#!/usr/bin/env python3
"""
MBBS Clinical Cases Study Guide PDF Generator
Topics: Jaundice & Diabetes Biochemistry
"""

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

OUTPUT_PATH = "/home/daytona/workspace/mbbs-cases/MBBS_ClinicalCases_Jaundice_Diabetes.pdf"

# ── Colour palette ──────────────────────────────────────────────────────────
C_DARK_BLUE   = colors.HexColor("#1a3a5c")
C_MED_BLUE    = colors.HexColor("#2e6da4")
C_LIGHT_BLUE  = colors.HexColor("#dbeaf7")
C_TEAL        = colors.HexColor("#1a6b6b")
C_LIGHT_TEAL  = colors.HexColor("#d4f0f0")
C_GOLD        = colors.HexColor("#c8860a")
C_LIGHT_GOLD  = colors.HexColor("#fef6e4")
C_RED         = colors.HexColor("#c0392b")
C_LIGHT_RED   = colors.HexColor("#fdecea")
C_GREEN       = colors.HexColor("#1e7a34")
C_LIGHT_GREEN = colors.HexColor("#e9f7ec")
C_PURPLE      = colors.HexColor("#6c3483")
C_LIGHT_PURPLE= colors.HexColor("#f4ecf7")
C_GREY_LIGHT  = colors.HexColor("#f5f5f5")
C_GREY_MID    = colors.HexColor("#cccccc")
C_BLACK       = colors.HexColor("#1a1a1a")
C_WHITE       = colors.white

# ── Styles ───────────────────────────────────────────────────────────────────
def build_styles():
    base = getSampleStyleSheet()

    styles = {}

    styles["cover_title"] = ParagraphStyle(
        "cover_title", fontName="Helvetica-Bold", fontSize=28,
        textColor=C_WHITE, alignment=TA_CENTER, spaceAfter=8, leading=34
    )
    styles["cover_sub"] = ParagraphStyle(
        "cover_sub", fontName="Helvetica", fontSize=14,
        textColor=colors.HexColor("#cce0f5"), alignment=TA_CENTER, spaceAfter=6
    )
    styles["cover_meta"] = ParagraphStyle(
        "cover_meta", fontName="Helvetica", fontSize=11,
        textColor=colors.HexColor("#a0c4e8"), alignment=TA_CENTER, spaceAfter=4
    )

    styles["h_part"] = ParagraphStyle(
        "h_part", fontName="Helvetica-Bold", fontSize=18,
        textColor=C_WHITE, alignment=TA_CENTER, spaceAfter=4, spaceBefore=6, leading=22
    )
    styles["h_section"] = ParagraphStyle(
        "h_section", fontName="Helvetica-Bold", fontSize=14,
        textColor=C_DARK_BLUE, spaceAfter=4, spaceBefore=14, leading=18
    )
    styles["h_case"] = ParagraphStyle(
        "h_case", fontName="Helvetica-Bold", fontSize=13,
        textColor=C_WHITE, spaceAfter=2, spaceBefore=2, leading=17
    )
    styles["h_sub"] = ParagraphStyle(
        "h_sub", fontName="Helvetica-Bold", fontSize=11,
        textColor=C_MED_BLUE, spaceAfter=3, spaceBefore=8, leading=14
    )
    styles["h_sub2"] = ParagraphStyle(
        "h_sub2", fontName="Helvetica-Bold", fontSize=10,
        textColor=C_TEAL, spaceAfter=2, spaceBefore=6, leading=13
    )
    styles["body"] = ParagraphStyle(
        "body", fontName="Helvetica", fontSize=9.5,
        textColor=C_BLACK, spaceAfter=4, leading=14, alignment=TA_JUSTIFY
    )
    styles["body_bold"] = ParagraphStyle(
        "body_bold", fontName="Helvetica-Bold", fontSize=9.5,
        textColor=C_BLACK, spaceAfter=4, leading=14
    )
    styles["bullet"] = ParagraphStyle(
        "bullet", fontName="Helvetica", fontSize=9.5,
        textColor=C_BLACK, spaceAfter=2, leading=13,
        leftIndent=12, firstLineIndent=-10
    )
    styles["quote"] = ParagraphStyle(
        "quote", fontName="Helvetica-Oblique", fontSize=9,
        textColor=colors.HexColor("#444444"), spaceAfter=4, leading=13,
        leftIndent=14, rightIndent=14, borderPad=4
    )
    styles["code"] = ParagraphStyle(
        "code", fontName="Courier", fontSize=8.5,
        textColor=C_DARK_BLUE, spaceAfter=3, leading=13,
        leftIndent=10, backColor=C_GREY_LIGHT
    )
    styles["table_hdr"] = ParagraphStyle(
        "table_hdr", fontName="Helvetica-Bold", fontSize=8.5,
        textColor=C_WHITE, alignment=TA_CENTER, leading=11
    )
    styles["table_cell"] = ParagraphStyle(
        "table_cell", fontName="Helvetica", fontSize=8.5,
        textColor=C_BLACK, alignment=TA_LEFT, leading=11
    )
    styles["table_cell_c"] = ParagraphStyle(
        "table_cell_c", fontName="Helvetica", fontSize=8.5,
        textColor=C_BLACK, alignment=TA_CENTER, leading=11
    )
    styles["source"] = ParagraphStyle(
        "source", fontName="Helvetica-Oblique", fontSize=8,
        textColor=colors.HexColor("#666666"), spaceAfter=2, leading=11
    )
    styles["footnote"] = ParagraphStyle(
        "footnote", fontName="Helvetica", fontSize=8,
        textColor=colors.HexColor("#777777"), spaceAfter=2, leading=11
    )
    return styles


# ── Helper flowables ─────────────────────────────────────────────────────────
def part_banner(text, color, styles):
    tbl = Table([[Paragraph(text, styles["h_part"])]], colWidths=[17*cm])
    tbl.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), color),
        ("ROUNDEDCORNERS", [6]),
        ("TOPPADDING",    (0,0), (-1,-1), 10),
        ("BOTTOMPADDING", (0,0), (-1,-1), 10),
        ("LEFTPADDING",   (0,0), (-1,-1), 12),
        ("RIGHTPADDING",  (0,0), (-1,-1), 12),
    ]))
    return tbl

def case_banner(text, color, styles):
    tbl = Table([[Paragraph(text, styles["h_case"])]], colWidths=[17*cm])
    tbl.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), color),
        ("ROUNDEDCORNERS", [4]),
        ("TOPPADDING",    (0,0), (-1,-1), 7),
        ("BOTTOMPADDING", (0,0), (-1,-1), 7),
        ("LEFTPADDING",   (0,0), (-1,-1), 10),
        ("RIGHTPADDING",  (0,0), (-1,-1), 10),
    ]))
    return tbl

def info_box(text, bg_color, border_color, styles, label=None):
    content = []
    if label:
        content.append(Paragraph(f"<b>{label}</b>", styles["body_bold"]))
    content.append(Paragraph(text, styles["body"]))
    tbl = Table([content], colWidths=[17*cm])
    tbl.setStyle(TableStyle([
        ("BACKGROUND",    (0,0), (-1,-1), bg_color),
        ("BOX",           (0,0), (-1,-1), 1.5, border_color),
        ("TOPPADDING",    (0,0), (-1,-1), 7),
        ("BOTTOMPADDING", (0,0), (-1,-1), 7),
        ("LEFTPADDING",   (0,0), (-1,-1), 10),
        ("RIGHTPADDING",  (0,0), (-1,-1), 10),
    ]))
    return tbl

def quote_box(text, source, styles):
    tbl = Table([
        [Paragraph(f'<i>"{text}"</i>', styles["quote"])],
        [Paragraph(f"— {source}", styles["source"])]
    ], colWidths=[17*cm])
    tbl.setStyle(TableStyle([
        ("BACKGROUND",    (0,0), (-1,-1), C_GREY_LIGHT),
        ("LINEAFTER",     (0,0), (0,-1), 3, C_MED_BLUE),
        ("TOPPADDING",    (0,0), (-1,-1), 6),
        ("BOTTOMPADDING", (0,0), (-1,-1), 4),
        ("LEFTPADDING",   (0,0), (-1,-1), 14),
        ("RIGHTPADDING",  (0,0), (-1,-1), 10),
    ]))
    return tbl

def make_table(headers, rows, styles, col_widths=None, header_color=None):
    if header_color is None:
        header_color = C_DARK_BLUE
    header_row = [Paragraph(h, styles["table_hdr"]) for h in headers]
    data = [header_row]
    for i, row in enumerate(rows):
        data.append([Paragraph(str(cell), styles["table_cell"]) for cell in row])
    if col_widths is None:
        n = len(headers)
        col_widths = [17*cm / n] * n
    tbl = Table(data, colWidths=col_widths, repeatRows=1)
    ts = [
        ("BACKGROUND",    (0,0), (-1,0),  header_color),
        ("TEXTCOLOR",     (0,0), (-1,0),  C_WHITE),
        ("ROWBACKGROUNDS",(0,1), (-1,-1), [C_WHITE, C_GREY_LIGHT]),
        ("BOX",           (0,0), (-1,-1), 0.8, C_GREY_MID),
        ("INNERGRID",     (0,0), (-1,-1), 0.4, C_GREY_MID),
        ("TOPPADDING",    (0,0), (-1,-1), 5),
        ("BOTTOMPADDING", (0,0), (-1,-1), 5),
        ("LEFTPADDING",   (0,0), (-1,-1), 6),
        ("RIGHTPADDING",  (0,0), (-1,-1), 6),
        ("VALIGN",        (0,0), (-1,-1), "MIDDLE"),
    ]
    tbl.setStyle(TableStyle(ts))
    return tbl

def pathway_box(lines, styles):
    """Monospaced pathway/reaction box."""
    content = [Paragraph(line.replace(" ", "&nbsp;"), styles["code"]) for line in lines]
    tbl = Table([[c] for c in content], colWidths=[17*cm])
    tbl.setStyle(TableStyle([
        ("BACKGROUND",    (0,0), (-1,-1), C_GREY_LIGHT),
        ("BOX",           (0,0), (-1,-1), 1, C_MED_BLUE),
        ("TOPPADDING",    (0,0), (-1,-1), 2),
        ("BOTTOMPADDING", (0,0), (-1,-1), 2),
        ("LEFTPADDING",   (0,0), (-1,-1), 8),
        ("RIGHTPADDING",  (0,0), (-1,-1), 8),
    ]))
    return tbl

def sp(n=1):
    return Spacer(1, n * 4 * mm)

