from reportlab.lib.pagesizes import A4
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.lib.units import cm, mm
from reportlab.lib.colors import HexColor, black, white
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.pdfgen import canvas
from reportlab.lib import colors

OUTPUT = "/home/daytona/workspace/jaundice-pathology/Jaundice_Pathology.pdf"

# ── Color palette ──────────────────────────────────────────────────────────────
DEEP_BLUE   = HexColor("#1A3A5C")
MID_BLUE    = HexColor("#2D6A9F")
LIGHT_BLUE  = HexColor("#D6E8F7")
ACCENT_GOLD = HexColor("#E8A020")
TABLE_HEAD  = HexColor("#1A3A5C")
TABLE_ALT   = HexColor("#EBF4FC")
SECTION_BG  = HexColor("#F0F7FF")
RED_ACCENT  = HexColor("#C0392B")
GREEN_ACCENT= HexColor("#1E8449")

# ── Page numbering canvas ──────────────────────────────────────────────────────
def on_page(canvas_obj, doc):
    canvas_obj.saveState()
    # Header bar
    canvas_obj.setFillColor(DEEP_BLUE)
    canvas_obj.rect(0, A4[1] - 1.2*cm, A4[0], 1.2*cm, fill=1, stroke=0)
    canvas_obj.setFillColor(white)
    canvas_obj.setFont("Helvetica-Bold", 9)
    canvas_obj.drawString(1.5*cm, A4[1] - 0.82*cm, "JAUNDICE — PATHOLOGY")
    canvas_obj.setFont("Helvetica", 8)
    canvas_obj.drawRightString(A4[0] - 1.5*cm, A4[1] - 0.82*cm,
                               "Robbins & Kumar | Harrison's | Pathophysiology")
    # Footer bar
    canvas_obj.setFillColor(DEEP_BLUE)
    canvas_obj.rect(0, 0, A4[0], 1.0*cm, fill=1, stroke=0)
    canvas_obj.setFillColor(white)
    canvas_obj.setFont("Helvetica", 8)
    canvas_obj.drawCentredString(A4[0]/2, 0.35*cm,
                                 f"Page {doc.page}")
    canvas_obj.restoreState()

# ── Styles ─────────────────────────────────────────────────────────────────────
styles = getSampleStyleSheet()

title_style = ParagraphStyle("TitleStyle",
    fontName="Helvetica-Bold", fontSize=28, textColor=white,
    alignment=TA_CENTER, spaceAfter=0, spaceBefore=0)

subtitle_style = ParagraphStyle("SubtitleStyle",
    fontName="Helvetica", fontSize=13, textColor=HexColor("#D6E8F7"),
    alignment=TA_CENTER, spaceAfter=0, spaceBefore=4)

h1 = ParagraphStyle("H1", fontName="Helvetica-Bold", fontSize=15,
    textColor=white, backColor=DEEP_BLUE, spaceBefore=14, spaceAfter=6,
    leftIndent=-12, rightIndent=-12, borderPadding=(6, 12, 6, 12),
    leading=20)

h2 = ParagraphStyle("H2", fontName="Helvetica-Bold", fontSize=12,
    textColor=DEEP_BLUE, spaceBefore=10, spaceAfter=4,
    borderPadding=(0,0,2,0), leading=16)

h3 = ParagraphStyle("H3", fontName="Helvetica-BoldOblique", fontSize=11,
    textColor=MID_BLUE, spaceBefore=8, spaceAfter=3, leading=14)

body = ParagraphStyle("Body", fontName="Helvetica", fontSize=10,
    leading=15, spaceAfter=5, alignment=TA_JUSTIFY, textColor=HexColor("#1C1C1C"))

bullet = ParagraphStyle("Bullet", fontName="Helvetica", fontSize=10,
    leading=14, spaceAfter=3, leftIndent=18, bulletIndent=6,
    alignment=TA_LEFT, textColor=HexColor("#1C1C1C"))

highlight_box = ParagraphStyle("HighlightBox", fontName="Helvetica", fontSize=10,
    leading=14, spaceAfter=4, leftIndent=10, rightIndent=10,
    backColor=SECTION_BG, borderPadding=(8,8,8,8),
    alignment=TA_JUSTIFY, textColor=HexColor("#1C1C1C"))

key_point = ParagraphStyle("KeyPoint", fontName="Helvetica-Bold", fontSize=10,
    leading=14, spaceAfter=4, leftIndent=10, rightIndent=10,
    backColor=HexColor("#FFF3E0"), borderPadding=(8,8,8,8),
    textColor=HexColor("#7D3C00"))

caption = ParagraphStyle("Caption", fontName="Helvetica-Oblique", fontSize=8.5,
    textColor=HexColor("#555555"), alignment=TA_CENTER, spaceAfter=6)

# ── Helper: section header flowable ───────────────────────────────────────────
def sec(text):
    return [Spacer(1, 0.3*cm),
            Paragraph(f"  {text}", h1),
            Spacer(1, 0.15*cm)]

def subsec(text):
    return [Spacer(1, 0.15*cm),
            Paragraph(text, h2),
            HRFlowable(width="100%", thickness=1, color=MID_BLUE, spaceAfter=4)]

def subsubsec(text):
    return [Paragraph(text, h3)]

def para(text):
    return Paragraph(text, body)

def bul(text):
    return Paragraph(f"• {text}", bullet)

def highlight(text):
    return Paragraph(text, highlight_box)

def keypoint(text):
    return Paragraph(f"KEY POINT: {text}", key_point)

def spacer(h=0.2):
    return Spacer(1, h*cm)

# ══════════════════════════════════════════════════════════════════════════════
# BUILD DOCUMENT
# ══════════════════════════════════════════════════════════════════════════════
story = []

# ── COVER PAGE ─────────────────────────────────────────────────────────────────
cover_data = [[Paragraph("JAUNDICE", title_style)],
              [Paragraph("Pathophysiology, Classification, Diagnosis & Management", subtitle_style)],
              [Spacer(1, 0.3*cm)],
              [Paragraph("Based on Robbins & Kumar Basic Pathology | Harrison's Principles of Internal Medicine 22E",
                         ParagraphStyle("src", fontName="Helvetica", fontSize=9,
                                        textColor=HexColor("#AED6F1"), alignment=TA_CENTER))]]

cover_table = Table(cover_data, colWidths=[17*cm])
cover_table.setStyle(TableStyle([
    ("BACKGROUND", (0,0), (-1,-1), DEEP_BLUE),
    ("ALIGN",      (0,0), (-1,-1), "CENTER"),
    ("TOPPADDING", (0,0), (-1,-1), 14),
    ("BOTTOMPADDING", (0,0), (-1,-1), 14),
    ("LEFTPADDING",  (0,0), (-1,-1), 20),
    ("RIGHTPADDING", (0,0), (-1,-1), 20),
    ("ROUNDEDCORNERS", [8]),
]))
story.append(Spacer(1, 3*cm))
story.append(cover_table)
story.append(Spacer(1, 1.0*cm))

