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Mechanisms of Disease > Week 12 Digestive Disorders > Flashcards

Week 12 Digestive Disorders Flashcards

1
Q

Liver diseases

A
  • Hepatic circulatory disorders
  • Viral hepatitis
  • Toxic liver damage (ethanol)
  • Eclampsia and pre-eclampsia
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2
Q

Gall bladder diseases

A
  • Cholestasis
  • Cholecystitis
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3
Q

Pancreas diseases

A
  • Neuroendocrine tumors
    * Gastrinoma
    * Insulinoma
    * Somatostinoma
  • Diabetes Mellitus (type 2)
  • Acute vs Chronic pancreatitis
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4
Q

What do hepatocytes of the liver do?

A
  • detoxification
  • bile production
  • blood proteins
  • glycogen storage–> to help maintain BG levels b/t meals
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5
Q

Parenchyma of liver

A

Hepatocytes
- large cells with lots of organelles
- divide so liver can regenerate

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6
Q

Stroma of liver

A
  • reticular fibers
  • kupffer cells
  • eto cells
  • endothelial cells
  • etc.
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7
Q

2 types of liver vasculature

A
  1. Systemic
    - providing support through proper hepatic artery
    - high O2 levels
  2. Functional
    - from digestive tract through portal vein
    - high nutrient levels
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8
Q

liver vasculature pathway

A
  • blood enters parenchyma (sinusoids)
  • drains into central vein
  • to sublobular vein
  • exits liver through hepatic vein
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9
Q

Blood flow through liver (image in ppt)

A
  • blood flowing towards central vein
  • bile flowing towards periphery
  • kupffer cells are resident macrophages of the liver
  • portal vein–> brings blood from GI tract into sinusoids
  • hepatic artery–> brings O2 rich blood to sinusoids
  • central vein–> sublobular vein–> hepatic vein
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10
Q

Liver perfusion

A
  • parenchyma organized into lobules
  • hepatocytes closes to entry receive most nutrients, as well as heaviest dose of toxins
    * this is zone 1–> closest to portal triad
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11
Q

What are the mechanisms used for liver response to injury?

A
  • Hepatocyte-based response
    * degeneration/intracellular accumulations
    * death- necrosis or apoptosis
  • Inflammation- often started by kupffer cells
  • Regeneration
  • Fibrosis- failure of regeneration
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12
Q

Name some clinical liver syndromes.

A
  1. Hepatic Failure
    - absence of general functions
    - cells do not function properly
  2. Cirrhosis
    - architectural disruption
    - fibrosis with nodules of hepatocytes
    - not always immediately apparent
  3. Portal Hypertension
    - increased resistance to blood flow in the liver
    - this can induce cirrhosis
  4. Bilirubin metabolism failure
    - causes jaundice
    - can be a result of cholestasis
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13
Q

Fibrosis in the liver

A

Fibrosis is due to activation of stellate cells
- secondary to activation of kupffer cells
- this is how you get cirrhosis

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14
Q

Describe Bilirubin

A
  • senescent (deteriorate w/ age) RBCs are destroyed by phagocytic cells
  • in spleen, liver, and bone marrow
  • bilirubin is a yellowish pigment
  • seen in fading bruises as RBCs from hemorrhage are removed
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15
Q

How does bilirubin travel in the body?

A

-NOT water soluble
- travels through blood bound to albumin
- conjugated to glucuronic acid for excretion in bile–> eventually in fecal matter
* bile salts are recycled, but conjugated bile is excreted

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16
Q

What is cholestasis?

A

impaired bile formation/flow

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17
Q

What results from excess bilirubin?

A
  • jaundice–> yellowing of skin
  • icterus–> yellowing of sclera (eye)
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18
Q

What is Hepatitis?

A
  1. Virus that infects hepatocytes
  2. Liver with hepatocytes infected by hepatitis virus
  3. Liver damage secondary to systemic infection
    Acute Hepatitis: massive hepatocyte damage (necrosis)
    Chronic Hepatitis:
    - end stage of progressive hepatocyte damage
    - liver recovers from initial injury, but then you have additional injuries occuring
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19
Q

What are some clinical syndromes associated with hepatitis?

