Found 3.12 Liver

Liver Anatomy

%BW, where?

lobes?

segments? I?

Largest internal organ

• ~1.5 kg, ~2% of body weight

• RUQ; spans ribs 7–11 at the right midaxillary line

Anatomic lobes

• Right and left lobes, divided by the falciform ligament

• Caudate and quadrate lobes inferiorly

8 Functional segments

• 8 Couinaud segments (I-VIII), defined by hepatic and portal veins

• Each has its own vascular inflow and biliary drainage

• Caudate lobe (segment I) drains directly into the IVC, so it is spared and hypertrophies in hepatic venous outflow obstruction.

Liver Vascular

blood flow chart

what organs drain into portal? 6

oral vs IV meds

unique characteristics about the portal system

So the liver is perfused by the portal vein and the hepatic artery. dual blood supply.

You have right, middle, and left hepatic veins, and all of those drain directly into the inferior vena cava.

So the portal vein drains, because it's made-up of the superior mesenteric vein and the splenic vein, it drains the stomach and the small and large intestine, spleen, pancreas, and the gallbladder

So this is why you have something called first pass metabolism because things that are taken orally or absorbed through the intestines first go through the liver before they go to the rest of the body.

And which is why IV medications tend to be a lower dose than PO medications because they're not subject to first pass metabolism like PO medications are.

The portal system is valveless. That's unique for the portal system. And because it's valveless, it's a low pressure venous inflow between two capillary beds.

Hepatic artery branches from the abdominal aorta via the celiac trunk

Liver Innervation

SNS from? aka? fx?

PSNS from? fx?

receptors on arteries/veins? control?

Sympathetic fibers T3–T11 (via celiac plexus)

• Constrict hepatic arterioles, sinusoids, and venules

• Parasympathetic (vagal): ACh and VIP relax arterioles and sinusoids

Hepatic artery: α and β receptors

Portal circulation: α only

• Venule tone sets hepatic blood volume (reservoir)

The Lobule: Structural Unit - makeup

portal triads vs central vein?

directional flow?

Shape: hexagonal cylinder, 0.8–2 mm in diameter; 50,000–100,000 lobules

Central vein drains into the hepatic veins, then the IVC

Portal triads at the corners: portal venule, hepatic arteriole, bile ductule, plus lymphatics and nerves

Hepatocyte plates radiate like spokes, usually 1–2 cells thick

Sinusoids carry mixed portal and arterial blood to the central vein

Bile canaliculi run between hepatocytes to bile ducts in the septa

Blood flows inward toward the central vein.

Bile flows outward toward the portal triad.

The Acinus & Metabolic Zonation

Zone 1: 2, aka?

Zone 2: 1, aka?

Zone 3: 3, aka?

hepatocytes are the cells; the acinus is an arrangement of those cells based on their blood supply.

P. Triad → Zone 1 → Zone 2 → Zone 3 → Central Vein

• Falling O₂ and nutrient content along the sinusoid

Zone 1 · Periportal

• Most O₂ and nutrients

• Oxidative metabolism: gluconeogenesis, β-oxidation, urea synthesis

Zone 2 · Midzonal

• Intermediate O₂ and function

Zone 3 · Centrilobular

• Least O₂; anaerobic metabolism

  • most vulnerable to hypoxia ("shock liver")

• Highest CYP450 content

• Reactive intermediates concentrate here

  • most vulnerable to toxic metabolites: acetaminophen (NAPQI), halothane.

Hepatic Cell Types

Hepatocytes 4

Kupffer cells 1

endothelium 3

Stellate cells 3

Hepatocytes

• 80% of total cellular volume

• Metabolism, synthesis, bile; smooth ER holds CYP450

Kupffer cells

• Resident macrophages from monocytes

• Phagocytize ≥99% of portal bacteria

Sinusoidal endothelium

• Pores up to ~1 µm

• no basement membrane

• Plasma proteins pass into the space of Disse

  • Space of Disse: perisinusoidal space between endothelium and hepatocytes; drains to lymphatics in the interlobular septa.

Stellate (Ito) cells

• Quiescent in the space of Disse; store vitamin A

• With prolonged injury, secrete collagen: fibrosis, cirrhosis

• So usually they're not very active.

