Liver Flashcards
Review anatomy of the liver blood supply
Maintains homeostasis of the body, acting as a barrier between GI tract and blood stream
Decreases toxins, regulates metabolism, can withstand MANY insults
Blood enters the liver through the PORTAL VEIN –> gets distributed through the liver SINUSOIDS then exists via the CENTRAL vein, which dump into the IVC
Small intestine (jejunum, ileum) drain into SMV, which drains into the PORTAL VEIN; Large intestine drains into the IMV which drains to the splenic vein which drains to the portal vein
Lobules vs. Acini
Lobules –> Central vein in the middle, portal tracts in a hexagonal arrangement around it; central, mid and peripheral lobular zones
Acini – 3D version; PORTAL TRACT at the center, surrounded by sphere sof tissue that extend out to the central veins (periphery); spheres labeled zones 1, 2 and 3
Zone 1 lies CLOSE TO THE PORTAL TRACT (so it gets nutrients/oxygen first, but also toxins so it is susceptible to damage)
Zone 3 gets the LEAST exposure to portal blood
Liver function
DUAL BLOOD SUPPLY – hepatic artery from the systemic circulation, portal vein fromt he GI
Liver is very efficient at excreting WASTE, TOXINS, DRUGS as the blood percolates through sinusoids –> stored, used to build compounds, broken down, secreted
Manufactures most of the PLASMA PROTEINS/COAGULATION FACTORS
Detoxifies toxins by making them more POLAR and thus more WATER-SOLUBLE and easier to excrete
Bilirubin Overview
When RBCs (120 d life span) are broken down, HEME is a byproduct of hemoglobin –> HEME is further broken down into BILIRUBIN
Bilirubin is a non-polar, non-soluble compound that is transported to the liver bound to albumin –> in hepatocytes, it is CONJUGATED w/ GLUCURONIC ACID to make it soluble and excreted –> some bilirubin goes back to the blood and is excreted by the kidney
Direct vs. Indirect bili –> Excess heme production (too much RBC breakdown), blocked secretion of bilirubin, or blocked liver uptake, will lead to EXCESS INDIRECT/UNCONJUGATED BILIRUBIN
Blocked EXCRETION from the liver = EXCESS DIRECT/CONJUGATED bilirubin
Increased levels of bilirubin lead to JAUNDICE! Common to many liver diseases. So direct or indirect can tell us if it is an uptake/too much RBC breakdown/secretion OR an excretion problem
Lipid Metabolism Review
Lipids absorbed in the small intestine as CHYLOMICRONS –> transported via thoracic duct to systemic circulation –> go to adipose tissue, stored as energy, and remnants taken up by the LIVER –> lipids stored in the liver are released into the blood stream as free fatty acids bound to albumin or packaged into VLDLs –> liver also picks up cholesterol – some secreted into blood as LDLs, some oxidized to BILE and used to emulsify lipids for absorption
Lipid metabolism DEFECTS
BLOCKAGE in the uptake of lipids by hepatocytes or secretion of too many VLDLs will cause HYPERLIPIDEMIA
If lipids are properly taken up but are not properly SECRETED –> FATTY LIVER
If the liver can’t make bile acids, lipids will not be absorbed from the gut, leading to STEATORRHEA and fat soluble vitamin deficiencies
Bile acids will INCREASE in the blood if they cannot be secreted –> PRURITIS
Nitrogen Metabolism
Liver takes up AA, ammonia (from AA metabolism), biogenic amines, plasma proteins
These are metabolized and used to make other proteins, especially ALBUMIN
Ammonia is detoxified by making UREA, which is soluble, non-toxic
LOW albumin results in EDEMA and ASCITES from decreased oncotic pressure
Low levels of circulating clotting factors = EXCESSIVE bleeding
Biogenic amines and ammonia are both TOXIC at high levels, especially to the BRAIN –> HEPATIC ENCEPHALOPATHY which can lead to coma and death
CIRRHOSIS overview
Injured liver tries to heal via scarring and fibrosis –> if it progresses enough, CIRRHOSIS
Diffuse process characterized by FIBROSIS, loss of normal acinar architecture, and formation of structurally abnormal nodules –> END STAGE of MOST LIVER DISEASES
Types - classified by the SIZE of nodules –>
MICROnodular cirrhosis = many nodules, all SMALLER than 3mm, come from pre-existing acinus, scar tissue between each nodule, surface is rough, pebbly, nodular
MACROnodule cirrhosis = nodules LARGER than 3 mm, irregular, coarse, scar tissue in between
Complications of Cirrhosis?
PORTAL HYPERTENSION –> portal vein forms the confluence of the SMV and SPLENIC VEIN, with the IMV dumping into the splenic
Normally a LOW pressure, HIGH flow system –> scarring of the liver impinges on its vessels, leading to SHUNTING and BACKUP OF BLOOD –> HIGH pressure, LOW flow now!