A
  1. Acute Hepatitis–> with submassive hepatic necrosis
    - Asymptomatic
    * serological evidence only
    * acute with recovery
    - Acute symptomatic hepatitis with recovery
    * anicteric or icteric (jaundice)
  2. Chronic hepatitis
    - with or without progression to cirrhosis
    - similar presentation to toxic liver injury
  3. Acute liver failure
    - with massive hepatic necrosis
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20
Q

Acute vs Chronic Hepatitis

A

Acute
- damage to hepatocytes themselves
* including cholestasis, apoptotic cell death, ballooning degeneration
- proliferation or increased deposition of macrophages of kupffer cells
Chronic
- differences in types of cells present
* lymphocytes
* Hep B= ground glass cells
* Hep C= fatty change
NOTE: acute may have bridging necrosis, but chronic WILL have it

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21
Q

Describe Viral Hepatitis

A
  • virus infects hepatocytes
  • hepatocytes express viral antigens
  • immune system targets hepatocytes
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22
Q

Causes of hepatitis

A

Acute
- primary viral (hep A,B,C,D,E)
- systemic viral (yellow fever, mononucleosis)
Chronic (the consonants)
- most likely with hep C; minimal with B/D
- E only in immunocompromised
- Never with hep A
- can be follow-up to unresolved acute injury, or result from subacute injury
Usually characterized by cirrhosis b/c you lose hepatocytes during infection and you have fibrosis to replace it
- often linked with hepatocellular carcinoma- b/c of viral infection

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23
Q

What causes the ground glass appearance in hepatocytes of Hep B infection?

A

accumulation of HBsAg that cause eosinophilic inclusions that give this appearance

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24
Q

Why is Hep C very likely to become chronic?

A
  • RNA never cleared from acute infection and then reactivation of endogenous HCV strain
  • emergence of new strain
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25
Q

What are the consequences of hepatitis?

A

Loss of liver function b/c losing hepatocytes
- Hypoproteinemia–> b/c hepatocytes no longer producing blood proteins
- Hyperbilirubinemia–> jaundice produced b/c of insufficient bilirubin conjugation/excretion through bile
- Anemia–> due to decreased overall liver function
*fatigue common
* many treatments can cause anemia
Infections/stress cause additional damage
- Cirrhosis may be undiagnosed

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26
Q

What are the symptoms of chronic hepatitis?

A
  • fatigue, malaise, loss of appetite, mild jaundice
    -blood tests
    * serum transaminase is elevated
    * hyperglobulinemia, hyperbilirubinemia
  • minor hepatomegaly/splenomegaly
  • hepatic tenderness
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27
Q

What is the treatment for hepatitis?

A

manage symptoms

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28
Q

What can happen with both toxic and viral liver damage?

A
  • produce acute or chronic disease
  • can result in an immune response
  • result in destruction of hepatocytes (cirrhosis)
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29
Q

Why must toxins always be eliminated as a potential cause of liver damage?

A

b/c the liver is the primary detoxifying organ of the body
- toxins must be eliminated as a cause while also looking for viral damage b/c it is possible someone could have both

30
Q

Why do you get an immune response with liver damage?

A
  • not just the death of the cells
  • sometimes exposure to toxins can convert cellular proteins into an immunogen by altering it enough that your immune system will recognize it as foreign
31
Q

Toxic vs Viral Zonal damage to liver

A

Toxic
- most damage in zone 3 (near central vein) b/c least O2, least supported
- zone 3 not exposed to the most toxin, but most likely to suffer effects from the toxin b/c of lack of support
Viral
- most damage in zone 1 (periphery)
- these cells are most exposed to the virus

32
Q

Name some common liver toxins

A

Acetaminophen
- conversion to reactive intermediates that can kill the cells
Chlorpromazine–> dopamine antagonist (treats schizophrenia)
- forms insoluble complexes in bile- can cause cholestasis by blocking bile ducts
- metabolites
* inhibit membrane enzymes
* impair cytoskeletal functions
Ethanol
- more complicated

33
Q

Mild vs Serious ethanol injury

A

Mild
- moderate alcohol intake (6 beers)
- steatosis (fatty deposits form in liver)
- normally cleared, but will accumulate with chronic alcohol intake
Serious
- massive intake or chronic effect
- hepatitis

34
Q

What effects does alcohol have on hepatocytes that it can cause alcoholic hepatitis?

