Every liver panel answers two questions. One: is the injury in the cells (AST and ALT leak out) or in the bile ducts (alkaline phosphataseALP: made by liver canaliculi, osteoblasts, placenta, and intestine. Context determines origin → GGT is the referee. climbs)? Two: when alkaline phosphatase is high, did it come from liver or bone? GGTGGT: canalicular enzyme induced by alcohol and obstructive cholestasis. Bone osteoblasts cannot produce GGT → high GGT alongside ALP = hepatobiliary, not bone. settles it, because bone makes no GGT. Read the panel in that order and the diagnosis falls out.
Commit: A 48-year-old teacher has weeks of fatigue and a vague itch. Alkaline phosphatase is nearly twice the upper limit. AST and ALT are normal. No bone pain, no pregnancy. Alkaline phosphatase can come from liver or bone, and you need to know which. Which single lab tells you the source?
Repeat alkaline phosphatase weekly until it behaves
Serum calcium alone because bones hoard calcium stories
Gamma-glutamyl transpeptidase (GGT)
Urinary bilirubin dipstick as first referee
Alkaline phosphatase does not tell you where it came from. Bone osteoblasts make it, and so do the bile canaliculi in the liver. GGT is the tiebreaker: the liver makes GGT, bone does not. So if GGT is also high, the alkaline phosphatase is hepatobiliary. If GGT is normal, the source is bone. Calcium does not localize the enzyme. Repeating the same alkaline phosphatase adds no new information. Rule: isolated, unexplained alkaline phosphatase elevation → check GGT first to split liver from bone.
Lab Lineup ER
Five patients waiting. Each has a hidden lab panel. Tap a lab to reveal it. Make the call with as few reveals as possible.
ER Queue · 5 Patients
Each lab card shows the value when tapped. Pick the diagnosis below each patient when ready. Score tracks how many reveals you used per case.
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solved
0
missed
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reveals used
From the Attending
Liver workup is a four-lab problem: AST / ALT / Alk Phos / GGT · add total + direct bilirubin and you've covered 90% of the differential. AST/ALT ratio > 2 with mild elevation = alcoholic (B6-dependent ALT drops). ALT > AST mild to moderate = NAFLD or chronic viral. Both > 1000 = acute viral, ischemic, acetaminophen. Alk Phos + GGT both up = cholestasis. Alk Phos up + GGT normal = bone source (Paget, fracture, growth). The lineup teaches by letting the pattern emerge one number at a time.
Ratios & Canalicular Labs
Flip between the two ratio patterns, then read the cholestasis lab panel below.
AST / ALT < 1
AST / ALT ≥ 1
ALT outruns AST
De Ritis ratioAST divided by ALT. Named after Fernando De Ritis who first described alcoholic liver disease patterns. >2:1 suggests alcoholic hepatitis; <1 suggests viral/NAFLD. below 1 means ALT is the bigger number.
Classic causesViral hepatitis and early fatty liver (NAFLD)
Still check alk phosBile-duct obstruction can shift enzymes too, so always read alkaline phosphatase alongside the ratio
Why ALT leadsCytosolic ALT leaks first in early hepatocyte injury, so ALT runs ahead of AST
TrapALT being high does not rule out bile-duct disease. Itch plus high alkaline phosphatase still means image the ducts.
AST catches ALT
AST climbs relative to ALT in alcohol, massive necrosis, advancing fibrosis, and from tissue outside the liver.
AlcoholAST tops ALT, ratio above 1.5, but AST stays under 400 IU/L. B6 depletion caps how high it can climb.
CirrhosisAs scar replaces hepatocytes, the ratio widens toward AST
Non-liver sourcesMassive necrosis, hepatocellular carcinoma, liver metastases, rhabdomyolysis, and MI all release AST
GGT clueGGT high while alkaline phosphatase stays normal points to chronic alcohol, not obstruction
The cholestasis lab pattern
When bile cannot drain (cholestasis), conjugated (direct) bilirubin backs up and alkaline phosphatase and GGT rise together.
Parameter
Board cheat sheet
Alkaline phosphatase
Made by liver bile canaliculi AND bone, plus placenta and intestine. A high value alone cannot name its source. Infiltrative liver disease and bone tumors both raise it.
GGT
Made in the bile canaliculi, not in bone. Rises fast with bile obstruction and with alcohol. A high GGT next to a high alkaline phosphatase confirms the liver is the source.
