Predictive Markers of Liver Function

"""
Clinical Reference Guide: Liver Function Tests
Builds a professional multi-page PDF using ReportLab.
"""

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

OUTPUT = "/tmp/workspace/lft-reference/LFT_Clinical_Reference_Guide.pdf"

# ─── Colour palette ───────────────────────────────────────────────────────────
NAVY       = colors.HexColor("#1B3A6B")
TEAL       = colors.HexColor("#0F7173")
LIGHT_TEAL = colors.HexColor("#D6EFEF")
AMBER      = colors.HexColor("#E87722")
LIGHT_AMBER= colors.HexColor("#FFF3E0")
GREY_LIGHT = colors.HexColor("#F4F6F9")
GREY_MID   = colors.HexColor("#CDD5E0")
WHITE      = colors.white
RED_LIGHT  = colors.HexColor("#FDECEA")
RED        = colors.HexColor("#C0392B")
GREEN_LIGHT= colors.HexColor("#E8F5E9")
GREEN      = colors.HexColor("#1B6B2F")

# ─── Document setup ───────────────────────────────────────────────────────────
doc = SimpleDocTemplate(
    OUTPUT,
    pagesize=A4,
    leftMargin=1.8*cm, rightMargin=1.8*cm,
    topMargin=2.0*cm, bottomMargin=2.0*cm,
    title="Liver Function Tests – Clinical Reference Guide",
    author="Orris Clinical Reference",
    subject="Hepatology / Biochemistry",
)

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

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

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

sTitle = ps("sTitle", "Title",
    fontSize=26, textColor=WHITE, leading=32,
    spaceAfter=4, alignment=TA_CENTER, fontName="Helvetica-Bold")

sSubtitle = ps("sSubtitle",
    fontSize=12, textColor=WHITE, leading=16,
    spaceAfter=2, alignment=TA_CENTER, fontName="Helvetica")

sH1 = ps("sH1",
    fontSize=13, textColor=WHITE, leading=18,
    spaceBefore=8, spaceAfter=4,
    fontName="Helvetica-Bold", alignment=TA_LEFT)

sH2 = ps("sH2",
    fontSize=11, textColor=NAVY, leading=15,
    spaceBefore=10, spaceAfter=3,
    fontName="Helvetica-Bold")

sH3 = ps("sH3",
    fontSize=10, textColor=TEAL, leading=14,
    spaceBefore=6, spaceAfter=2,
    fontName="Helvetica-Bold")

sBody = ps("sBody",
    fontSize=9, leading=13, spaceAfter=4,
    fontName="Helvetica", textColor=colors.HexColor("#1A1A2E"))

sBullet = ps("sBullet",
    fontSize=9, leading=13, spaceAfter=2,
    leftIndent=14, firstLineIndent=-10,
    fontName="Helvetica", textColor=colors.HexColor("#1A1A2E"))

sSmall = ps("sSmall",
    fontSize=7.5, leading=11, spaceAfter=2,
    fontName="Helvetica", textColor=colors.HexColor("#555555"))

sNote = ps("sNote",
    fontSize=8.5, leading=12, spaceAfter=2,
    fontName="Helvetica-Oblique", textColor=colors.HexColor("#444444"))

sFooter = ps("sFooter",
    fontSize=7, leading=10,
    fontName="Helvetica", textColor=colors.HexColor("#888888"),
    alignment=TA_CENTER)

sTH = ps("sTH",
    fontSize=8.5, leading=12, fontName="Helvetica-Bold",
    textColor=WHITE, alignment=TA_CENTER)

sTD = ps("sTD",
    fontSize=8.5, leading=12, fontName="Helvetica",
    textColor=colors.HexColor("#1A1A2E"), alignment=TA_LEFT)

sTDc = ps("sTDc",
    fontSize=8.5, leading=12, fontName="Helvetica",
    textColor=colors.HexColor("#1A1A2E"), alignment=TA_CENTER)

sTDbold = ps("sTDbold",
    fontSize=8.5, leading=12, fontName="Helvetica-Bold",
    textColor=NAVY, alignment=TA_LEFT)

sAlert = ps("sAlert",
    fontSize=8.5, leading=12, fontName="Helvetica-Bold",
    textColor=RED, alignment=TA_LEFT)