Dual Blood Supply Numbers

total CO%? ml/min? %O2 consumption?

portal vs hepatic art

• ml/min vs %

• %O2 consumption?

↑ %O2 requirements solution?

Total hepatic blood flow

• ~1350 mL/min

• ~25% of cardiac output

• liver uses ~20% of body O₂

Portal vein - low pressure

• ~1050 mL/min, ~75% of flow

• ~50% of O₂

  • partly deoxygenated

Hepatic artery - high pressure

• ~300 mL/min, ~25% of flow

• ~50% of O₂

  • even though the hepatic artery is a third of the amount of flow that the portal vein is, it provides just as much oxygen content as the portal vein

Increased hepatic O₂ demand is met mainly by increased O₂ extraction, not by further increases in flow.

• oxyhemoglobin dissociation curve, when it pushes more to the right

• It favors offloading that oxygen.

Hepatic venous pressure gradient (HVPG)

portal vs central pressure?

gradient in L/min?

normal vs abnormal?

HVPG = wedged hepatic venous pressure − free hepatic venous pressure

Portal vein ~7–10 mmHg

↓

Sinusoids very low resistance

↓

Hepatic vein ~0–5 mmHg

A gradient of only a few mmHg drives >1 L/min because sinusoidal resistance is so low.

• Normal 3–5 mmHg.

• A rise in hepatic venous pressure to >5 mmHg defines portal hypertension causes plasma-like fluid to transude from the liver surface: the basis of ascites.

• ≥10–12 mmHg: clinically significant; varices expected

Blood Reservoir

holds ml? % of blood volume?

can store extra ml?

SNS activation?

Holds ~450–500 mL (~10% of blood volume)

And so when it meets resistance and can't push the blood forward efficiently, that backflow, the liver catches a lot of it up to an additional 500 milliliters than it normally has.

Stores up to ~1L when right atrial pressure is high

• Ex: during a central line, if someone's really dry, you can actually press on their liver and you'll see that the internal jugular vein dilate whenever you press on the liver.

Sympathetic activation = venoconstriction → expels up to ~500 mL into IVC

Hepatic lymph

how much lymph goes through here? why?

Protein ~6 g/dL (near plasma)

1/3 to 1/2 of all body lymph

The hepatic lymph or the lymph flow, usually Whenever there's arterial perfusion to a part of the body, the veins pick up about 90% of the fluid that left the vascular space and brings it back into the venous space.

And that last remaining 5 to 10% is picked up by the lymph.

But in the liver, because of how high the protein concentration is in the cells themselves.

About one third to half of all the body lymph is actually in the liver as opposed to all the other tissues.

So even though it, you know, even though it gets roughly 25% of the blood flow in the body, it can have almost half of the body lymph compared to the rest of the body.

Regulation of Hepatic Blood Flow

Portal 3

Hepatic artery 3

SNS tone 3

Portal vein

• Passive, low-pressure system

• Flow set by splanchnic arteriolar tone and intrahepatic resistance

• Not autoregulated: follows gut and spleen outflow

Hepatic artery

• High-pressure, high-resistance system

• Depends on cardiac output and autonomic tone

• Local regulation via the HABR

Sympathetic tone

• Constricts arterioles, sinusoids, and venules: total flow falls

• Venule constriction shifts blood into the systemic circulation

• Key compensation in hemorrhage

Hepatic arterial buffer response (HABR)

flow r/ts for portal & artery

↑ SNS does what? 2

If Portal flow falls → Less adenosine washed out → Hepatic arterioles dilate → arterial flow rises to compensate and it may not fully replace the lost portal flow. (Doesn’t fix underlying issue)

• arterial flow can rise by as much as 100%

• HABR is semireciprocal: changes in portal flow inversely affect arterial flow.

When you have an ↑ in sympathetic tone, this constricts arterials and sinusoids and venules and ultimately decreases flow.

• And the venual constriction will shift blood into systemic circulation.

• lowers O₂ delivery to zone 3 and slows clearance of high-extraction drugs.

What Reduces Hepatic Blood Flow?

Volatile anesthetics

sevo

iso

des

halo

Dose-dependent ↑↑; desflurane moderate, isoflurane and sevoflurane minimal; halothane greatest. Isoflurane is a direct hepatic vasodilator, so safer.