Indirect bilirubin
Unconjugated, fat-soluble pigment from heme breakdown. Rises when red cells break down faster than the liver can conjugate the pigment (hemolysis).
Direct bilirubin
Conjugated pigment. Spills back into the blood when bile cannot drain, as in obstruction or hepatocyte injury.
5 prime nucleotidase
Older liver-specific marker. Like GGT, it confirms that a high alkaline phosphatase came from the liver, not bone.
Splitting bilirubin into direct and indirect separates obstruction (direct rises) from overproduction like hemolysis (indirect rises). Trapped bile salts also injure hepatocytes, which leaks some AST and ALT later.
Hepatocellular vs Cholestatic
Cover the table and recite each row first. Tap to reveal and check yourself.
tap to reveal
Feature
Hepatocellular
Cholestatic
Lead enzymes
AST and ALT high
Alk phos and GGT high
AST / ALT ratio
Drives the cause: over 2 alcohol, over 4 Wilson, under 1 viral or NAFLD
Not the discriminator here, transaminases are only mildly up
GGT
Usually normal or mildly up
High, and confirms the alk phos is liver not bone
Bilirubin
Variable, follows hepatocyte injury
Direct (conjugated) dominant from backed-up bile
R-factor (ALT/ULN over alk-phos/ULN)
Greater than 5
Less than 2 (2 to 5 is mixed)
What to image
Usually none first, work up cause by history and serologies
Ultrasound then MRCP for stone, stricture, or mass
Inside One Hepatocyte
Pick a state. Watch the two enzyme pools, the B6 cofactor, and the ratio move in real time. The picture is the answer.
De Ritis Engine · AST / ALT live model
AST lives in cytosol and mitochondria. ALT is mostly cytosolic and leans hard on vitamin B6. Change the injury and the ratio follows.
AST22
ALT25
B6 cofactor (pyridoxal-5'-phosphate), ALT depends on it more than AST
fully stocked
AST / ALT = 0.88
12
Membrane intact. Both pools sit quiet. ALT edges ahead, so the ratio parks just under 1.
From the Attending
Why does alcohol flip the ratio? Two hits at once. One: alcohol poisons mitochondria, and AST is the only one of the pair stored there, so mitochondrial AST pours out and AST climbs. Two: chronic drinkers run low on B6 (pyridoxal-5'-phosphate), the cofactor both enzymes need, and ALT leans on it more, so ALT synthesis throttles and ALT falls. AST up plus ALT down pushes the ratio over 2, while AST still rarely tops 400. Mitochondrial AST out plus B6-starved ALT down equals ratio over 2.
Decision Tree
Commit to a path before the answer reveals.
From the Attending
The AST/ALT ratio is a pattern, not a number to memorize blindly. AST > ALT (ratio > 2, "scotch and toast") · alcoholic liver disease. Mechanism: chronic alcohol depletes pyridoxal phosphate (B6), and ALT depends on B6 more than AST · so ALT drops out, AST rises relatively. ALT > AST · viral hepatitis, NAFLD, drug-induced (acetaminophen toxicity gives AST/ALT both >1000). Ratio >4 · think Wilson disease. Alk phos + GGT both up = hepatobiliary obstruction (cholestasis); alk phos up + GGT normal = bone source (Paget, fracture, growth). GGT is the bone-vs-liver splitter for alk phos.
1
A liver panel is back. Read it before you image anything. Which family of enzymes is doing the shouting?
AST and ALT lead (hepatocellular injury)
Alk phos and GGT lead (cholestatic pattern)
2
Hepatocellular injury. Now the AST/ALT ratio plus the magnitude pick the cause. Which line fits?
AST/ALT over 2, AST under 400, heavy alcohol history
AST and ALT both over 1000
AST/ALT over 4 in a young patient with hemolysis and low ceruloplasmin
ALT a bit over AST, obese diabetic, no alcohol
2
Cholestatic pattern. Alk phos is high, but alk phos alone cannot name its source. GGT is the referee. What does it read?
GGT is high too, rising right alongside alk phos
GGT is normal while alk phos stays high
The Lineup
Tap a card to flip it. Front: facts. Back: why it happens.
Blocked bile flow
Direct bilirubin and bile-duct enzymes rise; trapped bile salts then injure hepatocytes
DIRECT BILIRUBIN UP, WITH ALK PHOS AND GGT TOGETHER
tap to flip →
Why This Happens
Trace It
Bile cannot drain. Conjugated bilirubin backs up into the blood. Alkaline phosphatase and GGT rise from the stressed bile canaliculi. Trapped bile salts also damage hepatocyte membranes, so AST and ALT leak a little later.