# ─── Helper: coloured section header band ────────────────────────────────────
class SectionBand(Flowable):
    def __init__(self, text, bg=NAVY, width=None, height=24):
        super().__init__()
        self.text = text
        self.bg = bg
        self._width = width
        self.height = height

    def wrap(self, availW, availH):
        self._width = self._width or availW
        return self._width, self.height

    def draw(self):
        c = self.canv
        c.setFillColor(self.bg)
        c.roundRect(0, 0, self._width, self.height, 4, fill=1, stroke=0)
        c.setFillColor(WHITE)
        c.setFont("Helvetica-Bold", 11)
        c.drawString(10, 7, self.text)


class TitleBanner(Flowable):
    """Full-width decorative title banner."""
    def __init__(self, title, subtitle, width=None):
        super().__init__()
        self.title = title
        self.subtitle = subtitle
        self._width = width
        self.height = 90

    def wrap(self, availW, availH):
        self._width = self._width or availW
        return self._width, self.height

    def draw(self):
        c = self.canv
        w, h = self._width, self.height
        # Gradient-like block
        c.setFillColor(NAVY)
        c.roundRect(0, 0, w, h, 6, fill=1, stroke=0)
        # Accent stripe
        c.setFillColor(TEAL)
        c.rect(0, 0, 6, h, fill=1, stroke=0)
        # Amber accent line at top
        c.setFillColor(AMBER)
        c.rect(0, h-4, w, 4, fill=1, stroke=0)
        # Title text
        c.setFillColor(WHITE)
        c.setFont("Helvetica-Bold", 22)
        c.drawCentredString(w/2, h-36, self.title)
        # Subtitle
        c.setFont("Helvetica", 10)
        c.setFillColor(LIGHT_TEAL)
        c.drawCentredString(w/2, h-52, self.subtitle)
        # Footer line in banner
        c.setFillColor(colors.HexColor("#AACCCC"))
        c.setFont("Helvetica-Oblique", 8)
        c.drawCentredString(w/2, 8, "Sources: Harrison's Principles of Internal Medicine 22E · Henry's Clinical Diagnosis · Sleisenger & Fordtran")


def make_table(data, col_widths, header_bg=NAVY, stripe=True, font_size=8.5):
    """Build a styled table. data[0] is header row."""
    cell_data = []
    for i, row in enumerate(data):
        cell_row = []
        for j, cell in enumerate(row):
            if i == 0:
                cell_row.append(Paragraph(str(cell), sTH))
            else:
                p = sTDbold if j == 0 else sTD
                cell_row.append(Paragraph(str(cell), p))
        cell_data.append(cell_row)

    cmds = [
        ("BACKGROUND", (0,0), (-1,0), header_bg),
        ("ROWBACKGROUNDS", (0,1), (-1,-1), [WHITE, GREY_LIGHT]),
        ("GRID",         (0,0), (-1,-1), 0.4, GREY_MID),
        ("LINEBELOW",    (0,0), (-1,0),  1.0, header_bg),
        ("VALIGN",       (0,0), (-1,-1), "MIDDLE"),
        ("TOPPADDING",   (0,0), (-1,-1), 4),
        ("BOTTOMPADDING",(0,0), (-1,-1), 4),
        ("LEFTPADDING",  (0,0), (-1,-1), 6),
        ("RIGHTPADDING", (0,0), (-1,-1), 6),
    ]
    t = Table(cell_data, colWidths=col_widths, repeatRows=1)
    t.setStyle(TableStyle(cmds))
    return t


def make_alert_box(text, bg=LIGHT_AMBER, border=AMBER):
    """Coloured alert/tip box."""
    inner = Table(
        [[Paragraph(text, sBody)]],
        colWidths=[PAGE_W - 1.2*cm]
    )
    inner.setStyle(TableStyle([
        ("BACKGROUND",    (0,0), (-1,-1), bg),
        ("LINEAFTER",     (0,0), (0,-1),  3, border),
        ("LINEBEFORE",    (0,0), (0,-1),  3, border),
        ("TOPPADDING",    (0,0), (-1,-1), 6),
        ("BOTTOMPADDING", (0,0), (-1,-1), 6),
        ("LEFTPADDING",   (0,0), (-1,-1), 10),
        ("RIGHTPADDING",  (0,0), (-1,-1), 10),
    ]))
    return inner


# ═══════════════════════════════════════════════════════════════════════════════
# BUILD CONTENT
# ═══════════════════════════════════════════════════════════════════════════════
story = []
S = Spacer

def add_section(title, color=NAVY):
    story.append(S(1, 10))
    story.append(SectionBand(title, bg=color, width=PAGE_W))
    story.append(S(1, 6))


# ─── PAGE 1 : COVER / OVERVIEW ───────────────────────────────────────────────
story.append(TitleBanner(
    "Liver Function Tests",
    "Clinical Reference Guide  •  Orris Medical  •  2026",
    width=PAGE_W
))
story.append(S(1, 10))

story.append(Paragraph(
    "This guide provides a rapid-access reference for interpreting liver biochemistry panels in clinical practice. "
    "Tests are grouped by the hepatic system they reflect: <b>cell integrity</b>, <b>cholestasis</b>, "
    "<b>synthetic function</b>, and <b>non-invasive fibrosis staging</b>. "
    "No single test captures total liver function — a panel approach is required.",
    sBody
))
story.append(S(1, 8))

# KEY POINT BOX
story.append(make_alert_box(
    "<b>Key principle:</b> Use LFTs as a battery, not in isolation. "
    "Persistent or multi-test abnormalities increase specificity. "
    "Aminotransferases detect <i>cell damage</i>; albumin and PT/INR assess true <i>synthetic function</i>.",
    bg=LIGHT_TEAL, border=TEAL
))
story.append(S(1, 12))

