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GI II Exam II > Chapter 18: Liver > Flashcards

Chapter 18: Liver Flashcards

1
Q
  • Which 3 serum enzyme measurements represent a response to disrupted hepatocyte integrity?
A
  • Aspartate aminotransferase (AST)
  • Alanine aminotransferase (ALT)
  • Lactate dehydrogenase (LDH)
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2
Q
  • ___________ measure the biliary excretory function.
A
  1. Serum bilirubin
  2. Urine bilirubin
  3. Serum bile acids
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3
Q
  • Serum measurements of which 2 enzymes look for damage to bile canaliculus?​
A
  1. Serum alkaline phosphatase (ALP)
  2. Serum gamma-glutamyl transpeptidase (GGT)
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4
Q
  • What are the tests that look for hepatocyte synthetic function (synthethesis)?
A
  1. Serum albumin
  2. Coagulation factors: PT, PTT, fibrinogen, prothrombin, factors V, VII, IX, and X
  3. Hepatocyte metabolism:
    1. serum ammonia (↑ in L.D)
    2. aminopyrine breath test (hepatic demethylation): (↓ in L.D)
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5
Q

As liver function decreases = coag levels ______ = PT levels _____

A
  • decrease
  • increase
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6
Q

Alcoholic liver disease:

↑ ____ > ↑ ____

A

↑ AST > ↑ ALT (2:1)

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7
Q

Most types of hepatitis that damages hepatocytes

↑ ____ > ↑ ____

A

↑ ALT > ↑ AST

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8
Q

Alkaline Phosphotase (ALP) is a __________ that measures _________.

A

Enzyme from liver, bones and GI tract;

  • ↑ when bile flow is obstructed (cholestasis) =
  • can also rise in pregnancy (placenta); thyroid disease and bone disease
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9
Q

To determine if an ↑ in ALP is due to liver, biliary tree or bones, we measure _____.

A

GGT = ↑ in cholestasis and biliary obstruction, does not rise in bone disease.

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10
Q
  1. ↑ ALP & ↑ GGT = ______ cause.
  2. ↑ ALP & NL GGT = ____ cause.
A
  1. Hepatobiliary
  2. Bones
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11
Q
  • 2 reversible changes in hepatocytes (2)
A
  1. Steatosis: accumulation of fat in the liver
  2. Cholestasis: accumulation of bilirubin in the liver
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12
Q

When injury is not reversible, hepatocytes die via ______ or ______.

A
  • Necrosis
  • Apoptosis
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13
Q

_________ is the predominant mode of hepatocyte death seen in ischemic/hypoxic injury and responses to oxidative stress. Describe this mechanism.

A

Necrosis;

  1. Defect in osmotic resgulation causes fluid to enter the cell => cell swells and ruptures (lysis)
  2. MO accumulate at sites of necrosis
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14
Q

____________ is the type of cell death seen in acute and chronic hepatitis. Describe the process.

A

Apoptosis.

  1. Hepatocyte shrink
  2. Chromatin condenses (pyknosis)
  3. Fragmentation (karyorrhexis)
  4. Cellular fragmentation into acidophilic apoptotic bodies (adidophil bodies)
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15
Q

________ increase at sites of hepatocyte injury and mark sites of hepatocyte necrosis.

A

MO

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16
Q

Councilman bodies are the apoptotic bodies associated with what disease?

A

Yellow Fever

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17
Q

When there is widespread parenchymal loss, there is often evidence of ___________.

When does this occur?

A

Confluent necrosis; severe zonal loss of hepatocytes.

  • Begins as a zone of hepatocyte dropout around the central vein.
  • Produce a space filled with cellular debris, MO, and remnants of the reticular meshwork

Occurs in: acute toxic injury, ischemic injury, viral/AI hepatitis.

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18
Q

What is bridging necrosis?

What disease do we see this in?

A
  • Vascular insult (inflammation or thrombosis) causes zonal loss of hepatocytes to occur in between [central veins - portal tracts; portal tract - portal tract] => parenchymal extinction and collapse of the supporting network.
  • Cirrhosis
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19
Q

Regeneration of the liver occurs via 2 major mechanims, which are?

What is the predominant method?

A

1) Proliferation of hepatocytes adjacent to those that have died ***

2) Stem cell replenishmenemt

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20
Q

Is stem cell replenishment a big part of parenchymal repair when hepatocytes are regenerating?

A
  • NO
  • However, hepatocytes are almost stem-cell like; they can continue to replicate even in the setting of years of chronic injury.
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21
Q

When do stem cells begin to contribute significantly to restoring the liver parenchyma?

A

In chronic diseases via ductal reactions (heptocytes reach replicative senescence => + of stem cells => form ductular reactions => restore parenchyma).

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22
Q

__________ is the main type of liver cell involved in scar deposition => cirrhosis.

A

Stellate cell.