# Gold accent band
accent_table = Table([[""]], colWidths=[17*cm], rowHeights=[0.5*cm])
accent_table.setStyle(TableStyle([
    ("BACKGROUND", (0,0), (-1,-1), ACCENT_GOLD),
    ("ROUNDEDCORNERS", [4]),
]))
story.append(accent_table)
story.append(Spacer(1, 0.5*cm))

# Quick stat boxes
stat_data = [
    [Paragraph("<b>Normal Bilirubin</b><br/>0.3 – 1.2 mg/dL", ParagraphStyle("s", fontName="Helvetica", fontSize=10, alignment=TA_CENTER, textColor=DEEP_BLUE)),
     Paragraph("<b>Jaundice Visible at</b><br/>&gt; 2 – 2.5 mg/dL", ParagraphStyle("s", fontName="Helvetica", fontSize=10, alignment=TA_CENTER, textColor=DEEP_BLUE)),
     Paragraph("<b>Severe Disease</b><br/>Up to 30 – 40 mg/dL", ParagraphStyle("s", fontName="Helvetica", fontSize=10, alignment=TA_CENTER, textColor=DEEP_BLUE)),
     Paragraph("<b>Neonatal Jaundice</b><br/>Matures ~2 weeks", ParagraphStyle("s", fontName="Helvetica", fontSize=10, alignment=TA_CENTER, textColor=DEEP_BLUE))]
]
stat_table = Table(stat_data, colWidths=[4.1*cm]*4)
stat_table.setStyle(TableStyle([
    ("BACKGROUND", (0,0), (-1,-1), LIGHT_BLUE),
    ("BOX",        (0,0), (-1,-1), 1, MID_BLUE),
    ("INNERGRID",  (0,0), (-1,-1), 0.5, MID_BLUE),
    ("TOPPADDING",    (0,0), (-1,-1), 10),
    ("BOTTOMPADDING", (0,0), (-1,-1), 10),
    ("LEFTPADDING",   (0,0), (-1,-1), 8),
    ("RIGHTPADDING",  (0,0), (-1,-1), 8),
    ("ROUNDEDCORNERS", [4]),
]))
story.append(stat_table)
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 1 – DEFINITION & OVERVIEW
# ══════════════════════════════════════════════════════════════════════════════
story += sec("1. DEFINITION AND OVERVIEW")
story.append(para(
    "Jaundice (icterus) is the yellow discoloration of skin, sclerae, and mucous membranes "
    "caused by accumulation of bilirubin in tissues. It becomes clinically apparent when "
    "serum bilirubin exceeds <b>2–2.5 mg/dL</b>. Levels as high as <b>30–40 mg/dL</b> can occur in "
    "severe hepatobiliary disease. Jaundice is not a disease itself but a sign of an underlying "
    "disorder affecting bilirubin production, transport, conjugation, or excretion."
))
story.append(keypoint(
    "Jaundice is visible when serum bilirubin > 2–2.5 mg/dL. Sclerae are the most sensitive "
    "site because of the high elastin content that binds bilirubin avidly."
))

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 2 – BILIRUBIN METABOLISM
# ══════════════════════════════════════════════════════════════════════════════
story += sec("2. BILIRUBIN METABOLISM")
story.append(para(
    "Understanding bilirubin metabolism is fundamental to classifying jaundice pathologically."
))

story += subsec("2.1 Production")
story.append(para(
    "Bilirubin is the end product of heme catabolism. Approximately <b>80–85%</b> is derived from "
    "hemoglobin released during destruction of senescent red blood cells in the reticuloendothelial "
    "system (spleen, liver, bone marrow). The remaining 15–20% comes from myoglobin, cytochromes, "
    "and ineffective erythropoiesis."
))
story.append(para(
    "The enzyme <b>heme oxygenase</b> oxidatively cleaves the alpha-methene bridge of the porphyrin "
    "ring, producing <b>biliverdin</b>, carbon monoxide, and free iron. Biliverdin reductase then "
    "reduces biliverdin to <b>bilirubin</b> (unconjugated / indirect bilirubin)."
))

story += subsec("2.2 Transport in Blood")
story.append(para(
    "Unconjugated bilirubin is <b>virtually insoluble in water</b> due to tight internal hydrogen "
    "bonding between its propionic acid carboxyl groups and the imino/lactam groups of the opposite "
    "dipyrrolic half. To circulate in blood it binds <b>non-covalently to albumin</b>. Because it is "
    "albumin-bound and insoluble, unconjugated bilirubin:"
))
story.append(bul("Cannot be filtered by the renal glomerulus"))
story.append(bul("Does NOT appear in urine (acholuria)"))
story.append(bul("Is not excreted in bile in its unconjugated form"))
story.append(spacer(0.15))

story += subsec("2.3 Hepatic Uptake and Conjugation")
story.append(para(
    "At the hepatocyte sinusoidal membrane, unconjugated bilirubin dissociates from albumin "
    "and is taken up via <b>carrier-mediated transport</b> (specific transporter not fully "
    "characterized). Inside the hepatocyte, it binds cytosolic proteins (glutathione-S-transferases / "
    "ligandin), which reduce back-diffusion into blood."
))
story.append(para(
    "In the smooth endoplasmic reticulum, <b>bilirubin UDP-glucuronosyltransferase (UDPGT)</b> "
    "conjugates bilirubin to glucuronic acid, yielding bilirubin <b>monoglucuronide</b> and "
    "<b>diglucuronide</b> (conjugated / direct bilirubin). Conjugation disrupts the internal "
    "hydrogen bonds, making bilirubin water-soluble and non-toxic."
))

story += subsec("2.4 Biliary Excretion")
story.append(para(
    "Conjugated bilirubin is actively transported across the canalicular membrane into bile by "
    "<b>MRP2 (multidrug resistance-associated protein 2)</b>. A small fraction is transported "
    "into sinusoids by MRP3 and recaptured by OATP1B1/1B3 transporters (enterohepatic recycling "
    "of conjugated bilirubin)."
))

story += subsec("2.5 Intestinal Processing and Urobilinogen")
story.append(para(
    "Conjugated bilirubin is <b>not reabsorbed in the proximal bowel</b> due to its hydrophilicity. "
    "In the distal ileum and colon, bacterial beta-glucuronidases hydrolyze it back to unconjugated "
    "bilirubin, which is then reduced to a group of colorless compounds called <b>urobilinogens</b>. "
    "About 80–90% of these are excreted in feces (oxidized to orange <b>urobilins</b>, which give "
    "stool its color). The remaining 10–20% undergoes enterohepatic cycling:"
))
story.append(bul("Re-absorbed from colon, circulated to liver, re-excreted in bile"))
story.append(bul("A small fraction (&lt;3 mg/dL) escapes hepatic re-uptake and is excreted in urine"))
story.append(spacer(0.2))