# OVERVIEW TABLE
add_section("▸  Overview: Categories of Liver Function Tests", NAVY)

overview_data = [
    ["Category", "Tests", "What It Measures", "Rises / Falls"],
    ["Hepatocyte integrity", "ALT, AST, LDH", "Cell membrane damage / necrosis", "Rises with injury"],
    ["Cholestatic / biliary", "ALP, GGT, 5'-NT, Bilirubin (conjugated)", "Bile flow obstruction", "Rises with obstruction"],
    ["Synthetic function", "Albumin, PT/INR, Fibrinogen, Cholesterol", "Protein & factor production", "Falls with failure"],
    ["Excretory function", "Total & fractionated Bilirubin", "Conjugation & excretion of bilirubin", "Rises with impairment"],
    ["Detoxification", "Serum Ammonia", "Urea cycle capacity", "Rises when >80% liver lost"],
    ["Fibrosis staging", "FIB-4, APRI, ELF score, FibroScan", "Hepatic fibrosis extent", "Rises with fibrosis"],
    ["Prognostic scores", "MELD 3.0, Child-Pugh", "Decompensation / mortality", "Higher = worse prognosis"],
]

overview_cw = [3.5*cm, 4.5*cm, 5.0*cm, 3.5*cm]
story.append(make_table(overview_data, overview_cw, header_bg=NAVY))
story.append(S(1, 10))

# ─── PAGE 2 : HEPATOCYTE INTEGRITY ───────────────────────────────────────────
story.append(PageBreak())
story.append(TitleBanner(
    "Section 1: Hepatocellular Integrity Markers",
    "Aminotransferases — Detect cell injury before necrosis occurs",
    width=PAGE_W
))
story.append(S(1, 10))

add_section("▸  Aminotransferases (Transaminases)", TEAL)

aminotransferase_data = [
    ["Enzyme", "Full Name", "Primary Source", "Normal Range", "Specificity"],
    ["ALT", "Alanine aminotransferase", "Primarily liver", "7–56 U/L", "High for liver injury"],
    ["AST", "Aspartate aminotransferase", "Liver, cardiac & skeletal muscle,\nkidneys, brain, RBCs", "10–40 U/L", "Lower (multi-organ)"],
    ["LDH", "Lactate dehydrogenase", "Liver, heart, muscle, RBCs", "140–280 U/L", "Non-specific"],
]
aminotransferase_cw = [2.0*cm, 4.5*cm, 5.0*cm, 2.5*cm, 2.5*cm]
story.append(make_table(aminotransferase_data, aminotransferase_cw, header_bg=TEAL))
story.append(S(1, 8))

story.append(Paragraph("<b>Interpretation rules:</b>", sH3))
bullets_alt = [
    "Both ALT and AST are released into blood when hepatocyte membrane permeability increases — <b>cell necrosis is not required</b>.",
    "ALT is more liver-specific; AST elevations can originate from muscle, heart, or haemolysis.",
    "<b>Massive elevation (&gt;1000 U/L):</b> Acute viral hepatitis, ischaemic hepatitis ('shock liver'), or drug/toxin-induced injury.",
    "<b>Moderate elevation (5–15× ULN):</b> Chronic hepatitis B/C, alcoholic hepatitis, autoimmune hepatitis.",
    "<b>Mild elevation (&lt;5× ULN):</b> Non-alcoholic fatty liver disease (NAFLD), medications, thyroid disease, coeliac disease.",
]
for b in bullets_alt:
    story.append(Paragraph(f"• {b}", sBullet))

story.append(S(1, 8))
add_section("▸  AST:ALT Ratio — Diagnostic Clues", TEAL)

ratio_data = [
    ["AST:ALT Ratio", "Interpretation", "Classic Cause"],
    [">2:1", "Strongly suggests alcoholic aetiology", "Alcoholic liver disease (ALD)"],
    [">3:1", "Highly specific for ALD", "Alcoholic hepatitis"],
    ["~1:1", "Equal elevation", "Viral hepatitis, NAFLD"],
    ["ALT > AST", "ALT dominates", "Chronic viral hepatitis (HBV, HCV)"],
    ["Both >1000 U/L", "Massive hepatocellular necrosis", "Ischaemia, acetaminophen toxicity, acute viral hepatitis"],
]
ratio_cw = [3.0*cm, 6.0*cm, 7.0*cm]
story.append(make_table(ratio_data, ratio_cw, header_bg=TEAL))
story.append(S(1, 8))

story.append(make_alert_box(
    "<b>Pitfall:</b> AST:ALT ratio >2 in ALD is partly because pyridoxine (vitamin B6) deficiency impairs ALT synthesis more than AST. "
    "Elevated AST from myocardial infarction, myopathy, or haemolysis can mimic liver disease — always consider non-hepatic sources.",
    bg=RED_LIGHT, border=RED
))