A
  • affects membrane function (chemical)- inserts in the membrane and affects normal fluidity of membrane
  • induces/inhibits enzymes that detoxify foreign compounds
  • enhances O2 toxicity
  • oxidized to acetaldehyde
    * inhibits protein export/metabolism
    * alters redox potential
    NOTE: acetaldehyde is assoc. with alcoholics developing malnutrition
35
Q

What is steatosis?

A

Fatty deposits form in the liver

36
Q

What is steatofibrosis?

A

Fatty deposits with fibrosis
- subsequent to activation of stellate cells

37
Q

Interplay of Hepatic Injury

A

Normal liver
Steatosis
- fatty change
- perivenular fibrosis
Hepatitis
- liver cell necrosis
- inflammation
- Mallory bodies
- fatty change
Cirrhosis
- fibrosis
- hyperplastic nodules
NOTE: all 3 conditions can develop independently and they can happen with other types of liver injury

38
Q

Non-alcoholic fatty liver disease phenotypes (NAFLD)

A

80% isolated fatty liver
- none to minimal progression to cirrhosis
- no increased risk of death compared with general population
Non-alcoholic steatohepatitis (NASH)
- NASH cirrhosis in 11% over 15 years
* Decomposition in 31% over 8 years
* Hepatocellular carcinoma in 7% over 6.5 years

39
Q

Hepatic vascular disease/ circulatory disorders

A

Impaired blood flow–> Esophageal varices
- portal vein obstruction
- intra or extrahepatic thrombosis
Impaired intrahepatic blood flow–> esophageal varices; ascites (cirrhosis)
- cirrhosis
- sinusoidal occulusion
Hepatic vein outflow obstruction–> jaundice
- hepatic vein thrombosis
- sinusoidal obstructive syndrome

40
Q

Describe sickle cell disease in the liver.

A
  • sickles can cause occlusion of sinusoids
  • impaired intrahepatic blood flow–> obstructing/occluding the sinusoid
  • liver damage in sickle cell patients is secondary to occlusion of the sinusoids
41
Q

Prehepatic causes of portal hypertension

A
  • obstructive thrombosis of portal vein
  • structural abnormalities such as narrowing of portal vein before it ramifies in the liver
42
Q

Intrahepatic causes of portal hypertension

A
  • cirrhosis from any cause
  • primary biliary cirrhosis (even in absence of cirrhosis)
  • massive fatty change
  • diffuse, fibrosing granulomatous disease (ex: sarcoidosis)
  • amyloidosis
43
Q

Posthepatic causes of portal hypertension

A
  • severe right-sided heart failure (cor pulmonale)
  • constrictive pericarditis
  • hepatic vein outflow obstruction
44
Q

What is pre-eclampsia vs eclampsia

A

-Sx: maternal HTN, proteinuria, peripheral edema, coagulation abnormalities (hypercoagulability)
- may also manifest as liver disease (HELLP syndrome)
* H= hemolysis
* EL= elevated liver enzymes
* LP= low platelets
* if coagulation is impacted, may be fatal
- hemorrhage into the space of Disse in liver
- fibrin deposits develop in periportal sinusoids (sinusoids closest to portal triads)
- develop coagulative necrosis of hepatocytes
- hematoma may form under Glisson’s capsule (thick CT capsule of the liver)
* can lead to catastrophic hepatic rupture if gets large enough

45
Q

What are cholestatic syndromes?

A

diseases related to the movement of bile, but the damage is w/in the liver

46
Q

What is cholestasis?