# Metabolism summary table
story.append(Spacer(1, 0.15*cm))
met_data = [
    ["Step", "Process", "Key Enzyme/Protein", "Location"],
    ["1", "Heme → Biliverdin", "Heme oxygenase", "RES (spleen/liver/marrow)"],
    ["2", "Biliverdin → Unconjugated Bilirubin", "Biliverdin reductase", "RES"],
    ["3", "Blood transport", "Albumin (non-covalent)", "Plasma"],
    ["4", "Hepatocyte uptake", "Carrier-mediated transport", "Hepatocyte sinusoidal membrane"],
    ["5", "Cytosolic binding", "Ligandin / GST", "Hepatocyte cytoplasm"],
    ["6", "Conjugation → Bilirubin glucuronide", "UDPGT", "Smooth ER"],
    ["7", "Biliary excretion", "MRP2", "Canalicular membrane"],
    ["8", "Gut reduction → Urobilinogen", "Bacterial beta-glucuronidase", "Colon"],
]
met_table = Table(met_data, colWidths=[1.0*cm, 5.0*cm, 5.5*cm, 5.5*cm])
met_table.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,0), TABLE_HEAD),
    ("TEXTCOLOR",     (0,0), (-1,0), white),
    ("FONTNAME",      (0,0), (-1,0), "Helvetica-Bold"),
    ("FONTSIZE",      (0,0), (-1,-1), 8.5),
    ("ROWBACKGROUNDS",(0,1), (-1,-1), [white, TABLE_ALT]),
    ("BOX",           (0,0), (-1,-1), 0.75, MID_BLUE),
    ("INNERGRID",     (0,0), (-1,-1), 0.4, HexColor("#AAAAAA")),
    ("TOPPADDING",    (0,0), (-1,-1), 5),
    ("BOTTOMPADDING", (0,0), (-1,-1), 5),
    ("LEFTPADDING",   (0,0), (-1,-1), 6),
    ("RIGHTPADDING",  (0,0), (-1,-1), 6),
    ("ALIGN",         (0,0), (-1,-1), "LEFT"),
    ("VALIGN",        (0,0), (-1,-1), "MIDDLE"),
]))
story.append(met_table)
story.append(Paragraph("Table 1: Steps in normal bilirubin metabolism", caption))
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 3 – CLASSIFICATION
# ══════════════════════════════════════════════════════════════════════════════
story += sec("3. CLASSIFICATION OF JAUNDICE")
story.append(para(
    "Jaundice is classified anatomically into three types based on the site of the defect in "
    "bilirubin metabolism. This classification guides diagnosis and management."
))

# Classification overview table
story.append(Spacer(1, 0.2*cm))
class_data = [
    ["Feature", "Pre-hepatic\n(Hemolytic)", "Hepatic\n(Hepatocellular)", "Post-hepatic\n(Obstructive/Cholestatic)"],
    ["Primary defect", "Excessive bilirubin production", "Defective uptake, conjugation, or excretion", "Bile duct obstruction"],
    ["Bilirubin type", "Unconjugated ↑↑", "Both types (↑ conjugated predominates in severe disease)", "Conjugated ↑↑"],
    ["Urine bilirubin", "Absent (acholuria)", "Present (bilirubinuria)", "Present (dark urine)"],
    ["Urine urobilinogen", "Increased", "Variable (↑ early; ↓ late in severe disease)", "Absent or very low"],
    ["Stool color", "Normal or dark", "Pale/light", "Pale/clay-colored"],
    ["Liver enzymes", "Normal", "AST/ALT markedly ↑", "ALP/GGT markedly ↑"],
    ["Bilirubin in urine", "No", "Yes (conjugated)", "Yes (conjugated)"],
    ["Pruritus", "Absent", "Variable", "Prominent (bile salts)"],
    ["Examples", "Hemolytic anemia, G6PD deficiency, spherocytosis, ineffective erythropoiesis", "Hepatitis, cirrhosis, drug-induced hepatitis, Gilbert, Crigler-Najjar, Dubin-Johnson", "Gallstones, pancreatic head cancer, cholangiocarcinoma, biliary stricture, PSC"],
]
class_table = Table(class_data, colWidths=[3.5*cm, 4.5*cm, 4.5*cm, 4.5*cm])
class_table.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,0), TABLE_HEAD),
    ("TEXTCOLOR",     (0,0), (-1,0), white),
    ("FONTNAME",      (0,0), (-1,0), "Helvetica-Bold"),
    ("FONTNAME",      (0,0), (0,-1), "Helvetica-Bold"),
    ("BACKGROUND",    (0,1), (0,-1), LIGHT_BLUE),
    ("FONTSIZE",      (0,0), (-1,-1), 8),
    ("ROWBACKGROUNDS",(0,1), (-1,-1), [white, TABLE_ALT]),
    ("BOX",           (0,0), (-1,-1), 0.75, DEEP_BLUE),
    ("INNERGRID",     (0,0), (-1,-1), 0.4, HexColor("#AAAAAA")),
    ("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), "TOP"),
]))
story.append(class_table)
story.append(Paragraph("Table 2: Comparison of the three types of jaundice", caption))
story.append(Spacer(1, 0.3*cm))

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 4 – PRE-HEPATIC JAUNDICE
# ══════════════════════════════════════════════════════════════════════════════
story += sec("4. PRE-HEPATIC JAUNDICE (HEMOLYTIC)")
story.append(para(
    "Pre-hepatic jaundice results from excessive production of bilirubin that overwhelms the "
    "liver's conjugating capacity, or from impaired hepatic uptake/conjugation."
))

story += subsec("4.1 Pathophysiology")
story.append(para(
    "In hemolytic disease, accelerated RBC destruction releases large amounts of heme, which is "
    "catabolized to unconjugated bilirubin. Although the liver upregulates UDPGT, the conjugating "
    "capacity is exceeded, leading to unconjugated hyperbilirubinemia. The excess unconjugated "
    "bilirubin drives more urobilinogen production in the gut, resulting in increased urinary and "
    "fecal urobilinogen."
))
story.append(keypoint(
    "In pre-hepatic jaundice the bilirubin CANNOT be excreted in urine (it is unconjugated and "
    "albumin-bound) — hence 'acholuric jaundice' despite elevated serum bilirubin."
))

story += subsec("4.2 Causes")
causes_pre = [
    ["Category", "Examples"],
    ["Inherited hemolytic", "Hereditary spherocytosis, G6PD deficiency, sickle cell disease, thalassemia, pyruvate kinase deficiency"],
    ["Acquired hemolytic", "Autoimmune hemolytic anemia (warm/cold), microangiopathic HA (TTP, HUS, DIC), malaria, paroxysmal nocturnal hemoglobinuria"],
    ["Ineffective erythropoiesis", "Iron deficiency, megaloblastic anemia, lead poisoning, thalassemia major"],
    ["Neonatal", "Physiologic jaundice, hemolytic disease of newborn (Rh/ABO incompatibility), G6PD deficiency"],
    ["Hereditary disorders of conjugation", "Gilbert syndrome (mild ↓ UDPGT), Crigler-Najjar type I (absent UDPGT — fatal), Crigler-Najjar type II (severely ↓ UDPGT)"],
]
causes_pre_table = Table(causes_pre, colWidths=[5*cm, 12*cm])
causes_pre_table.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,0), MID_BLUE),
    ("TEXTCOLOR",     (0,0), (-1,0), white),
    ("FONTNAME",      (0,0), (-1,0), "Helvetica-Bold"),
    ("FONTNAME",      (0,0), (0,-1), "Helvetica-Bold"),
    ("BACKGROUND",    (0,1), (0,-1), LIGHT_BLUE),
    ("FONTSIZE",      (0,0), (-1,-1), 8.5),
    ("ROWBACKGROUNDS",(0,1), (-1,-1), [white, TABLE_ALT]),
    ("BOX",           (0,0), (-1,-1), 0.75, MID_BLUE),
    ("INNERGRID",     (0,0), (-1,-1), 0.4, HexColor("#AAAAAA")),
    ("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), "TOP"),
]))
story.append(causes_pre_table)
story.append(Paragraph("Table 3: Causes of pre-hepatic jaundice", caption))