• meaning the higher the dose, the more hepatic blood flow is decreased.

Mostly vasodilate, but they can still reduce total hepatic blood flow. The main reason is that volatile anesthetics can lower cardiac output and blood pressure, which reduces portal-vein flow. The hepatic artery may dilate to compensate, but that compensation may not fully make up the difference

For liver perfusion, isoflurane is generally considered safer than halothane. Isoflurane tends to preserve hepatic arterial flow; halothane can reduce both hepatic arterial and portal flow, with larger decreases reported in some studies

What Reduces Hepatic Blood Flow?

Induction of anesthesia - why?

↓ HBF as much as %?

HBF may fall 30–50%, mainly via ↓ MAP and ↓ cardiac output with reflex splanchnic vasoconstriction

Induction of anesthesia can decrease hepatic blood flow and really flow of everything, but it's primarily because of its effects on map and cardiac output.

What Reduces Hepatic Blood Flow?

Neuraxial block - causes? outcome?

Sympathectomy-induced HPT = ↓ splanchnic flow

A spinal (subarachnoid) anesthetic causes a rapid sympathectomy, so blood pressure may drop before compensatory responses can catch up

• Ex: used in C-section or joint replacement

An epidural can also cause sympathectomy, but its onset is generally slower and less abrupt.

What Reduces Hepatic Blood Flow?

Positive pressure ventilation, PEEP

↑ Intrathoracic and hepatic venous pressure, ↓ venous return and cardiac output, reflex sympathetic tone

Positive pressure ventilation and PEEP, this increase in angiothoracic pressure and hepatic venous pressure will ultimately decrease venous return and cardiac output.

So if you have less blood returning to the left side of the heart, then you have less to actually pump out of the heart. Therefore, cardiac output decreases.

What Reduces Hepatic Blood Flow?

PaCO₂ - ph?

Hypercapnia and acidosis vasodilate (↑ flow); hypocapnia and alkalosis vasoconstrict (↓ flow)

PACO2, hypercapnia and acidosis, vasodilate vessels to the liver so that it increases flow

hypocapnia and alkalosis vasoconstrict and ultimately decrease flow.

What Reduces Hepatic Blood Flow?

Upper abdominal surgery - 3

Largest decreases: traction, compression, catecholamine release

This is the largest decreases whenever there's traction or compression or catecholamine release, especially if the procedure involves the liver itself.

If they put some traction on the liver and pinch off the IVC or something, you can have a very, very large abrupt acute drop in blood pressure.

Liver Fx:

Carbohydrate - buffer system?

Gluconeogenesis

Glycogenolysis

clears % insulin on first pass

Glucose buffer function: when BGL ↓, Glycogen stored after meals is releases into blood stream triggering glycogenolysis resulting in ↑ BGL

Poor liver function: postprandial glucose can rise 2–3× normal

Gluconeogenesis from lactate, pyruvate, amino acids, and glycerol

Glycogenolysis triggered by epinephrine and glucagon

Clears ~50% of insulin on first pass

Liver Fx:

Fat

Beta Oxi?

Synthesizes 3

% of what? become what?

β-oxidation produces acetyl-CoA beyond the liver's needs; exported as acetoacetate

Synthesizes most cholesterol, lipoproteins and phospholipids

• Nearly all fat synthesis comes from carbohydrate and protein

• ~80% of hepatic cholesterol becomes bile salts

Liver Fx:

Protein

synthesis of which type of AA? albumin?

Deamination

Urea cycle?

synthesis of nonessential amino acids

makes ~90% of plasma proteins (not γ-globulins); 15–50 g/day

Albumin: main determinant of oncotic pressure; t½ ~3 weeks

Deamination of amino acids for energy or conversion

Urea cycle removes ammonia from gut and tissues

• Loss of urea formation, or portal flow that bypasses the liver, lets ammonia accumulate: the basis of hepatic encephalopathy.

