "  Hyperosmolality → water + K⁺ exit cells together",
],CK)
grid(story,[
    [Paragraph("<b>Disorder</b>",BOLD), Paragraph("<b>ECG changes</b>",BOLD), Paragraph("<b>Causes</b>",BOLD), Paragraph("<b>Treatment</b>",BOLD)],
    ["Hyperkalaemia\n(K⁺ > 5.5)","Peaked T waves → wide QRS → sine wave → VF","DKA (initial), ACE-I, renal failure, Addison's","IV calcium gluconate (membrane stabilization); insulin+dextrose (drive K⁺ in); sodium bicarbonate; dialysis"],
    ["Hypokalaemia\n(K⁺ < 3.5)","Flat T waves, U waves → arrhythmias","Diuretics, vomiting, insulin treatment of DKA, alkalosis, Conn's syndrome (hyperaldosteronism)","Oral/IV KCl replacement; treat cause"],
],[3*cm,4*cm,4*cm,None],CK)
story.append(Spacer(1,6))

# ── Case G3: Dehydration ──────────────────────────────────────────────────────
case_hdr(story,"G3","Dehydration — Water & Sodium Balance",
         "Isotonic, hypotonic, hypertonic types | TBW regulation | Osmolality",CK)
sec(story,"Physiology & Types of Dehydration",CK)
pathbox(story,[
    "TOTAL BODY WATER (TBW):",
    "  Adult male: ~60% body weight = ICF (2/3) + ECF (1/3)",
    "  ECF = Interstitial fluid (75%) + Plasma (25%)",
    "  Plasma osmolality = 2[Na⁺] + glucose/18 + BUN/2.8  (normal 285–295 mOsm/kg)",
    "",
    "DEHYDRATION TYPES (based on serum Na⁺):",
    "  ISOTONIC (Na⁺ 135–145): fluid & electrolytes lost equally — e.g., diarrhoea, burns",
    "     → No shift between ICF/ECF; ECF contracts; skin turgour ↓, tachycardia",
    "     → Treatment: Isotonic saline (0.9% NaCl)",
    "  HYPOTONIC (Na⁺ < 135): more Na⁺ lost than water — e.g., Addison's, cerebral salt wasting",
    "     → Osmolality ↓ → water shifts INTO cells (brain swells)",
    "     → Treatment: Normal saline ± hypertonic saline",
    "  HYPERTONIC (Na⁺ > 145): more water lost than Na⁺ — e.g., diabetes insipidus, fever, heat stroke",
    "     → Osmolality ↑ → water exits cells (brain shrinks → subdural haematoma risk)",
    "     → Treatment: Free water (5% dextrose or oral water)",
],CK)
grid(story,[
    [Paragraph("<b>Type</b>",BOLD), Paragraph("<b>Serum Na⁺</b>",BOLD), Paragraph("<b>Mechanism</b>",BOLD), Paragraph("<b>Treatment</b>",BOLD)],
    ["Isotonic","135–145","Proportional Na⁺ + H₂O loss","0.9% NaCl (isotonic)"],
    ["Hypotonic","< 135","More Na⁺ lost than water","Isotonic → hypertonic saline"],
    ["Hypertonic","˃ 145","More water lost than Na⁺ (or Na⁺ gain)","Free water — 5% dextrose"],
],[3*cm,3*cm,5.5*cm,None],CK)
story.append(PageBreak())

# ── MASTER SUMMARY ────────────────────────────────────────────────────────────
hdr_t = Table([[Paragraph(
    "<b>MASTER SUMMARY — All Metabolism Categories</b>",
    S("ms", fontName="Helvetica-Bold", fontSize=12, textColor=WHITE,
      alignment=TA_CENTER))]],colWidths=[UW])
hdr_t.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,-1),DARK_NAVY),
    ("TOPPADDING",(0,0),(-1,-1),8),
    ("BOTTOMPADDING",(0,0),(-1,-1),8),
]))
story.append(hdr_t)