  • NL: stellate cells are dormant and store lipids (vitamin A).
  • However, when there it acute or chronic injury, they becomes fibrogenic myofibroblasts => secrete TGF-B and initiate fibrosis.
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23
Q

Describe the process of activation of stellate cell from a lipid-storing cell => fibrogenic myofibroblast => fibrosis.

A
    • Kupffer cells are + => release mutuple cytokines:
      1. PDGF-B and TNF (others: TGF-B, MMP-2 and TIMP-1/2) => proliferation and (+) stellate cells (lipid-storing => myofibroblasts).
      2. Stellate cells transform into myofibroblasts that contract when stimulated by ET-1 (endothelin-1)​
      3. Chemotaxis of + stellate cells to areas of injury are promoted by PDGF and MCP-1 (Monocyte chemotactic protein-1.
    1. Stellate cells begin to secrete TGF-B => produce collagen and initate fibrosis.
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24
Q

What stimulates (+) of stellate cells & scar formation?

A
  1. Chronic inflammation, with production of inflammatory cytokines (TNF, IL-1B and lymphotoxin)
  2. Cytokines and chemokines made from Kupffer cells, endothelial cells, hepatocytes and bile duct epithelial cells
  3. Disruption of ECM
  4. Direct stimulation by toxins

If injury persists => scar deposition begins, often in the Space of Disse .

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25
Q

In chronic inflammation which inflammatory cytokines are made and act as stimuli for Stellate Cell activation?

A
  1. - TNF
  2. - Lymphotoxin
  3. - IL-1β
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26
Q

What role does ductular reactions have in scar deposition?

A
      • and recruit fibrogenic cells
    1. Epithelial-mesenchymal transition
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27
Q

If the chronic liver injury leading to scar formation is interrupted (i.e., clearance of hepatitis virus infection, cessation of alcohol use), what happens?

A

Scar formation reverses.

    • Stellate cells stop being activated
    • Scars condense –> become more dense and thin
    • Metalloproteinases produced by hepatocytes break the scar apart.
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28
Q

When does liver failure occur?

Without a liver transplant, the mortality rate is _____.

A
  • When 80-90% of hepatic function is lost.
  • 80%
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29
Q

Liver failure may be due to what 3 reasons?

A

1. Acute injury

2. Chronic, progressive injury*

3. Acute-on-chronic injury

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30
Q

What is acute liver failure?

A

Acute liver illness associated with encephalopthy and coagulopathy that occurs within 26 weeks of the initial liver injury, in the abscence of a pre-existing disease.

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31
Q

Acute live failure is caused by what type of tisuse injury?

A

Massive hepatic necrosis, often due to drugs/toxins.

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32
Q

What is the major cause of acute liver failure in the US?

What accounts for the rest of cases?

A
    • Acetominophen OD (accidental or deliberate) => 50%
    • Autoimmune hepatitis
    • Drugs/toxins
    • Acute HepA and B
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33
Q

What are all causes of Acute Liver Failure?

A

MNEUMONIC

  • A: Acetominophen, HepA, AI hepatitis
  • B: Hep B
  • C: Hep C; cryptogenic
  • D: Drugs/toxins, HepD
  • E: Hep E, esoteric causes (Wilson’s Disease, Budd-Chiari disease)
  • F: Fatty changes of the microvascular type (fatty liver of pregnancy, valproate, tetracyclin, Reyes syndrome)
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34
Q

How quickly does liver failure occur with acetominophin toxicity vs. hepatitis?

A
  • In acetominophen toxicity, LF occurs within one week of the onset of sx’s.
  • LF in hepatitis takes longer to develop.
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35
Q

What is the morphology of Acute Liver Failure?

  1. Microscopic?
  2. Gross?
  3. Scar formation and ductular reactions?
A
  1. Massive hepatic necrosis with broad regions of parenchymal loss around islands of regnerating hepatocytes.
  2. Small and shrunken
  3. Scar formation & ductular reactions depends on the type and duration of insult:
    1. Toxic injuries = like acetominophen = failure occurs hours to days = too short to allow scars to form
    2. Acute viral injuries = failure occurs from weeks - months = hepatocyte injury outweighs repair = early scarring occurs in areas of parenchymal loss
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36
Q

Rarely, in acute liver failure diffuse microvesicular steatosis can occur.

What is this and what disorders is this commonly seen in?

A
  • Small intracytoplasmic fat vacuoles (liposomes) accumulate in the cell => poison, without causing cell death and parenchymal collapse.
  • Occurs in fatty liver of pregnancy or reactions to toxins (tetracycline/ valproate)
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37
Q

Diffuse microvesicular steatosis causes intracytoplasmic accumulation of liposomes, causing hepatocytes not to be able to perform their metabolic function due to…

A

Damage to the mT

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38
Q

Which 4 viruses are most often the cause of acute liver failure in patients who are immunodeficient?