Liver Fx:

Hemostasis

Makes all clotting factors except? 3

Vitamin K-dependent proteins 6

Thrombopoietin

All clotting factors except III, IV, VIII

Vitamin K-dependent proteins which helps activate the following: II, VII, IX, X, C, S

Thrombopoietin: which signals the bone marrow to make platelets

Liver Fx:

Storage

Vit A

Vit D

Vit B

Fe
Glycogen
Blood

Fx reserve

Vitamin A: up to ~10 months' supply

Vitamin D: ~3–4 months

Vitamin B12: ≥1 year

Iron: apoferritin binds iron as ferritin, a blood iron buffer

Glycogen: ready glucose state meant to be broken down asap for ↑ BGL

Blood (reservoir 500-1000 ml)

Large functional reserve: significant disease can exist before laboratory tests become abnormal.

Liver Fx:

Bile Formation & the Biliary Tree

production ml/day?

how and where is it released? relax it? 2

Fx of bile? 3

Production

• ~500 mL/day

• Bile salts, bilirubin, cholesterol, phospholipids

• Route for drug and metabolite excretion

Release

• Between meals: high Oddi tone diverts bile to gallbladder

• Duodenal fat in small intestine → release of cholecystokinin (CCK) → GB contracts, Oddi relaxes → content comes out

• All opioids can cause sphincter of Oddi spasm; the more potent the opioid, the greater the rise in biliary pressure.

  • But one of the ways is reversing the opioids with Narcan (not recommended)

  • Glucagon is another one that can cause the sphincter to relax

Function

• Micelles absorb fat and vitamins A, D, E, K

• Enterohepatic recycling of bile salts

• No bile = steatorrhea, vitamin K deficiency in days

Now, just because someone's had a cholecystectomy or having their gallbladder removed doesn't mean that they can't excrete drugs through the bile.

• They still can. They just won't be in the gallbladder. It'll go from the liver straight to the duodenum.

Liver Fx:

Detoxification & excretion

drugs leave via? 2

hormone inactivation 3 (3)

Kupffer kill rate?

Drugs excreted into bile or made renally excretable

Hormones inactivated: thyroxine, catecholamines, steroids (estrogen, cortisol, aldosterone)

Liver damage → hormone excess from buildup

Kupffer cells filter 99% of gut bacteria

Liver Regeneration

restore up to %?

growth factor? 3

halted by? impaired by?

Restores mass after loss of up to ⅔–70%

Driven by hepatocyte growth factor, EGF, TNF, IL-6

TGF-β halts proliferation

Impaired by fibrosis, inflammation, viral infection

• a fibrotic liver that essentially can't regenerate.

When Function Fails: Physiologic Consequences

Albumin synthesis 2

Clotting factors 2

Plasma cholinesterase 2

Albumin synthesis

• Falls slowly (t½ ~3 weeks)

• ↓ Oncotic pressure (edema, ascites); ↑ free fraction of protein-bound drugs (drugs bound to protein are inactive)

• If someone's emaciated, or someone has low albumin, then they're more sensitive to the propofol because there's not as much protein for it to be bound to

Clotting factors

• ↓ Synthesis; short half-lives (factor VII)

• PT/INR prolongs quickly with acute injury

Plasma cholinesterase

• ↓ Synthesis

• Helps in succs metabolism = prolonged action; ↑ ester local anesthetic exposure

When Function Fails: Physiologic Consequences

Glucose homeostasis

Urea cycle

Fluid compartments

Glucose homeostasis

• ↓ Glycogen stores, gluconeogenesis, insulin clearance

• Hypoglycemia (severe disease) or hyperinsulinemia

Urea cycle

• ammonia can't be converted into urea to be removed by the kidneys = ammonia accumulation

• Encephalopathy; ↑ sensitivity to sedatives

Fluid compartments

• ↓ Oncotic pressure, Na retention

• ↑ Volume of distribution of many drugs

  • more drugs outside the bloodstream—into tissues or body fluids—so less remains in the plasma.

Bilirubin Formation & Conjugation

rbc age? goes where? to make? 2

how much unconjugated bili is made?

what happens in hepatocytes?

1. After ~120 days, macrophages in spleen (RES: reticuloendothelial system), split hemoglobin into globin and heme

2. Heme oxygenase → biliverdin → unconjugated (free) bilirubin ~200–300 mg bilirubin/day

3. Unconjugated bilirubin is lipid-soluble and travels bound to albumin to liver

4. In hepatocytes: ~80% glucuronide (UGT), ~10% sulfate, ~10% other; now water-soluble

5. Actively secreted into canaliculi → bile → intestine

6. Bacteria form urobilinogen: some → stercobilin (stool); some reabsorbed,

   1. ~5% reaches urine as urobilin, even w/ liver failure % doesn’t change

Jaundice

normal? abnormal?

is there a specific lab test?

