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Patho II > Liver and Gallbladder Part I > Flashcards

Liver and Gallbladder Part I Flashcards

1
Q

The Functional Unit of the Liver is known as?

A

Lobule

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2
Q

Hepatocytes: What are they? Role in liver?

A

-the major parenchymal cells in the liver -play pivotal roles in metabolism, detoxification, and protein synthesis

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3
Q

Kupffer cells: What are they? Role in liver?

A

the resident macrophage in the liver • critical mediators of both liver injury and repair • can be protective • dysregulation can cause chronic inflammation in the liver

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4
Q

Dysregulation of Kupffer cells can cause ?

A

can cause chronic inflammation in the liver

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5
Q

Activation of stellate cells causes? This leads to ?

A

their activation in damaged liver causes secretion of collagen and formation of scar tissue → chronic fibrosis or cirrhosis

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6
Q

Describe the liver’s dual blood supply

A

• The portal vein providing 60% to 80% of hepatic blood flow • The hepatic artery supplying the remaining 20% to 40%

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7
Q

Describe the flow of blood from the aorta to the inferior vena cava?

A
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8
Q

In regards to liver microcirculation what “model” defines areas or zones?

A

acinar model

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9
Q

Describe the zones of the acinar model

A
  • The center of the acinus (peri-portal) is zone 1: • main functions include gluconeogenesis, oxidation of fatty acids, amino acid catabolism, ureagenesis, cholesterol synthesis, and bile acid secretion
  • The periphery (peri-venular) as zone 3: • particularly vulnerable to a circulatory failure • more involved with glycolysis and lipogenesis
  • The region in between as zone 2
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10
Q

Why is zone 3 particularly vulnerable to circulatory failure?

A

It is the farthest away from the portal triad which means its farther away from oxygen and nutrients → makes it vulnerable to ischemia and circulatory issues

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11
Q

Hepatic oxygen delivery is related to the ?

A

oxygen content of blood going to the liver and total hepatic blood flow

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12
Q

What occurs to hepatic blood under systemic stress, such as sepsis?

A

• In sepsis: insufficient cardiac output cannot supply demands of the brain → hepatocellular hypoxia (in zone 3)

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13
Q

How does reperfusion injury occur in the liver?

A

• Mediated by generation of ROS once ischemic hepatocytes are re-exposed to oxygen → cell injury • Kupffer cells produce cytokines (inflammatory response)

Reperfusion of ischemic tissues is often associated with microvascular injury, particularly due to increased permeability of capillaries and arterioles that lead to an increase of diffusion and fluid filtration across the tissues. Activated endothelial cells produce more reactive oxygen species but less nitric oxide following reperfusion, and the imbalance results in a subsequent inflammatory response.[1] The inflammatory response is partially responsible for the damage of reperfusion injury.

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14
Q

There is an increased risk of ischemia is patients who have?

A
  • Patients who have preexisting liver disease and portal hypertension are particularly susceptible since total hepatic blood flow may already be reduced. Splanchnic (aka splenic) blood that normally enters the liver may be shunted through collateral circulation, so bypassing the liver (and potentially resulting in varices). Also, decreased liver functions in patients with chronic liver disease makes them vulnerable to development of liver decompensation when there is added injury from an ischemic insult.

-Liver decompensations mainly are: ascites, variceal bleeding and hepatic encephalopathy

  • Patients who have preexisting passive congestion of the liver are also at increased risk for ischemic injury. Increased central venous pressure (seen with heart failure) is transmitted to the hepatic veins and small hepatic venules that drain the hepatic acini. This increased pressure is associated with atrophy of hepatocytes in zone 3 of the liver acinus. The mechanism leading to atrophy is because of exudation of protein-rich fluid into the space of Disse due to the sinusoidal congestion. The resulting sinusoidal edema decreases the diffusion of oxygen and flow of nutrients to hepatocytes.

In addition to the atrophy of hepatocytes, chronic hepatic congestion can cause fibrosis, which fibrosis, in turn, decreases diffusion of nutrients to hepatocytes.

