Liver Path 1

Question 1

Liver blood flow

Answer 1

60-70 % incoming blood flow Portal System (splanchnic; blood returning to heart from spleen and bowel)
30-40 % incoming blood flow Hepatic Artery (off celiac artery)
Under normal conditions ~25% of cardiac output

Question 2

Normal liver

Answer 2

portal vein- 17-20 orders of branches

1-2 mm diameter lobules/acini are oriented around terminal hepatic veins and portal tracts

Question 3

Kupfer cells

Answer 3

macrophages that clean the blood coming back from the GI tract

Question 4

What happens at the sinusoid?

Answer 4

where the hepatic and portal capillaries come together and blood is mixed
obstruction here leads to various symptoms of portal hypertension that signify filtration is not happening at the liver

Question 5

Porta Hepatis

Answer 5

Where everything enters and leaves the liver
Disease processes happen here
Bile duct, portal vein, and hepatic artery travel together in the liver and have 17-20 orders of branches

Question 6

ascites

Answer 6

increased vascular pressures in the liver with blockage at the sinusoids–> lymph production increases and can’t make it to the thoracic duct
it seeps out the capsule of the liver –> liters of fluid entering the abdomen in patients with cirrhosis

Question 7

blood flow within the lobule

Answer 7

from the portal zone to the central hepatic vein

resistance to blood flow within the liver is normally very low due to the tons of fenestrations, etc.

Question 8

Classic Liver Lobule

Answer 8

The liver lobule is composed of anastomosing plates of hepatocytes separated by hepatic sinusoids. Hepatocytes are oriented radially to periphery of lobule.

In the center of the lobule is the central vein which takes blood into the hepatic veins to inferior vena cava.

Question 9

Portal triad

Answer 9

interlobular bile duct, vein, and artery

lymphatics are also here

Question 10

Space of Disse

Answer 10

very miniscule space between the endothelial cells and the sinusoidal blood
interstitial fluid flows here back out to the drainage via lymphatic duct

Question 11

when does fluid begin to transude?

Answer 11

When the pressure in the hepatic veins rises only 3 to 7 mm Hg above normal, excessive amounts of fluid begin to transude into the lymph and leak through the outer surface of the liver capsule directly into the abdominal cavity = Ascites

Question 12

Cell of Ito

Answer 12

stores fat vitamin A and lipids, usually inert

but when it gets going, releases collagen and is the primary cause of fibrosis in the liver

turned on by inflammatory cytokines, etc.

Question 13

bile canaliculi

Answer 13

Bile canaliculi are anatomically separated from sinusoids by tight junctions that can be disrupted by hepatocyte injury allowing canalicular bile contents to leak into sinusoidal blood flow –> jaundice.

Fenestrated endothelium

Not just bile duct obstruction can cause jaundice.

Question 14

Space of Mall

Answer 14

Lymph originates in the perisinusoidal space, flows backward, in the space of Disse, toward the terminal lymphatic channels in the portal triad.

When it reaches the triad, the space of Disse is continuous with the virtual space of Mall between the limiting plate hepatocytes and the portal tract connective tissue.

Question 15

The endothelial layer

Answer 15

is fenestrated and not supported by a basal lamina (“liver sieve”). Hepatocytes are directly exposed to plasma. Pathology impairs this normal diffusion

Question 16

shapes of sinusoids

Answer 16

toruous and anastomtic

Question 17

Hepatic Cords & Sinusoids

Answer 17

Structure: Continuous plates (cords) of hepatocytes with surrounding sinusoids and intervening ‘Space of Disse’

Cells:
Hepatocytes
Sinusoidal endothelial cells
Kupffer cells (attached macrophages, intrasinusoidal)
Stellate (Ito) cells (perisinusoidal, in Space of Disse, fat/vitamin/fibrous tissue metabolism)

Question 18

Sinusoidal blood

Answer 18

= mix of portal vein and hepatic artery

Question 19

Zones of the liver acinus

Answer 19

Low oxygen tension around central vein leads to certain types of pathology

This results in part from the zonal gradient of oxygenation and metabolic activities.