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


# ── Cover page ───────────────────────────────────────────────────────────────
def build_cover(styles):
    els = []

    # Full-width cover banner via a large table
    cover_data = [[
        Paragraph("MBBS BIOCHEMISTRY", styles["cover_title"]),
    ]]
    cover = Table(cover_data, colWidths=[17*cm])
    cover.setStyle(TableStyle([
        ("BACKGROUND",    (0,0), (-1,-1), C_DARK_BLUE),
        ("TOPPADDING",    (0,0), (-1,-1), 30),
        ("BOTTOMPADDING", (0,0), (-1,-1), 10),
        ("LEFTPADDING",   (0,0), (-1,-1), 10),
        ("RIGHTPADDING",  (0,0), (-1,-1), 10),
    ]))
    els.append(cover)

    sub_data = [[Paragraph("Clinical Cases Study Guide", styles["cover_sub"])]]
    sub = Table(sub_data, colWidths=[17*cm])
    sub.setStyle(TableStyle([
        ("BACKGROUND",    (0,0), (-1,-1), C_DARK_BLUE),
        ("TOPPADDING",    (0,0), (-1,-1), 2),
        ("BOTTOMPADDING", (0,0), (-1,-1), 20),
        ("LEFTPADDING",   (0,0), (-1,-1), 10),
        ("RIGHTPADDING",  (0,0), (-1,-1), 10),
    ]))
    els.append(sub)

    els.append(sp(3))

    topic_data = [
        [Paragraph("TOPICS COVERED", ParagraphStyle("tc", fontName="Helvetica-Bold",
            fontSize=11, textColor=C_MED_BLUE, alignment=TA_CENTER))],
        [Paragraph("Jaundice &nbsp;|&nbsp; Diabetes Mellitus &nbsp;|&nbsp; Biochemistry Integration",
            ParagraphStyle("tcs", fontName="Helvetica", fontSize=12,
            textColor=C_DARK_BLUE, alignment=TA_CENTER, leading=18))],
    ]
    topic_tbl = Table(topic_data, colWidths=[17*cm])
    topic_tbl.setStyle(TableStyle([
        ("BACKGROUND",    (0,0), (-1,-1), C_LIGHT_BLUE),
        ("BOX",           (0,0), (-1,-1), 1.5, C_MED_BLUE),
        ("TOPPADDING",    (0,0), (-1,-1), 10),
        ("BOTTOMPADDING", (0,0), (-1,-1), 10),
    ]))
    els.append(topic_tbl)
    els.append(sp(3))

    # Year labels
    year_rows = [
        ["1st & 2nd Year",  "Biochemistry • Pathway Mechanisms • Physiology of Insulin & Bilirubin"],
        ["3rd Year (MBBS)", "Clinical Cases • Diagnosis • Management • Exam-Ready Discussions"],
    ]
    year_tbl = Table(year_rows, colWidths=[5*cm, 12*cm])
    year_tbl.setStyle(TableStyle([
        ("BACKGROUND",    (0,0), (0,-1), C_MED_BLUE),
        ("BACKGROUND",    (1,0), (1,-1), C_LIGHT_BLUE),
        ("TEXTCOLOR",     (0,0), (0,-1), C_WHITE),
        ("FONTNAME",      (0,0), (0,-1), "Helvetica-Bold"),
        ("FONTSIZE",      (0,0), (-1,-1), 10),
        ("TOPPADDING",    (0,0), (-1,-1), 9),
        ("BOTTOMPADDING", (0,0), (-1,-1), 9),
        ("LEFTPADDING",   (0,0), (-1,-1), 12),
        ("INNERGRID",     (0,0), (-1,-1), 0.5, C_WHITE),
        ("BOX",           (0,0), (-1,-1), 1, C_MED_BLUE),
    ]))
    els.append(year_tbl)
    els.append(sp(3))

    # Contents list
    toc_items = [
        "PART 1 — 3rd Year MBBS: Clinical Cases",
        "  J1  Prehepatic Jaundice (Autoimmune Hemolytic Anemia)",
        "  J2  Hepatocellular Jaundice (Viral Hepatitis A)",
        "  J3  Obstructive / Posthepatic Jaundice (Ca Pancreas)",
        "  J4  Gilbert's Syndrome",
        "  D1  Type 1 DM — DKA (New Onset)",
        "  D2  Type 2 DM — Incidental Detection",
        "  D3  Hyperosmolar Hyperglycemic State (HHS)",
        "  D4  Drug-induced Liver Injury in a Diabetic",
        "  D5  Metformin-associated Lactic Acidosis",
        "",
        "PART 2 — 1st & 2nd Year MBBS: Biochemistry Deep Dives",
        "  J1  Bilirubin Pathway — Full Mechanism & Gilbert's Syndrome",
        "  J2  Physiological Neonatal Jaundice & Kernicterus",
        "  J3  Obstructive Jaundice — Why Pale Stools & Dark Urine?",
        "  D1  Insulin Biosynthesis — Gene to Granule",
        "  D2  Beta-cell Secretion — K_ATP Channel & Sulfonylureas",
        "  D3  Insulin's Metabolic Actions — GLUT4, Glycogen, Lipogenesis",
        "  D4  DKA Biochemistry — Ketone Bodies & Anion Gap",
        "  D5  HbA1c — Glycation, Amadori Product, Interpretation",
        "",
        "PART 3 — Quick Reference Tables (Exam Ready)",
    ]
    toc_data = [[Paragraph("CONTENTS", ParagraphStyle("toc_h", fontName="Helvetica-Bold",
        fontSize=11, textColor=C_DARK_BLUE))]]
    for item in toc_items:
        style = ParagraphStyle("toc_i", fontName="Helvetica-Bold" if "PART" in item else "Helvetica",
            fontSize=9, textColor=C_DARK_BLUE if "PART" in item else C_BLACK, leading=14)
        toc_data.append([Paragraph(item, style)])
    toc_tbl = Table(toc_data, colWidths=[17*cm])
    toc_tbl.setStyle(TableStyle([
        ("BACKGROUND",    (0,0), (0,0),  C_LIGHT_BLUE),
        ("BACKGROUND",    (0,1), (-1,-1), C_WHITE),
        ("BOX",           (0,0), (-1,-1), 1, C_MED_BLUE),
        ("TOPPADDING",    (0,0), (-1,-1), 4),
        ("BOTTOMPADDING", (0,0), (-1,-1), 4),
        ("LEFTPADDING",   (0,0), (-1,-1), 12),
        ("RIGHTPADDING",  (0,0), (-1,-1), 12),
    ]))
    els.append(toc_tbl)
    els.append(sp(2))

    meta = Table([[
        Paragraph("Based on: Harrison's 22nd Ed • Goldman-Cecil Medicine • Schwartz's Surgery • "
                  "Harper's Biochemistry • Tietz Lab Medicine • Medical Physiology",
                  ParagraphStyle("src", fontName="Helvetica-Oblique", fontSize=8,
                  textColor=colors.HexColor("#555"), alignment=TA_CENTER))
    ]], colWidths=[17*cm])
    meta.setStyle(TableStyle([
        ("BACKGROUND",    (0,0), (-1,-1), C_GREY_LIGHT),
        ("TOPPADDING",    (0,0), (-1,-1), 6),
        ("BOTTOMPADDING", (0,0), (-1,-1), 6),
    ]))
    els.append(meta)
    els.append(PageBreak())
    return els


# ── PAGE HEADER / FOOTER ─────────────────────────────────────────────────────
def on_page(canvas, doc):
    canvas.saveState()
    w, h = A4
    # Header bar
    canvas.setFillColor(C_DARK_BLUE)
    canvas.rect(doc.leftMargin, h - doc.topMargin + 4*mm,
                w - doc.leftMargin - doc.rightMargin, 6*mm, fill=1, stroke=0)
    canvas.setFont("Helvetica-Bold", 8)
    canvas.setFillColor(C_WHITE)
    canvas.drawString(doc.leftMargin + 3*mm, h - doc.topMargin + 6*mm,
                      "MBBS Biochemistry — Jaundice & Diabetes Clinical Cases")
    canvas.drawRightString(w - doc.rightMargin - 3*mm, h - doc.topMargin + 6*mm,
                           "Quick Revision Study Guide")
    # Footer
    canvas.setFillColor(C_MED_BLUE)
    canvas.rect(doc.leftMargin, doc.bottomMargin - 4*mm,
                w - doc.leftMargin - doc.rightMargin, 5*mm, fill=1, stroke=0)
    canvas.setFont("Helvetica", 7.5)
    canvas.setFillColor(C_WHITE)
    canvas.drawCentredString(w/2, doc.bottomMargin - 2*mm, f"Page {doc.page}")
    canvas.restoreState()


