Introduction to Liver Diseases

Question 1

What forms the parenchymal cells of the liver and how?

Answer 1

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

Question 2

What will the mesenchyme of the septum transversum become?

Answer 2

Forms the connective tissue of the liver -> fibroblasts and stellate cells, as well as Kupffer cells and **hematopoietic stem cells in fetal liver

Question 3

What forms the endothelial cells of the liver sinusoids?

Answer 3

Remnants of the yolk sac circulation -> vitelline and umbilical vessels

Question 4

What separates the right from the left lobe of the liver? What does it contain?

Answer 4

The falciform ligament

Contains the round ligament (ligamentum teres) -> remnant of umbilical vein, plays a role in caput medusae

Question 5

How is the liver suspended off of the diaphragm?

Answer 5

Anterior and posterior coronary ligaments, which have sharp lateral transitions called the triangular ligaments

Question 6

What visceral lobes are contained in the right anatomical lobe of the liver?

Answer 6

Right visceral lobe, caudate lobe (posterior), quadrate lobe (anterior)

Question 7

What are the boundaries of the quadrate and caudate lobes?

Answer 7

Caudate - IVC laterally, porta hepatis anteriorly, ligamentum venosum medially

Quadrate - Gall bladder laterally, porta hepatis posteriorly, ligamentum teres medially

Question 8

How does bile travel in the liver from hepatocytes to GI tract?

Answer 8

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

Question 9

What is a lobule vs an acinus as functional units of the liver?

Answer 9

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

Question 10

What are the three zones of hepatocytes in the acinus?

Answer 10

Zone 1 - closest to incoming blood supply (periportal)
Zone 2 - intermediate
Zone 3 - nearest the central vein (centrilobular)

Question 11

Which zone does the most oxidative metabolism, gluconeogenesis, transamination, protein, cholesterol, and urea synthesis? Why?

Answer 11

Zone 1 - closest to blood inflow, has highest oxygen content and numerous mitochondria

Question 12

What are zone 3 hepatocytes important for? Where in the cell do these processes occur?

Answer 12

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

Question 13

What zone of hepatocytes are most susceptible to drugs / toxins / hypoxia / ischemia?

Answer 13

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)

Question 14

What zone is most susceptible to hemochromatosis?

Answer 14

Zone 1 - due to it seeing the most blood first -> takes up the most iron

Question 15

What type of endothelial cells line the sinusoids? Why?

Answer 15

Fenestrated, discontinous endothelium lacking a basement membrane
-> allows for diffusion of materials into the space of Disse (btwn endothelial cells and hepatocytes)

Question 16

What are stellate cells also called and what is their function?

Answer 16

Cells of Ito - function to store vitamin A, and are important in the pathogenesis of cirrhosis

Question 17

What determines if the liver can be regenerated with normal anatomy following damage?

Answer 17

Loss or preservation of reticulin (Type III collagen) framework

Question 18

What is the function of the Kupffer cells?

Answer 18

Phagocytic cells in sinusoids involved in clearance of exogenous (i.e. bacteria) and endogenous (i.e. immune complexes) substances

Question 19

How does cholestasis cause hepatocellular damage?

Answer 19

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

Question 20

What is the hallmark of Hepatocellular injury (hepatitis syndromes) and what labs will be elevated? Which is more specific for liver?

Answer 20

Hepatocellular damage and necrosis, with associated inflammation depending on etiology

Labs elevated: ALT and AST
ALT is more specific for liver

Think ALT = AliverT

Question 21

What is the hallmark of cholestatic disorders and what labs will be elevated? How do you confirm these elevated labs are from the liver?

Answer 21

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

Question 22

What is cirrhosis?

Answer 22

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

Question 23

What is the definition of acute liver failure?

Answer 23

Loss of 80-90% of hepatic function within weeks, most commonly caused by fulminant hepatitis

Question 24

What are the symptoms of acute liver failure and whhy?

