Liver Flashcards
What is the functional unit of the liver?
lobule
What are the liver cells called?
hepatocytes
What run through the hepatocytes?
sinusoids
Where is bile secreted from?
bile canaliculi
What is the hepatic portal system?
One capillary bed is connected by a vein to a second capillary bed; hepatic a. connects with portal v.
Where is the first capillary bed of the hepatic portal system located and what occurs here?
Stomach and Intestine
Nutrients and toxins are absorbed
Where is the second capillary bed of the hepatic portal system located and what occurs here?
in the liver sinusoids
Nutrients and toxins leave and go to the hepatocytes
What provides 60-70% of hepatic blood flow?
portal vein
What supplies 30-40% of hepatic blood flow?
hepatic artery
What is blood flow dependent?
Hepatic clearance of many drugs and important hormones
What declines with age?
hepatic blood flow
What can cause temporary protection of hepatocytes?
ischemia or hypoxia
What does cellular acidosis protect the liver from?
oxidant chemicals
What does adenosine protect the liver from?
hepatoprotector against liver damage induced by CCl4 and ethanol
How does cellular acidosis occur in the liver?
When liver is ischemic of hypoxic, lactic acid builds up and causes the pH to decrease in the hepatocytes. This acidic pH keeps the hydrolytic enzymes that are produced from hypoxia and ischemia from detroying hepatocytes
What are the major functions of the liver?
1) Detoxification
2) Metabolism of carbs, proteins, and fats
3) Formation of coagulation factors
4) Formation of bile
5) Formation and storage of blood
6) Storage of vitamins and iron
What enzymes can be found in the liver?
CYP 450 enzymes
What is Phase I of liver metabolism?
drugs are lipophilic and are hydroxylated or oxidized to become hydrophillic
Reactive metabolites are formed
What is Phase II of liver metabolism?
the reactive metabolites formed in Phase I are conjugated and become unreactive in order to be excreted
What are found in liver sinusoids as liver macrophages?
Kupffer cells
What is the function of Kupffer cells?
Removes particulate materials and microbes from circulation
Removes 99% of bacteria from gut that flows to liver through portal system
What is glycogenesis?
excess glucose after a meal is converted to glycogen
What is glycogenolysis?
Decreased glucose between meals stimulates breakdown of glycogen
What is gluconeogenesis?
Exhaustion of glycogen reserves stimulates glucose production from amino acids and sugars
What three things are carried out in the liver in order to maintain blood glucose?
Glycogenesis
Glycogenolysis
Gluconeogenesis
How does the liver metabolize protein?
1) Deamination of amino acids
2) Removal of ammonia by synthesis of urea
3) Formation of plasma proteins
4) Synthesis of non-essential amino acids
Where does ammonia come from in liver protein metabolism?
bacterial degradation of amines, amino acids, purines, and urea in gut
How does the liver metabolize fat?
Carbs and proteins must first be converted to fat then:
1) beta oxidation of fatty acids
2) synthesis of lipoproteins, cholesterol, and phospholipids
What coagulation factors does the liver form?
Prothrombin
Factors VII, IX, and X
What does the liver require in order to make the coagulation factors?
Vitamin K
What factors effect the cause of abnormal hemostasis resulting from abnormal liver function?
1) Abnormal coagulation factor synthesis
2) Synthesis of dysfunctional coagulation factors
3) Increased consumption of coagulation factors
4) Platelet disorders
How is bilirubin formed?
be the breakdown of heme present in hemoglobin, myoglobin, cytochromes, catalase, peroxidase
What enzyme is responsible for the breakdown of heme and where can it be found?
Heme oxygenase
Found in spleen and Kupffer cells in the liver
What is associated with unconjugated bilirubin?
very poorly water soluble at physiologic pH
toxic effects
How dose bilirubin get excreted?
Unconjugated bilirubin must first be conjugated by glucoronic acid in the liver in order to be excreted in urine
How is urobilinogen produced?
by the bacterial breakdown of bilirubin excreted in bile into the bowel
How is urobilinogen excreted?
