Liver Path 1 Flashcards
Liver blood flow
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
Normal liver
portal vein- 17-20 orders of branches
1-2 mm diameter lobules/acini are oriented around terminal hepatic veins and portal tracts
Kupfer cells
macrophages that clean the blood coming back from the GI tract
What happens at the sinusoid?
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
Porta Hepatis
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
ascites
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
blood flow within the lobule
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.
Classic Liver Lobule
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.
Portal triad
interlobular bile duct, vein, and artery
lymphatics are also here
Space of Disse
very miniscule space between the endothelial cells and the sinusoidal blood
interstitial fluid flows here back out to the drainage via lymphatic duct
when does fluid begin to transude?
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
Cell of Ito
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.
bile canaliculi
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.
Space of Mall
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.
The endothelial layer
is fenestrated and not supported by a basal lamina (“liver sieve”). Hepatocytes are directly exposed to plasma. Pathology impairs this normal diffusion
shapes of sinusoids
toruous and anastomtic
Hepatic Cords & Sinusoids
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)
Sinusoidal blood
= mix of portal vein and hepatic artery
Zones of the liver acinus
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
Distribution of hepatocyte enzymes
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
how do you tell a bile duct from portal vein, etc.?
bile duct will have duct epithelial cells (blue) lining the lumen (ideally)
portal vein usually very dilated, has largest lumen
small arterioles– smooth muscle
Zone 1
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)
Zone 3
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).
Liver Metabolic Functions Review
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
late vs early indicators of liver problems
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.
Causes of Liver Injury
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
much of the injury to the liver occurs because of
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
Cellular injury in the liver occurs in the following general settings
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.
Accumulation of metals that can be toxic or misfolded proteins –>
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
Acute liver failure
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
What should we do in acute liver failure?
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
Meld Scores
Model for End-state Liver Disease
less than 15 not a candidate for transplantation
(not a linear relationship to mortality)
Manifestations of Acute Liver Failure
Jaundice
Neurologic symptoms
Encephalopathy
Portal hypertension
Hepatorenal syndrome
Info on acute liver failure
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
Hepatorenal syndrome is thought to be triggered by
vasodilation in the splanchnic circulation leading to decreased renal perfusion and glomerular filtration.
Most often associated with portal hypertension secondary to alcoholic cirrhosis or severe alcoholic hepatitis.
Rise in creatinine
Low sodium excretion
Oliguria
Laboratory Assessment of Liver Injury
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)
The initial evaluation of liver disease involves a battery of blood tests, which can assess
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.
Key Concepts (Robbins): Liver Failure
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.
Mnemonic for causes of acute liver failure
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)