  • Passive congestion by itself does not seem to be sufficient to cause significant hepatic necrosis without a related decrease in hepatic blood flow. Also, there is no clear correlation between the degree of congestion (as assessed by right atrial pressure) and zone 3 necrosis in patients with heart failure. Significant zone 3 necrosis caused by acute left-sided heart failure has been shown in the absence of right heart failure, suggesting that a decrease in cardiac output rather than congestion alone is the critical factor causing hepatic necrosis.
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15
Q

What are the major functions of the liver?

A

-Secretory -Excretory -Metabolic → metabolism of carbs, lipids, and proteins -Synthetic -Detoxification -Storage

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16
Q

What is glycogenesis ? When does it occur?

A

When excess glucose (after meals) is converted to glycogen

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17
Q

What is glycogenolysis? When does it occur?

A

Decreased glucose between meals stimulates breakdown of glycogen: glycogenolysis

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18
Q

What is gluconeogenesis? When does it occur?

A

• Exhaustion of glycogen reserves stimulates glucose production from amino acids and sugars: gluconeogenesis

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19
Q

What is gluconeogenesis? When does it occur?

A

• Exhaustion of glycogen reserves stimulates glucose production from amino acids and sugars: gluconeogenesis

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20
Q

Transamination leads to?

A

keto acids

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21
Q

Deamination leads to ?

A

ammonia

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22
Q

What is the process of protein metabolism?

A
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23
Q

Where does ammonia come from ?

A

bacterial degradation of amines, amino acids, purines, and urea in the gut

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24
Q

Describe the process of lipolysis ?

A
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25
Q

Fatty acid oxidation is the process where ?

A

triglycerides get broken down into glycerol and fatty acids (VLDL)

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26
Q

Phospholipid and cholesterol synethsis?

A

During phospholipid and cholesterol synthesis which also occurs in the liver, they are bound to lipoproteins and excreted through bile as cholesterol, then converted into bile acids

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27
Q

How does the formation of cofactors relate to the liver?

A

Liver requires vitamin K to manufacture prothrombin factors 7, 9, and 10

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28
Q

What is the etiology of abnormal hemostasis (arrest of bleeding) caused by abnormal liver function?

A
  • abnormal coagulation factor synthesis
  • synthesis of dysfunctional coagulation factors
  • increased consumption of coagulation factors
  • platelet disorders
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29
Q

What type of endogenous substances does the liver excrete?

A
  • bilirubin
  • steroid hormones
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30
Q

What type of exogenous substances does the liver excrete?

A

drug metabolites

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31
Q

What does enterohepatic circulation refer to?

A

Any substance secreted in bile which is reabsorbed from the intestine and returns to the liver to appear once again in bile may be said to undergo an enterohepatic circulation.

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32
Q

What are the vascular functions of the liver ?

A

-Acts as a reservoir of blood -Synthesizes about 50% of the circulating lymph

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33
Q

The liver secretes bile containing ?

A

the liver secretes bile containing:

  • bilirubin,
  • water
  • bile acids
  • electrolytes
  • phospholipids and cholesterol
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34
Q

What is the purpose of bile acids?

A

digestion and absorption of fat and fat-soluble vitamins (D,A,K,E) from the small intestine

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35
Q

Kupffer cells in the liver act as ?

A

-The Kupffer cells in the liver act as macrophages and form part of the phagocytic system in the body

36
Q

How is bilirubin formed?

A

by breakdown of heme by heme oxygenase

37
Q

Bilirubin is found in what form in the body? why is this important to know?

A

• Water-insoluble unconjugated bilirubin is associated with all toxic effects of bilirubin

38
Q

How does the body successfully remove bilirubin?

A

• Conversion of bilirubin to a water-soluble is essential for the elimination via conjugation

39
Q

How is urobilinogen formed? where is it absorbed? where is it excreted?

A
  • Urobilinogen: produced by bacterial breakdown of bilirubin in the bowel
  • It is partly absorbed in the bowel
  • The other fraction excreted in urine Formation:
40
Q

Urinary urobilinogen excretion may be increased in?

A
  • Excessive bilirubin production
  • Inefficient hepatic clearance of the urobilinogen
  • Excessive exposure of bilirubin to intestinal bacteria
41
Q

Urinary urobilinogen excretion can be reduced in?

