Introduction to Liver Diseases Flashcards
What forms the parenchymal cells of the liver and how?
Endodermal foregut gives rise to liver bud (hepatic diverticulum) around 4 weeks.
Endoderm of diverticulum grows into the mesoderm-derived mesenchyme of the septum transversum
Endoderm forms the biliary tree as well as the parenchymal cells of the liver
What will the mesenchyme of the septum transversum become?
Forms the connective tissue of the liver -> fibroblasts and stellate cells, as well as Kupffer cells and **hematopoietic stem cells in fetal liver
What forms the endothelial cells of the liver sinusoids?
Remnants of the yolk sac circulation -> vitelline and umbilical vessels
What separates the right from the left lobe of the liver? What does it contain?
The falciform ligament
Contains the round ligament (ligamentum teres) -> remnant of umbilical vein, plays a role in caput medusae
How is the liver suspended off of the diaphragm?
Anterior and posterior coronary ligaments, which have sharp lateral transitions called the triangular ligaments
What visceral lobes are contained in the right anatomical lobe of the liver?
Right visceral lobe, caudate lobe (posterior), quadrate lobe (anterior)
What are the boundaries of the quadrate and caudate lobes?
Caudate - IVC laterally, porta hepatis anteriorly, ligamentum venosum medially
Quadrate - Gall bladder laterally, porta hepatis posteriorly, ligamentum teres medially
How does bile travel in the liver from hepatocytes to GI tract?
From hepatocytes -> bile canaliculi -> canals of Hering (intralobular bile ductules, lining sides) -> bile ducts in portal tracts -> hepatic ducts (from each lobe)-> common hepatic duct -> common bile duct (where it combines with cystic duct from gallbladder) -> duodenum, stopped by ampulla of Vater
What is a lobule vs an acinus as functional units of the liver?
Lobule - hexagon centered around central vein
Acinus - functional triangle with apex centered on central vein, and opposite side formed by hepatic vessels from the portal triad
What are the three zones of hepatocytes in the acinus?
Zone 1 - closest to incoming blood supply (periportal)
Zone 2 - intermediate
Zone 3 - nearest the central vein (centrilobular)
Which zone does the most oxidative metabolism, gluconeogenesis, transamination, protein, cholesterol, and urea synthesis? Why?
Zone 1 - closest to blood inflow, has highest oxygen content and numerous mitochondria
What are zone 3 hepatocytes important for? Where in the cell do these processes occur?
Have lower oxygen content, primarily function in biotransformation - phase 1 and phase 2 reactions
Phase 1 reactions - Smooth ER
Phase 2 - conjugation reactions occur in cytosol
What zone of hepatocytes are most susceptible to drugs / toxins / hypoxia / ischemia?
Hypoxia / Ischemia - zone 3, furthest from blood supply
Drugs / toxins - Zone 3 as well, due to phase 1 reactions (ethanol and acetaminophen toxicity causes centrilobular necrosis)
What zone is most susceptible to hemochromatosis?
Zone 1 - due to it seeing the most blood first -> takes up the most iron
What type of endothelial cells line the sinusoids? Why?
Fenestrated, discontinous endothelium lacking a basement membrane
-> allows for diffusion of materials into the space of Disse (btwn endothelial cells and hepatocytes)
What are stellate cells also called and what is their function?
Cells of Ito - function to store vitamin A, and are important in the pathogenesis of cirrhosis
What determines if the liver can be regenerated with normal anatomy following damage?
Loss or preservation of reticulin (Type III collagen) framework
What is the function of the Kupffer cells?
Phagocytic cells in sinusoids involved in clearance of exogenous (i.e. bacteria) and endogenous (i.e. immune complexes) substances
How does cholestasis cause hepatocellular damage?
Bile builds up -> pressure builds -> break through tight junctions on ductule cells -> bile leaks through and solubilizes cholesterol in cell membranes
-> damage to cell membranes
What is the hallmark of Hepatocellular injury (hepatitis syndromes) and what labs will be elevated? Which is more specific for liver?
Hepatocellular damage and necrosis, with associated inflammation depending on etiology
Labs elevated: ALT and AST
ALT is more specific for liver
Think ALT = AliverT
What is the hallmark of cholestatic disorders and what labs will be elevated? How do you confirm these elevated labs are from the liver?
Abnormalities in bile flow leads to liver damage, and increased conjugated bilirubin in blood
Alkaline phosphatase will be elevated, with gamma-glutamyl transferase (GGT) and 5’-nucleotidase as specific markers which can be ordered showing damage is from liver
What is cirrhosis?
The CHF of liver disease -> endstage of all diseases which can progress to chronic liver failure
Marked by diffuse fibrosis of liver associated with formation of abnormal nodules and vascular alterations
What is the definition of acute liver failure?