story += subsec("4.3 Hereditary Hyperbilirubinemias (Detailed)")
# Gilbert syndrome
story += subsubsec("Gilbert Syndrome")
story.append(para(
    "Common autosomal recessive condition affecting <b>4–16%</b> of various populations. Caused by a "
    "mutation in the promoter of the <b>UGT1A1</b> gene, leading to mildly decreased glucuronosyltransferase "
    "expression and mildly decreased hepatic conjugation. Manifests as fluctuating mild unconjugated "
    "hyperbilirubinemia, often precipitated by fasting, stress, or illness. <b>Benign — no morbidity.</b>"
))

story += subsubsec("Crigler-Najjar Syndrome")
story.append(para(
    "Caused by other mutations in <b>UGT1A1</b> that result in severe UDPGT deficiency. <b>Type I</b>: "
    "complete absence of enzyme — <b>fatal in infancy</b> without liver transplantation (phototherapy "
    "temporarily maintains safe bilirubin levels). <b>Type II (Arias syndrome)</b>: severely reduced "
    "but not absent UDPGT — less severe, responds to phenobarbital."
))

story += subsubsec("Dubin-Johnson Syndrome")
story.append(para(
    "Autosomal recessive disorder caused by defect in the <b>MRP2 canalicular transporter</b>, "
    "impairing hepatocellular excretion of conjugated bilirubin. Results in conjugated "
    "hyperbilirubinemia. Distinctive gross pathology: <b>dark-pigmented liver</b> (polymerized "
    "epinephrine metabolites, not bilirubin). <b>Clinically benign</b>."
))
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 5 – HEPATIC JAUNDICE
# ══════════════════════════════════════════════════════════════════════════════
story += sec("5. HEPATIC (HEPATOCELLULAR) JAUNDICE")
story.append(para(
    "Hepatocellular jaundice results from diffuse damage to hepatocytes, impairing their capacity "
    "to take up, conjugate, and/or excrete bilirubin. Both conjugated and unconjugated bilirubin "
    "may accumulate depending on the nature and severity of the injury."
))

story += subsec("5.1 Pathophysiology")
story.append(para(
    "Widespread hepatocyte necrosis or dysfunction disrupts one or more steps in bilirubin "
    "metabolism. Damaged hepatocytes may regurgitate conjugated bilirubin back into sinusoidal "
    "blood, causing conjugated hyperbilirubinemia and bilirubinuria. Impaired conjugation causes "
    "unconjugated accumulation. Canalicular damage and intrahepatic cholestasis may coexist. "
    "Both AST/ALT (hepatocyte damage) and ALP/GGT (cholestatic component) may be elevated."
))

story += subsec("5.2 Causes")
hep_causes = [
    ["Category", "Examples"],
    ["Viral hepatitis", "Hepatitis A, B, C, D, E; EBV hepatitis; CMV hepatitis"],
    ["Drug-induced liver injury (DILI)", "Predictable (dose-dependent): acetaminophen, methotrexate\nIdiosyncratic: isoniazid, halothane, statins, many others"],
    ["Toxic", "Amanita phalloides mushrooms, vinyl chloride, CCl4, kava"],
    ["Alcoholic liver disease", "Steatohepatitis → fibrosis → cirrhosis"],
    ["Autoimmune hepatitis", "Anti-smooth muscle Ab, ANA positive; elevated IgG"],
    ["Metabolic/hereditary", "Wilson's disease (↑ copper), hemochromatosis (↑ iron), alpha-1-antitrypsin deficiency"],
    ["Cirrhosis (end-stage)", "Any cause; impaired overall hepatocyte function"],
    ["Ischemic hepatitis", "Shock, cardiac failure, Budd-Chiari syndrome"],
]
hep_table = Table(hep_causes, colWidths=[5*cm, 12*cm])
hep_table.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,0), MID_BLUE),
    ("TEXTCOLOR",     (0,0), (-1,0), white),
    ("FONTNAME",      (0,0), (-1,0), "Helvetica-Bold"),
    ("FONTNAME",      (0,0), (0,-1), "Helvetica-Bold"),
    ("BACKGROUND",    (0,1), (0,-1), LIGHT_BLUE),
    ("FONTSIZE",      (0,0), (-1,-1), 8.5),
    ("ROWBACKGROUNDS",(0,1), (-1,-1), [white, TABLE_ALT]),
    ("BOX",           (0,0), (-1,-1), 0.75, MID_BLUE),
    ("INNERGRID",     (0,0), (-1,-1), 0.4, HexColor("#AAAAAA")),
    ("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), "TOP"),
]))
story.append(hep_table)
story.append(Paragraph("Table 4: Causes of hepatocellular jaundice", caption))
story.append(Spacer(1, 0.2*cm))

story += subsec("5.3 Morphology of Hepatocellular Injury")
story.append(para(
    "The morphologic features vary with the causative agent but common patterns include:"
))
story.append(bul("<b>Ballooning degeneration:</b> hepatocyte swelling due to inability to maintain ion pumps; "
    "cytoplasm becomes pale and rarefied"))
story.append(bul("<b>Apoptosis (acidophil bodies / Councilman bodies):</b> shrunken, eosinophilic hepatocytes "
    "with condensed nuclei, seen especially in viral hepatitis"))
story.append(bul("<b>Steatosis (fatty change):</b> large or small lipid vacuoles; prominent in alcoholic "
    "and metabolic liver disease"))
story.append(bul("<b>Mallory-Denk bodies:</b> eosinophilic intracytoplasmic inclusions of aggregated "
    "intermediate filaments (cytokeratin 8/18); classic for alcoholic hepatitis but also in NAFLD, "
    "Wilson's, primary biliary cirrhosis"))
story.append(bul("<b>Necrosis patterns:</b> spotty lobular necrosis (viral), centrilobular (zone 3) "
    "necrosis (ischemia/drug toxicity), bridging necrosis (severe hepatitis), massive necrosis "
    "(fulminant hepatic failure)"))
story.append(bul("<b>Lobular disarray:</b> loss of normal hepatic plate architecture due to diffuse "
    "hepatocyte dropout and regeneration"))
story.append(Spacer(1, 0.3*cm))