Normal plasma bilirubin ~0.5 mg/dL, almost all unconjugated

Skin yellows >1.5 mg/dL (≈3× normal)

The Van den Bergh reaction is a lab test: It distinguishes bilirubin in a blood sample by how it reacts: conjugated bilirubin reacts directly, while unconjugated bilirubin needs an added accelerator.

Jaundice: Classification

Prehepatic (hemolytic) -

Unconjugated rises

Production exceeds hepatic excretory capacity

↑ Urobilinogen in gut and urine

Normal stool color

Jaundice: Classification

Hepatocellular -

Mixed picture

Impaired uptake, conjugation, or secretion

Hepatitis, cirrhosis, drugs

Gilbert syndrome; immature neonatal conjugation

Jaundice: Classification

Obstructive - aka

s/s 3

how does renal help?

sx?

aka cholestatic jaundice

No bile in gut → fat-soluble vitamin K malabsorption

Delayed excretion of drugs and metabolites cleared in bile

↓ Factors II, VII, IX, X and proteins C, S

Conjugated rises; refluxes into blood

Total obstruction: no urinary urobilinogen, clay-colored stools

• Rarely >35 mg/dL (renal excretion)

• because the kidneys can remove some of the water-soluble, conjugated bilirubin into the urine (dark)

PT corrects with parenteral vitamin K if hepatocytes can still synthesize factors

blockage: need cholecystectomy

Unconjugated bilirubin effects on body - 3

Vitamin K administration? 2

Lipid-soluble; when unbound it crosses the blood-brain barrier and is neurotoxic

Albumin binding is protective; drugs competing for albumin raise free bilirubin

Conversely, bilirubin and bile acids displace drugs from binding sites, raising free drug fraction

Neonates: immature glucuronidation raises risk of bilirubin encephalopathy (kernicterus)

Vitamin K response separates malabsorption (obstruction) from synthetic failure (hepatocellular disease).

• Bile duct obstruction: Little bile reaches the intestine, so vitamin K isn’t absorbed well. The liver may still be able to make clotting factors, but it lacks vitamin K. Giving vitamin K by injection bypasses the gut; PT/INR improves.

• Hepatocellular synthetic failure: The liver cells can’t make enough clotting factors. Adding vitamin K doesn’t fix that, so PT/INR stays prolonged or improves little.

Drug Metabolism

Phase I: functionalization - 3

Oxidation (most common): CYP450 'mixed function oxidase' needs NADPH and O₂

Reduction: occurs when O₂ is low (e.g., halothane)

Hydrolysis: ester bonds, often outside the liver: remifentanil, succinylcholine, esmolol, ester local anesthetics

• Products may be inactive, active, or toxic (reactive epoxides detoxified by glutathione)

Fx Most affected by liver disease and aging

Both phases convert lipophilic → hydrophilic.

Some drugs go through Phase I, then Phase II. vice versa.

Some only does one or the other

Drug Metabolism

Phase II: conjugation - 2

“attaching a water-friendly tag” so the drug or its metabolite can leave in urine or bile.

Glucuronidation (UGT), sulfation, acetylation, glutathione conjugation

Adds a large polar group: water-soluble for bile or urine

Propofol (glucuronide), morphine (M3G inactive, M6G active), midazolam's active α₁-hydroxy metabolite

N-acetylation: isoniazid

Relatively preserved until late liver disease: not as affected during early liver disease

Both phases convert lipophilic → hydrophilic.

Lorazepam, oxazepam, temazepam need only phase II.

Drug Metabolism

The Cytochrome P450 System - fx, where? 2

So cytochrome P450 is really important for metabolism in the liver and upregulation and downregulation of cytochrome P450 enzymes can increase or decrease metabolism of a lot of medications that you'll see.

Heme proteins on hepatocyte smooth ER ("microsomal") and these are riches in zone 3 of the liver. Also in gut, kidney, lung, adrenal, but it's primarily in the liver.

So these cytochrome P450 enzymes have different names and different ones metabolize different medications.

The Cytochrome P450 System Table -

CYP2D6 in Pediatrics

which drug?