A

• Biliary obstruction- tumor • Severe cholestasis-gall bladder issue

42
Q

Bilirubin is a balance between?

A

a balance between production and clearance

43
Q

Causes of elevated serum bilirubin?

A
  • Overproduction of bilirubin
  • Abnormal uptake, conjugation, or excretion of bilirubin
  • Damaged hepatocytes or bile ducts
44
Q

What are the potential beneficial effects of bilirubin?

A
  • Antioxidant
  • ↑ serum bilirubin levels –> leads to ↓risk of ischemic coronary artery disease and cancer mortality
  • Induction of heme oxygenase reduces the replication of hepatitis C virus
45
Q

What are the physiologic mechanisms that protect against bilirubin toxicity?

A
  • binding to plasma albumin → unbound bilirubin is more damaging the bound bilirubin
  • rapid uptake
  • conjugation
  • clearance
46
Q

Unconjugated bilirubin levels can become high in plasma due to?

A
  • overproduction of bilirubin → conjugation system will become saturated
  • abnormal bilirubin uptake
  • abnormalities conjugation
47
Q

Unconjugated and Conjugated bilirubin levels can become high in the plasma due to?

A

• hepatocellular diseases:

→ alcoholic or non alcoholic liver disease

→ hepatititis

  • defective reuptake of conjugated bilirubin
  • biliary obstruction
48
Q

Causes of unconjugated hyperbilirubinemia can occur in what three ways?

A
  • Increased production of bilirubin
  • Decreased clearance of bilirubin
  • Increased enterohepatic circulation of bilirubin
49
Q

What are the clinical features of unconjugated hyperbilirubinemia? Why do newborns experience physiological jaundice normally?

A

• Jaundice in the first 24 hours of life (bili level is way to high, higher than physiologic jaundice)

→ babies have immature liver and deal with fetal RBC’s which only live for 85 days

  • Total serum or plasma bilirubin (TB) level greater than the hour: specific 95th percentile
  • Conjugated bilirubin concentration >1 mg/dL
  • Rate of TB rise greater than 0.2 mg/dL per hour (rises gradually)
  • Jaundice in a term newborn after two weeks of age
50
Q

What components participates in regeneration of a normal liver?

A
  • Macrophages
  • Hepatic Stellate cells (ARE NOT ACTIVATED)
  • Liver sinusoidal endothelial cells (LSECs)

→ all these cells (except stellate) use extrinsic factors and growth hormone to signal hepatocytes to enter into mitosis = proliferation

51
Q

How does regeneration occur in the abnormal, chronically damaged liver?

A
  • The hepatic stellate cells are activated to myofibroblasts and excessive scar tissue inhibits regeneration
  • Excessive cellular debris inhibits efficient liver regeneration
52
Q

1) Acute liver failure is defined as ?
2) How many weeks of having liver failure differentiates acute from chronic liver failure?
3) What are the causes of acute liver failure?

A
  1. severe acute liver injury with encephalopathy (brain damage) and elevated prothrombin time in a patient without cirrhosis or preexisting liver disease
  2. cutoff between acute and chronic liver failure is a disease duration of <26 weeks
  3. viral and drug induced hepatitis A (acetaminophen) are the most common causes
53
Q

Patients with acute liver failure will have what three things? What are the lesser other factors?

A
  1. ) severe acute liver injury, leading to liver test abnormalities ( ↑ ALT)
  2. ) hepatic encephalopathy
  3. ) prolonged prothrombin time/INR ( b/c liver can’t produce coagulation factors) Other factors:
  • jaundice
  • hepatomegaly
  • right upper quadrant tenderness
  • coagulopathy
  • increased portal hypertension
54
Q

Hepatic encephalopathy is defined as? What is the main culprit of this disease?

A

• Definition: a reversible syndrome of impaired brain function occurring in patients with advanced liver failure -ammonia

55
Q

What is the pathogenesis of hepatic encephalopathy?