Answer 24

Encephalopathy -> increased nitrogen wastes

Hypoglycemia -> decreased glucose homeostasis maintenance by liver

Coagulopathy -> decreased production of coagulation factors

Renal failure -> not well understood

Question 25

What viruses can cause hepatitis?

Answer 25

Hepatitis viruses A-E Systemic viruses - EBV, CMV, HSV, enterovirus

Question 26

What drugs / toxins can cause hepatitis? Metabolic disorders and derangements?

Answer 26

Drugs / toxins - alcohol, acetaminophen, Amatoxin (mushroom) -> just a shortlist Ischemia Metabolic disorders - non-alcoholic fatty liver disease, Wilson disease

Question 27

What is autoimmune hepatitis, who tends to get it, and how is it treated?

Answer 27

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

Question 28

What are the symptoms of acute viral hepatitis?

Answer 28

Constitutional symptoms from inflammation -> Malaise, nausea, anorexia, fever, arthralgias RUQ tenderness -> expansion of liver capsule from cellular infiltrate Jaundice / icterus -> impaired bilirubin conjugation / excretion

Question 29

How does acute hepatitis appear pathologically?

Answer 29

Lobular disarray - disruption of architecture Random hepatocyte injury w/ ballooning degeneration, cytolysis, apoptosis Inflammatory infiltrate, reactive Kupffer cells, and hepatocyte regeneration

Question 30

How will inflammatory infiltrate appear in acute hepatitis, and what are Councilman bodies?

Answer 30

Will appear differently based on etiology, i.e. Viral = lymphocytes Alcohol = PMNs Councilman bodies - dense, eosinophilic apoptotic bodies

Question 31

What usually causes fulminant hepatitis?

Answer 31

Drugs - especially acetaminophin, sometimes halothane or mushrooms Rarely - viral causes, esp. HBV/HDV coinfection

Question 32

How will fulminant hepatitis appear grossly and what is the treatment?

Answer 32

Small, soft liver with mottled cut surface and wrinkled capsule -> shrinking due to rapid necrosis Treatment is liver transplant -> this is severe acute hepatitis

Question 33

How does fulminant hepatitis appear microscopically?

Answer 33

Extensive hepatocyte necrosis with parenchymal collapse (lobular collapse) If patient survives, there will be eventual inflammatory infiltrate and cellular regeneration

Question 34

What is the definition of chronic hepatitis?

Answer 34

Evidence of hepatocellular injury continuing for >6 months

Question 35

What are the causes of chronic hepatitis?

Answer 35

Same as acute, but especially: HCV HBV if acquired neonatally HBV + HDV

Question 36

What is the hallmark of mild chronic hepatitis pathologically?

Answer 36

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)

Question 37

What is the hallmark of severe chronic hepatitis pathologically?

Answer 37

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

Question 38

What are the unique features of HBV vs HCV chronic hepatitis?

Answer 38

HBV - eosinophilic ground glass appearance of hepatocytes due to accumulated HBsAg HCV - focal macrovesicular fatty change, and large periportal lymphoid aggregates

Question 39

What are the unique features of autoimmune chronic hepatitis?

Answer 39

Prominent plasma cell infiltrates in portal tracts

Question 40

Where does inflammation tend to occur in acute / fulminant hepatitis, and is there fibrosis?

Answer 40

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

Question 41

What are some examples of intrahepatic cholestasis?

Answer 41

Space-occupying lesions in liver (i.e. metastases, granulomas) Destruction of intrehaptic ducts Cirrhosis, hepatocyte injury / swelling Medications (more on this later, cause stasis)

Question 42

What are some examples of extrahepatic cholestasis?

Answer 42

1. Choledocholithiasis (gallstones in common bile duct) | 2. Internal compromise or external compression of extrahepatic bile ducts due to malignancy or fibrosis

Question 43

What will happen to hepatocytes in terms of injury pattern in cholestasis disorders?

Answer 43

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

Question 44

Other than feathery degeneration, what are some other characteristic pathologic liver changes which occur in cholestasis?