Zone 1- High levels of oxygen; encircles the portal tracts where the oxygenated blood from hepatic arteries enters
Zone 2- Intermediate levels of oxygen
Zone 3- Low levels of oxygen- located around central veins, where oxygenation is poor

Question 20

Distribution of hepatocyte enzymes

Answer 20

in metabolism are not uniformly distributed–> different toxins and drugs injury pattern
Large concentration of mitochondria around central vein, area responsible for detoxification and generation of metabolic byproducts which can be toxic to the liver i.e. Tylenol

Question 21

how do you tell a bile duct from portal vein, etc.?

Answer 21

bile duct will have duct epithelial cells (blue) lining the lumen (ideally)

portal vein usually very dilated, has largest lumen

small arterioles– smooth muscle

Question 22

Zone 1

Answer 22

Zone 1 – represents the portion of parenchyma closest to the portal vein and hepatic artery – it is the first to receive oxygen and nutrients. Oxidative metabolism predominates here (e.g. gluconeogenesis and protein synthesis)

Question 23

Zone 3

Answer 23

lies farthest from portal vein and hepatic artery (closest to the central veins) – the least oxygen gradient. Reduction processes are predominant in this location – e.g. detoxication and are more active in glycolysis and lipogenesis (processes requiring less oxygen).

Question 24

Liver Metabolic Functions Review

Answer 24

Formation and excretion of bile during bilirubin metabolism

Regulation of carbohydrate homeostasis

Lipid synthesis and secretion of plasma lipoproteins

Control of cholesterol metabolism

Formation of urea, serum albumin, clotting factors, enzymes, and numerous other proteins

Metabolism or detoxification of drugs and other foreign substances

Question 25

late vs early indicators of liver problems

Answer 25

Most coagulation factor half lives <24-48 hrs --> early sign of abnormal liver function. (Some Vitamin K dependent factors 2,7,9,10) Albumin half life 20 days --> late indicator of abnormal liver function Patients with advanced liver disease can have either or both bleeding tendency and risk of thombosis. Many of the anti-coagulation factors are also synthesized in the liver Decreased synthesis of anticoagulants such as antithrombin and protein C.

Question 26

Causes of Liver Injury

Answer 26

Infectious - Viral hepatitis Immune Mediated - Autoimmune hepatitis Drug and Toxin - Acetaminophen - Ethanol Metabolic - Non-alcoholic fatty liver disease (diabetes and obesity) Genetic - Hemochromatosis - Wilson’s disease - Alpha-1 antitrypsin deficiency Autoimmune Cholangiopathy - Primary biliary cirrhosis - Primary sclerosing cholangitis

Question 27

much of the injury to the liver occurs because of

Answer 27

our own immune system that is for the most part viral infection of hepatocytes causes minimal cell injury it is the immune response to the viral antigens associated with hepatocytes that causes the injury and surprisingly patients that mount a mild or moderate immune reaction with very little initial liver injury frequently go onto chronic liver disease whereas those that experience moderate to severe acute hepatitis with hepatocyte injury and sell necrosis frequently clear the virus more effectively

Question 28

Cellular injury in the liver occurs in the following general settings

Answer 28

oxygen deprivation (either hypoxic or ischemic); chemical or drug injury; infection; immunological injury; genetic misprogramming (alpha 1 antitrypsin) and metabolic imbalance Short of hepatocellular death, these changes are essentially reversible phenomena, in that with removal of the offending agent or correction of the disease condition hepatocytes presumably can recover both morphologically and functionally.