A

Normally the body uses the urea cycle to convert ammonia to urea so it can be removed from the body but in acute liver failure the urea cycle does not occur

• The synergistic action of ammonia with other toxins may cause:

→ the changes in blood-to- brain transport (ammonia goes to brain)

→ oxidative stress

→ astrocyte swelling

• The above changes may cause abnormal neurotransmission and an increase in ICP→ can lead to Sepsis/neuroinflammation

56
Q

Acetaminophen-Induced Liver Injury is the most common cause of ?

A

acute liver failure in the United States

57
Q

Why can acetaminophen be cytotoxic to hepatocytes?

A

• Acetaminophen is directly cytotoxic to hepatocytes through its conversion to N-acetyl-p- benzoquinoneimine (NAPQI)

58
Q

Selective clinical factors influencing cytotoxicity: → Acute alcohol ingestion? → Chronic alcohol ingestion?

A
  • Acute alcohol ingestion: is NOT a risk factor for hepatotoxicity and may even be protective by competing with acetaminophen for CYP450 (CYP 2E1)
  • Chronic alcohol ingestion: increases CYP450 activity two-fold and reduces glutathione levels → increase in NAPQI
59
Q

Liver damage from acetaminophen ingestion can happen in what three circumstances?

A
  • Excessive intake of acetaminophen
  • Excessive cytochrome P450
  • Decreased capacity for glucuronidation or sulfation
60
Q

Proposed mechanism of mitophagy in APAP-induced hepatotoxicity?

A
  • A toxic dose of APAP is metabolized to NAPQI in the liver
  • NAPQI can deplete hepatic GSH and bind to proteins → increased ROS and mitochondrial damage
  • Damaged mitochondria necrotic cell death and more ROS production
  • DAMP signals → activation of inflammatory responses
61
Q

How does the liver metabolize alcohol (ethanol)?

A
  • The primary hepatic pathway generates acetaldehyde in the liver via by the enzyme alcohol dehydrogenase (ADH)
  • The acetaldehyde → acetate by acetaldehyde dehydrogenase (ALDH)
  • Acetaldehyde (toxic product of alcohol metabolism) may be a potential accelerant to liver injury
62
Q

How does the stomach (gastric) metabolize alcohol?

A
  • The stomach has sufficient ADH activity → less in women
  • Helicobacter pylori and gastritis can reduce the activity of gastric ADH
63
Q

In alcoholic liver disease, heavy ethanol consumption leads to wide spectrum of hepatic lesions, what are they (3 types)? Describe each one?

A
  • fatty liver (i.e., steatosis) → is the earliest, most common response in problem drinkers (4 to 5 standard drinks per day over decades) → reversible condition with a good prognosis
  • hepatitis → a more severe, inflammatory type
  • fibrosis/cirrhosis → the deposition of abnormal amounts of ECM proteins, mainly by activated stellate cells
64
Q

Mechanisms Involved in alcoholic steatosis?

A
  • alcohol Accelerates hepatic lipogenesis → leads to ↑ lipid peroxidation and oxidative damage
  • alcohol decelerates hepatic lipid breakdown
  • alcohol causes defective hepatic lipid export
65
Q

Mechanisms Involved in alcoholic steatohepatitis?

A
  • Alcohol-induced hepatocyte damage and apoptosis → apoptotic bodies → stimulate Kupffer cells to secrete TNFα and IFN-γ
  • NK cells attracted to the liver to worsen the inflammatory process
  • Activated stellate cells secrete ECM proteins → destroying the liver’s internal structure and functions
66
Q

Cirrhosis is defined as (3 bullet points)?

A
  • a late stage of progressive hepatic fibrosis
  • characterized by distortion of the hepatic architecture
  • irreversible in its advanced stages, at which point the only treatment option: liver transplant
67
Q

Cirrhosis is most often associated with?

A

• Note: Liver failure in chronic liver disease is most often associated with cirrhosis

68
Q

What are the causes of cirrhosis ?

A
  • Chronic viral hepatitis (hepatitis B, C) → hep C is more damaging
  • Alcoholic liver disease
  • Hemochromatosis
  • Nonalcoholic fatty liver disease
69
Q

The ECM in fibrotic liver is made of? The composition of the hepatic scar is similar in?

A

insoluble scar is similar in all forms of fibrosing liver injury

70
Q

What cell is the main source of the ECM in hepatic fibrosis, including alcoholic liver disease?