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 6 – POST-HEPATIC JAUNDICE / CHOLESTASIS
# ══════════════════════════════════════════════════════════════════════════════
story += sec("6. POST-HEPATIC JAUNDICE (CHOLESTASIS / OBSTRUCTIVE)")
story.append(PageBreak())
story.append(para(
    "Post-hepatic jaundice is caused by obstruction of bile flow at any level from the intrahepatic "
    "bile canaliculi to the ampulla of Vater. The hallmark is <b>conjugated hyperbilirubinemia</b> "
    "with elevated alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGT), "
    "because these enzymes are located on the apical (canalicular) membrane of hepatocytes and "
    "cholangiocytes."
))

story += subsec("6.1 Pathophysiology of Cholestasis")
story.append(highlight(
    "Cholestasis is defined as impaired bile flow, resulting in accumulation of bile constituents "
    "(bilirubin, bile salts, cholesterol) in blood and tissues. It may be extrahepatic "
    "(obstruction of major bile ducts) or intrahepatic (impairment of hepatocyte bile secretion "
    "or small duct disease). The distinction is clinically critical because extrahepatic obstruction "
    "is often surgically correctable, while intrahepatic cholestasis is not improved by surgery."
))
story.append(para(
    "Elevated serum bile salts are responsible for the characteristic <b>pruritus</b> of cholestasis. "
    "Malabsorption of fat-soluble vitamins (A, D, E, K) results from reduced bile entering the gut. "
    "Vitamin K deficiency leads to a coagulopathy that is reversible with parenteral vitamin K "
    "(distinguishing it from the coagulopathy of hepatocellular failure, which is not)."
))

story += subsec("6.2 Morphology of Cholestasis (Robbins Pathology)")
story.append(para(
    "The morphologic features of cholestasis depend on severity, duration, and cause. "
    "Characteristic findings include:"
))
story.append(bul("<b>Bile pigment accumulation:</b> elongated green-brown plugs of bile in dilated "
    "bile canaliculi — the most characteristic finding"))
story.append(bul("<b>Feathery degeneration of hepatocytes:</b> a fine, foamy cytoplasmic appearance "
    "as bile accumulates within hepatocytes"))
story.append(bul("<b>Kupffer cell bile pigment:</b> rupture of canaliculi leads to extravasation of "
    "bile, which is rapidly phagocytosed by Kupffer cells"))
story.append(bul("<b>Apoptotic hepatocytes:</b> occasional acidophilic bodies may be seen"))
story.append(bul("<b>Ductular reaction:</b> proliferation of reactive bile ductules at the "
    "portal-parenchymal interface in chronic or extrahepatic obstruction"))
story.append(bul("<b>Stromal edema and neutrophils:</b> hallmark of superimposed ascending cholangitis"))
story.append(Spacer(1, 0.15*cm))
story.append(para(
    "If obstruction is prolonged and uncorrected, periportal fibrosis develops, eventually producing "
    "<b>secondary (obstructive) biliary cirrhosis</b>. Periportal hepatocytes show extensive feathery "
    "degeneration, often with Mallory hyaline bodies, and bile infarcts form from the detergent "
    "effects of extravasated bile."
))

story += subsec("6.3 Causes of Post-Hepatic Jaundice")
post_causes = [
    ["Level", "Cause"],
    ["Common bile duct — stones", "Choledocholithiasis (most common cause in adults)"],
    ["Common bile duct — malignant", "Pancreatic head adenocarcinoma (classic painless jaundice), cholangiocarcinoma, ampullary carcinoma"],
    ["Common bile duct — benign stricture", "Post-cholecystectomy stricture, post-inflammatory stricture"],
    ["Biliary tree inflammation", "Primary sclerosing cholangitis (PSC), ascending cholangitis"],
    ["Pediatric causes", "Biliary atresia (most common surgical cause in neonates), choledochal cyst, Alagille syndrome (paucity of intrahepatic bile ducts), cystic fibrosis"],
    ["Extrinsic compression", "Lymphoma, metastatic lymph nodes, mirizzi syndrome"],
    ["Intrahepatic cholestasis", "Drug-induced (chlorpromazine, OCP), intrahepatic cholestasis of pregnancy, PBC, viral hepatitis cholestatic variant"],
]
post_table = Table(post_causes, colWidths=[5*cm, 12*cm])
post_table.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,0), MID_BLUE),
    ("TEXTCOLOR",     (0,0), (-1,0), white),
    ("FONTNAME",      (0,0), (-1,0), "Helvetica-Bold"),
    ("FONTNAME",      (0,0), (0,-1), "Helvetica-Bold"),
    ("BACKGROUND",    (0,1), (0,-1), LIGHT_BLUE),
    ("FONTSIZE",      (0,0), (-1,-1), 8.5),
    ("ROWBACKGROUNDS",(0,1), (-1,-1), [white, TABLE_ALT]),
    ("BOX",           (0,0), (-1,-1), 0.75, MID_BLUE),
    ("INNERGRID",     (0,0), (-1,-1), 0.4, HexColor("#AAAAAA")),
    ("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), "TOP"),
]))
story.append(post_table)
story.append(Paragraph("Table 5: Causes of post-hepatic (obstructive) jaundice", caption))
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 7 – NEONATAL JAUNDICE
# ══════════════════════════════════════════════════════════════════════════════
story += sec("7. NEONATAL JAUNDICE")
story.append(para(
    "Neonatal jaundice deserves special attention because of its frequency and the risk of "
    "neurologic damage (kernicterus) from unconjugated bilirubin toxicity in the immature brain."
))

story += subsec("7.1 Physiologic Jaundice of the Newborn")
story.append(para(
    "The hepatic machinery for conjugating and excreting bilirubin does not fully mature until "
    "approximately <b>2 weeks of age</b>. As a result, nearly every newborn develops transient, "
    "mild <b>unconjugated hyperbilirubinemia</b> — termed physiologic (neonatal) jaundice. This is "
    "compounded by:"
))
story.append(bul("High rate of fetal RBC destruction (higher hemoglobin turnover at birth)"))
story.append(bul("Immature hepatic UDPGT activity"))
story.append(bul("<b>Breastfeeding jaundice:</b> bilirubin-deconjugating enzymes present in breast milk "
    "can exacerbate hyperbilirubinemia (breast milk jaundice)"))
story.append(Spacer(0.1, 0.1*cm))
story.append(para(
    "<b>Treatment:</b> Phototherapy with blue light converts bilirubin to a water-soluble isomer "
    "that can be excreted in urine without conjugation, maintaining safe levels until hepatic "
    "maturation. Sustained jaundice beyond 2 weeks in a neonate is abnormal and requires workup."
))

story += subsec("7.2 Kernicterus")
story.append(highlight(
    "When serum unconjugated bilirubin exceeds the albumin-binding capacity, free (unbound) "
    "unconjugated bilirubin crosses the immature blood-brain barrier and is deposited in neurons "
    "of the basal ganglia, hippocampus, cerebellum, and brainstem nuclei, causing toxic injury. "
    "This condition — kernicterus (bilirubin encephalopathy) — can lead to cerebral palsy, "
    "sensorineural hearing loss, gaze palsy, and intellectual disability. It is the major "
    "complication of hemolytic disease of the newborn (erythroblastosis fetalis) due to "
    "Rh or ABO incompatibility."
))

story += subsec("7.3 Neonatal Cholestasis")
story.append(para(
    "Prolonged <b>conjugated</b> hyperbilirubinemia in the neonate (neonatal cholestasis) affects "
    "~1 in 2500 live births and is always pathological. Major causes:"
))
story.append(bul("<b>Biliary atresia:</b> fibro-inflammatory obliteration of the extrahepatic biliary tree; "
    "most common surgical cause; presents in first 2–8 weeks; requires Kasai portoenterostomy"))
story.append(bul("<b>Neonatal hepatitis:</b> heterogeneous group including alpha-1-antitrypsin deficiency, "
    "galactosemia, tyrosinemia, PFIC (progressive familial intrahepatic cholestasis), CMV, rubella, "
    "toxoplasma, syphilis, and idiopathic causes (&gt;10–15% of cases)"))
story.append(bul("<b>Alagille syndrome:</b> paucity of intrahepatic bile ducts (bile duct:portal tract ratio "
    "&lt;0.5); associated with JAG1/NOTCH2 mutations; butterfly vertebrae, peripheral pulmonic stenosis"))
story.append(Spacer(1, 0.3*cm))