Next step
Image the bile ducts. Look for a stone, a stricture, or a mass. Trap: calling it viral hepatitis ignores the high direct bilirubin pointing to an obstruction.
Alcohol pattern
Alcohol switches on GGT and releases mitochondrial AST, so AST leads ALT
AST OVER ALT, GGT HIGH, ALK PHOS NORMAL
tap to flip →
Why This Happens
Trace It
Alcohol damages mitochondria, so mitochondrial AST pours out while ALT stays lower. Alcohol also switches on GGT production, so GGT can be high even when alkaline phosphatase is still normal.
Next step
Get an honest drinking history. Trap: calling it acute viral hepatitis when the AST-over-ALT ratio and isolated GGT point to alcohol.
Massive transaminases
Hepatocytes die in bulk, so both AST and ALT spill into the thousands
AST AND ALT OVER 1000, RATIO STOPS MATTERING
tap to flip →
Why This Happens
Trace It
Acetaminophen toxicity, ischemic hepatitis (shock liver), and severe acute viral hepatitis kill hepatocytes wholesale, so the cytosolic and mitochondrial pools both dump at once and values rocket past 1000.
Next step
Hunt the trigger fast. Trap: ratio shopping when AST and ALT are in the thousands. An empty acetaminophen bottle means give N-acetylcysteine now.
ALT leads
Cytosolic ALT leaks first, so ALT sits a bit above AST
ALT OVER AST, MILD TO MODERATE, RATIO UNDER 1
tap to flip →
Why This Happens
Trace It
Chronic viral hepatitis (B and C) and fatty liver (NAFLD, now MASLD) injure hepatocytes gently, so the cytosolic ALT pool leaks ahead of mitochondrial AST and the ratio stays under 1.
Next step
Order hepatitis serologies and a metabolic workup. Trap: labeling an obese diabetic alcoholic when the ratio is under 1 and the history has no alcohol.
Indirect only
A conjugation hiccup raises unconjugated bilirubin with clean enzymes
INDIRECT BILIRUBIN UP, ALL ENZYMES NORMAL
tap to flip →
Why This Happens
Trace It
Gilbert syndrome is a part-time shortage of UGT1A1, the enzyme that conjugates bilirubin. Fasting, illness, or stress unmasks it, so indirect bilirubin rises while AST, ALT, alk phos, and GGT all stay normal.
Next step
Reassure, no treatment needed. Trap: chasing hemolysis. Here Hgb, reticulocytes, and LDH are normal, so production is fine and only conjugation lags.
Memory Hooks
Tap to unblur. Test yourself before peeking.
🦴
Bone makes no GGT
Bone osteoblasts make alkaline phosphatase but not GGT. So a high alkaline phosphatase with a normal GGT means the bone, not the liver.
tap to reveal
🍺
GGT alone means alcohol
Alcohol switches on GGT production, so GGT can rise on its own, before any bile-duct blockage and before alkaline phosphatase moves.
tap to reveal
⚖️
De Ritis ratio
De Ritis ratio is AST divided by ALT. Below 1, ALT leads (viral, NAFLD). Above 2, AST leads (alcohol).
tap to reveal
The Enzyme Hunt
Watch the labs drop. Make the call. One patient, three clues.
ENZYME DETECTIVE · CASE 1
MARCUS
AGE 47
"Fatigue for six weeks. Noticed his eyes looked yellowish last Tuesday."
✓
LABS INCOMING
ALP248 IU/L HIGH
GGT186 IU/L HIGH
AST62 IU/L normal
ALT48 IU/L normal
Direct bili2.8 mg/dL HIGH
Canalicular leakALP and GGT rise together from stressed canaliculi
Distal blockagedirect (conjugated) bilirubin backs up into blood
BILE TRAPPEDflow stalls at the block, conjugated bilirubin refluxes toward the liver
ALP and GGT are both high. Direct bilirubin is up too. What is the pattern?
Medically reviewed by Fatima Ali, DO and Kaitlyn Cocuzzo, MD · Last reviewed June 2026
Bone Wizardry is an independent educational resource for visual learning in the medical sciences. It is not affiliated with, endorsed by, or sponsored by any licensing or examination board, contains no real or recalled examination questions, and does not guarantee any educational or examination outcome.