Codeine is a prodrug that CYP2D6 converts to morphine.

Poor metabolizers may get little pain relief; ultrarapid metabolizers can produce too much morphine, causing dangerous respiratory depression

Codeine is contraindicated for patients under 18 after tonsil or adenoid surgery

If you have to give it, make sure its in PACU and they don’t go home after

Enzyme Induction vs. Inhibition

↑ Enzyme expression; develops over days to weeks

Parent drug levels fall → tolerance, ↑ dose requirement

More reactive intermediates possible (glutathione depletion)

Inducers: ethanol, barbiturates (phenobarbital), phenytoin, carbamazepine, rifampin, smoking

Example: ↑ requirement for sedatives, opioids, vecuronium, rocuronium

This is why alcoholics require more anesthesia is because of their cytochrome P450 induction.

Prodrugs reverse the rule: induction raises active metabolite; inhibition lowers it (e.g., codeine via 2D6).

Enzyme Induction vs. Inhibition

Drugs compete for the enzyme's active site; onset within hours

Parent drug levels rise → prolonged effect or toxicity

Inhibitors: cimetidine, azole antifungals, macrolides, ritonavir, amiodarone, diltiazem, verapamil, grapefruit juice (3A4)

Example: erythromycin + midazolam → prolonged sedation

So is there the timing of reversing their paralytic will be longer if you know the patient takes something like cimetidine or another medication that inhibits subchrome P-450.

Prodrugs reverse the rule: induction raises active metabolite; inhibition lowers it (e.g., codeine via 2D6).

Liver Disease & Drug Disposition Table -

Volatile Agents & the Liver

Sevo

Iso

Des

Halo

• Sevo: no TFA; forms HFIP and inorganic fluoride

  • 2% metabolized

• Iso and des form trace TFA: rare cross-sensitivity

  • 0.2% and 0.02% metabolized

• Halothane

  • CYP2E1 oxidation → trifluoroacetyl (TFA) adducts on liver proteins → neoantigens

    • 20% metabolized

  • Mild ALT rise in ~10–30%; fulminant hepatitis ~1 in 10,000–30,000

  • Risks: female, middle age, obesity, repeat exposure; zone 3 necrosis

Cirrhosis & Portal Hypertension

backward vs forward?

outcomes? 5

Backward: fibrosis and regenerative nodules ↑ intrahepatic resistance = hard going out

• Stellate cells drive fibrosis; portal pressure can reach 20–30 mmHg.

Forward: splanchnic vasodilation (nitric oxide) ↑ portal inflow = alot coming in

↓

PORTAL HYPERTENSION - HVPG >5 mmHg (≥10–12 clinically significant)

• Esophageal and gastric varices; portosystemic shunting

• Splenomegaly: Platelet sequestration → thrombocytopenia

• Ascites: Sinusoidal hypertension + ↓ albumin + Na retention

• Encephalopathy: Gut toxins bypass the liver

• Hyperdynamic state: ↓ SVR, ↑ CO; RAAS/ADH → HRS

Hyperdynamic Circulation

of cirrhosis/portal hypertension - 4 steps

This card is describing the hyperdynamic circulation of cirrhosis/portal hypertension. The confusing part is that total blood volume can be high while the arteries are still underfilled.

1. Splanchnic vessels dilate, largely due to nitric oxide (NO).

2. Blood pools in the expanded abdominal vascular bed, so effective arterial volume falls.

3. The heart compensates with ↑ heart rate and ↑ cardiac output. But because vessel resistance falls (↓ SVR), blood pressure may still be low or low-normal.

4. Vasodilation also makes vessels less responsive to sympathetic signals and vasopressors.

Here, NO means nitric oxide—not nitrous oxide (N₂O), the anesthetic gas.

Cirrhotic Cardiomyopathy

r/ts of CO vs peripheral vascular resistance

response to stress? 2

Autonomic neuropathy %

1. Even with ↑ CO there is ↓ peripheral vascular resistance

2. Systolic and diastolic dysfunction; blunted response to stress

• β-adrenergic hyporesponsiveness

• Electrophysiologic changes: prolonged QTc in 30% (Child A) to 60% (Child C)

Autonomic neuropathy in ~43%

So you have remodeling and decreased responsiveness to medications with chronic liver failure.

the heart may have a normal ejection fraction at rest but still have poor reserves and a blunted response when stress requires it to increase cardiac output.