It is partly absorbed by bowel or it enters the general circulation and is excreted in urine
When would urinary urobilinogen excretion be increased?
1) excessive bilirubin production
2) Inefficient hepatic clearance of the urobilinogen
3) Excessive exposure of bilirubin to intestinal bacteria
When would urinary urobilinogen excretion be reduced?
1) biliary obstruction
2) Severe cholestasis
What are causes of elevated serum bilirubin?
1) overproduction of bilirubin
2) Impaired uptake, conjugation, or excretion of bilirubin
3) Backward leakage from damaged hepatocytes or bile ducts
What are the potential beneficial effects of bilirubin?
1) Antioxidant
2) Inverse relationship between serum bilirubin levels and risk of ischemic coronary artery disease and cancer mortality
3) Induction/overexpression of heme oxygenase reduces the replication of Hepatitis C virus
What are the physiologic mechanisms that protect against bilirubin toxicity?
1) Binding to plasma albumin
2) Rapid uptake
3) Conjugation
4) Clearance
What is urobilinogen excreted in feces?
Stercobilin
What is urobilinogen excreted in urine?
urobilin
What is the third way that urobilinogen can be excreted
By enterohepatic circulation
What is jaundice?
Refers to yellowish tint to the body tissues, including a yellowness of the skin and deep tissues
What are common causes of jaundice?
1) increased destruction of RBCs, with rapid release of unconjugated bilirubin into the blood
2) Obstruction of the bile ducts or damage to the liver cells so that even the usual amounts of bilirubin cannot be excreted into the GI tract
What are the two types of Jaundice?
Hemolytic and Obstructive
What is Hemolytic jaundice?
rapid turnover of RBCs and body can’t get rid of them fast enough
Unconjugated bilirubin is majority
What is obstructed jaundice?
Bilirubin is conjugated but can’t get to intestine to be converted into urobilinogen to be excreted
What is the normal plasma concentration of bilirubin?
0.5 mg/dL of plasma
When does the skin typically appear jaundice?
when the concentration of plasma bilirubin is 3X the normal amount
What tests are used to detect liver injury?
ALT
AST
What tests are used to test liver capacity to transport organic anions and metabolize drugs?
Bilirubin and bile acids
What enzyme when elevated reflects cholestasis?
Alkaline phosphatase
What are the liver function markers?
Albumin Prothrombin Time (PTT)
What is the function of serum aminotransferases?
these enzymes are normally intracellular but are released when hepatocytes are injured
What is the function of bilirubin and bile acids?
Measure the liver’s ability to clear endogenous or exogenous substances from circulation
What marker is impaired in plasma if heme catabolism isn’t working properly?
Bilirubin
What marker is impaired in plasma if carbohydrate metabolism isn’t working properly?
Decreased Glucose
What marker is impaired in plasma if protein synthesis isn’t working properly?
Decreased Albumin
Prolonged PTT
What marker is impaired in plasma if protein catabolism isn’t working properly?
Increased Ammonia
Decreased Urea
What marker is impaired if lipid metabolism isn’t working properly?
Increased cholesterol
Increased triglycerides
What marker is impaired if drug metabolism isn’t working properly?
Biological half time of a drug
What marker is impaired if bile acid metabolism isn’t working properly?
Increased bile acids
Where is 50% of body lymph formed?
liver
What space does porous fenestrations in sinusoidal endothelial cells leak fluid and proteins into?
Space of Disse
What is LSEC?
Liver Sinusoidal Endothelial Cells
What is the significance of the LSEC and Space of Disse?
increased sinusoidal pressure increases lymph production and fluid will leak out and accumulate in abdominal cavity as ascitic fluid
What occurs in regeneration of normal liver?
Macrophages, Hepatic stellate cells, and LSECs signal hepatocytes to enter mitosis
Hepatic stellate cells are NOT ACTIVATED
What occurs in regeneration of abnormal, chronically damaged liver?