master = [
    [Paragraph("<b>Case</b>",S("mh",fontName="Helvetica-Bold",fontSize=7.5,textColor=WHITE)),
     Paragraph("<b>Diagnosis</b>",S("mh2",fontName="Helvetica-Bold",fontSize=7.5,textColor=WHITE)),
     Paragraph("<b>Enzyme/Defect</b>",S("mh3",fontName="Helvetica-Bold",fontSize=7.5,textColor=WHITE)),
     Paragraph("<b>Key Feature</b>",S("mh4",fontName="Helvetica-Bold",fontSize=7.5,textColor=WHITE)),
     Paragraph("<b>Key Test</b>",S("mh5",fontName="Helvetica-Bold",fontSize=7.5,textColor=WHITE)),
     Paragraph("<b>Treatment</b>",S("mh6",fontName="Helvetica-Bold",fontSize=7.5,textColor=WHITE))],
    # CARB
    ["A1","Von Gierke","G-6-Pase deficiency","Hypoglycemia + hepatomegaly + lactic acidosis","Fasting glucose ↓, lactate ↑, TG ↑","Cornstarch feeds; frequent feeds"],
    ["A2","Galactosemia","GALT deficiency","Jaundice + cataracts + E. coli sepsis","Urine reducing substances; GALT activity","Galactose-free diet"],
    ["A3","T1DM","Insulin deficiency","Hyperglycemia + glycosuria + osmotic diuresis","Fasting glucose ≥126, HbA1c ≥6.5%","Insulin therapy"],
    # PROT
    ["B1","PKU","PAH deficiency","Mousy odor + hypopigmentation + ID","Guthrie test; serum Phe > 20 mg/dL","Low-Phe diet ± sapropterin"],
    ["B2","OTC Deficiency","Ornithine transcarbamylase (X-linked)","Neonatal coma + hyperammonemia","NH₃ ↑↑, urine orotic acid ↑↑","Na benzoate + Na phenylbutyrate; liver Tx"],
    ["B3","Kwashiorkor","Protein deficiency","Oedema + pot belly + skin rash","Albumin ↓, TG ↑","Gradual protein refeeding"],
    # LIPID
    ["C1","Fam. Hypercholesterolemia","LDLR mutation","Xanthomas + premature CAD","LDL > 300, LDLR gene","Statins, PCSK9 inhibitors"],
    ["C2","DKA","Insulin absence","Kussmaul + fruity breath + acidosis","pH < 7.3, AG ↑, β-OHB ↑","IV insulin + fluids + K⁺"],
    ["C3","NAFLD/NASH","Insulin resistance","Hepatomegaly + obesity","AST:ALT <1, USG bright liver","Weight loss, GLP-1 agonist"],
    ["C4","Gaucher Disease","Glucocerebrosidase ↓","Hepatosplenomegaly + pancytopenia","Gaucher cells, enzyme activity","ERT (imiglucerase)"],
    ["C5","Alcoholic Fatty Liver","↑ NADH/NAD⁺","Jaundice + ascites + GGT ↑↑","AST:ALT > 2, GGT markedly ↑","Abstinence; corticosteroids (severe)"],
    # NUCLEIC
    ["D1","Gout","XO overactivity / HGPRT partial","Podagra + tophi + urate stones","MSU crystals (neg. birefringent); uric acid ↑","Allopurinol (chronic); colchicine (acute)"],
    ["D2","Lesch-Nyhan","HGPRT absent (X-linked)","Self-mutilation + chorea + gout","Uric acid ↑↑, HGPRT activity absent","Allopurinol + supportive"],
    # VITAMIN
    ["E1","Scurvy","Vit C ↓ → collagen defect","Bleeding gums + perifollicular haemorrhages + corkscrew hair","↓ Serum/urine ascorbic acid, clinical diagnosis","Vit C 500 mg/day"],
    ["E2","Rickets","Vit D ↓ → Ca²⁺/PO₄ ↓","Bow legs + rachitic rosary + craniotabes","25-OH-D ↓, Ca ↓, PO₄ ↓, ALP ↑","Vit D + Calcium supplementation"],
    ["E3a","Pellagra","Niacin (B3) ↓ → NAD⁺ ↓","4Ds: Dermatitis, Diarrhoea, Dementia, Death","↓ urine N-methylnicotinamide","Nicotinamide 300 mg/day"],
    ["E3b","Beriberi","Thiamine (B1) ↓ → PDH defect","Wet: cardiac failure. Dry: neuropathy","Pyruvate ↑, lactate ↑; RBC transketolase ↓","IV Thiamine (before glucose in Wernicke)"],
    # MINERAL
    ["F1","Iron Deficiency","Iron ↓ → Hb ↓","Pallor + koilonychia + angular stomatitis","Ferritin ↓↓ (earliest); MCV ↓; TIBC ↑","Oral ferrous sulphate 200 mg TDS"],
    ["F2","Wilson Disease","ATP7B → Cu accumulation","KF rings + liver disease + neuro/psych","Ceruloplasmin ↓, 24-hr urine Cu ↑↑","D-penicillamine or trientine; zinc"],
    # WATER/ELEC
    ["G1","SIADH","ADH excess → free water retention","Confusion + euvolaemic hyponatremia","Na ↓, serum osm ↓, urine osm ↑, urine Na ↑","Fluid restriction; hypertonic saline (severe)"],
    ["G2a","Hyperkalemia","Acidosis → K⁺ out of cells","Peaked T waves → arrhythmia","K⁺ > 5.5; ECG changes","Ca gluconate; insulin + dextrose; dialysis"],
    ["G2b","Hypokalemia","Alkalosis/insulin → K⁺ into cells","Muscle weakness + U waves","K⁺ < 3.5; flat T, U waves on ECG","Oral/IV KCl replacement"],
    ["G3","Dehydration","Water/Na imbalance","Tachycardia + ↓ skin turgor + dry mucosa","Serum Na, osmolality, urine specific gravity","Isotonic/hypotonic/hypertonic saline per type"],
]