A

The hepatic stellate cell

71
Q

How does fibrosis of the liver occur?

A

• With liver injury, these cells undergo an “ activation” → become fibrogenic • At the same time, Kupffer cells and lymphocytes release cytokines → the expression of fibrogenic genes in stellate cells

72
Q

Prognosis of compensated cirrhosis?

A

Patients with cirrhosis who have not developed major complications

• The median survival of patients with compensated cirrhosis is >12 years

73
Q

Prognosis of decompensated cirrhosis?

A
  • Patients who have developed complications of cirrhosis, such as: → variceal hemorrhage → ascites → hepatocellular carcinoma
  • have a worse prognosis than those with compensated cirrhosis (6 months or less)
74
Q

Portal hypertension is the result of?leads to? It is most commonly caused by?

A

• the result of resistance to portal blood flow → variceal bleeding and ascites • It is most commonly caused by cirrhosis

75
Q

Pathophysiology of portal hypertension (structural and dynamic changes)?

A
  • Structural changes occur in the setting of liver microcirculation → scar formation causes ↑ resistance
  • Dynamic changes are caused by increased production of vasoconstrictors and reduced release of vasodilators -splenic vasodilation→ systemic hypotension → increased cardiac output → ascites (leakage of fluid into the abdominal cavity)
76
Q

Main selective clinical consequences of portal hypertension are?

A

• ascites • hepatic encephalopathy

77
Q

Ascites is defined as? It is caused by?

A

• Definition: → The accumulation of excess fluid in the peritoneal cavity is called ascites • Etiology: → Portal hypertension causes profound changes in the splanchnic circulation in the setting of cirrhosis

78
Q

Normal iron stores consist of ?

A
  • Hemoglobin
  • Iron-containing proteins
  • Iron bound to transferrin in plasma
  • Storage iron: ferritin or hemosiderin
  • Total body iron content → balance between dietary iron and iron loss from bleeding
79
Q

Causes of iron overload?

A

Increased intake

→ transfusional overload

→ bone marrow failure syndromes

→ hemolytic anemia

→ myelodysplastic anemia

→ aplastic anemia Increased absorption:

→ mutations (e.g. ferroportin, hemojuvelin, hepcidin, ceruloplasmin)

80
Q

Elimination of iron excess occurs in three ways?

A
  • Intake
  • Loss (GI tract, skin-sweat)
  • Recycling: Iron is recycled from the breakdown of senescent RBCs in the macrophages in the liver, spleen and bone marrow
81
Q

Pathophysiology of the clinical consequences of iron overload?

A
  • Iron burden → transferrin becomes saturated → iron binds to other proteins and molecules
  • This iron is referred to as non-transferrin- bound iron (NTBI)
  • NTBI is taken up by the cells of the liver, heart and endocrine organs
  • NTBI can chemically interact with hydrogen peroxide → more ROS production → tissue damage, inflammation and fibrosis (organ damage)
82
Q

Hereditary Hemochromatosis most commonly occurs because of ? which leads to?

A

Most commonly due to HFE gene mutation → increased intestinal iron absorption

83
Q

3 mechanisms of liver injury in hereditary hemochromatosis?

A
  • Lipid peroxidation via iron-catalyzed free radical reactions
  • Interaction of ROS and iron itself with DNA causing lethal cell injury and predisposition to hepatocellular carcinoma
  • Stimulation of collagen formation: by activation of hepatic stellate cells
84
Q

Clinical consequence of hereditary hemochromatosis

A

The complications of fibrosis and cirrhosis developing in patients increase with a significant iron overload, called hepatic iron concentration ( HIC) greater than 3x the upper limit of normal → BUT excess iron accumulation happens over years so patient might not experience symptoms until later on

85
Q

Hemochromatosis Pathogenesis?

A
  • Mutation of the HFE gene causes → Hepcidin’s (regulates the transfer of iron from macrophages to plasma: targets transferrin) transcriptional activity to become reduced
  • The effect of reduced levels of circulating hepcidin causes: → unchecked iron-export by ferroportin in the macrophage → That is responsible for excess plasma iron load → tissue iron accumulation and tissue damage

Patho II (12 decks)

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