1) Hepatocytes are very senescent and unable to divide efficiently
2) The hepatic stellate cells are ACTIVATED to myofibroblasts and excessive scar tissue inhibits regeneration
3) excessive cellular debris inhibits efficient liver regeneration
What is the function of hepatic stellate cells?
to Store Vitamin A
What are the major primary diseases of the liver?
Viral Hepatitis Nonalcoholic fatty liver disease (NAFLD) Alcoholic liver disease Hepatocellular carcinoma (HCC) Secondary to heart failure and metastatic cancer
What is liver disease?
an insidious process, except for acute
What is acute liver failure?
development of severe acute liver injury with encephalopathy and elevated PTT in a patient without cirrhosis or preexisting liver disease
What is the cutoff to define acute vs. chronic liver disease?
Illness duration less than or greater than 26 weeks
What is the major cause of acute liver failure?
Viral and drug induced hepatitis caused by APAP
What are the clinical manifestations of acute liver failure?
Hepatic Encephalopathy Severe acute liver injury, leading to liver test abnormalities Prolonged PTT/INR Jaudice Hepatomegaly RUQ tenderness Coagulopathy Increased portal hypertension
What is hepatic Encephalopathy (HE)?
reversible syndrome of impaired brain function occurring in patients with advanced liver failure
What is the pathogenesis of HE?
Hyperammonemia
Oxidative stress
Oxindole
What occurs with hyperammonemia?
Increase in brain uptake of neutral amino acids altering the synthesis of Dopamine, NE, and serotonin
Increase in intracellular osmolarity in astrocytes causign astrocyte swelling
Altered neural electric activity
What is oxindole and what does it cause in HE?
Tryptophan metabolite formed by gut bacteria that causes sedation, muscle weakness, hypotension, and coma
What are the three major pathways of APAP metabolism?
1) conjugation and excreted in urine by glutathione (90%)
2) Small portion is excreted in urine without being metbaolized
3) 10% is oxidized and forms NAPQUI
What is the substrate for alcohol metabolism in the liver?
CYP 2E1
What does acute alcohol ingestion cause?
NOT risk factor for hepatotoxicity and is actually protective by competing with APAP for CYP450 and therefore decreasing NAPQUI
What does chronic alcohol ingestion cause?
increased CYP 450 activity two fold and reduces glutathione levels
Liver damage from APAP ingestion can happen in what 3 circumstances?
Excessive intake of APAP
Excessive cytochrome P450
Decreased capacity for glucuronidation or sulfation
What are key processes of hepatocyte necrosis in humans?
Cellular Swelling
Inflammation
Release of ALT
What is most associated with chronic liver disease?
cirrhosis
What is cirrhosis?
Late stage of progressive hepatic fibrosis characterized by distortion of the hepatic architecture
Considered irreversible in its advanced stages and treatment would be liver transplant
What are the causes of cirrhosis?
Chronic viral hepatitis (Hep b or c)
Alcoholic liver disease
Hemochromatosis
Nonalcoholic fatty liver disease
What is the principle source of ECM in hepatic fibrosis?
stellate cells
What happens to stellate cells in liver injury?
They undergo activation in which they lose vitamin A, proliferate, and become fibrogenic
What is portal hypertension?
Result of resistance to portal blood flow and may lead to complications such a variceal bleeding and ascites
When does portal hypertension often develop?
when a patient has cirrhosis
What are the structural changes that occur that cause portal hypertension?
Distortion of the liver microcirculation by fibrosis
Angiogenesis
Vascular Occlusion
What are the dynamic changes that occur that cause portal hypertension?
Increased production of vasoconstrictors and reduced release of endothelial vasodilators
What are the main clinical consequences of portal hypertension?
Ascites
Congestive splenomegaly
hepatic Splenomegaly
What is Ascites?
accumulation of excess fluid in the peritoneal cavity
What is ascites caused by?
85% of the time = cirrhosis
What does portal hypertension cause profound changes in?
splanchnic circulation
What are the Circulatory abnormalities seen in patients with cirrhosis or ascites?