Loss of 80-90% of hepatic function within weeks, most commonly caused by fulminant hepatitis
What are the symptoms of acute liver failure and whhy?
Encephalopathy -> increased nitrogen wastes
Hypoglycemia -> decreased glucose homeostasis maintenance by liver
Coagulopathy -> decreased production of coagulation factors
Renal failure -> not well understood
What viruses can cause hepatitis?
Hepatitis viruses A-E
Systemic viruses - EBV, CMV, HSV, enterovirus
What drugs / toxins can cause hepatitis? Metabolic disorders and derangements?
Drugs / toxins - alcohol, acetaminophen, Amatoxin (mushroom) -> just a shortlist
Ischemia
Metabolic disorders - non-alcoholic fatty liver disease, Wilson disease
What is autoimmune hepatitis, who tends to get it, and how is it treated?
Increased IgG titers to hepatocytes including ANA, anti-smooth muscle, anti-liver/kidney microsomal Abs.
Associated with autoimmune diseases, and thus occurs in women
Treated with immunosuppression
What are the symptoms of acute viral hepatitis?
Constitutional symptoms from inflammation -> Malaise, nausea, anorexia, fever, arthralgias
RUQ tenderness -> expansion of liver capsule from cellular infiltrate
Jaundice / icterus -> impaired bilirubin conjugation / excretion
How does acute hepatitis appear pathologically?
Lobular disarray - disruption of architecture
Random hepatocyte injury w/ ballooning degeneration, cytolysis, apoptosis
Inflammatory infiltrate, reactive Kupffer cells, and hepatocyte regeneration
How will inflammatory infiltrate appear in acute hepatitis, and what are Councilman bodies?
Will appear differently based on etiology, i.e.
Viral = lymphocytes
Alcohol = PMNs
Councilman bodies - dense, eosinophilic apoptotic bodies
What usually causes fulminant hepatitis?
Drugs - especially acetaminophin, sometimes halothane or mushrooms
Rarely - viral causes, esp. HBV/HDV coinfection
How will fulminant hepatitis appear grossly and what is the treatment?
Small, soft liver with mottled cut surface and wrinkled capsule -> shrinking due to rapid necrosis
Treatment is liver transplant
-> this is severe acute hepatitis
How does fulminant hepatitis appear microscopically?
Extensive hepatocyte necrosis with parenchymal collapse (lobular collapse)
If patient survives, there will be eventual inflammatory infiltrate and cellular regeneration
What is the definition of chronic hepatitis?
Evidence of hepatocellular injury continuing for >6 months
What are the causes of chronic hepatitis?
Same as acute, but especially:
HCV
HBV if acquired neonatally
HBV + HDV
What is the hallmark of mild chronic hepatitis pathologically?
Inflammation of portal tracts, but minimal detectable hepatocyte injury
-> for viral hepatitis, will be lymphocytes which don’t really leave the portal tract area (chronic inflammatory infiltrate)
What is the hallmark of severe chronic hepatitis pathologically?
Chronic inflammatory infiltrate spilling out of the portal tracts into the liver parenchyma
- > piecemeal fibrosis (one cell at a time)
- > “interface hepatitis” - inflammation in interface between portal triad and liver
- > bridging necrosis - necrosis between portal tracts, or from tracts to central veins, leads to fibrosis and cirrhosis
What are the unique features of HBV vs HCV chronic hepatitis?
HBV - eosinophilic ground glass appearance of hepatocytes due to accumulated HBsAg
HCV - focal macrovesicular fatty change, and large periportal lymphoid aggregates
What are the unique features of autoimmune chronic hepatitis?
Prominent plasma cell infiltrates in portal tracts
Where does inflammation tend to occur in acute / fulminant hepatitis, and is there fibrosis?
Tends to occur in mostly lobular areas (vs periportal in chronic)
There is no fibrosis in acute / fulminant, but can be lots in chronic hepatitis
What are some examples of intrahepatic cholestasis?
Space-occupying lesions in liver (i.e. metastases, granulomas)
Destruction of intrehaptic ducts
Cirrhosis, hepatocyte injury / swelling
Medications (more on this later, cause stasis)
What are some examples of extrahepatic cholestasis?
- Choledocholithiasis (gallstones in common bile duct)
2. Internal compromise or external compression of extrahepatic bile ducts due to malignancy or fibrosis
What will happen to hepatocytes in terms of injury pattern in cholestasis disorders?
Feathery degeneration - actually doesn’t look that different, but we call it feathery degeneration when it is in the presence of dilated bile ducts and smooth green to golden-brown globular pigment
Other than feathery degeneration, what are some other characteristic pathologic liver changes which occur in cholestasis?
- Bile ductular proliferation - compensatory response which doesn’t help
- Portal tract edema with acute inflammation, even bile lakes forming
- Portal tract fibrosis leading to biliary cirrhosis
What are the early vs late lab manifestations of cholestasis?