Answer 44

1. Bile ductular proliferation - compensatory response which doesn't help 2. Portal tract edema with acute inflammation, even bile lakes forming 3. Portal tract fibrosis leading to biliary cirrhosis

Question 45

What are the early vs late lab manifestations of cholestasis?

Answer 45

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)

Question 46

What are the clinical manifestations of cholestasis?

Answer 46

1. Pruritis - from retention of bile salts / acids 2. Jaundice / icterus -> conjugated bilirubin increases 3. Xanthomata / xanthelasma - lipid-laden Macs deposit in dermis due to increased serum cholesterol

Question 47

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?

Answer 47

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

Question 48

What is the definition of cirrhosis?

Answer 48

Diffuse process characterized by interconnecting fibrous bands, converting normal liver architecture into abnoral nodules and significant vascular alterations

Question 49

Describe the general pathogenesis of cirrhosis.

Answer 49

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

Question 50

Why does cirrhosis increase risk of hepatocellular carcinoma?

Answer 50

Ongoing replication of injured cells (hepatocyte regeneration) in the presence of inflammation DNA damage + replication -> cancer

Question 51

What are some etiologies of cirrhosis?

Answer 51

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)

Question 52

What are the two shitty categories of cirrhosis?

Answer 52

1. Micronodular - uniform, small nodules separated by thin fibrous septae -> hepatocytes replicating from a single lobule or portion of a lobule, forming nodules 2. Macronodular - variably-sized, often larger nodules encircled by irregular bands of broad connective tissue, originating from multiple lobules

Question 53

What causes micronodular vs macronodular cirrhosis? Why are these classifications shitty?

Answer 53

Macronodular - usually postviral cirrhosis Micronodular - everything else, esp. alcoholism, biliary cirrhosis, hemochromatosis Each subtype can transform into the other subtype later

Question 54

What are the three broad causes of portal hypertension in cirrhosis?

Answer 54

1. Increased sinusoidal vascular resistance 2. Intrahepatic portosystemic shunts 3. Increased portal venous blood flow

Question 55

Why does sinusoidal vascular resistance increase?

Answer 55

1. Active vasoconstriction -> stellate cell contraction, and increased endothelial production of endothelin 2. Circulatory compression from fibrous tissue and regenerating parenchymal nodules

Question 56

Why do intrahepatic portosystemic shunts contribute to portal hypertension?

Answer 56

Anastomoses between branches of portein vein and hepatic artery in fibrous septae -> hepatic arterial pressures are pushed into portal venous system

Question 57

Why does portal venous blood flow increase in cirrhosis?

Answer 57

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

Question 58

What are the complications of cirrhosis due to portal hypertension?

Answer 58

1. Ascites (due to increased fluid congestion in portal system leading to pressure backflow through capillies) -> peritonitis 2. Extrahepatic portosystemic shunts can lead to significant hemorrhage 3. Hypersplenism / congestive splenomegaly 4. Hepatic encephaloathy - intrahepatic shunts avoid hepatic parenchyma for waste removal

Question 59

Where are the two most important portosystemic shunts and which is most likely to bleed?

Answer 59

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

Question 60

What causes Caput medusae?

Answer 60

Anastamoses of paraumbilical (portal) and small epigastric veins of anterior abdominal wall

Question 61

What are the consequences of loss of hepatic function in cirrhosis?

Answer 61

1. Hypoalbuminemia 2. Coagulopathy 3. Hepatorenal / hepatopulmonary symptoms 4. Hyperestrogenism 5. Jaundice / icterus with cholestasis 6. Hepatic encephalopathy

Question 62

Why does hyperestrogenism happen in liver disease and what are the clinical signs / symptoms

Answer 62

Decreased sex hormone binding globulin and decreased inactivation of estrogen and testosterone leads to more formation and maintenance of estrogen levels. 1. Spider angiomas and palmar erythema (not well understood) 2. Gynecomastia