# ── CONTENT BUILDERS ─────────────────────────────────────────────────────────

def section_3rd_year(styles):
    els = []

    # ── PART 1 BANNER ──
    els.append(part_banner("PART 1 — 3rd Year MBBS: Clinical Cases", C_DARK_BLUE, styles))
    els.append(sp(2))
    els.append(Paragraph(
        "Each case presents a real-world clinical vignette followed by investigations, "
        "diagnosis, and a structured biochemical discussion mapped to the MBBS curriculum.",
        styles["body"]))
    els.append(sp(1))
    els.append(hr(C_MED_BLUE, 1.5))

    # ────────────────────────────────────────────────────────────────
    # JAUNDICE CASES
    # ────────────────────────────────────────────────────────────────
    els.append(Paragraph("JAUNDICE — CLINICAL CASES", styles["h_section"]))

    # ── Case J1 ──────────────────────────────────────────────────────
    els.append(case_banner("Case J1 — Prehepatic Jaundice | Autoimmune Hemolytic Anemia", C_MED_BLUE, styles))
    els.append(sp(1))
    els.append(info_box(
        "<b>Presenting Complaint:</b> 22-year-old male with yellowish eyes and skin for 3 days. "
        "Dark urine. No abdominal pain, no fever, no alcohol use. Cousin has similar history.",
        C_LIGHT_BLUE, C_MED_BLUE, styles))
    els.append(sp(1))
    els.append(Paragraph("Investigations", styles["h_sub"]))
    els.append(make_table(
        ["Test", "Result", "Interpretation"],
        [
            ["Total bilirubin", "5.8 mg/dL", "Elevated"],
            ["Direct (conjugated) bilirubin", "0.6 mg/dL", "Normal"],
            ["Indirect (unconjugated) bilirubin", "5.2 mg/dL", "Markedly elevated"],
            ["Urine bilirubin", "ABSENT", "Key finding — acholuric jaundice"],
            ["Urine urobilinogen", "Markedly elevated", "Excess bile in gut"],
            ["Haemoglobin", "7.8 g/dL", "Anaemia"],
            ["Reticulocyte count", "8%", "Elevated — active haemolysis"],
            ["Peripheral smear", "Spherocytes, polychromasia", "Haemolytic pattern"],
            ["Direct Coombs (DCT)", "Positive", "Immune-mediated haemolysis"],
            ["AST/ALT/ALP", "Near normal", "Liver intact"],
        ],
        styles, [5.5*cm, 5*cm, 6.5*cm]
    ))
    els.append(sp(1))
    els.append(info_box("<b>Diagnosis:</b> Autoimmune Haemolytic Anaemia → Prehepatic (Haemolytic) Jaundice",
        C_LIGHT_GREEN, C_GREEN, styles))
    els.append(sp(1))
    els.append(Paragraph("Biochemical Explanation", styles["h_sub"]))
    for line in [
        "• Excess RBC breakdown → massive unconjugated (indirect) bilirubin load",
        "• Unconjugated bilirubin is <b>water-insoluble</b> (bound to albumin) → cannot be filtered by glomeruli → <b>no bilirubin in urine</b> (acholuric jaundice)",
        "• Liver conjugates and excretes excess bile → more urobilinogen in gut → reabsorbed → excreted in urine → <b>urine urobilinogen very high</b>",
        "• Stools are dark (excess stercobilin)",
        "• ALT/AST are normal — the liver itself is undamaged",
    ]:
        els.append(Paragraph(line, styles["bullet"]))
    els.append(sp(1))
    els.append(quote_box(
        "Prehepatic jaundice as a result of elevated levels of unconjugated bilirubin occurs from "
        "faulty prehepatic metabolism and usually arises from conditions that interfere with proper "
        "conjugation of bilirubin in the hepatocyte.",
        "Schwartz's Principles of Surgery, 11th Ed."
    ))
    els.append(sp(2))

    # ── Case J2 ──────────────────────────────────────────────────────
    els.append(case_banner("Case J2 — Hepatocellular Jaundice | Acute Viral Hepatitis A", C_TEAL, styles))
    els.append(sp(1))
    els.append(info_box(
        "<b>Presenting Complaint:</b> 19-year-old male, jaundice 5 days. Prodrome: fatigue, nausea, "
        "anorexia, low-grade fever for 2 weeks. Recently returned from rural camp. "
        "Clay-colored stools, dark urine.",
        C_LIGHT_TEAL, C_TEAL, styles))
    els.append(sp(1))
    els.append(Paragraph("Investigations", styles["h_sub"]))
    els.append(make_table(
        ["Test", "Result", "Interpretation"],
        [
            ["Total bilirubin", "9.2 mg/dL", "Elevated"],
            ["Direct bilirubin", "6.4 mg/dL", "Predominantly conjugated"],
            ["Indirect bilirubin", "2.8 mg/dL", "Also elevated"],
            ["Urine bilirubin", "Positive (3+)", "Conjugated spills into urine"],
            ["ALT", "1840 U/L", "Markedly elevated — hepatocellular damage"],
            ["AST", "1240 U/L", "Elevated; ALT > AST (viral pattern)"],
            ["ALP", "180 U/L", "Mildly elevated"],
            ["INR", "1.4", "Mildly prolonged synthetic dysfunction"],
            ["Anti-HAV IgM", "Positive", "Confirms Hepatitis A"],
        ],
        styles, [5.5*cm, 5*cm, 6.5*cm]
    ))
    els.append(sp(1))
    els.append(info_box("<b>Diagnosis:</b> Acute Hepatitis A — Hepatocellular Jaundice",
        C_LIGHT_GREEN, C_GREEN, styles))
    els.append(sp(1))
    els.append(Paragraph("Biochemical Explanation", styles["h_sub"]))
    for line in [
        "• Viral injury → hepatocyte damage → impaired bilirubin uptake, conjugation AND excretion",
        "• Both conjugated and unconjugated bilirubin rise",
        "• Conjugated bilirubin (water-soluble) leaks into blood → filtered by kidneys → <b>bilirubinuria (dark urine)</b>",
        "• <b>ALT > AST</b> pattern: ALT is cytoplasmic and highly specific for hepatocytes; AST is mitochondrial (rises later, also in cardiac/muscle injury)",
        "• AST:ALT ratio >2 suggests alcoholic hepatitis; <1 favours viral hepatitis",
        "• Mildly prolonged INR: liver impairment reduces synthesis of clotting factors (II, VII, IX, X)",
    ]:
        els.append(Paragraph(line, styles["bullet"]))
    els.append(sp(1))
    els.append(quote_box(
        "In hepatocellular dysfunction caused by viral hepatitis, aminotransferase levels are elevated, "
        "with the serum ALT level higher than the AST level.",
        "Goldman-Cecil Medicine, International Ed."
    ))
    els.append(sp(2))

    # ── Case J3 ──────────────────────────────────────────────────────
    els.append(case_banner("Case J3 — Obstructive Jaundice | Carcinoma Head of Pancreas", C_GOLD, styles))
    els.append(sp(1))
    els.append(info_box(
        "<b>Presenting Complaint:</b> 55-year-old male, progressive deep jaundice 3 weeks, "
        "clay-colored stools, dark urine, <b>intense pruritus</b>, 6 kg weight loss. "
        "No fever. <b>Courvoisier's sign positive</b> (palpable non-tender gallbladder).",
        C_LIGHT_GOLD, C_GOLD, styles))
    els.append(sp(1))
    els.append(Paragraph("Investigations", styles["h_sub"]))
    els.append(make_table(
        ["Test", "Result", "Interpretation"],
        [
            ["Total bilirubin", "18 mg/dL", "Markedly elevated"],
            ["Direct bilirubin", "15.8 mg/dL", "Predominantly conjugated"],
            ["ALP", "680 U/L", "Markedly elevated — cholestatic"],
            ["GGT", "420 U/L", "Markedly elevated — cholestatic"],
            ["ALT/AST", "120/90 U/L", "Mildly elevated (secondary)"],
            ["Urine bilirubin", "4+", "Bilirubinuria"],
            ["Urine urobilinogen", "ABSENT", "No bile reaching gut"],
            ["CA 19-9", "Markedly elevated", "Pancreatic tumour marker"],
            ["USG / CECT Abdomen", "Dilated CBD, pancreatic head mass", "Confirms obstruction"],
        ],
        styles, [5.5*cm, 5*cm, 6.5*cm]
    ))
    els.append(sp(1))
    els.append(info_box("<b>Diagnosis:</b> Carcinoma Head of Pancreas → Obstructive (Posthepatic) Jaundice",
        C_LIGHT_RED, C_RED, styles))
    els.append(sp(1))
    els.append(Paragraph("Biochemical Explanation", styles["h_sub"]))
    for line in [
        "• CBD obstruction → conjugated bilirubin cannot enter duodenum → backs up into bloodstream",
        "• Water-soluble conjugated bilirubin → filtered by kidneys → <b>bilirubinuria (dark urine)</b>",
        "• No bile in gut → no urobilinogen → <b>absent urine urobilinogen</b> → pale/clay stools",
        "• <b>ALP and GGT markedly elevated</b>: back-pressure induces ALP synthesis in bile duct epithelium",
        "• <b>Pruritus</b>: bile salt deposition in skin stimulates cutaneous nerve fibres",
        "• <b>Prolonged PT</b>: bile blockage → Vitamin K malabsorption → reduced synthesis of factors II, VII, IX, X",
        "• Courvoisier's sign = palpable non-tender gallbladder + jaundice → malignancy until proved otherwise",
    ]:
        els.append(Paragraph(line, styles["bullet"]))
    els.append(sp(2))