Early - Elevated Alk Phos, with corresponding elevated GGT / 5’-nucleotidase
Late - Increased serum bilirubin levels and increased cholesterol levels (all of the bile must be blocked, very late)
What are the clinical manifestations of cholestasis?
- Pruritis - from retention of bile salts / acids
- Jaundice / icterus -> conjugated bilirubin increases
- Xanthomata / xanthelasma - lipid-laden Macs deposit in dermis due to increased serum cholesterol
What is the definition of chronic liver failure (this includes one symptom you haven’t seen in acute) and what entity is it caused by?
Definition - Loss of 80-90% of liver function, marked by symptoms of acute liver failure + portal hypertension
Usually the progression of long-standing severe liver damage -> cirrhosis -> chronic liver failure
What is the definition of cirrhosis?
Diffuse process characterized by interconnecting fibrous bands, converting normal liver architecture into abnoral nodules and significant vascular alterations
Describe the general pathogenesis of cirrhosis.
Chronic liver injury -> cytokine production by Kupffer cells, lymphocytes, and endothelial cells
Ito cells become myofibroblast-like cells due to cytokines, which causes contraction and synthesis of Types I and III collagen into space of Disse
Fibrosis impairs blood flow and diffusion of metabolites -> formation of fibrous septae and portosystemic shunts, impaired endothelial fenestrations
Why does cirrhosis increase risk of hepatocellular carcinoma?
Ongoing replication of injured cells (hepatocyte regeneration) in the presence of inflammation
DNA damage + replication -> cancer
What are some etiologies of cirrhosis?
Alcohol abuse
Non-alcoholic fatty liver disease -> associated with metabolic syndrome + insulin resistance
Viral hepatitis (HBV/HCV)
Cholestasis
Metabolic disorders (hemochromatosis, Wilson’s, A1AT deficiency)
Cryptogenic (idiopathic)
What are the two shitty categories of cirrhosis?
- Micronodular - uniform, small nodules separated by thin fibrous septae -> hepatocytes replicating from a single lobule or portion of a lobule, forming nodules
- Macronodular - variably-sized, often larger nodules encircled by irregular bands of broad connective tissue, originating from multiple lobules
What causes micronodular vs macronodular cirrhosis? Why are these classifications shitty?
Macronodular - usually postviral cirrhosis
Micronodular - everything else, esp. alcoholism, biliary cirrhosis, hemochromatosis
Each subtype can transform into the other subtype later
What are the three broad causes of portal hypertension in cirrhosis?
- Increased sinusoidal vascular resistance
- Intrahepatic portosystemic shunts
- Increased portal venous blood flow
Why does sinusoidal vascular resistance increase?
- Active vasoconstriction -> stellate cell contraction, and increased endothelial production of endothelin
- Circulatory compression from fibrous tissue and regenerating parenchymal nodules
Why do intrahepatic portosystemic shunts contribute to portal hypertension?
Anastomoses between branches of portein vein and hepatic artery in fibrous septae -> hepatic arterial pressures are pushed into portal venous system
Why does portal venous blood flow increase in cirrhosis?
Circulation becomes hyperdynamic
- > cardiac output increases due to peripheral vasodilation which is not fully understood, mediated by nitric oxide and decreased response to vasoconstrictors
- > mesenteric / splanchnic vasodilation -> increased blood flow to portal system
- > systemic arterial vasodilation also decreases effective arterial volume -> increased RAA activation
What are the complications of cirrhosis due to portal hypertension?
- Ascites (due to increased fluid congestion in portal system leading to pressure backflow through capillies) -> peritonitis
- Extrahepatic portosystemic shunts can lead to significant hemorrhage
- Hypersplenism / congestive splenomegaly
- Hepatic encephaloathy - intrahepatic shunts avoid hepatic parenchyma for waste removal
Where are the two most important portosystemic shunts and which is most likely to bleed?
Gastroesophageal shunts -> most likely to cause esophageal varices and cause major upper GI bleed. Left gastric anatamoses with azygous vein
Rectal -> superior rectal of portal anastomases with middle and inferior rectal of systemic
What causes Caput medusae?
Anastamoses of paraumbilical (portal) and small epigastric veins of anterior abdominal wall
What are the consequences of loss of hepatic function in cirrhosis?
- Hypoalbuminemia
- Coagulopathy
- Hepatorenal / hepatopulmonary symptoms
- Hyperestrogenism
- Jaundice / icterus with cholestasis
- Hepatic encephalopathy
Why does hyperestrogenism happen in liver disease and what are the clinical signs / symptoms
Decreased sex hormone binding globulin and decreased inactivation of estrogen and testosterone leads to more formation and maintenance of estrogen levels.
- Spider angiomas and palmar erythema (not well understood)
- Gynecomastia