# ─── PAGE 3 : CHOLESTASIS MARKERS ────────────────────────────────────────────
story.append(PageBreak())
story.append(TitleBanner(
    "Section 2: Cholestatic & Biliary Markers",
    "ALP · GGT · 5'-NT · Bilirubin",
    width=PAGE_W
))
story.append(S(1, 10))

add_section("▸  Alkaline Phosphatase (ALP)", NAVY)
story.append(Paragraph(
    "ALP is located on the <b>canalicular surface</b> of hepatocytes. Elevated in biliary obstruction, cholestasis, and infiltrative liver disease. "
    "Also elevated in bone disease, pregnancy, and normal childhood growth (non-hepatic isoforms). "
    "If ALP is elevated in isolation, fractionation or GGT/5'-NT measurement confirms hepatic origin.",
    sBody
))
story.append(S(1,4))

alp_data = [
    ["ALP Level", "Likely Significance"],
    ["1–3× ULN", "May be non-specific; check GGT/5'-NT"],
    ["3–10× ULN", "Suggestive of cholestasis or infiltrative disease"],
    [">10× ULN", "High likelihood of biliary obstruction or primary biliary cholangitis (PBC)"],
    ["Elevated + normal GGT", "Likely bone origin (Paget's, growth, fracture, bone mets)"],
    ["Elevated + elevated GGT", "Confirms hepatic origin"],
]
alp_cw = [3.5*cm, 13.0*cm]
story.append(make_table(alp_data, alp_cw, header_bg=NAVY))
story.append(S(1, 10))

add_section("▸  Gamma-Glutamyl Transferase (GGT)", NAVY)
story.append(Paragraph(
    "GGT is on the <b>hepatic (sinusoidal) surface</b> of canalicular membranes. Highly sensitive but not specific. "
    "Elevated by cholestasis, alcohol, many drugs (phenytoin, barbiturates, warfarin), and fatty liver disease. "
    "<b>Not elevated in bone disease</b> — useful to differentiate hepatic vs. bone ALP.",
    sBody
))
story.append(S(1, 10))

add_section("▸  5'-Nucleotidase (5'-NT)", NAVY)
story.append(Paragraph(
    "Like GGT, 5'-NT confirms the hepatic origin of an elevated ALP. Elevated specifically in biliary/cholestatic conditions. "
    "Not influenced by alcohol, drugs, or pregnancy to the same degree as GGT.",
    sBody
))
story.append(S(1, 10))

add_section("▸  Serum Bilirubin", NAVY)

bili_data = [
    ["Fraction", "Solubility", "Normal", "Elevated When", "Key Point"],
    ["Total bilirubin", "—", "0.2–0.9 mg/dL\n(ULN ~1–1.5)", "Any liver/biliary disease,\nhaemolysis", "Used in MELD 3.0"],
    ["Unconjugated\n(indirect)", "Water-insoluble\n(albumin-bound)", "<85% of total", "Haemolysis, Gilbert's,\nCrigler-Najjar", "Not filtered by kidney;\nno bilirubinuria"],
    ["Conjugated\n(direct)", "Water-soluble", "<0.3 mg/dL\n(<15% of total)", "Liver disease,\nbiliary obstruction", "Almost always\nimplies hepatobiliary disease"],
]
bili_cw = [2.8*cm, 3.0*cm, 2.8*cm, 4.2*cm, 3.7*cm]
story.append(make_table(bili_data, bili_cw, header_bg=NAVY))
story.append(S(1, 8))

story.append(Paragraph("<b>Prognostic value of total bilirubin:</b>", sH3))
bili_prog = [
    "Higher bilirubin = greater hepatocellular damage in acute viral hepatitis.",
    "Strongly correlates with mortality in <b>alcoholic hepatitis</b>.",
    "Key component of <b>MELD 3.0</b> (predicts 90-day mortality, guides transplant allocation).",
    "Prognostic marker in <b>primary biliary cholangitis (PBC)</b>.",
    "Elevation in drug-induced liver injury signals more severe injury.",
    "<b>Bilirubinuria</b> (dipstick) = conjugated bilirubin in urine → implies hepatobiliary disease (nearly 100% accurate).",
]
for b in bili_prog:
    story.append(Paragraph(f"• {b}", sBullet))