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 8 – DIAGNOSTIC APPROACH
# ══════════════════════════════════════════════════════════════════════════════
story += sec("8. DIAGNOSTIC APPROACH TO JAUNDICE")

story += subsec("8.1 History and Physical Examination")
history_data = [
    ["Finding", "Suggests"],
    ["History of blood transfusion/IV drug use", "Viral hepatitis (B, C)"],
    ["Alcohol use disorder", "Alcoholic hepatitis, cirrhosis"],
    ["Recent medication changes", "Drug-induced liver injury (DILI)"],
    ["Fever + rigors + RUQ pain + jaundice (Charcot's triad)", "Ascending cholangitis"],
    ["Painless progressive jaundice in elderly", "Pancreatic head or cholangiocarcinoma"],
    ["Colicky RUQ pain + jaundice", "Choledocholithiasis"],
    ["Pruritus without pain", "Intrahepatic cholestasis, PBC, sclerosing cholangitis"],
    ["Pregnancy", "Intrahepatic cholestasis of pregnancy, HELLP syndrome, acute fatty liver"],
    ["Family history of jaundice", "Hereditary disorder (Gilbert, Wilson's, hemolytic anemia)"],
]
hist_table = Table(history_data, colWidths=[8*cm, 9*cm])
hist_table.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,0), TABLE_HEAD),
    ("TEXTCOLOR",     (0,0), (-1,0), white),
    ("FONTNAME",      (0,0), (-1,0), "Helvetica-Bold"),
    ("FONTSIZE",      (0,0), (-1,-1), 8.5),
    ("ROWBACKGROUNDS",(0,1), (-1,-1), [white, TABLE_ALT]),
    ("BOX",           (0,0), (-1,-1), 0.75, DEEP_BLUE),
    ("INNERGRID",     (0,0), (-1,-1), 0.4, HexColor("#AAAAAA")),
    ("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), "TOP"),
]))
story.append(hist_table)
story.append(Paragraph("Table 6: Clinically relevant history findings in jaundice", caption))

story += subsec("8.2 Laboratory Investigations")
story.append(para(
    "Initial blood work should include serum bilirubin fractionation (direct/conjugated vs. "
    "indirect/unconjugated), liver function tests, and a complete blood count."
))
lab_data = [
    ["Test", "Pre-hepatic", "Hepatocellular", "Cholestatic"],
    ["Total bilirubin", "↑ (mild–moderate)", "↑↑↑", "↑↑↑"],
    ["Direct bilirubin", "Normal or minimal ↑", "↑↑ (predominates late)", "↑↑↑"],
    ["Indirect bilirubin", "↑↑ (predominates)", "↑↑ (early)", "Normal / mild ↑"],
    ["AST / ALT", "Normal", "↑↑↑ (>1000 U/L in acute viral)", "Normal or mildly ↑"],
    ["ALP / GGT", "Normal", "Normal or mildly ↑", "↑↑↑ (ALP >3x ULN)"],
    ["PT/INR", "Normal", "↑ (hepatic failure)", "↑ (corrects with vit K)"],
    ["Albumin", "Normal", "↓ (chronic disease)", "Normal"],
    ["CBC", "Anemia ± reticulocytosis, spherocytes", "May be normal", "Normal"],
    ["Peripheral smear", "Spherocytes, schistocytes, sickle cells", "Normal or hypersplenism changes", "Normal"],
    ["Urine bilirubin", "Absent", "Present", "Present"],
    ["Urine urobilinogen", "↑↑", "Variable", "↓ or absent"],
    ["Haptoglobin", "↓ or absent", "Normal", "Normal"],
    ["LDH", "↑", "↑ (hepatic necrosis)", "Normal"],
]
lab_table = Table(lab_data, colWidths=[3.5*cm, 4.5*cm, 4.5*cm, 4.5*cm])
lab_table.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,0), TABLE_HEAD),
    ("TEXTCOLOR",     (0,0), (-1,0), white),
    ("FONTNAME",      (0,0), (-1,0), "Helvetica-Bold"),
    ("FONTNAME",      (0,0), (0,-1), "Helvetica-Bold"),
    ("BACKGROUND",    (0,1), (0,-1), LIGHT_BLUE),
    ("FONTSIZE",      (0,0), (-1,-1), 8),
    ("ROWBACKGROUNDS",(0,1), (-1,-1), [white, TABLE_ALT]),
    ("BOX",           (0,0), (-1,-1), 0.75, DEEP_BLUE),
    ("INNERGRID",     (0,0), (-1,-1), 0.4, HexColor("#AAAAAA")),
    ("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), "TOP"),
]))
story.append(lab_table)
story.append(Paragraph("Table 7: Laboratory differentiation of jaundice types", caption))
story.append(PageBreak())

story += subsec("8.3 Diagnostic Algorithm (Harrison's Framework)")
story.append(para(
    "The following stepwise approach is recommended for evaluating jaundice "
    "(based on Harrison's Principles of Internal Medicine 22E):"
))
algo_steps = [
    ("Step 1", "Determine if bilirubin elevation is ISOLATED or associated with other liver test abnormalities"),
    ("Step 2", "Fractionate bilirubin: is it predominantly UNCONJUGATED or CONJUGATED?"),
    ("Step 3", "If unconjugated: is there hemolysis (CBC, reticulocytes, haptoglobin, LDH, peripheral smear) or a hereditary conjugation defect (Gilbert, Crigler-Najjar)?"),
    ("Step 4", "If conjugated + other LFT abnormalities: is the pattern HEPATOCELLULAR (↑AST/ALT) or CHOLESTATIC (↑ALP/GGT)?"),
    ("Step 5 — Cholestatic", "Perform ULTRASOUND first to detect biliary dilation. Dilation = extrahepatic obstruction; no dilation = intrahepatic cholestasis"),
    ("Step 6 — Extrahepatic", "Further imaging: CT, MRCP, ERCP (gold standard for choledocholithiasis), EUS, or PTC"),
    ("Step 7 — Intrahepatic", "Serologic tests: viral hepatitis panel, ANA, ASMA, AMA (for PBC), ceruloplasmin (Wilson's), ferritin/transferrin saturation (hemochromatosis), IgG4 (autoimmune)"),
    ("Step 8", "Liver biopsy when diagnosis remains uncertain after non-invasive workup"),
]
for step, desc in algo_steps:
    algo_row_data = [[Paragraph(f"<b>{step}</b>", ParagraphStyle("s1", fontName="Helvetica-Bold", fontSize=9, textColor=white)),
                      Paragraph(desc, ParagraphStyle("s2", fontName="Helvetica", fontSize=9, textColor=HexColor("#1C1C1C")))]]
    bg = DEEP_BLUE if "Step 1" in step or "Step 2" in step else MID_BLUE if "Step 3" in step or "Step 4" in step else HexColor("#4A90D9")
    algo_row = Table(algo_row_data, colWidths=[3*cm, 14*cm])
    algo_row.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (0,0), bg),
        ("BACKGROUND", (1,0), (1,0), SECTION_BG),
        ("BOX", (0,0), (-1,-1), 0.5, MID_BLUE),
        ("TOPPADDING", (0,0), (-1,-1), 6),
        ("BOTTOMPADDING", (0,0), (-1,-1), 6),
        ("LEFTPADDING", (0,0), (-1,-1), 8),
        ("VALIGN", (0,0), (-1,-1), "MIDDLE"),
    ]))
    story.append(algo_row)
    story.append(Spacer(1, 0.1*cm))