cw = [1.2*cm, 4*cm, 4.5*cm, 4*cm, 4*cm, None]
mt = Table(master, colWidths=cw, repeatRows=1)
# color header + alternating rows
cat_ranges = {
    "CARB":  [(1,3)],
    "PROT":  [(4,6)],
    "LIPID": [(7,11)],
    "NUC":   [(12,13)],
    "VIT":   [(14,17)],
    "MIN":   [(18,19)],
    "WE":    [(20,23)],
}
ts = [
    ("BACKGROUND",    (0,0),(-1,0), DARK_NAVY),
    ("TEXTCOLOR",     (0,0),(-1,0), WHITE),
    ("FONTNAME",      (0,0),(-1,0), "Helvetica-Bold"),
    ("FONTSIZE",      (0,0),(-1,-1), 7),
    ("LEADING",       (0,0),(-1,-1), 9),
    ("TOPPADDING",    (0,0),(-1,-1), 3),
    ("BOTTOMPADDING", (0,0),(-1,-1), 3),
    ("LEFTPADDING",   (0,0),(-1,-1), 4),
    ("GRID",          (0,0),(-1,-1), 0.4, HexColor("#cccccc")),
    ("VALIGN",        (0,0),(-1,-1), "TOP"),
]
for ck, ranges in cat_ranges.items():
    for (r1,r2) in ranges:
        ts.append(("BACKGROUND", (0,r1),(0,r2), CAT_COLORS[ck]))
        ts.append(("TEXTCOLOR",  (0,r1),(0,r2), WHITE))
        ts.append(("FONTNAME",   (0,r1),(0,r2), "Helvetica-Bold"))
        # light background for data cols
        for r in range(r1,r2+1):
            col = CAT_LIGHT[ck] if r%2==1 else WHITE
            ts.append(("BACKGROUND", (1,r),(-1,r), col))

mt.setStyle(TableStyle(ts))
story.append(mt)
story.append(Spacer(1,6))
story.append(HRFlowable(width=UW, thickness=0.5, color=MGREY))
story.append(Spacer(1,3))
story.append(Paragraph(
    "Sources: Robbins & Kumar Basic Pathology | Harrison's Principles of Internal Medicine 22e | "
    "Thompson & Thompson Genetics 9e | Lippincott's Illustrated Biochemistry 8e | "
    "Tietz Textbook of Laboratory Medicine 7e | Mulholland Surgery 7e | Ganong's Medical Physiology 26e",
    S("src2", fontName="Helvetica-Oblique", fontSize=6, leading=8,
      textColor=MGREY, alignment=TA_CENTER)))
story.append(Paragraph(
    "Generated by Orris AI · For educational/exam preparation use only · Not for clinical use",
    S("disc2", fontName="Helvetica", fontSize=6, leading=8,
      textColor=MGREY, alignment=TA_CENTER)))

# ── BUILD ─────────────────────────────────────────────────────────────────────
doc.build(story, onFirstPage=add_pg, onLaterPages=add_pg)
print("SUCCESS:", OUT)

Successfully replaced 1 instance(s) of the string in '/tmp/workspace/lipid-cases/generate_all_metabolism.py'

Successfully replaced 1 instance(s) of the string in '/tmp/workspace/lipid-cases/generate_all_metabolism.py'

Successfully replaced 1 instance(s) of the string in '/tmp/workspace/lipid-cases/generate_all_metabolism.py'

Successfully replaced 1 instance(s) of the string in '/tmp/workspace/lipid-cases/generate_all_metabolism.py'

Successfully replaced 1 instance(s) of the string in '/tmp/workspace/lipid-cases/generate_all_metabolism.py'