Reduced systemic vascular resistance Reduced arterial pressure Increased HR Increased cardiac index Increase plasma volume reduced renal blood flow Increased portal blood flow
What are the vascular abnormalities seen in patients with cirrhosis or ascites?
Splanchnic vasodilation
Renal artery vasoconstriction
Pulmonary vasodilation
What are the functional abnormalities seen in patients with cirrhosis or ascites?
Activation of systemic vasodilator factors
Activation of systemic vasoconstrictor factors
Activation of renal vasodilator factors
Reduced glomerular filtration rate
What are the biochemical abnormalities seen in patients with cirrhosis or ascites?
Sodium retention Water retention Increased systemic prostaglandins Increased systemic nitric oxide Increased renal nitric oxide and prostaglandins
What two places in the body is alcohol metabolized?
Liver and stomach
What enzyme converts alcohol to acetaldehyde?
Alcohol dehydrogenase (ADH)
What enzyme converts acetaldehyde to acetate?
Acetaldehyde dehydrogenase (ALDH)
What metabolizes the alcohol in the stomach?
Alcohol dehydrogenase
What infections can reduce the activity of gastric ADH?
Helicobacter pylori
Gastritis
What is alcoholic steatosis?
Reduced oxidation of hepatic fatty acids
Increased lipogenesis
Chronic consumption
No inflammation associated; increased fat production
What is alcoholic steatohepatitis?
Cytokines and inflammation
Antigenic adduct formation
Immunolgic
Where is iron normally stored?
Hemoglobin in RBCs
Iron containing proteins other than hemoglobin
Iron bound to transferrin in plasma
Storage iron in the form of ferritin or hemosiderin
How does the body eliminate iron excess?
Intake
Loss
Recycling
What are the causes of iron overload?
Increased intake = transfusions
Increased absorption with normal intake = Hereditary hemochromocytosis due to HFE mutation or chronic liver disease
What is the clinical consequence of excess iron stores?
organ damage from ROS
How does excess iron storage cause organ damage?
Transferring becomes saturated causing iron to bind to other proteins and molecules
These non-transferring bound iron (NTBI) are taken up parenchymal cells of the liver, heart, and endocrine organs
The excess iron in these organs interact with hydrogen peroxide to cause a fenton reaction which created fenton reagant (ROS)
What is hereditary hemochromatosis?
caused by HFE mutation in which there is increased intestinal iron absorption
What are the mechanisms of liver injury in HH?
1) lipid peroxidation
2) interaction of ROS and iron with DNA
3) Stimulation of collagen formation by activation of stellate cells
What is the clinical consequence of HH?
fibrosis and cirrhosis which occurs when hepatic iron concentration is greater than 3X its normal limit
What is the pathogenesis of Hemochromatosis?
HFE gene mutation causing hepcidin transcriptional activity to be reduced
decreased hepcidin causes unchecked iron-export by ferroportin in the macrophage which is responsible for excess plasma iron load, tissue iron accumulation, and tissue damage
What is Hepatitis A Virus (HAV)?
Self limited illness that does not become chronic
Infection confers lifelong immunity
How to you prevent HAV?
Vaccination
Immune Globulin
Attention to hygienic practices
How is HAV spread?
Ingestion of contaminated water and foods and is shed in the stool
Consumption of raw or steamed shellfish
What is the pathogenesis of HAV?
Viral replication occurs in hepatocyte cytoplasm
Hepatocellular damage and destruction of infected hepatocytes is mediated by HAV specific CD8+ lymphocytes and NKCs
Interferon-gamma have a central role in promoting clearance of infected hepatocytes
What is the incubation period of HAV?
28 days
What is are the physical findings of HAV?
Fever Jaundice Scleral icterus Hepatomegaly Abdominal Pain
What are the laboratory abnormalities found in HAV?
Increased serum aminotransferase, serum bilirubin, and alkaline phosphatase
What are the clinical manifestations of HAV?
Sudden onset of nausea, vomiting, anorexia, fever, malaise, and abdominal pain
How long are individuals infected for?