story.append(Spacer(1, 0.3*cm))

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 9 – IMAGING
# ══════════════════════════════════════════════════════════════════════════════
story += sec("9. IMAGING IN JAUNDICE")
story.append(para(
    "Imaging is essential to distinguish extrahepatic from intrahepatic cholestasis and to "
    "identify the cause and level of obstruction."
))
imaging_data = [
    ["Modality", "Role", "Key Advantages / Notes"],
    ["Ultrasound (USG)", "First-line imaging in all jaundiced patients", "Cheap, no radiation, detects biliary dilation with high sensitivity; poor visualization of distal CBD due to bowel gas"],
    ["CT abdomen", "Second-line; characterize mass, level of obstruction", "Better for pancreatic head, lymph nodes; shows level of obstruction well"],
    ["MRCP", "Non-invasive cholangiogram; replaced ERCP as initial test in most cases", "Excellent for visualizing bile ducts, stones, strictures, without radiation or contrast injection"],
    ["ERCP", "Gold standard for choledocholithiasis; also therapeutic", "Allows stone extraction, stent placement; invasive; risk of post-ERCP pancreatitis"],
    ["EUS", "Detection of distal CBD stones; allows FNA of masses", "Sensitivity comparable to MRCP for CBD obstruction; invasive but lower risk than ERCP"],
    ["PTC", "When ERCP fails (altered anatomy)", "Allows biliary drainage and stent placement percutaneously"],
    ["Liver biopsy", "Intrahepatic cholestasis with uncertain diagnosis", "Defines histologic pattern: hepatitis, PBC, PSC, DILI, hereditary disorders"],
]
img_table = Table(imaging_data, colWidths=[3.2*cm, 5.5*cm, 8.3*cm])
img_table.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,0), TABLE_HEAD),
    ("TEXTCOLOR",     (0,0), (-1,0), white),
    ("FONTNAME",      (0,0), (-1,0), "Helvetica-Bold"),
    ("FONTNAME",      (0,0), (0,-1), "Helvetica-Bold"),
    ("BACKGROUND",    (0,1), (0,-1), LIGHT_BLUE),
    ("FONTSIZE",      (0,0), (-1,-1), 8.5),
    ("ROWBACKGROUNDS",(0,1), (-1,-1), [white, TABLE_ALT]),
    ("BOX",           (0,0), (-1,-1), 0.75, DEEP_BLUE),
    ("INNERGRID",     (0,0), (-1,-1), 0.4, HexColor("#AAAAAA")),
    ("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), "TOP"),
]))
story.append(imaging_data and img_table)
story.append(Paragraph("Table 8: Imaging modalities in jaundice", caption))
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 10 – COMPLICATIONS
# ══════════════════════════════════════════════════════════════════════════════
story += sec("10. COMPLICATIONS OF JAUNDICE")

story += subsec("10.1 Complications of Unconjugated Hyperbilirubinemia")
story.append(bul("<b>Kernicterus (Bilirubin Encephalopathy):</b> unconjugated bilirubin crosses the "
    "blood-brain barrier in neonates (and in adults with severely impaired BBB), depositing in "
    "basal ganglia and brainstem nuclei, causing permanent neurologic damage — cerebral palsy, "
    "sensorineural deafness, gaze palsies"))
story.append(bul("<b>Renal tubular effects:</b> unbound unconjugated bilirubin may be directly toxic "
    "to renal tubular cells in hemolytic crises"))

story += subsec("10.2 Complications of Conjugated Hyperbilirubinemia / Cholestasis")
story.append(bul("<b>Pruritus:</b> bile salts deposited in skin cause severe, debilitating itching"))
story.append(bul("<b>Fat-soluble vitamin deficiencies:</b> reduced intraluminal bile acids impair "
    "absorption of vitamins A (night blindness), D (metabolic bone disease / osteoporosis), "
    "E (neuropathy), and K (coagulopathy)"))
story.append(bul("<b>Steatorrhea:</b> malabsorption of dietary fat due to reduced bile acid pool"))
story.append(bul("<b>Skin xanthomas:</b> focal deposition of cholesterol in skin from hypercholesterolemia "
    "(cholesterol excretion impaired)"))
story.append(bul("<b>Secondary biliary cirrhosis:</b> prolonged extrahepatic obstruction leads to "
    "periportal fibrosis → bridging fibrosis → cirrhosis"))
story.append(bul("<b>Ascending cholangitis (Charcot's triad / Reynolds pentad):</b> bacterial infection "
    "of bile (E. coli, Klebsiella, Enterococcus) — fever, RUQ pain, jaundice; if septic shock "
    "and confusion (Reynolds pentad) → medical emergency"))
story.append(bul("<b>Acute renal failure:</b> bile salts can cause renal vasoconstriction and direct "
    "tubular toxicity (hepatorenal syndrome in cirrhotic patients)"))
story.append(Spacer(1, 0.3*cm))