# ─── PAGE 4 : SYNTHETIC FUNCTION ─────────────────────────────────────────────
story.append(PageBreak())
story.append(TitleBanner(
    "Section 3: Hepatic Synthetic Function",
    "Albumin · PT/INR · Coagulation Factors · Ammonia",
    width=PAGE_W
))
story.append(S(1, 10))

story.append(Paragraph(
    "True synthetic markers fall <b>only when &gt;80% of functional liver tissue is destroyed</b>. "
    "They are the most reliable indicators of overall hepatic reserve.",
    sBody
))
story.append(S(1, 6))

add_section("▸  Serum Albumin", TEAL)

alb_rows = [
    ["Parameter", "Detail"],
    ["Synthesis", "Exclusively by hepatocytes; accounts for >50% of plasma protein synthesis"],
    ["Normal range", "3.5–5.0 g/dL"],
    ["Half-life", "~21 days (3 weeks) — NOT useful for acute injury assessment"],
    ["Best use", "Chronic liver disease staging (cirrhosis, chronic hepatitis)"],
    ["Falls with", ">80% hepatocyte destruction, malnutrition, protein-losing states (nephrotic syndrome, protein-losing enteropathy)"],
    ["Limitations", "Long half-life means slow response; also falls in systemic inflammation (negative acute-phase reactant)"],
]
alb_cw = [4.0*cm, 12.5*cm]
story.append(make_table(alb_rows, alb_cw, header_bg=TEAL))
story.append(S(1, 10))

add_section("▸  Prothrombin Time (PT) / INR", TEAL)

story.append(Paragraph(
    "The <b>single best acute measure</b> of hepatic synthetic function. All clotting factors except Factor VIII are made exclusively in hepatocytes.",
    sBody
))
story.append(S(1, 4))

factors_data = [
    ["Coagulation Factor", "Half-life", "Measured by PT?", "Vitamin K-dependent?"],
    ["Factor I (Fibrinogen)", "~5 days", "Indirectly", "No"],
    ["Factor II (Prothrombin)", "~3 days", "Yes", "Yes"],
    ["Factor V", "~1 day", "Yes", "No"],
    ["Factor VII", "~6 hours", "Yes", "Yes"],
    ["Factor X", "~2 days", "Yes", "Yes"],
    ["Factor VIII", "~12 hours", "No", "No (produced by endothelium)"],
]
factors_cw = [5.0*cm, 2.5*cm, 3.0*cm, 3.5*cm]
story.append(make_table(factors_data, factors_cw, header_bg=TEAL))
story.append(S(1, 8))

story.append(Paragraph("<b>Interpreting PT/INR in liver disease:</b>", sH3))
pt_points = [
    "<b>Factor VII</b> has the shortest half-life (6 h) → PT/INR is the most rapidly responsive test for acute synthetic failure.",
    "PT prolonged &gt;5 s above control, <b>not corrected by parenteral vitamin K</b>, is a poor prognostic sign in acute hepatitis.",
    "<b>Vitamin K deficiency</b> (cholestasis, fat malabsorption) also prolongs PT — responds to IV vitamin K. True synthetic failure does NOT respond.",
    "INR is a core component of <b>MELD 3.0</b>.",
    "Administer IV vitamin K (10 mg) before attributing PT prolongation to synthetic failure.",
]
for b in pt_points:
    story.append(Paragraph(f"• {b}", sBullet))
story.append(S(1, 8))

add_section("▸  Other Synthetic Markers", TEAL)

other_syn_data = [
    ["Marker", "Direction in Failure", "Key Use / Notes"],
    ["Fibrinogen", "Decreases", "Short half-life; sensitive in acute failure; also consumed in DIC"],
    ["Serum Cholesterol", "Decreases", "Falls in severe hepatocellular failure (liver makes cholesterol). Rises in cholestasis"],
    ["Plasma Pseudocholinesterase", "Decreases", "Liver-synthesised; reduced in cirrhosis; relevant in anaesthesia (suxamethonium sensitivity)"],
    ["Blood Glucose", "Decreases (hypoglycaemia)", "Impaired gluconeogenesis/glycogenolysis in acute fulminant failure"],
    ["Total Protein", "Decreases", "Falls when >80% liver is destroyed; less sensitive than albumin alone"],
]
other_syn_cw = [4.5*cm, 3.5*cm, 8.5*cm]
story.append(make_table(other_syn_data, other_syn_cw, header_bg=TEAL))
story.append(S(1, 10))

add_section("▸  Serum Ammonia", TEAL)

ammonia_points = [
    "The liver is the <b>only organ</b> that metabolises ammonia to urea (Krebs-Henseleit cycle).",
    "Ammonia rises when >80% of hepatic tissue is destroyed or in significant <b>portosystemic shunting</b>.",
    "<b>Poor correlation</b> with the presence or severity of hepatic encephalopathy (HE) — do not use alone for HE diagnosis.",
    "<b>Elevated arterial ammonia</b> does correlate with outcome in <b>fulminant hepatic failure</b>.",
    "Useful to identify occult liver disease in patients with unexplained mental status changes.",
    "Muscle wasting in cirrhosis worsens hyperammonaemia (muscle also detoxifies ammonia → glutamine).",
]
for b in ammonia_points:
    story.append(Paragraph(f"• {b}", sBullet))