    # ── Case J4 ──────────────────────────────────────────────────────
    els.append(case_banner("Case J4 — Gilbert's Syndrome | Hereditary Unconjugated Hyperbilirubinaemia", C_PURPLE, styles))
    els.append(sp(1))
    els.append(info_box(
        "<b>Presenting Complaint:</b> 24-year-old medical student, incidental yellow eyes during physical exam. "
        "Episodes with prolonged fasting and exam stress. Father also has 'yellow eyes'. "
        "No dark urine, no abdominal symptoms.",
        C_LIGHT_PURPLE, C_PURPLE, styles))
    els.append(sp(1))
    els.append(make_table(
        ["Test", "Result"],
        [
            ["Total bilirubin", "3.2 mg/dL"],
            ["Direct bilirubin", "0.3 mg/dL (indirect = 2.9 mg/dL)"],
            ["LFTs, albumin, INR", "All NORMAL"],
            ["CBC, reticulocytes, peripheral smear", "All NORMAL"],
            ["Urine bilirubin", "Absent"],
        ],
        styles, [8*cm, 9*cm]
    ))
    els.append(sp(1))
    els.append(info_box(
        "<b>Diagnosis:</b> Gilbert's Syndrome — benign hereditary unconjugated hyperbilirubinaemia. "
        "Defect: TA-repeat polymorphism in UGT1A1 promoter → ~30% reduced UDP-glucuronosyltransferase "
        "activity. Autosomal recessive. Affects 4-7% of population. No treatment needed.",
        C_LIGHT_GREEN, C_GREEN, styles))
    els.append(sp(2))

    # ────────────────────────────────────────────────────────────────
    # DIABETES CASES
    # ────────────────────────────────────────────────────────────────
    els.append(hr(C_DARK_BLUE, 1.5))
    els.append(Paragraph("DIABETES MELLITUS — CLINICAL CASES", styles["h_section"]))

    # ── Case D1 ──────────────────────────────────────────────────────
    els.append(case_banner("Case D1 — Type 1 DM | New-onset Diabetic Ketoacidosis (DKA)", C_RED, styles))
    els.append(sp(1))
    els.append(info_box(
        "<b>Presenting Complaint:</b> 14-year-old girl, 4 weeks of polyuria, polydipsia, polyphagia, "
        "5 kg weight loss despite eating well. Today: drowsy, deep rapid breathing, fruity breath. "
        "BMI 17. BP 90/60, HR 122, RR 28/min (Kussmaul breathing).",
        C_LIGHT_RED, C_RED, styles))
    els.append(sp(1))
    els.append(Paragraph("Investigations", styles["h_sub"]))
    els.append(make_table(
        ["Test", "Result", "Significance"],
        [
            ["Blood glucose", "520 mg/dL", "Hyperglycaemia"],
            ["Serum Na", "128 mEq/L", "Pseudohyponatraemia (osmotic shift)"],
            ["Serum K", "5.4 mEq/L", "Initially high; total body deficit"],
            ["Serum HCO₃", "10 mEq/L", "Low — metabolic acidosis"],
            ["Arterial pH", "7.16", "Acidosis (severe if <7.0)"],
            ["Anion gap", "22 mEq/L", "High anion gap = ketoacids"],
            ["Serum ketones", "Strongly positive", "Ketoacidosis confirmed"],
            ["HbA1c", "11.2%", "Chronic uncontrolled hyperglycaemia"],
            ["C-peptide", "Very low", "Absent endogenous insulin"],
            ["Anti-GAD antibody", "Positive", "Autoimmune T1DM confirmed"],
        ],
        styles, [5*cm, 4.5*cm, 7.5*cm]
    ))
    els.append(sp(1))
    els.append(info_box("<b>Diagnosis:</b> New-onset Type 1 DM presenting as Diabetic Ketoacidosis (DKA)",
        C_LIGHT_RED, C_RED, styles))
    els.append(sp(1))
    els.append(Paragraph("DKA Diagnostic Criteria", styles["h_sub"]))
    els.append(make_table(
        ["Parameter", "Mild", "Moderate", "Severe"],
        [
            ["Blood glucose", ">250 mg/dL", ">250 mg/dL", ">250 mg/dL"],
            ["Arterial pH", "7.25 – 7.30", "7.00 – 7.24", "<7.00"],
            ["Serum HCO₃", "15 – 18 mEq/L", "10 – 15 mEq/L", "<10 mEq/L"],
            ["Ketones (serum/urine)", "Positive", "Positive", "Positive"],
            ["Anion gap", ">10", ">12", ">12"],
        ],
        styles, [5*cm, 4*cm, 4*cm, 4*cm], header_color=C_RED
    ))
    els.append(sp(1))
    els.append(Paragraph("Biochemical Pathogenesis of DKA", styles["h_sub"]))
    for line in [
        "<b>1. No insulin → hyperglycaemia:</b> No GLUT4 translocation → glucose not taken up by muscle/fat → hyperglycaemia → osmotic diuresis → polyuria → dehydration",
        "<b>2. No insulin → ketogenesis:</b> Glucagon dominates → activates hormone-sensitive lipase → FFAs flood liver → β-oxidation → excess acetyl-CoA → ketone bodies → metabolic acidosis",
        "<b>3. No insulin → protein catabolism:</b> Muscle proteolysis → gluconeogenic amino acids → even more hyperglycaemia",
        "<b>Kussmaul breathing:</b> Respiratory compensation for metabolic acidosis — hyperventilation blows off CO₂ to raise blood pH",
        "<b>Fruity breath:</b> From acetone (spontaneous decarboxylation of acetoacetate) — acetone is volatile and exhaled",
        "<b>Pseudohyponatraemia:</b> High glucose is osmotically active → draws water into vascular space → dilutes sodium",
    ]:
        els.append(Paragraph(line, styles["bullet"]))
    els.append(sp(1))
    els.append(quote_box(
        "The clinical history of DKA typically involves deterioration during several hours to days, with "
        "progressive polyuria, polydipsia... physical findings include dry skin and mucous membranes, "
        "reduced jugular venous pressure, tachycardia, orthostatic hypotension, depressed mental "
        "function, and deep rapid respirations (Kussmaul breathing).",
        "Goldman-Cecil Medicine, International Ed."
    ))
    els.append(sp(2))

    # ── Case D2 ──────────────────────────────────────────────────────
    els.append(case_banner("Case D2 — Type 2 DM | Incidental Detection + Metabolic Syndrome", C_TEAL, styles))
    els.append(sp(1))
    els.append(info_box(
        "<b>Presenting Complaint:</b> 52-year-old obese man for routine check-up. Fatigue, nocturia. "
        "Hypertension on amlodipine. Father had diabetes. BMI 29, waist 98 cm. "
        "<b>Acanthosis nigricans</b> at neck and axillae (skin marker of insulin resistance).",
        C_LIGHT_TEAL, C_TEAL, styles))
    els.append(sp(1))
    els.append(make_table(
        ["Test", "Result", "Reference / Significance"],
        [
            ["Fasting plasma glucose (×2)", "148 mg/dL", "Diagnostic: ≥126 mg/dL"],
            ["2-hr OGTT (75g)", "230 mg/dL", "Diagnostic: ≥200 mg/dL"],
            ["HbA1c", "8.1%", "Diagnostic: ≥6.5%"],
            ["Fasting insulin", "Elevated", "Insulin resistance"],
            ["Urine microalbumin/creatinine", "38 mg/g", "Early nephropathy (>30 = microalbuminuria)"],
            ["TG / HDL", "290 / 32 mg/dL", "Dyslipidaemia — metabolic syndrome"],
        ],
        styles, [5.5*cm, 4*cm, 7.5*cm]
    ))
    els.append(sp(1))
    els.append(info_box(
        "<b>Diagnosis:</b> Type 2 DM with early diabetic nephropathy. Metabolic Syndrome "
        "(HTN + central obesity + dyslipidaemia + impaired glucose).",
        C_LIGHT_GREEN, C_GREEN, styles))
    els.append(sp(1))
    els.append(Paragraph("ADA Diagnostic Criteria for Diabetes (any one of the following):", styles["h_sub"]))
    for line in [
        "• FPG ≥126 mg/dL (7.0 mmol/L) on 2 occasions",
        "• 2-hr plasma glucose ≥200 mg/dL during 75g OGTT",
        "• HbA1c ≥6.5% (48 mmol/mol)",
        "• Random glucose ≥200 mg/dL with classic symptoms",
    ]:
        els.append(Paragraph(line, styles["bullet"]))
    els.append(sp(2))