• Ex: stress of induction of anesthesia = pt coding

Hemostasis in Liver Disease:

Coagulation factors

what ↓ and ↑?

VTE risk?

↓ fibrinogen in %?

lab accuracies?

↓ Procoagulants and ↓ anticoagulants (protein C, antithrombin)

↑ Factor III, VIII and vWF (made outside hepatocytes) - to compensate

Thrombin generation often normal; VTE risk not reduced

Dysfibrinogenemia in 70–80%

PT/INR measures only procoagulants, so it predicts bleeding poorly in cirrhosis. The balance is fragile and tips either way.

Hemostasis in Liver Disease:

Platelets

thrombocytopenia in %?

Thrombocytopenia in 30–64%

Splenic sequestration (up to 90% of platelets)

• solution there is to do a splenectomy because cirrhosis raises pressure in the portal vein system. That pressure backs up into the splenic vein, making the spleen congested and enlarged.

↓ Thrombopoietin; marrow suppression

↑ vWF partly compensates adhesion

Hemostasis in Liver Disease:

Fibrinolysis - slow down or increase?

Hyperfibrinolysis in 30–46% of end-stage disease: break clots down too quickly

Liver normally clears tPA and makes plasminogen, PAI-1, TAFI

Net balance, not one value, determines bleeding between clot-building and clot-breaking proteins matters. Cirrhosis doesn’t automatically mean the blood can’t clot; the balance can shift toward either bleeding or clotting

Renal Dysfunction

what is activated for too long? what e-?

↓ Effective arterial volume → SNS, RAAS, vasopressin prolonged activation

Na and water retention; dilutional hyponatremia, hypokalemia

Renal prostaglandins maintain perfusion = ↑ NSAID sensitivity

HRS: functional prerenal failure; kidneys work after transplant

Type 1: creatinine doubles in <2 weeks; Type 2: indolent, refractory ascites

• So functionally they have pre renal failure because of the restricted blood flow to the kidneys. But if you correct the liver problems, then the kidneys will correct also as long as they're not failing.

Ascites - 3 combo

SAAG?

threshold?

what organ is next?

Most common complication of cirrhosis

Sinusoidal hypertension + ↓ oncotic pressure + renal Na retention

Fluid is protein-rich; can cause relative intravascular hypovolemia

SAAG ≥1.1 g/dL indicates portal hypertension (~97% accuracy)

↓ FRC and atelectasis from diaphragmatic splinting

Onset of ascites marks a threshold: ~50% mortality within 3 years. HRS risk with ascites: 18% at 1 year, 39% at 5 years.

• hepatorenal syndrome—kidney dysfunction that can develop in advanced liver disease, often when ascites is present.

Pulmonary Complications: HPS - IPVD

dead space vs shunt?

aa gradiet?

hallmark?

response to O2?

Hepatopulmonary syndrome (HPS)

Core problem

• Intrapulmonary vascular dilation (IPVD)

Mechanism

• Capillaries dilate from 8–15 µm to 50–500 µm: diffusion–perfusion defect, functional shunt

Criteria

• Liver disease + PaO₂ <80 mmHg or A–a gradient ≥15 mmHg on room air + IPVD on bubble echo

Hallmark

• Orthodeoxia: hypoxemia worsens upright, improves supine

• Also common: ascites and hepatic hydrothorax restrict lung volumes; 50–70% of patients report dyspnea.

Response to O₂

• Type I improves with 100% O₂; failure suggests true shunt

Prevalence

• Up to 20% of transplant candidates

Pulmonary Complications: PoPH - patho

Hallmark 2

Portopulmonary hypertension (PoPH)

Core problem

• Portal hypertension/liver disease → pulmonary artery narrowing and remodeling → ↑ pulmonary vascular resistance (PVR) → ↑ pressure the right ventricle must pump against → right ventricular strain.