This is PORTAL HTN, and is causes BACKUP OF BLOOD INTO VISCERA, which then tries escaping via collateral circulation
Leads to –> Hemorrhoids, caput medusa, esophageal varices, congestion of the spleen, ascites –> all dangerous, ESP Esophageal Varices –> lots of dilated veins, area susceptible to trauma –> SERIOUS bleeds
HEPATIC INSUFFICIENCY –> leads to HEPATIC ENCEPHALOPATHY (can’t metabolize nitrogen), JAUNDICE (too much bili), GYNECOMASTIA (not removing estrogen), ASCITES (low albumin)
ALCOHOL Induced Liver Injury
Most common cause of toxic liver injury
Alcohol directly damages the liver hepatocytes
10-25% of heavy drinkers END UP WITH CIRRHOSIS
Effects on liver function –> altered lipid metabolism (fatty liver), mitochondrial damage (acetaldehyde damages mitochondria), collagen synthesis and cytoskeletal damage (MALLORY BODIES, bunched up intermediate filaments –> these mallory bodies are CHEMOTACTIC for neutrophils –> Inflammation –> ALCOHOLIC HEPATITIS)
Stellate cells normally store lipid and are large; if they are damaged, they may convert to MYELOFIBROBLASTS –> most of the fat stored is Vit A –> when these cells become myelofibroblasts, Vitamin A decreases, COLLAGEN SYNTHESIS INCREASES
If these processes continue, COLLAGEN BUILDS UP, until it OBLITERATES the central veins and bridges the portal veins –> Surviving hepatocytes try to REGENERATE and form NODULES = CIRRHOSIS!
Biggest cause of cirrhosis in the 1980s? ALCOHOL
Biggest cause of cirrhosis in the later 90s to present? HEP C
Review of Normal IRON Metabolism
Mainly used for making Hb for RBCs
RBCs survive for 120 days, disposed of by macrophages in the BM, liver, spleen
This process releases 20 mg of iron PER DAY –> we need the same amount in BM for RBC production
We also ingest and excrete ~1-2 mg of iron a day
Liver is responsible for this balance/homeostasis
HEPCIDIN –> liver produces this enzyme which regulates iron in our serum –> when serum iron is HIGH, HEPCIDIN is also HIGH –> this DOWNREGULATES FERROPORTIN, which normally transports iron to hepatocytes, enterocytes, macrophages, placental cells (dumps iron into serum) –> SO, HIGH hepcidin = HIGH iron = LOW ferroportin = lowers blood iron
When serum iron is LOW, HEPCIDIN LOW, FERROPORTIN UPREGULATES, BLOOD IRON INCREASES
Genetic Hemochromatosis
Iron in DOES NOT equal iron out
Patients accumulate more and more iron via INCREASED INTESTINAL ABSORPTION
Eventually (6th or 7th decade) this will manifest in disease
Gene responsible = HFE found on chromosome 6, linked to the HLA gene (CYS-TYR mutation at codon 282 on HFE)
This mutation breaks up disulfide bonds formed between cysteines that are essential to the protein’s function (HIS-ASP is a similar mutation that DOES NOT matter)
HFE normally allows transferrin (carries iron in the blood) to bind transferrin receptors in the liver –> when a lot of transferrin binds the HFE+transferrin receptor comples, it tells hepatocytes to make MORE hepcidin, thus DECREASES ferroportin transport and LOWERING IRON IN BLOOD
With this MUTATION, there is NO HEPCIDIN when iron is too high –> INCREASE FERROPORTIN –> INCREASED IRON ABSORPTION –> TOOOOOO MUCH IRON!!!!!
Clinical Manifestations of Genetic Hemochromatosis
Liver and skin ALWAYS affected
Islets of the pancreas can be damaged – diabetes
Pituitary affected –> hypothyroid or other
Heart can accumulate iron = heart failure
Joints can accumulate iron = arthritis
Too much iron as hemosiderin/ferritin is NOT toxic, but when there is a lot of Fe, there will also be lots of FREE IRON (Fe2+ and Fe3+) which becomes TOXIC –> Oxidative damage to cell membranes, lysosomal rupture, hepatocyte necrosis, hepatic fibrogenesis –> all of this leads to CIRRHOSIS
Treating Genetic Hemochromatosis?
Pretty easy and effective –> regular phlebotomies to get rid of blood and thus iron; or chelators to bind up iron
Thus, only 10% or so of patients get actual cirrhosis with this condition
Acute Hepatitis
T cell response to a virus, drug or autoimmune antigen; antibodies have a minor role; T cells injuring liver = hepatitis
Acute patients present with nausea, loss of taste/appetite, JAUNDICE, dark urine, some abdominal pain, malaise
Histo –> liver cell apoptosis with LYMPHOCYTIC inflammatory response portally and peri-portally; KUPFER cell hypertrophy and regeneration
These patients can recover and liver can become fully functional/perfectly normal again
Most commonly caused by DRUGS or VIRUSES
Drugs –> ACETAMINOPHEN causes direct cell injury; HALOTHANE too;
Hep Viruses themselves are NOT toxic, but they produce proteins that insert into hepatocyte membranes, causing T cell responses against the hepatocytes
