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Pathophysiology - Gastrointestinal > Introduction to Liver Diseases > Flashcards

Introduction to Liver Diseases Flashcards

1
Q

What forms the parenchymal cells of the liver and how?

A

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

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2
Q

What will the mesenchyme of the septum transversum become?

A

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

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3
Q

What forms the endothelial cells of the liver sinusoids?

A

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

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4
Q

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

A

The falciform ligament

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

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5
Q

How is the liver suspended off of the diaphragm?

A

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

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6
Q

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

A

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

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7
Q

What are the boundaries of the quadrate and caudate lobes?

A

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

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

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8
Q

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

A

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

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9
Q

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

A

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

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10
Q

What are the three zones of hepatocytes in the acinus?

A

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

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11
Q

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

A

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

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12
Q

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

A

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

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13
Q

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

A

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)

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14
Q

What zone is most susceptible to hemochromatosis?

A

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

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15
Q

What type of endothelial cells line the sinusoids? Why?

A

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

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16
Q

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

A

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

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17
Q

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

A

Loss or preservation of reticulin (Type III collagen) framework

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18
Q

What is the function of the Kupffer cells?

A

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

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19
Q

How does cholestasis cause hepatocellular damage?

A

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

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20
Q

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

A

Hepatocellular damage and necrosis, with associated inflammation depending on etiology

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

Think ALT = AliverT

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21
Q

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

A

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

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22
Q

What is cirrhosis?

A

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

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23
Q

What is the definition of acute liver failure?

A

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

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24
Q

What are the symptoms of acute liver failure and whhy?

A

Encephalopathy -> increased nitrogen wastes

Hypoglycemia -> decreased glucose homeostasis maintenance by liver

Coagulopathy -> decreased production of coagulation factors

Renal failure -> not well understood

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25
Q

What viruses can cause hepatitis?

A

Hepatitis viruses A-E

Systemic viruses - EBV, CMV, HSV, enterovirus

26
Q

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

A

Drugs / toxins - alcohol, acetaminophen, Amatoxin (mushroom) -> just a shortlist

Ischemia

Metabolic disorders - non-alcoholic fatty liver disease, Wilson disease

27
Q

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

A

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

28
Q

What are the symptoms of acute viral hepatitis?

A

Constitutional symptoms from inflammation -> Malaise, nausea, anorexia, fever, arthralgias

RUQ tenderness -> expansion of liver capsule from cellular infiltrate

Jaundice / icterus -> impaired bilirubin conjugation / excretion

29
Q

How does acute hepatitis appear pathologically?

A

Lobular disarray - disruption of architecture

Random hepatocyte injury w/ ballooning degeneration, cytolysis, apoptosis

Inflammatory infiltrate, reactive Kupffer cells, and hepatocyte regeneration

30
Q

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

A

Will appear differently based on etiology, i.e.
Viral = lymphocytes
Alcohol = PMNs

Councilman bodies - dense, eosinophilic apoptotic bodies

31
Q

What usually causes fulminant hepatitis?

A

Drugs - especially acetaminophin, sometimes halothane or mushrooms

Rarely - viral causes, esp. HBV/HDV coinfection

32
Q

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

A

Small, soft liver with mottled cut surface and wrinkled capsule -> shrinking due to rapid necrosis

Treatment is liver transplant
-> this is severe acute hepatitis

33
Q

How does fulminant hepatitis appear microscopically?

A

Extensive hepatocyte necrosis with parenchymal collapse (lobular collapse)

If patient survives, there will be eventual inflammatory infiltrate and cellular regeneration

34
Q

What is the definition of chronic hepatitis?

A

Evidence of hepatocellular injury continuing for >6 months

35
Q

What are the causes of chronic hepatitis?

A

Same as acute, but especially:

HCV
HBV if acquired neonatally
HBV + HDV

36
Q

What is the hallmark of mild chronic hepatitis pathologically?

A

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)

37
Q

What is the hallmark of severe chronic hepatitis pathologically?

A

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
38
Q

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

A

HBV - eosinophilic ground glass appearance of hepatocytes due to accumulated HBsAg

HCV - focal macrovesicular fatty change, and large periportal lymphoid aggregates

39
Q

What are the unique features of autoimmune chronic hepatitis?

A

Prominent plasma cell infiltrates in portal tracts

40
Q

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

A

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

41
Q

What are some examples of intrahepatic cholestasis?

A

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

42
Q

What are some examples of extrahepatic cholestasis?

A
  1. Choledocholithiasis (gallstones in common bile duct)

2. Internal compromise or external compression of extrahepatic bile ducts due to malignancy or fibrosis

43
Q

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

A

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

44
Q

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

A
  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
45
Q

What are the early vs late lab manifestations of cholestasis?

A

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)

46
Q

What are the clinical manifestations of cholestasis?

A
  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
47
Q

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?

A

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

48
Q

What is the definition of cirrhosis?

A

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

49
Q

Describe the general pathogenesis of cirrhosis.

A

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

50
Q

Why does cirrhosis increase risk of hepatocellular carcinoma?

A

Ongoing replication of injured cells (hepatocyte regeneration) in the presence of inflammation

DNA damage + replication -> cancer

51
Q

What are some etiologies of cirrhosis?

A

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)

52
Q

What are the two shitty categories of cirrhosis?

A
  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
53
Q

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

A

Macronodular - usually postviral cirrhosis

Micronodular - everything else, esp. alcoholism, biliary cirrhosis, hemochromatosis

Each subtype can transform into the other subtype later

54
Q

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

A
  1. Increased sinusoidal vascular resistance
  2. Intrahepatic portosystemic shunts
  3. Increased portal venous blood flow
55
Q

Why does sinusoidal vascular resistance increase?

A
  1. Active vasoconstriction -> stellate cell contraction, and increased endothelial production of endothelin
  2. Circulatory compression from fibrous tissue and regenerating parenchymal nodules
56
Q

Why do intrahepatic portosystemic shunts contribute to portal hypertension?

A

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

57
Q

Why does portal venous blood flow increase in cirrhosis?

A

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
58
Q

What are the complications of cirrhosis due to portal hypertension?

A
  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
59
Q

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

A

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

60
Q

What causes Caput medusae?

A

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

61
Q

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

A
  1. Hypoalbuminemia
  2. Coagulopathy
  3. Hepatorenal / hepatopulmonary symptoms
  4. Hyperestrogenism
  5. Jaundice / icterus with cholestasis
  6. Hepatic encephalopathy
62
Q

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

A

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

Pathophysiology - Gastrointestinal (24 decks)

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