# ─── PAGE 5 : FIBROSIS + SCORES ──────────────────────────────────────────────
story.append(PageBreak())
story.append(TitleBanner(
    "Section 4: Non-Invasive Fibrosis Staging & Prognostic Scores",
    "FIB-4 · APRI · ELF · Child-Pugh · MELD 3.0",
    width=PAGE_W
))
story.append(S(1, 10))

add_section("▸  Non-Invasive Fibrosis Scores", NAVY)

fib_data = [
    ["Score / Test", "Formula / Components", "Threshold", "Use"],
    ["FIB-4", "Age × AST / (Platelets × √ALT)", "<1.30 = low fibrosis\n>2.67 = high fibrosis", "NAFLD, HCV, HBV staging"],
    ["APRI", "(AST/ULN) / Platelets × 100", "<0.5 = low\n>1.0 = significant fibrosis", "HCV fibrosis, cirrhosis"],
    ["ELF Score", "TIMP-1 + PIIINP + Hyaluronic acid", ">9.8 = advanced fibrosis", "Chronic liver disease"],
    ["FibroScan\n(Transient Elastography)", "Liver stiffness (kPa) via ultrasound probe", "<7 kPa = F0–F1\n>12–14 kPa = cirrhosis", "Gold-standard non-invasive; most validated"],
    ["NFS (NAFLD Fibrosis Score)", "Age, BMI, IFG/DM, AST:ALT ratio,\nplatelets, albumin", "<-1.455 = low risk\n>0.676 = high risk", "Specifically validated in NAFLD/MASLD"],
]
fib_cw = [3.0*cm, 5.5*cm, 4.0*cm, 4.0*cm]
story.append(make_table(fib_data, fib_cw, header_bg=NAVY))
story.append(S(1, 10))

add_section("▸  Prognostic Scoring Systems", AMBER)

score_data = [
    ["Score", "Components", "Score Range", "Clinical Use"],
    ["MELD 3.0", "Bilirubin + INR + Creatinine +\nAlbumin + Sodium (+ 1.33 if female)", "6–40 (higher = worse)", "90-day mortality; transplant organ allocation; surgical risk in cirrhosis"],
    ["Child-Pugh", "Bilirubin + Albumin + PT +\nAscites + Encephalopathy", "A (5–6): mild\nB (7–9): moderate\nC (10–15): severe", "Cirrhosis staging; surgical risk; prognosis in chronic liver disease"],
    ["Maddrey's DF", "(PT – control × 4.6) + Bilirubin", "≥32 = severe alcoholic hepatitis", "Steroid treatment decision in alcoholic hepatitis"],
    ["Glasgow AH Score", "Age + WBC + Urea + PT ratio + Bilirubin", "≥9 = poor prognosis", "Alcoholic hepatitis 28-day survival"],
]
score_cw = [2.5*cm, 5.0*cm, 4.0*cm, 5.0*cm]
story.append(make_table(score_data, score_cw, header_bg=AMBER))
story.append(S(1, 10))

story.append(make_alert_box(
    "<b>MELD 3.0 Formula:</b>  "
    "4.56 × ln(bilirubin) + 9.09 × ln(INR) + 11.14 × ln(creatinine) + 1.85 × (138 – sodium) – 0.24 × (138 – sodium) × ln(creatinine) – 7 × albumin + 1.33 (if female) + 9.09  "
    "| Score ≥15: benefit from transplantation. Score ≥40: ~100% 3-month mortality without transplant.",
    bg=LIGHT_AMBER, border=AMBER
))

# ─── PAGE 6 : DIAGNOSTIC PATTERNS ────────────────────────────────────────────
story.append(PageBreak())
story.append(TitleBanner(
    "Section 5: Diagnostic Pattern Recognition",
    "Interpreting the test battery — pattern approach to liver disease",
    width=PAGE_W
))
story.append(S(1, 10))

add_section("▸  Classic Biochemical Patterns", NAVY)

pattern_data = [
    ["Pattern", "ALT / AST", "ALP / GGT", "Bilirubin", "Albumin / PT", "Classic Aetiology"],
    ["Acute hepatocellular\ninjury", "Markedly elevated\n(>10× ULN)", "Mildly elevated\n(1–3×)", "Moderately raised\n(conjugated+unconj.)", "PT may prolong\nacutely", "Viral hepatitis, drug toxicity,\nischaemic hepatitis"],
    ["Chronic hepatocellular\ndisease", "Mildly–moderately\nelevated (1–10×)", "Mildly elevated", "Normal or\nmildly raised", "Albumin low;\nPT prolonged", "Cirrhosis, chronic HCV/HBV,\nNAFLD"],
    ["Cholestatic\n(obstructive)", "Mildly elevated\n(<3×)", "Markedly elevated\n(>4×)", "Conjugated bili-\nrubin dominates", "Normal unless\nprolonged cholestasis", "Gallstones, cholangiocarcinoma,\nPSC, PBC, drug-induced"],
    ["Alcoholic hepatitis", "AST:ALT >2:1\n(rarely >300 U/L)", "GGT markedly elevated;\nALP variable", "Elevated", "Albumin low;\nPT prolonged", "Alcohol use disorder"],
    ["Infiltrative disease\n(e.g. malignancy,\ngranuloma)", "Normal or mildly\nelevated", "ALP markedly\nelevated", "Mildly elevated\nor normal", "Normal (early)", "Hepatic metastases, sarcoidosis,\ntuberculosis, amyloid"],
    ["Isolated unconjugated\nhyperbilirubinaemia", "Normal", "Normal", "Unconjugated\nfraction only", "Normal", "Gilbert's syndrome,\nhaemolysis"],
    ["Fulminant hepatic\nfailure", "Very high\n(>1000 U/L)", "Elevated", "Very high", "Albumin falls;\nPT/INR markedly\nprolonged", "Acute viral hepatitis,\nacetaminophen, Wilson's disease"],
]
pattern_cw = [2.8*cm, 2.8*cm, 2.8*cm, 2.8*cm, 2.8*cm, 3.5*cm]
story.append(make_table(pattern_data, pattern_cw, header_bg=NAVY))
story.append(S(1, 10))