Contagious during incubation period (3 weeks) and remain so for about a week after jaundice appears
How long until patient has full recovery of HAV?
6 months
What is Hepatitis B Virus (HBV)?
global public health concern
Spectrum of clinical manifestations of infection varies in both acute and chronic disease
Clinical outcome of HBV infection depends upon the age at infection, level of HBV replication, and immune status of the host
How is HBV spread?
Blood
Semen
Other bodily fluids
What is the pathogenesis of infection of HBV?
Immune mediated liver injury caused by cytotoxic T cell-mediated lysis of infected hepatocytes
Direct cytotoxic liver injury
HBV mutations affect severity
Development of CHRONIC infection
What is associated with HBV?
cccDNA which serves as template for virus to trasncribe and translate
What is the clinical course of acute hepatitis?
Mainly have subclinical or anicteric hepatitis
More sever inpatients co-infected with other hepatitis viruses or with underlying liver disease
What are the phases of chronic HBV infection?
1) Immune tolerance
2) Immune clearance = HBeAG-positive chronic hepatitis
3) Inactive carrier
4) reactivation = HBeAg-negative chronic hepatitis
Is there a vaccine for Hepatitis C (HCV)?
No
What are the hallmarks of HCV?
Persistent infection
Chronic hepatitis
How is HCV spread?
blood-borne virus
Sharing needles to inject drugs
What causes hepatocellular carcinoma?
Combination of indirect-host mediated and direct HCV-mediated mechanisms
Persistent immune-mediated inflammation which causes ROS to trigger oxidative DNA damage
HCV infection impairs DNA repair pathways
Repeated cycles of hepatocellular destruction with regenerative proliferation and progressive fibrosis within this pro-mutagenic environment results in “cancer field”
What is Nonalcoholic Fatty Liver Disease (NAFLD)?
represents a spectrum of disorders that have in common the presence of hepatic steatosis in individuals who do not consume alcohol
What are the two types of NAFLD?
NAFL
NASH
What is nonalcoholic fatty liver (NAFL)?
hepatic steatosis is present without evidence of inflammation
What is nonalcoholic steatohepatitis (NASH)?
NAFLD that may progress to cirrhosis; NAFLD with evidence of inflammation
Which patients are at a lower risk of developing significant fibrosis?
Those with simple steatosis (NAFL)
What causes the inflammation seen in NASH/NAFLD?
Free cholesterol accumulates causing liver injury by the activation of Kupffer cells, Stellate cells, and Hepatoctyes
What do Kupffer cells cause when activated in NAFLD?
Causes secretion of proinflammatory mediators and pro-fibrotic factors
What do stellate cells cause when activated in NAFLD?
Increase liver fibrogenesis
What do hepatocytes cause when activated in NAFLD?
induces itself lipid peroxidation and lipotoxicity leading to cellular dysfunction and death
What happens in NAFLD when free cholesterol accumulates in mitochondria?
Mitochondrial dysfunction and an increase in ROS
How does insulin resistance cause hepatic steatosis?
Insulin resistance causes hyperglycemia and hyperinsulinemia which in turn further increases heptic lipogenesis which increases free fatty acids and keeps the process of liver damage going
What symptoms do patients with simple steatosis have?
they are asymptomatic
What clinical features are found in patients with NASH?
Serum AST and ALT are elevated
CVD is a frequent cause of death
Metabolic Syndrome
What is cholestatic disease?
decrease in bile flow
What are the two mechanisms that cause cholestatic disease?
hepatocellular
Obstructive
What is hepatocellular cholestatic disease?
An impairment of bile formation causes decreased bile flow
What is obstructive cholestatic disease?
An abnormal bile flow occurs after it is formed causine decreased bile flow
What does tissue deposition of bile look like in patients with cholestatic disease?
yellow discoloration of skin = jaundice
sclera due to retention of bilirubin = icterus
What symptoms are associated with cholestatic disease?
Pruritus
What is the pathogenesis of pruritus?
Bile Acids
Endogenous Opioids
Lysophosphatidic acid and autotaxin