    # ── Case D3 ──────────────────────────────────────────────────────
    els.append(case_banner("Case D3 — Hyperosmolar Hyperglycaemic State (HHS)", C_GOLD, styles))
    els.append(sp(1))
    els.append(info_box(
        "<b>Presenting Complaint:</b> 70-year-old man, known T2DM, brought in confused and lethargic. "
        "Poor oral intake + vomiting × 5 days (gastroenteritis). Missed medications × 3 days. "
        "GCS 11/15. Severe dehydration. No Kussmaul breathing, no fruity odour.",
        C_LIGHT_GOLD, C_GOLD, styles))
    els.append(sp(1))
    els.append(Paragraph("DKA vs HHS — Key Differences", styles["h_sub"]))
    els.append(make_table(
        ["Feature", "DKA", "HHS"],
        [
            ["Usual diabetes type", "Type 1 (also Type 2)", "Type 2"],
            ["Age", "Younger", "Older (>60 yrs)"],
            ["Blood glucose", "250–600 mg/dL", ">600 mg/dL (often >800)"],
            ["Ketones", "Marked (4+)", "Absent / trace"],
            ["Arterial pH", "<7.30", "Normal (>7.35)"],
            ["Serum HCO₃", "<18 mEq/L", "Normal (>18 mEq/L)"],
            ["Serum osmolality", "Variable / <320", ">320 mOsm/kg"],
            ["Onset", "Hours to days", "Days to weeks"],
            ["Kussmaul breathing", "Present", "Absent"],
            ["Mortality", "~1–5%", "~10–20%"],
        ],
        styles, [5*cm, 6*cm, 6*cm], header_color=C_GOLD
    ))
    els.append(sp(1))
    els.append(info_box(
        "<b>Why no ketosis in HHS?</b> In T2DM, residual insulin secretion is sufficient to suppress "
        "hormone-sensitive lipase and halt lipolysis/ketogenesis — but insufficient to prevent severe "
        "hyperglycaemia. In T1DM (DKA), absolute zero insulin → unrestrained lipolysis.",
        C_LIGHT_GOLD, C_GOLD, styles))
    els.append(sp(2))

    # ── Cases D4 and D5 (shorter) ────────────────────────────────────
    els.append(case_banner("Case D4 — Drug-induced Liver Injury (DILI) in a Diabetic Patient", C_PURPLE, styles))
    els.append(sp(1))
    els.append(info_box(
        "<b>Scenario:</b> 45-yr-old T2DM on metformin + statin, jaundice × 10 days after starting "
        "herbal supplement. No fever, normal USG (no ductal dilatation). Viral hepatitis screen: negative. "
        "ALT 960 U/L, Total Bilirubin 7.2 mg/dL, Direct 5.8, INR 1.9. HbA1c 9.8%.",
        C_LIGHT_PURPLE, C_PURPLE, styles))
    els.append(sp(1))
    for line in [
        "<b>Diagnosis:</b> Drug/herbal supplement-induced hepatocellular jaundice",
        "• Diabetics are at higher risk of NAFLD and hepatotoxicity — fatty liver as background",
        "• Hepatocellular pattern: ALT >> ALP; both conjugated and unconjugated bilirubin elevated",
        "• Impaired synthetic function: raised INR (reduced clotting factor synthesis)",
        "• Always take full drug/supplement history in any jaundice case",
        "• Poor HbA1c (9.8%) suggests chronic hyperglycaemia promoting hepatic steatosis",
    ]:
        els.append(Paragraph(line, styles["bullet"]))
    els.append(sp(2))

    els.append(case_banner("Case D5 — Metformin-associated Lactic Acidosis (MALA)", C_RED, styles))
    els.append(sp(1))
    els.append(info_box(
        "<b>Scenario:</b> 58-yr-old T2DM on metformin 2g/day + CKD (eGFR 28). Recent IV contrast CT. "
        "Presents: breathlessness, confusion, abdominal pain. "
        "ABG: pH 7.08, HCO₃ 8, Lactate 14 mmol/L. Glucose 180 mg/dL. <b>Ketones: absent.</b>",
        C_LIGHT_RED, C_RED, styles))
    els.append(sp(1))
    for line in [
        "<b>Diagnosis:</b> Metformin-associated Lactic Acidosis — HIGH ANION GAP metabolic acidosis",
        "<b>Mechanism:</b> Metformin inhibits mitochondrial Complex I (NADH dehydrogenase) → pyruvate cannot enter TCA → accumulates → converted to <b>lactate (anaerobic glycolysis)</b>",
        "• In renal failure, metformin accumulates (renally excreted) → toxicity worsens",
        "• Contrast-induced nephropathy further precipitates AKI → even less metformin clearance",
        "<b>Rule:</b> Metformin contraindicated when eGFR <30 mL/min; withhold before contrast procedures",
        "<b>Differentiates from DKA:</b> glucose only mildly elevated, NO ketones, very high lactate",
    ]:
        els.append(Paragraph(line, styles["bullet"]))

    els.append(PageBreak())
    return els


def section_1st_2nd_year(styles):
    els = []

    els.append(part_banner("PART 2 — 1st & 2nd Year MBBS: Biochemistry Deep Dives", C_TEAL, styles))
    els.append(sp(2))
    els.append(Paragraph(
        "Mechanism-focused cases linking biochemical pathways to clinical presentations. "
        "Ideal for 1st and 2nd year students preparing for theory examinations.",
        styles["body"]))
    els.append(sp(1))
    els.append(hr(C_TEAL, 1.5))

    # ────────────────────────────────────────────────────────────────
    # JAUNDICE BIOCHEMISTRY
    # ────────────────────────────────────────────────────────────────
    els.append(Paragraph("JAUNDICE — BIOCHEMISTRY", styles["h_section"]))

    # J1 Bilirubin pathway
    els.append(case_banner("J1 — The Complete Bilirubin Pathway (Gilbert's Syndrome as Model)", C_MED_BLUE, styles))
    els.append(sp(1))
    els.append(Paragraph("Step 1 — Bilirubin Formation (Reticuloendothelial System)", styles["h_sub"]))
    els.append(pathway_box([
        "Haemoglobin  →  [globin released + heme extracted]",
        "Heme (ferroprotoporphyrin IX)",
        "  ↓  heme oxygenase (microsomal, ER of macrophages in spleen/liver/BM)",
        "  ↓  → CO released (1 mol/mol heme)  +  Fe²⁺ released (recycled to transferrin)",
        "Biliverdin  (green pigment)",
        "  ↓  biliverdin reductase (cytosol)",
        "Bilirubin  (yellow-orange pigment)  ← water-INSOLUBLE",
    ]))
    els.append(sp(1))
    els.append(Paragraph(
        "80–85% of bilirubin comes from senescent RBC breakdown (RBC lifespan ~120 days). "
        "Remaining 15–20% from premature erythroid cell destruction in bone marrow and turnover "
        "of myoglobin, cytochromes.",
        styles["body"]))
    els.append(sp(1))
    els.append(quote_box(
        "The formation of bilirubin occurs in reticuloendothelial cells, primarily in the spleen and liver. "
        "The first reaction, catalyzed by the microsomal enzyme heme oxygenase, oxidatively cleaves the "
        "alpha bridge of the porphyrin group. The second reaction, catalyzed by biliverdin reductase, "
        "reduces the central methylene bridge of biliverdin and converts it to bilirubin.",
        "Harrison's Principles of Internal Medicine, 22nd Ed. (2025)"
    ))
    els.append(sp(1))

    els.append(Paragraph("Step 2 — Transport in Blood", styles["h_sub"]))
    for line in [
        "• Bilirubin is <b>water-insoluble</b> — internal hydrogen bonds between propionic acid groups and imino/lactam groups make it hydrophobic",
        "• Binds reversibly and non-covalently to <b>albumin</b> for transport → called <b>unconjugated (indirect) bilirubin</b>",
        "• Protein-bound → too large to be glomerularly filtered → <b>NEVER appears in normal urine</b>",
        "• Clinically: urine bilirubin ABSENT in prehepatic/unconjugated jaundice = 'acholuric jaundice'",
    ]:
        els.append(Paragraph(line, styles["bullet"]))
    els.append(sp(1))

    els.append(Paragraph("Step 3 — Hepatic Uptake and Conjugation", styles["h_sub"]))
    els.append(pathway_box([
        "Unconjugated bilirubin–albumin complex arrives at hepatocyte sinusoidal membrane",
        "  ↓  carrier-mediated uptake (OATP transporters) — bilirubin taken in, albumin stays in blood",
        "  ↓  intracellular binding to ligandin (glutathione-S-transferase) — prevents back-diffusion",
        "Smooth ER:  Bilirubin + UDP-glucuronic acid",
        "  ↓  UDP-glucuronosyltransferase (UGT1A1)  ← KEY ENZYME",
        "Bilirubin monoglucuronide  →  Bilirubin diglucuronide  (water-SOLUBLE)",
        "  ↓  MRP2 transporter (active, ATP-dependent) at canalicular membrane",
        "Secreted into bile canaliculi  →  bile ducts  →  duodenum",
    ]))
    els.append(sp(1))
    els.append(info_box(
        "<b>Gilbert's Syndrome:</b> TA-repeat polymorphism in UGT1A1 promoter → ~30% reduced UGT1A1 "
        "activity. Autosomal recessive. Fasting/stress → FFAs compete for albumin, displace bilirubin, "
        "flooding the already-reduced conjugation system. Result: mild unconjugated hyperbilirubinaemia "
        "during fasting/illness. Completely benign — no treatment. 4–7% population prevalence.",
        C_LIGHT_BLUE, C_MED_BLUE, styles))
    els.append(sp(1))