add_section("▸  Differential by Degree of ALT/AST Elevation", TEAL)

elevation_data = [
    ["Elevation Level", "ALT/AST Range", "Typical Causes"],
    ["Mild", "<3× ULN", "NAFLD, medications (statins, antibiotics), thyroid disease, coeliac disease, early cirrhosis"],
    ["Moderate", "3–10× ULN", "Chronic viral hepatitis (HBV/HCV), autoimmune hepatitis, alcoholic liver disease, haemochromatosis"],
    ["Marked", "10–40× ULN", "Acute viral hepatitis, drug-induced liver injury (DILI), acute biliary obstruction"],
    ["Massive (>1000 U/L)", ">40× ULN", "Ischaemic/shock hepatitis, acetaminophen toxicity, severe acute viral hepatitis, Budd-Chiari (acute)"],
]
elevation_cw = [2.5*cm, 3.0*cm, 11.0*cm]
story.append(make_table(elevation_data, elevation_cw, header_bg=TEAL))

# ─── PAGE 7 : QUICK REFERENCE CARD ──────────────────────────────────────────
story.append(PageBreak())
story.append(TitleBanner(
    "Section 6: Quick Reference Card",
    "Normal ranges · clinical red flags · follow-up thresholds",
    width=PAGE_W
))
story.append(S(1, 10))

add_section("▸  Normal Reference Ranges (Adult)", NAVY)

normal_data = [
    ["Test", "Conventional Units", "SI Units", "Notes"],
    ["ALT", "7–56 U/L", "0.12–0.93 µkat/L", "Female ULN slightly lower in many labs"],
    ["AST", "10–40 U/L", "0.17–0.67 µkat/L", "Higher in neonates"],
    ["ALP", "44–147 U/L", "0.73–2.45 µkat/L", "Elevated in children, pregnancy (placental isoform)"],
    ["GGT", "9–48 U/L (M)\n7–25 U/L (F)", "—", "Age/sex-dependent; rises with alcohol, drugs"],
    ["Total Bilirubin", "0.2–1.2 mg/dL", "3.4–20.5 µmol/L", "95th percentile: 0.2–0.9 mg/dL"],
    ["Direct (Conj.) Bilirubin", "<0.3 mg/dL", "<5.1 µmol/L", ">15% of total = conjugated hyperbilirubinaemia"],
    ["Albumin", "3.5–5.0 g/dL", "35–50 g/L", "Nutritional status also affects levels"],
    ["Prothrombin Time", "11–13.5 sec", "INR: 0.9–1.1", "Reagent-dependent; INR standardises comparison"],
    ["Ammonia (venous)", "15–45 µg/dL", "9–33 µmol/L", "Arterial sample preferred for critical illness"],
    ["Fibrinogen", "200–400 mg/dL", "2.0–4.0 g/L", "Acute-phase reactant; may initially rise in inflammation"],
]
normal_cw = [3.5*cm, 3.5*cm, 3.0*cm, 6.5*cm]
story.append(make_table(normal_data, normal_cw, header_bg=NAVY))
story.append(S(1, 10))

add_section("▸  Clinical Red Flags Requiring Urgent Action", RED)

redflag_data = [
    ["Finding", "Clinical Significance", "Action"],
    ["PT/INR >1.5 + jaundice\n(not corrected by vitamin K)", "Acute liver failure (ALF) or\nsevere synthetic failure", "Admit, liver transplant centre referral, N-acetylcysteine if acetaminophen"],
    ["Bilirubin rising + PT\nprolonging in viral hepatitis", "Pending acute liver failure", "Urgent hepatology review"],
    ["ALT/AST falling but PT rising\nin acute hepatitis", "\"Burned-out\" necrosis —\nparadoxical sign of deterioration", "Urgent review; mass necrosis"],
    ["Ammonia >150 µmol/L\n+ encephalopathy", "Severe hyperammonaemia in\nfultminant failure", "ICU level care; transplant evaluation"],
    ["Maddrey DF ≥32", "Severe alcoholic hepatitis:\n~50% 30-day mortality", "Consider corticosteroids (Prednisolone 40 mg/day) if no contraindication"],
    ["Child-Pugh C\n(score 10–15)", "Advanced cirrhosis; high\noperative mortality", "Avoid elective surgery; transplant assessment"],
]
redflag_cw = [4.0*cm, 5.5*cm, 7.0*cm]
story.append(make_table(redflag_data, redflag_cw, header_bg=RED))
story.append(S(1, 10))