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 11 – TREATMENT OVERVIEW
# ══════════════════════════════════════════════════════════════════════════════
story += sec("11. PRINCIPLES OF MANAGEMENT")
story.append(para(
    "Treatment of jaundice is directed at the underlying cause rather than the jaundice itself."
))
mgmt_data = [
    ["Type of Jaundice", "Management Principles"],
    ["Hemolytic (pre-hepatic)", "Treat underlying hemolytic disorder; folic acid supplementation; transfusion if severe; exchange transfusion for severe neonatal jaundice; phototherapy for neonatal unconjugated jaundice"],
    ["Gilbert syndrome", "No treatment needed; reassurance"],
    ["Crigler-Najjar type I", "Phototherapy 10–12 hr/day; liver transplantation is curative"],
    ["Crigler-Najjar type II", "Phenobarbital (induces residual UDPGT); phototherapy"],
    ["Viral hepatitis", "Supportive; antivirals for HBV/HCV; avoid hepatotoxins; liver transplant for fulminant failure"],
    ["Drug-induced", "Stop offending drug; N-acetylcysteine for acetaminophen toxicity; supportive care"],
    ["Alcoholic hepatitis", "Alcohol abstinence; steroids (prednisolone) for severe disease (Maddrey Discriminant Function >32); pentoxifylline as alternative"],
    ["Autoimmune hepatitis", "Prednisolone ± azathioprine"],
    ["Wilson's disease", "D-penicillamine or trientine; zinc to reduce absorption; liver transplant for fulminant failure"],
    ["Choledocholithiasis (obstructive)", "ERCP with sphincterotomy and stone extraction; cholecystectomy"],
    ["Malignant obstruction", "Biliary stenting (ERCP/PTC); surgical resection if operable; palliative drainage"],
    ["Biliary atresia (neonate)", "Kasai portoenterostomy; liver transplantation"],
    ["Primary Biliary Cholangitis (PBC)", "Ursodeoxycholic acid (UDCA); obeticholic acid for incomplete responders"],
    ["Primary Sclerosing Cholangitis (PSC)", "UDCA (controversial); endoscopic dilation of dominant strictures; liver transplantation"],
    ["Cholestasis — pruritus", "Cholestyramine (bile acid sequestrant), rifampicin, naltrexone, sertraline"],
]
mgmt_table = Table(mgmt_data, colWidths=[5*cm, 12*cm])
mgmt_table.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,0), TABLE_HEAD),
    ("TEXTCOLOR",     (0,0), (-1,0), white),
    ("FONTNAME",      (0,0), (-1,0), "Helvetica-Bold"),
    ("FONTNAME",      (0,0), (0,-1), "Helvetica-Bold"),
    ("BACKGROUND",    (0,1), (0,-1), LIGHT_BLUE),
    ("FONTSIZE",      (0,0), (-1,-1), 8.5),
    ("ROWBACKGROUNDS",(0,1), (-1,-1), [white, TABLE_ALT]),
    ("BOX",           (0,0), (-1,-1), 0.75, DEEP_BLUE),
    ("INNERGRID",     (0,0), (-1,-1), 0.4, HexColor("#AAAAAA")),
    ("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), "TOP"),
]))
story.append(mgmt_table)
story.append(Paragraph("Table 9: Management principles by type of jaundice", caption))
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 12 – QUICK REVISION SUMMARY
# ══════════════════════════════════════════════════════════════════════════════
story += sec("12. QUICK REVISION SUMMARY")

story.append(Spacer(1, 0.2*cm))

# Mnemonics / key facts
key_facts = [
    ("Bilirubin Normal", "0.3 – 1.2 mg/dL total; &lt;0.3 mg/dL direct"),
    ("Jaundice visible", "&gt; 2 – 2.5 mg/dL"),
    ("Conjugated bilirubin", "Water-soluble, excreted in urine → bilirubinuria → dark urine"),
    ("Unconjugated bilirubin", "Water-insoluble, albumin-bound, NOT in urine → acholuric jaundice"),
    ("Pre-hepatic marker", "↑ Indirect bilirubin, ↑ LDH, ↓ haptoglobin, ↑ urobilinogen, normal ALP/ALT"),
    ("Hepatic marker", "↑↑ AST/ALT ('hepatocellular enzymes'), both fractions elevated"),
    ("Post-hepatic marker", "↑↑ ALP + GGT + Direct bilirubin; pale stool, dark urine, pruritus"),
    ("Charcot's triad", "Fever + RUQ pain + Jaundice = Ascending cholangitis"),
    ("Reynolds pentad", "Charcot's triad + Shock + Confusion = Suppurative cholangitis (emergency)"),
    ("Painless jaundice", "Pancreatic head malignancy until proven otherwise (Courvoisier's sign)"),
    ("Kernicterus risk", "Unconjugated bilirubin > albumin-binding capacity → free bilirubin → brain damage"),
    ("Courvoisier's law", "Painless jaundice + palpable non-tender gallbladder → malignant obstruction"),
    ("Gilbert syndrome", "Most common hereditary hyperbilirubinemia; ↓ UGT1A1 promoter; benign; exacerbated by fasting"),
    ("Dubin-Johnson", "Dark liver (pigmented) + conjugated hyperbilirubinemia; ↓ MRP2; benign"),
    ("Feathery degeneration", "Hepatocyte cytoplasmic swelling with bile pigment in cholestasis — pathognomonic morphology"),
    ("1st line imaging", "Ultrasound for all patients with jaundice"),
]

for term, fact in key_facts:
    fact_row = Table([[Paragraph(f"<b>{term}</b>", ParagraphStyle("t1", fontName="Helvetica-Bold", fontSize=9, textColor=DEEP_BLUE)),
                       Paragraph(fact, ParagraphStyle("t2", fontName="Helvetica", fontSize=9, textColor=HexColor("#1C1C1C")))
                      ]], colWidths=[5*cm, 12*cm])
    fact_row.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (0,0), LIGHT_BLUE),
        ("BACKGROUND", (1,0), (1,0), white),
        ("BOX", (0,0), (-1,-1), 0.4, MID_BLUE),
        ("TOPPADDING",    (0,0), (-1,-1), 5),
        ("BOTTOMPADDING", (0,0), (-1,-1), 5),
        ("LEFTPADDING",   (0,0), (-1,-1), 8),
        ("VALIGN", (0,0), (-1,-1), "MIDDLE"),
    ]))
    story.append(fact_row)
    story.append(Spacer(1, 0.05*cm))

story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# REFERENCES
# ══════════════════════════════════════════════════════════════════════════════
story += sec("REFERENCES")
refs = [
    "Kumar V, Abbas AK, Aster JC. Robbins & Kumar Basic Pathology, 11th Edition. Elsevier; 2023. "
    "Chapter 14: Liver and Biliary Tract — Pathophysiology of Jaundice, pp. 619–621.",
    "Loscalzo J, Fauci A, Kasper D, et al. Harrison's Principles of Internal Medicine, 22nd Edition. "
    "McGraw-Hill; 2025. Chapter 52: Jaundice, Evaluation of the Patient with Jaundice, pp. 364–370.",
    "Sleisenger MH, Fordtran JS. Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, "
    "Management. 11th Edition. Elsevier; 2021.",
    "Yamada T. Yamada's Textbook of Gastroenterology, 7th Edition. Wiley-Blackwell; 2022. "
    "Chapter: Cholestatic Liver Injury and Hyperbilirubinemia.",
    "Goldman L, Cooney KA. Goldman-Cecil Medicine, 27th Edition (International Edition). "
    "Elsevier; 2024.",
]
for i, ref in enumerate(refs, 1):
    story.append(Paragraph(f"{i}. {ref}", ParagraphStyle("ref", fontName="Helvetica", fontSize=9,
        leading=13, spaceAfter=5, leftIndent=15, firstLineIndent=-15, textColor=HexColor("#1C1C1C"))))

# ── BUILD PDF ─────────────────────────────────────────────────────────────────
doc = SimpleDocTemplate(
    OUTPUT,
    pagesize=A4,
    topMargin=1.6*cm,
    bottomMargin=1.4*cm,
    leftMargin=1.5*cm,
    rightMargin=1.5*cm,
    title="Jaundice — Pathology",
    author="Orris Medical Library",
    subject="Pathology of Jaundice",
)

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