    els.append(Paragraph("Step 4 — Intestinal Fate and Van den Bergh Reaction", styles["h_sub"]))
    els.append(pathway_box([
        "Conjugated bilirubin in intestine",
        "  ↓  bacterial beta-glucuronidases (distal ileum/colon)",
        "Unconjugated bilirubin  →  gut bacterial reduction",
        "Urobilinogens (colourless tetrapyrroles)",
        "  ↓  oxidation in stool → STERCOBILIN  (brown stool colour)",
        "  ↓  10–20% reabsorbed → portal blood → liver → re-excreted (enterohepatic circulation)",
        "  ↓  small fraction → kidney → URINE UROBILINOGEN (normal ≤1 mg/dL)",
    ]))
    els.append(sp(1))
    els.append(Paragraph(
        "<b>Van den Bergh reaction</b> (still used in labs): Bilirubin + diazotized sulfanilic acid "
        "→ purple azopigment (absorbance at 540 nm). "
        "<b>Direct fraction</b> = reacts without accelerator = conjugated bilirubin. "
        "<b>Indirect fraction</b> = reacts after adding alcohol (breaks albumin bond) = unconjugated bilirubin. "
        "Normal total bilirubin: 0.2–1.0 mg/dL. Jaundice clinically visible at >3 mg/dL.",
        styles["body"]))
    els.append(sp(2))

    # J2 Neonatal jaundice
    els.append(case_banner("J2 — Physiological Neonatal Jaundice and Kernicterus", C_GOLD, styles))
    els.append(sp(1))
    els.append(info_box(
        "<b>Vignette:</b> 3-day-old full-term male, jaundice extending to chest (Kramer zone II–III). "
        "Total bilirubin 12 mg/dL, direct 0.4 mg/dL. DCT negative. Hb normal. Breastfeeding well.",
        C_LIGHT_GOLD, C_GOLD, styles))
    els.append(sp(1))
    els.append(Paragraph("Why Does Physiological Jaundice Occur?", styles["h_sub"]))
    els.append(make_table(
        ["Reason", "Explanation"],
        [
            ["High RBC breakdown", "Fetal RBCs have shorter lifespan (70–90 days). Massive bilirubin load postnatally"],
            ["Immature UGT1A1", "Neonatal UGT1A1 only ~1% of adult activity at birth. Reaches adult levels by 4–8 weeks"],
            ["High enterohepatic circulation", "High beta-glucuronidase in gut; sterile gut (no bacteria); slow motility → more reabsorption"],
            ["Low albumin", "Reduced binding capacity → more free unconjugated bilirubin circulates"],
        ],
        styles, [5*cm, 12*cm]
    ))
    els.append(sp(1))
    els.append(Paragraph("Kernicterus", styles["h_sub"]))
    for line in [
        "• Unconjugated bilirubin (lipophilic + unbound to albumin = 'free bilirubin') crosses the blood-brain barrier",
        "• Neonatal BBB is immature → especially vulnerable",
        "• Deposits in: <b>basal ganglia (globus pallidus)</b>, cochlear nuclei, cerebellum",
        "• Results in: opisthotonos, high-pitched cry, sensorineural hearing loss, choreoathetosis, intellectual disability",
        "<b>Phototherapy:</b> Blue light (420–480 nm) converts bilirubin to water-soluble photo-isomers (lumirubin) → excreted in bile/urine without conjugation",
    ]:
        els.append(Paragraph(line, styles["bullet"]))
    els.append(sp(1))
    els.append(Paragraph("Physiological vs Pathological Neonatal Jaundice", styles["h_sub"]))
    els.append(make_table(
        ["Feature", "Physiological", "Pathological"],
        [
            ["Onset", "Day 2–3", "Within 24 hours of birth"],
            ["Duration", "Resolves by day 7–10 (term)", "Persists >14 days"],
            ["Rate of rise", "<5 mg/dL/day", ">5 mg/dL/day"],
            ["Bilirubin type", "Unconjugated only", "Conjugated (always pathological)"],
            ["Common causes", "Normal physiology", "Haemolysis, infection, metabolic"],
        ],
        styles, [4*cm, 6.5*cm, 6.5*cm], header_color=C_GOLD
    ))
    els.append(sp(2))

    # J3 Obstructive biochemistry
    els.append(case_banner("J3 — Obstructive Jaundice: Why Pale Stools and Dark Urine?", C_TEAL, styles))
    els.append(sp(1))
    els.append(info_box(
        "<b>Vignette:</b> 40-year-old obese woman, Charcot's triad: RUQ pain + fever + jaundice. "
        "Cola urine, pale stools, intense pruritus. "
        "USG: gallstones, dilated CBD 12 mm, stone at CBD. Diagnosis: Choledocholithiasis.",
        C_LIGHT_TEAL, C_TEAL, styles))
    els.append(sp(1))
    els.append(pathway_box([
        "NORMAL:  Conjugated bilirubin → bile → intestine → urobilinogen → stercobilin → BROWN stool",
        "                                                      ↓ (enterhepatic)  → trace urobilinogen in urine",
        "",
        "OBSTRUCTION:",
        "  Conjugated bilirubin BLOCKED → backs up into bloodstream (high direct bilirubin)",
        "  Water-soluble → filtered by kidney → DARK URINE (bilirubinuria, +4)",
        "  No bile reaches gut → NO urobilinogen formed → ABSENT urine urobilinogen",
        "  No stercobilin → PALE / CLAY-COLOURED STOOLS",
    ]))
    els.append(sp(1))
    els.append(Paragraph("Why is ALP markedly elevated in obstruction?", styles["h_sub"]))
    els.append(Paragraph(
        "Back-pressure from bile induces synthesis of <b>alkaline phosphatase (ALP)</b> in cholangiocytes "
        "(bile duct epithelial cells). Bile acids also solubilize ALP from hepatocyte canalicular membranes. "
        "GGT rises by the same mechanism. Pattern: ALP ↑↑↑, GGT ↑↑↑, ALT/AST mildly elevated = "
        "<b>cholestatic (obstructive) pattern</b>.",
        styles["body"]))
    els.append(sp(1))
    els.append(Paragraph("Why is PT prolonged?", styles["h_sub"]))
    els.append(Paragraph(
        "Bile is required for absorption of <b>fat-soluble vitamins A, D, E, K</b>. "
        "Vitamin K activates (gamma-carboxylates) clotting factors <b>II, VII, IX, X</b> via carboxylase enzyme. "
        "Bile blockage → Vit K deficiency → prolonged PT. "
        "<b>Key test:</b> PT corrects with parenteral Vit K in obstructive jaundice but NOT in hepatocellular "
        "(liver too damaged to synthesise factors regardless of Vit K supply).",
        styles["body"]))
    els.append(sp(2))

    # ────────────────────────────────────────────────────────────────
    # DIABETES BIOCHEMISTRY
    # ────────────────────────────────────────────────────────────────
    els.append(hr(C_TEAL, 1.5))
    els.append(Paragraph("DIABETES — BIOCHEMISTRY", styles["h_section"]))

    # D1 Insulin biosynthesis
    els.append(case_banner("D1 — Insulin: From Gene to Secretory Granule", C_MED_BLUE, styles))
    els.append(sp(1))
    els.append(pathway_box([
        "Insulin gene  (short arm chromosome 11)",
        "  ↓  transcription → mRNA",
        "  ↓  translation on ribosomes → PREPROINSULIN (110 amino acids)",
        "    [contains: signal peptide + B chain + C peptide + A chain]",
        "  ↓  signal peptidase cleaves 24-aa leader in ER lumen",
        "PROINSULIN  (86 aa)  =  B + C + A  [linear chain; 3 disulfide bonds form]",
        "  ↓  packaged into secretory granules (trans-Golgi)",
        "  ↓  PC1/3 and PC2 proteases cleave at 2 sites",
        "INSULIN (51 aa: A-chain 21 aa + B-chain 30 aa)  +  C-PEPTIDE (31 aa)",
        "  ↓  stored in granule with Zinc",
        "  ↓  glucose stimulus → exocytosis → both secreted 1:1 into portal blood",
    ]))
    els.append(sp(1))
    els.append(make_table(
        ["Component", "Size", "Key Point"],
        [
            ["Preproinsulin", "110 amino acids", "Initial translation product; enters RER"],
            ["Proinsulin", "86 amino acids", "After signal peptide cleavage; folds in RER"],
            ["C-peptide", "31 amino acids", "Cleaved in Golgi; co-secreted 1:1 with insulin"],
            ["Insulin (mature)", "51 amino acids", "A-chain (21 aa) + B-chain (30 aa); 2 interchain + 1 intrachain disulfide bonds"],
        ],
        styles, [3.5*cm, 4*cm, 9.5*cm]
    ))
    els.append(sp(1))
    els.append(info_box(
        "<b>C-peptide clinical use:</b> Measures endogenous insulin secretion. "
        "Low C-peptide = Type 1 DM (beta cells destroyed). "
        "High insulin + low C-peptide = exogenous insulin injection. "
        "High insulin + high C-peptide = insulinoma (autonomous secretion).",
        C_LIGHT_BLUE, C_MED_BLUE, styles))
    els.append(sp(1))
    els.append(quote_box(
        "Insulin is initially synthesized as a single-chain 86-amino-acid precursor polypeptide, preproinsulin. "
        "Cleavage of an internal 31-residue fragment from proinsulin generates C-peptide with the A (21 amino "
        "acids) and B (30 amino acids) chains connected by disulfide bonds. The mature insulin molecule and "
        "C-peptide are stored together and co-secreted from secretory granules in the beta cells.",
        "Harrison's Principles of Internal Medicine, 22nd Ed. (2025)"
    ))
    els.append(sp(2))