# ─── PAGE 8 : APPROACH & SOURCES ─────────────────────────────────────────────
story.append(PageBreak())
story.append(TitleBanner(
    "Section 7: Stepwise Clinical Approach",
    "When you receive an abnormal LFT panel",
    width=PAGE_W
))
story.append(S(1, 10))

add_section("▸  Step-by-Step Evaluation Algorithm", TEAL)

steps = [
    ("<b>Step 1 — Identify the dominant pattern</b>",
     "Is it hepatocellular (ALT/AST ↑↑), cholestatic (ALP/GGT ↑↑), or mixed? Look at the ratio of transaminases to ALP."),
    ("<b>Step 2 — Assess severity</b>",
     "Check synthetic markers (albumin, PT/INR) and bilirubin. Prolonged PT not corrected by vitamin K = true synthetic failure."),
    ("<b>Step 3 — Acute vs. chronic?</b>",
     "Albumin falls over weeks; PT/INR changes within hours–days. Low albumin + normal PT suggests chronic disease. Very high AST/ALT (>500) suggests acute injury."),
    ("<b>Step 4 — Confirm hepatic origin of ALP</b>",
     "If ALP is elevated, check GGT or 5'-NT. If both elevated = hepatic origin. If GGT normal = likely bone or pregnancy."),
    ("<b>Step 5 — Fractionate bilirubin if needed</b>",
     "Unconjugated dominant → haemolysis or Gilbert's. Conjugated dominant → hepatobiliary disease. Mixed elevation = most liver diseases."),
    ("<b>Step 6 — Directed aetiological workup</b>",
     "Hepatocellular pattern → Hepatitis B/C serology, autoimmune panel (ANA, ASMA, anti-LKM), iron studies, ceruloplasmin (age <40), ferritin, alcohol history, drug review. "
     "Cholestatic pattern → Ultrasound first; if ducts not dilated → AMA (PBC); if dilated → CT/MRCP/ERCP."),
    ("<b>Step 7 — Stage fibrosis in chronic disease</b>",
     "Use FIB-4, APRI, or FibroScan to assess fibrosis non-invasively before considering biopsy."),
    ("<b>Step 8 — Calculate a prognostic score</b>",
     "MELD 3.0 for transplant/mortality risk. Child-Pugh for surgical planning. Maddrey DF for alcoholic hepatitis treatment decision."),
]

for i, (heading, body) in enumerate(steps):
    story.append(Paragraph(heading, sH3))
    story.append(Paragraph(body, sBody))
    story.append(S(1, 4))

story.append(S(1, 10))
add_section("▸  Sources & References", GREY_MID if False else colors.HexColor("#3D3D5C"))

refs = [
    "Harrison's Principles of Internal Medicine, 22nd Edition (2025, McGraw Hill) — Chapter 348: Evaluation of Liver Function (Bethea ED, Pratt DS)",
    "Henry's Clinical Diagnosis and Management by Laboratory Methods — Chapter: Liver Function Tests",
    "Sleisenger and Fordtran's Gastrointestinal and Liver Disease — Tests to Establish the Presence and Severity of Liver Disease",
    "Morgan & Mikhail's Clinical Anesthesiology, 7th Edition — Liver Function Testing",
    "Barash, Cullen & Stoelting's Clinical Anesthesia, 9th Edition — Assessment of Hepatic Function",
    "MELD 3.0: Kim WR et al. MELD 3.0: The Model for End-Stage Liver Disease Updated for the 21st Century. Hepatology. 2021;74(4):1instance68–1177.",
    "European Association for the Study of the Liver (EASL) Clinical Practice Guidelines — Non-invasive tests for evaluation of liver disease",
]
for r in refs:
    story.append(Paragraph(f"• {r}", sSmall))

story.append(S(1, 14))
story.append(HRFlowable(width=PAGE_W, thickness=0.5, color=GREY_MID))
story.append(S(1, 6))
story.append(Paragraph(
    "This reference guide is intended for qualified healthcare professionals. Clinical decisions must integrate patient-specific context, "
    "institutional guidelines, and current evidence. Always verify reference ranges against your local laboratory's validated intervals.",
    sNote
))
story.append(S(1, 4))
story.append(Paragraph("Orris Clinical Reference  •  Liver Function Tests Guide  •  July 2026", sFooter))

# ─── BUILD ────────────────────────────────────────────────────────────────────
doc.build(story)
print(f"PDF written to: {OUTPUT}")