A

Systemic retention of bilirubin and other solutes–> b/c they are excreted by the liver, usually damage is in the liver
- excess cholesterol
- xenobiotics
- other waste products that are not water soluble
Impaired bile formation and flow
- accumulation of bile in hepatocytes
- obstruction of bile channels (extra- or intrahepatic)
- defects in hepatocyte bile secretion

47
Q

What are symptoms of cholestasis?

A
  • jaundice
  • pruritis
  • skin xanthomas (cholesterol accumulation)
  • malabsorption (failure to digest/absorb fat in intestines)
48
Q

What are the 3 mechanisms involved in sepsis causing cholestasis?

A
  1. Direct effects due to infection w/in liver (abscess or cholangitis)
  2. Ischemia due to hypotension (esp. if liver is cirrhotic)
  3. Circulating microbial products
    - most likely to lead to cholestasis, esp. w/ gram-negative bacteria
    Most commonly leads to canalicular cholestasis
    - bile plugs w/in centrilobular bile canaliculi
    - activated kupffer cells
    - mild portal inflammation
    Ductular cholestasis is more serious
    - dilated canals of hering and bile ductules w/ bile plugs
    - edema and presence of neutrophils in stroma
    - hepatocyte death possible
49
Q

What does the gall bladder do?

A

stores and concentrates bile
- simple columnar epithelium to absorb water to concentrate the bile
- gall bladder rests under liver
- shares a bile duct
- if bile is not secreted into duodenum, it will back up to cystic duct to be stored in gall bladder

50
Q

What is cholecystitis?

A

Inflammation of the gall bladder
- may be acute or chronic
- may be both
- almost always assoc. with gall stones

51
Q

Describe acute cholecystitis

A
  • enlarged, tense gall bladder–> produces pain
  • wall is thickened and fluid-filled (edematous)
  • serosa may have hemorrhages beneath–> hemorrhages in wall of gall bladder
  • may be covered with fibrinous exudate on surface of gall bladder
    * fibrinosuppurative (pus) is a sign of more severe disease
52
Q

Describe chronic cholecystitis

A

Mucosal inflammatory infiltrate
- puts a lot of pressure on the wall
- can get large sinuses forming–> disrupts muscularis externa of the gall bladder
Rokitansky-Aschoff sinus
- assoc. with proliferation of epithelial cells
- considered pre-cancerous lesion

53
Q

Name the tumors of the endocrine pancreas

A

Glucagonoma
Insulinoma
Somatostatinoma
NOTE: all benign tumors

54
Q

What are neuroendocrine tumors?

A
  • <2% of pancreatic tumors; most assoc. with exocrine pancreas
  • symptoms relate to excessive hormone release by these benign tumors
  • overgrowth of specific cell type
    * alpha= glucagonoma
    * beta= insulinoma
    * delta= somatostatinoma
55
Q

Details of somatostatinoma

A
  • somatostatin inhibits alpha and beta cells
    * diabetes–> altered glucose uptake–> due to downregulation of insulin production
    * cholethiasis–> impaired bile secretion (gall stones)
    * steatorrhea–> impaired exocrine pancreatic excretion (excess fat in fecal matter)
  • both cholethiasis and steatorrhea due to lack of glucagon
56
Q

Describe glucagonoma

A

-overgrowth of alpha cells
- excessive glucose mobilization
- produces hyperglycemia
- patients have characteristic rash
* due to malnutrition
* excessive AA uptake for use as fuel to produce more glucose

57
Q

What is happening with glucose production due to glucagonoma?

A
  • glucagon activates gluconeogenesis, which will use amino acids as fuel to produce more glucose
  • instead of using AAs in the body to make proteins, patients will have malnutrition b/c AAs are being used to make more glucose
58
Q

Describe insulinoma

A
  • excess glucose - uptake so glucose levels in blood drop dramatically
  • clinically, hypoglycemia producing neurological symptoms (confusion, stupor, loss of consciousness)
  • symptoms relieved by food intake or receiving glucose
  • precipitated by exercise or fasting–> causes BG levels to drop even faster
59
Q

What is the main difference in classification between type 1 diabetes and type 2 diabetes?