    # D2 Beta cell secretion
    els.append(case_banner("D2 — Beta-cell Insulin Secretion: K_ATP Channel and Sulfonylureas", C_TEAL, styles))
    els.append(sp(1))
    els.append(pathway_box([
        "Glucose rises in blood post-meal",
        "  ↓  enters beta cell via GLUT2 (constitutive; not insulin-dependent)",
        "  ↓  GLUCOKINASE phosphorylates glucose → Glucose-6-phosphate  ← RATE-LIMITING STEP",
        "  ↓  glycolysis + oxidative phosphorylation → ATP generated (ATP:ADP ratio rises)",
        "  ↓  ATP-sensitive K⁺ channel (K_ATP) CLOSES",
        "  ↓  K⁺ cannot leave → membrane DEPOLARISES (–70 mV → 0 mV)",
        "  ↓  Voltage-gated Ca²⁺ channels OPEN",
        "  ↓  Ca²⁺ influx into beta cell",
        "  ↓  Secretory granules fuse with plasma membrane → EXOCYTOSIS",
        "  ↓  Insulin + C-peptide + proinsulin released into portal circulation",
    ]))
    els.append(sp(1))
    els.append(info_box(
        "<b>How do sulfonylureas work?</b> They bind directly to the <b>SUR1 subunit</b> of the K_ATP channel, "
        "keeping it closed regardless of glucose levels — mimicking ATP inhibition. This causes membrane "
        "depolarisation → Ca²⁺ influx → insulin release. "
        "Risk: hypoglycaemia even at normal blood glucose (unlike metformin).",
        C_LIGHT_TEAL, C_TEAL, styles))
    els.append(sp(1))
    els.append(Paragraph("Two-Phase Insulin Secretion", styles["h_sub"]))
    els.append(make_table(
        ["Phase", "Timing", "Source", "Lost in T2DM?"],
        [
            ["First phase (rapid spike)", "0–10 min", "Pre-formed granules already docked at membrane", "YES — lost early"],
            ["Second phase (sustained)", "10–60 min", "Newly synthesized + mobilized granules", "Partially preserved initially"],
        ],
        styles, [3.5*cm, 3*cm, 6*cm, 4.5*cm]
    ))
    els.append(sp(1))
    els.append(info_box(
        "<b>Key exam point:</b> Loss of first-phase insulin secretion is one of the earliest detectable "
        "abnormalities in Type 2 DM. It causes the post-meal glucose spike that eventually drives microvascular "
        "and macrovascular complications.",
        C_LIGHT_GOLD, C_GOLD, styles))
    els.append(sp(2))

    # D3 DKA biochemistry
    els.append(case_banner("D3 — DKA Biochemistry: Ketone Bodies, Anion Gap, Oxaloacetate Depletion", C_RED, styles))
    els.append(sp(1))
    els.append(Paragraph("Ketone Body Formation — Full Pathway", styles["h_sub"]))
    els.append(pathway_box([
        "No insulin → glucagon dominates → activates hormone-sensitive lipase (adipose)",
        "Triglycerides → Glycerol + Free Fatty Acids (FFAs)",
        "  ↓  FFAs enter liver",
        "  ↓  Carnitine acyltransferase I (CPTI) transports FAs into mitochondria",
        "  ↓  Beta-oxidation → massive Acetyl-CoA production",
        "",
        "WHY can't Acetyl-CoA enter TCA? → Oxaloacetate (OAA) is depleted!",
        "  (OAA is drained for gluconeogenesis via PEPCK → PEP)",
        "",
        "Acetyl-CoA overflow → KETOGENESIS:",
        "  2× Acetyl-CoA → Acetoacetyl-CoA",
        "  + Acetyl-CoA → HMG-CoA  [HMG-CoA synthase — mitochondrial]",
        "  HMG-CoA → Acetoacetate + Acetyl-CoA  [HMG-CoA lyase]",
        "  Acetoacetate → Beta-hydroxybutyrate  [NADH-dependent; beta-HB dehydrogenase]",
        "  Acetoacetate → Acetone + CO₂  [spontaneous decarboxylation → FRUITY BREATH]",
    ]))
    els.append(sp(1))
    els.append(info_box(
        "<b>Why can the liver make but not use ketones?</b> The liver lacks "
        "<b>3-ketoacid CoA transferase (thiophorase)</b> — the enzyme needed to convert acetoacetate back "
        "to acetoacetyl-CoA. So the liver makes ketones and ships them to muscle and brain (which have "
        "thiophorase) to use as fuel.",
        C_LIGHT_RED, C_RED, styles))
    els.append(sp(1))
    els.append(Paragraph("Anion Gap Calculation", styles["h_sub"]))
    els.append(Paragraph(
        "Anion Gap = Na⁺ − (Cl⁻ + HCO₃⁻)  |  Normal = 8–12 mEq/L",
        styles["body_bold"]))
    els.append(Paragraph(
        "In DKA: Ketoacids (acetoacetate + beta-hydroxybutyrate) are unmeasured anions → gap widens. "
        "Example: Na 130, Cl 96, HCO₃ 9 → AG = 130 − (96+9) = <b>25 mEq/L</b> (high). "
        "The 'missing' anions = ketoacids.",
        styles["body"]))
    els.append(sp(1))
    els.append(quote_box(
        "During prolonged starvation, or whenever carbohydrate metabolism is severely impaired as in "
        "untreated type 1 diabetes mellitus, the formation of acetyl-CoA exceeds the supply of oxaloacetate. "
        "The resulting excess acetyl-CoA is diverted to form acetoacetic acid, beta-hydroxybutyric acid, "
        "and acetone — three compounds known collectively as ketone bodies.",
        "Tietz Textbook of Laboratory Medicine, 7th Ed."
    ))
    els.append(sp(2))

    # D4 HbA1c
    els.append(case_banner("D4 — HbA1c: Glycation, Amadori Product, Clinical Interpretation", C_PURPLE, styles))
    els.append(sp(1))
    els.append(pathway_box([
        "Step 1 — Schiff Base (reversible, hours):",
        "  Glucose (aldehyde group) + NH₂-terminal valine of Hb beta chain",
        "  → Unstable Schiff base (aldimine)",
        "",
        "Step 2 — Amadori Rearrangement (irreversible):",
        "  Schiff base undergoes molecular rearrangement",
        "  → Stable ketoamine = HbA1c  ← persists for life of RBC",
    ]))
    els.append(sp(1))
    els.append(Paragraph(
        "Rate of HbA1c formation is directly proportional to ambient glucose concentration (mass-action). "
        "Reflects <b>weighted average blood glucose over 8–12 weeks</b> (recent weeks contribute more "
        "due to RBC age distribution). This is <b>non-enzymatic glycosylation (glycation)</b> — no enzyme involved.",
        styles["body"]))
    els.append(sp(1))
    els.append(make_table(
        ["HbA1c Value", "Interpretation", "Action"],
        [
            ["<5.7% (<39 mmol/mol)", "Normal", "No action"],
            ["5.7–6.4% (39–46 mmol/mol)", "Prediabetes (high risk)", "Lifestyle modification"],
            ["≥6.5% (≥48 mmol/mol)", "Diabetes mellitus", "Diagnostic + treat"],
            ["<7.0%", "Target for most T2DM patients", "Good control"],
            [">8.0%", "Poor glycaemic control", "Intensify therapy"],
        ],
        styles, [4.5*cm, 6.5*cm, 6*cm], header_color=C_PURPLE
    ))
    els.append(sp(1))
    els.append(Paragraph("Conditions Affecting HbA1c Accuracy", styles["h_sub"]))
    els.append(make_table(
        ["Falsely LOW HbA1c", "Falsely HIGH HbA1c"],
        [
            ["Haemolytic anaemia (RBCs destroyed early)", "Iron deficiency anaemia (older RBCs; more time for glycation)"],
            ["Recent blood transfusion (new donor RBCs)", "Asplenia (prolonged RBC lifespan)"],
            ["Pregnancy (increased RBC turnover)", "Renal failure (carbamylated Hb interferes)"],
            ["HbS, HbC variants (assay interference)", "Alcoholism"],
        ],
        styles, [8.5*cm, 8.5*cm], header_color=C_PURPLE
    ))

    els.append(PageBreak())
    return els


def section_quick_reference(styles):
    els = []

    els.append(part_banner("PART 3 — Quick Reference Tables (Exam Ready)", C_RED, styles))
    els.append(sp(2))