Mechanism

• Endothelin, shear stress from high CO, hormonal and immune factors

Criteria

• Portal HTN + mPAP ≥25 mmHg, PAOP <15 mmHg, PVR >240 dyn·s·cm⁻⁵ (3 WU)

Hallmark

• Right ventricular strain; severity by mPAP (<35, 35–50, >50)

Response to O₂

• Hypoxemia is not the main feature

Prevalence

• 2% of portal HTN; 4–6% of transplant candidates

Hepatic Encephalopathy

ammonia from?

liver dmg?

astrocytes

• glutamine

• GABA tone (reversal?)

Main pathway:

• Gut bacteria produce ammonia

  • Other toxins: mercaptans, short-chain fatty acids, manganese

• A damaged liver or blood bypassing the liver (shunting) lets more of them reach the bloodstream and brain.

• Brain support cells called astrocytes convert ammonia into glutamine as a detox step.

• Glutamine can build up inside astrocytes, drawing in water and causing swelling, edema.

• “↑ GABA tone” means the brain’s inhibitory, calming signal is stronger—like turning up the brain’s “brakes.” That can contribute to sleepiness and slowed thinking in hepatic encephalopathy.

• “Endogenous benzodiazepine-like substances” means naturally occurring substances in the body that may enhance signaling at the same receptor as benzodiazepines. It doesn’t mean the person took a benzodiazepine.

  • Flumazenil helps transiently

Hepatic Encephalopathy: Risk Factors - 4

ammonia r/ts severity

The precipitants lists things that can push someone with liver disease into an episode:

• GI bleeding (protein load)

• Infection, sepsis

• Sedatives, especially benzodiazepines

• Hypokalemia, alkalosis, hypoxia, hypovolemia

Ammonia levels correlate poorly with severity

West Haven grade - 4

Grades 1-4

1. Trivial lack of awareness, euphoria or anxiety, short attention span

2. Lethargy, minimal disorientation, personality change, inappropriate behavior

3. Somnolence to semistupor but responsive; confusion, gross disorientation

4. Coma, unresponsive to verbal or noxious stimuli

The liver test, you can read through these. I'm not really worried about super memorizing like normal levels. I do think it's important to know like the interpretation if it's high or low. -

No single test measures liver function. Use the pattern and the trend.

Patterns of Injury:

Hepatocellular

what labs are affected?

disease?

AST and ALT markedly ↑

ALP mildly ↑

Hepatitis (viral, toxic, ischemic)

Patterns of Injury:

Cholestatic

what labs are affected?

ALP, GGT, 5′-NT markedly ↑

Direct bilirubin ↑

AST and ALT mildly ↑

Patterns of Injury:

Synthetic failure

what labs are affected?

Albumin ↓ (chronic)

PT/INR ↑, not vitamin K-responsive

Platelets often ↓

Beware Misdirection of:

Passing a CBD stone

Isolated mild ↑ unconjugated bilirubin or GGT

early what labs are affected? looks like?

later what labs are affected? looks like?

Passing a common bile duct stone:

1. Passed CBD stone; AST/ALT rise early and can mimic hepatitis → Hepatocellular pattern.

2. ALP and GGT rise later → Cholestatic pattern.

Isolated mild ↑ unconjugated bilirubin or GGT often needs no workup.

Severity Scoring: Child-Pugh

Class A: good prognosis. -

Class C: limited life expectancy and high perioperative risk.

Severity Scoring: MELD

4 labs tracked

Bilirubin, INR, creatinine (± sodium)

Predicts 3-month mortality

Used for transplant allocation

Renal function is one of only three core variables: reflects HRS physiology

High-Yield Takeaways - MK

portal vs hepatic artery (flow & O2 req)

zone 3: 4

HABR 3

HVPG 4

↑ vs ↓ ER drugs

cirrhosis 5

PT/INR and albumin

Portal vein: ~75% of flow, ~50% of O₂. Hepatic artery: ~25% of flow, ~50% of O₂

Zone 3: least O₂, most CYP450 → first hit by hypoxia, acetaminophen, halothane

HABR: ↓ portal flow → adenosine accumulates → hepatic artery dilates

HVPG >5 mmHg = portal hypertension; ≥10–12 = varices and systemic disease

High-ER drugs are flow-limited; low-ER drugs are capacity- and binding-limited

Cirrhosis: hyperdynamic (↑CO, ↓SVR), rebalanced hemostasis, HRS, HPS/PoPH, HE

PT/INR reflects acute synthesis (factor VII); albumin reflects chronic (t½ ~3 wk)