Question 29

Accumulation of metals that can be toxic or misfolded proteins -->

Answer 29

apoptosis and susceptibility to enzymatic digestions (lungs, pancreas liver) Remember that the portal venous flow brings large volumes of new antigens, bacterial products, metabolites to the liver the local liver immune system is regulated in some unique ways to prevent injurious immune reactions Knife edge of tolerance and vigorous immune response --> chronic viral infections

Question 30

Acute liver failure

Answer 30

evidence of *coagulation abnormality and any degree of *mental alteration in a patient without pre-existing cirrhosis and with an illness less than 26 weeks duration Onset of liver failure within 26 weeks after onset of new liver disease Defined by evidence of impaired liver function: increased prothrombin time encephalopathy Caused by: >80% loss of hepatocytes Mortality rate: 40-80% Approach: Hospitalize and consider liver transplantation

Question 31

What should we do in acute liver failure?

Answer 31

It is vital to promptly get viral hepatitis serologies, including A-E as well as autoimmune serologies, because these often seem to be neglected at the initial presentation. Fulminant Wilson’s disease can be diagnosed most effectively not by waiting for copper levels (too slow to obtain) or by obtaining ceruloplasmin levels (low in half of all ALF patients, regardless of etiology), but by simply looking for the more readily available bilirubin level (very high) and alkaline phosphatase (ALP; very low), such that the bilirubin/ALP ratio exceeds 2.0. Any patient with very high aminotransferases and low bilirubin on admission with ALF very likely has acetaminophen overdose, with the one possible exception being those patients who enter with ischemic injury

Question 32

Meld Scores

Answer 32

Model for End-state Liver Disease less than 15 not a candidate for transplantation (not a linear relationship to mortality)

Question 33

Manifestations of Acute Liver Failure

Answer 33

Jaundice Neurologic symptoms Encephalopathy Portal hypertension Hepatorenal syndrome

Question 34

Info on acute liver failure

Answer 34

80% loss of liver is not irreversible  ne to survive the initial injury Neurologic symptoms can include a asterixis (flapping tremor) and hyperactive reflexes. Hepatic encephalopathy can range from sleep disturbance  lethargy deep somnolence  coma Portal hypertension is secondary to increased resistance to blood flow through the liver to the vena cava

Question 35

Hepatorenal syndrome is thought to be triggered by

Answer 35

vasodilation in the splanchnic circulation leading to decreased renal perfusion and glomerular filtration.

Question 36

Most often associated with portal hypertension secondary to alcoholic cirrhosis or severe alcoholic hepatitis.

Answer 36

Rise in creatinine Low sodium excretion Oliguria

Question 37

Laboratory Assessment of Liver Injury

Answer 37

Hepatocyte injury - Serum aminotransferases (AST, ALT) Cholestatic biliary tract dysfunction - Serum bilirubin (direct and indirect) - Alkaline phosphatase Synthetic function - Serum albumin (20 day half life) - Coagulation factors (5-48 hrs half life)

Question 38

The initial evaluation of liver disease involves a battery of blood tests, which can assess

Answer 38

hepatic necroinflammation (serum aminotransferases), recent 12-24 hrs cholestatic biliary tract dysfunction (alkaline phosphatase, γ-glutamyl transpeptidase) obstruction or hepatocyte injury tight junction excretory function (bilirubin), and synthetic function (coagulation factors, albumin Coagulopathy, decreased serum albumin, and hyperbilirubinemia are observed in more profound hepatocellular injury.

Question 39

Key Concepts (Robbins): Liver Failure

Answer 39

Liver failure may follow acute injury or chronic injury, but may also occur as an acute insult superimposed on an otherwise well-compensated chronic liver disease. Serious and sometimes fatal sequelae of liver failure include coagulopathy, encephalopathy, portal hypertension, bleeding esophageal varices, hepatorenal syndrome, and portopulmonary hypertension.

Question 40

Mnemonic for causes of acute liver failure

Answer 40

A: Acetaminophen, hepatitis A, autoimmune hepatitis B: Hepatitis B C: Hepatitis C, cryptogenic D: Drugs/toxins, hepatitis D E: Hepatitis E, esoteric causes (Wilson disease, Budd-Chiari) F: Fatty change of the microvesicular type (fatty liver of pregnancy, valproate, tetracycline, Reye syndrome)