    # Jaundice comparison mega-table
    els.append(Paragraph("Jaundice — Master Comparison Table", styles["h_section"]))
    els.append(make_table(
        ["Feature", "Prehepatic", "Hepatocellular", "Posthepatic"],
        [
            ["Serum bilirubin", "Unconjugated (indirect) ↑↑", "Both ↑ (conjugated + unconjugated)", "Conjugated (direct) ↑↑"],
            ["Urine bilirubin", "ABSENT (acholuric)", "PRESENT (+1 to +3)", "PRESENT (+4)"],
            ["Urine urobilinogen", "↑↑↑ (excess production)", "Variable (↑ then ↓)", "ABSENT"],
            ["Stool colour", "Dark (excess stercobilin)", "Normal or pale", "Pale / clay-coloured"],
            ["ALT / AST", "Normal", "↑↑↑ (ALT > AST viral)", "Mildly elevated"],
            ["ALP / GGT", "Normal", "Mild ↑", "↑↑↑ (markedly)"],
            ["Serum albumin", "Normal", "Low in chronic disease", "Normal initially"],
            ["Prothrombin time", "Normal", "Prolonged (hepatocellular)", "Prolonged; corrects with Vit K"],
            ["Splenomegaly", "Common (haemolysis)", "May occur", "Absent usually"],
            ["Example causes", "Haemolysis, Gilbert's, G6PD", "Viral hepatitis, drugs, alcohol", "Gallstones, Ca pancreas, PSC"],
        ],
        styles, [4*cm, 4.3*cm, 4.3*cm, 4.4*cm]
    ))
    els.append(sp(2))

    # Bilirubin pathway enzyme table
    els.append(Paragraph("Bilirubin Pathway — Enzymes and Defects", styles["h_section"]))
    els.append(make_table(
        ["Step", "Enzyme", "Product", "Disease if Defective"],
        [
            ["Heme → Biliverdin", "Heme oxygenase", "Biliverdin + CO + Fe²⁺", "—"],
            ["Biliverdin → Bilirubin", "Biliverdin reductase", "Unconjugated bilirubin", "—"],
            ["Bilirubin → Glucuronide", "UGT1A1 (UDP-glucuronosyltransferase)", "Conjugated bilirubin", "Gilbert's (30% ↓), Crigler-Najjar (absent)"],
            ["Hepatocyte → Bile", "MRP2 transporter (ABCC2)", "Bilirubin excreted in bile", "Dubin-Johnson syndrome"],
            ["Gut deconjugation", "Bacterial beta-glucuronidase", "Urobilinogen", "—"],
        ],
        styles, [3.5*cm, 5*cm, 4.5*cm, 4*cm]
    ))
    els.append(sp(2))

    # Diabetes comparison
    els.append(Paragraph("Diabetes — Type 1 vs Type 2 vs DKA vs HHS", styles["h_section"]))
    els.append(make_table(
        ["Feature", "Type 1 DM", "Type 2 DM"],
        [
            ["Pathophysiology", "Autoimmune destruction of beta cells → absolute insulin deficiency", "Insulin resistance + relative beta cell failure"],
            ["Age of onset", "Usually <30 years (peak childhood)", "Usually >40 years (now increasingly younger)"],
            ["Body habitus", "Thin / normal BMI", "Obese (typically)"],
            ["Autoantibodies", "Anti-GAD, anti-IA2, anti-islet", "Absent"],
            ["C-peptide", "Very low / absent", "Normal or high initially"],
            ["Insulin needed", "Always (absolute requirement)", "May not require initially"],
            ["Acute complication", "Diabetic Ketoacidosis (DKA)", "Hyperosmolar Hyperglycaemic State (HHS)"],
            ["Ketosis", "Yes (no insulin → unrestrained lipolysis)", "No (residual insulin suppresses lipolysis)"],
            ["HLA association", "HLA-DR3, DR4", "Not HLA-associated"],
        ],
        styles, [4.5*cm, 6.3*cm, 6.2*cm]
    ))
    els.append(sp(2))

    # Insulin biosynthesis quick ref
    els.append(Paragraph("Insulin Biosynthesis — Quick Reference", styles["h_section"]))
    els.append(make_table(
        ["Fact", "Answer"],
        [
            ["Insulin gene chromosome", "Short arm of chromosome 11"],
            ["Initial translation product", "Preproinsulin (110 amino acids)"],
            ["After signal peptide cleavage", "Proinsulin (86 amino acids)"],
            ["Mature insulin size", "51 amino acids (A-chain 21 + B-chain 30)"],
            ["Number of disulfide bonds", "3 (2 interchain A-B + 1 intrachain in A chain)"],
            ["Co-secreted with insulin", "C-peptide (31 aa) in 1:1 molar ratio"],
            ["C-peptide clinical use", "Measures endogenous insulin secretion"],
            ["Beta cell glucose sensor enzyme", "Glucokinase (hexokinase IV)"],
            ["Channel closed by ATP in beta cell", "K_ATP channel (SUR1 + Kir6.2 subunits)"],
            ["Sulfonylurea binding site", "SUR1 subunit of K_ATP channel"],
            ["Insulin-dependent glucose transporter", "GLUT4 (in muscle and adipose)"],
            ["Constitutive glucose transporters", "GLUT1 (brain/RBC), GLUT2 (liver/beta cell), GLUT3 (neurons)"],
        ],
        styles, [7*cm, 10*cm]
    ))
    els.append(sp(2))

    # Ketone bodies table
    els.append(Paragraph("Ketone Bodies — Key Facts", styles["h_section"]))
    els.append(make_table(
        ["Ketone Body", "Formation", "Smell", "Detected By"],
        [
            ["Acetoacetate", "First formed — from HMG-CoA cleavage", "Slightly fruity", "Nitroprusside (Ketostix) — detects this"],
            ["Beta-hydroxybutyrate", "Reduction of acetoacetate (NADH-dependent)", "None", "NOT detected by Ketostix! Specific assay needed"],
            ["Acetone", "Spontaneous decarboxylation of acetoacetate", "Fruity / pear drops", "Exhaled in breath; Ketostix weakly positive"],
        ],
        styles, [4.5*cm, 5*cm, 3*cm, 4.5*cm]
    ))
    els.append(sp(1))
    els.append(info_box(
        "<b>Exam trap:</b> In severe DKA, beta-hydroxybutyrate may predominate over acetoacetate "
        "(because NADH is high, driving the equilibrium). Ketostix (nitroprusside) tests only detect "
        "acetoacetate — so severe DKA may appear 'ketone-negative' on dipstick. "
        "Always measure serum beta-hydroxybutyrate directly.",
        C_LIGHT_RED, C_RED, styles))
    els.append(sp(2))

    # HbA1c
    els.append(Paragraph("HbA1c — Diagnostic Reference", styles["h_section"]))
    els.append(make_table(
        ["HbA1c %", "mmol/mol", "Meaning", "Estimated Average Glucose (eAG)"],
        [
            ["<5.7%", "<39", "Normal", "<117 mg/dL"],
            ["5.7–6.4%", "39–46", "Prediabetes", "117–137 mg/dL"],
            ["6.5%", "48", "Diabetes (diagnostic cut-off)", "140 mg/dL"],
            ["7.0%", "53", "Target (most T2DM)", "154 mg/dL"],
            ["8.0%", "64", "Poor control — intensify", "183 mg/dL"],
            ["10.0%", "86", "Very poor control", "240 mg/dL"],
        ],
        styles, [3*cm, 3.5*cm, 5.5*cm, 5*cm]
    ))
    els.append(sp(1))
    els.append(Paragraph(
        "eAG formula: eAG (mg/dL) = (28.7 × HbA1c%) − 46.7",
        styles["body_bold"]))
    els.append(sp(2))

    # Sources footer
    els.append(hr(C_DARK_BLUE, 1))
    els.append(Paragraph("Primary Sources", styles["h_sub"]))
    sources = [
        "Harrison's Principles of Internal Medicine, 22nd Ed. (2025, McGraw-Hill) — Bilirubin metabolism, Insulin biosynthesis/secretion",
        "Goldman-Cecil Medicine, International Ed. — Jaundice diagnosis, DKA clinical features and management",
        "Schwartz's Principles of Surgery, 11th Ed. — Surgical jaundice, biliary obstruction",
        "Harper's Illustrated Biochemistry, 32nd Ed. — Liver function tests, aminotransferases",
        "Tietz Textbook of Laboratory Medicine, 7th Ed. — Ketogenesis, HbA1c, diabetes diagnosis",
        "Medical Physiology (Boron & Boulpaep) — Beta-cell physiology, insulin synthesis, GLUT transporters",
    ]
    for s in sources:
        els.append(Paragraph(f"• {s}", styles["source"]))

    return els


# ── Main build ────────────────────────────────────────────────────────────────
def build_pdf():
    os.makedirs(os.path.dirname(OUTPUT_PATH), exist_ok=True)

    doc = SimpleDocTemplate(
        OUTPUT_PATH,
        pagesize=A4,
        leftMargin=2*cm, rightMargin=2*cm,
        topMargin=2.2*cm, bottomMargin=2.2*cm,
        title="MBBS Clinical Cases Study Guide — Jaundice & Diabetes",
        author="Orris Medical Study Guide",
        subject="Biochemistry | Jaundice | Diabetes | MBBS",
    )

    styles = build_styles()

    story = []
    story += build_cover(styles)
    story += section_3rd_year(styles)
    story += section_1st_2nd_year(styles)
    story += section_quick_reference(styles)

    doc.build(story, onFirstPage=on_page, onLaterPages=on_page)
    print(f"PDF created: {OUTPUT_PATH}")

if __name__ == "__main__":
    build_pdf()