A

Type 1: beta cell destruction
- usually leading to absolute insulin deficiency
Type 2: combination of insulin resistance and beta cell dysfunction

60
Q

What are the clinical manifestations of diabetes?

A
  • b/c breaking down more adipose tissue, free fatty acids will increase appetite
  • protein catabolism in muscle will also increase appetite
  • free fatty acids increase ketogenesis, which increases ketoacidosis, which can cause diabetic coma
    * ketoacidosis also affects kidneys, producing excess ketones in urine
  • hyperglycemia produces glycosuria
  • ketoacidosis and glycosuria both increase urine volume by affecting uptake of H2O in collecting ducts
    * volume depletion= increased thirst
61
Q

What are the diseases of the exocrine pancreas discussed?

A

Acute and Chronic Pancreatitis
- inflammation assoc. with damage to exocrine tissue
- acute–> reversible damage
- chronic–> irreversible damage
* can present as repeated incidents of acute damage that do not fully resolve
* losing more tissue with each incident

62
Q

Acute pancreatitis

A

reversible parenchyma injury with inflammation

63
Q

Common causes of acute pancreatitis

A
  • biliary tract disease
  • alcoholism mostly
  • toxins
  • trauma
  • vascular disease
64
Q

Why can biliary tract disease cause acute pancreatitis?

A

It can affect the pancreas b/c pancreatic secretions go through the same ampulla of otti just like the common bile duct
- any damage along there can affect movement of product from the pancreas

65
Q

What does activation of trypsin have to do with pancreatitis?

A
  • changes assoc. with acute pancreatitis suggest autodigestion of the pancreas by its own digestive enzymes causes initial damage, which then induces inflammatory response
  • trypsin is activated in pancreas rather than in the duodenum
  • supported by hereditary pancreatitis
    * mutation in cleavage site–> fail safe; important for de-activation–> mutation means you cannot deactivate trypsin
    * mutation in trypsin inhibitor–> increases risk of irregular activation of trypsin if it’s mutated and cannot inhibit trypsin
66
Q

What is the normal activation of trypsin?

A

Normally, pancreatic enzymes are secreted and go to duodenum, where trypsin is activated
- trypsin then activates most of the other pancreatic enzymes

67
Q

What enzymes are linked to autodigestion of the pancreas?

A

Microvascular leakage (edema)
- Elastase damages vessel walls
Fat necrosis
- activation of Lipases
Parenchymal degradation
- Proteases (trypsin, chymotrypsin, etc.)
Thromboses damage weak vessels
- Clotting defects
Hemorrhage
- Kallikrein–> type of kinin related to BP and inflammation
* also involves plasma, which degrades clots and activates clotting factors

68
Q

Acute vs Chronic pancreatitis

A

Both
- acinar cell injury
Acute
- resolution
Chronic
- loss of cells with fibrosis occurring

69
Q

Describe chronic pancreatitis

A
  • Inflammation with irreversible damage to exocrine parenchyma
    * irreversible damage= distinction from acute
  • eventually, fibrosis develops, and may even impact endocrine parenchyma–> start seeing effects on glucagon, insulin, and somatostatin
  • most common cause is long-term alcohol abuse
    * increased excretion of pancreatic enzymes–> duct obstruction
    * directly toxic to acinar cells
70
Q

Pathogenesis of chronic pancreatitis

A

Similar to acute
- duct obstruction
- cell injury
Oxidative stress has a role in chronic
Repeated acute episodes
- perilobular fibrosis
- duct distortion
- altered secretion
Results in fibrosis and parenchyma loss

71
Q

Describe clinical pancreatitis

A
  • upper abdominal pain due to inflammation of pancreas
  • nausea, vomiting, fever, tachycardia, sweating
  • icterus/jaundice–> especially if pancreatitis is caused by obstruction in ampulla of otti b/c you have damage to pancreas and damage to liver and gall bladder as well
72
Q

Treatments for pancreatitis

A
  • IV fluids
  • NO food–> food ingestion activates exocrine pancreas
  • medicine for pain

Mechanisms of Disease (10 decks)

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