A
  • 1. HIV
  • 2. CMV
  • 3. HSV
  • 4. Adenovirus
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39
Q

Clinically, what symptoms do we see in a patient with acute liver failure?

A
  1. Jaundice and N/V => progresses to life-threatening encephalopthy and coagulopathy
  2. Moderate increase in liver transaminases
  3. Hepatomegaly (d/t swelling, infiltrates and edema) => parenchyma is destroyed => shrunken liver and ↓ in serum transamineases bc less viable hepatocytes
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40
Q

When does acute liver failure = poor prognosis?

A
  • ↓ in liver enzymes, meaning that we have a few remaining hepatocytes,
  • Jaundice, coagulopathy and encephalopathy worsens
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41
Q

What are other manifestations of acute liver failure? (5)

A
    1. Jaundice, icterus and cholestasis
    1. Hepatic encephalopthy
    1. Coagulopathy
    1. Portal HTN (most common in chronic LF)
    1. Hepatorenal syndrome
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42
Q

Cholestasis increase the risk of _____.

A

Life-threatening bacterial infection.

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43
Q

What is hepatic encephalopthy?

A
  • ↑ levels of ammonia => disturbances in consciousness (ranging from behavioral abnormalities => confusion => deep coma and death).
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44
Q

What is a characteristic sign of Hepatic Encephalopathy?

How does it present?

A
    • Rigidity and hyperreflexia
    • Asterixis = nonrhythmic, rapid extension-flexion movements of head and extremities
    • Best seen w/ arms in extension w/ dorsiflexed wrists
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45
Q

Which disorders of coagulopathy may be seen in acute liver failure?

Earliest sign?

A
  1. Liver is responsbile for making Vit K dependent clotting factors and other CF. LF = > no clotting factors =>
    1. Earliest sign is easy bruising => can lead to fatal intracranial bleeds
  2. Liver also removes activated coagulation factors from blood.
    1. If fx is lost => Disseminated intravascular coagulation (DIC) => a condition in which blood clots form throughout the body, blocking small blood vessels. As clotting factors and platelets are used up, bleeding may occur.
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46
Q

Portal HTN is more common in chronic liver failure, but if it occurs in acute liver failure, it is most likely due to ______________ , which can cause ________________.

A

- Intrahepatic obstruction

  • Ascites and hepatic encephalopathy
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47
Q

What is hepatorenal syndrome?

The syndrome’s onset begins with a drop in what and rising?

A
  • A form of renal failure in people with liver failure, whose kidneys are NL.
    • Decreased renal perfusion pressure/GFR => renal vasoconstriction => Na+ retention and impaired free-water excretion.
  • *Begins w/ a ↓ in urine output + ↑ BUN/Cr.
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48
Q

Does all cirrhosis lead to chronic liver failure and is all end-stage chronic liver disease cirrhotic?

A

No. Although, they are often associated with one another.

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49
Q

What are the most comon causes of chronic liver failure?

A
  1. Chronic HepB/C
  2. Non-alcoholic fatty liver disease (NAFLD)
  3. Alcoholic fatty liver disease
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50
Q

What is cirrhosis?

A

Formation of regenerative nodules on the liver parenchyma surrounded by:

  1. Bands of fibrotic tissue
  2. Vascular shunting (often portosystemic).
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51
Q

___________ describes cirrhosis when there is no clear cause.

A

Cryptogenic cirrhosis

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52
Q

What are the 3 morpphological characteristics of cirrohosis?

A
    1. Bridging fibrosis links portal tracts to each other and to central veins
    1. Parenchymal nodules due to hepatocyte regeneration when encircled by fibrosis.
    1. Disruption of the architecture of the parenchyma.
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53
Q

What is the Child-Pugh classification of cirrhosis?

A

Monitor the track of decline in patients with chronic liver failure.

  1. *Class A (well compensated);
  2. Class B (partial comp.);
  3. Class C (decompensated)*
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54
Q

As chronic liver disease worsens, ductular reactions _____.

  • They occur most often in ______.
A

Increase

Cirrhosis

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55
Q

Why is cirrhosis no longer considered end-stage liver diasese?

A
  • the fibrosis is potentially reversible with increasing numbers of effective treatments for cirrhosis-causing conditions
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56
Q

On biopsy, what do we see that is most likely linked to end-stage disease?

A
  1. Broad bands of dense scar
  2. Dilated lymphatic spaces
  3. Less parenchyma

are more likely to progress to portal HTN and thus, end stage disease.

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57
Q

When do patients with cirrhosis become symptomatic?

A

40% of individuals with cirrhosis are asymptomatic until the most advanced stage of the disease.

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58
Q

What are the clinical symptoms of cirrhosis (chronic liver failure)?

A
  1. Chronic jaundice + intense pruritus => pt may scratch skin raw.
  2. Hypoalbuminemia –> systemic edema
  3. Hyperammonemia -> heptic encepholopathy
  4. Fetor hepaticus: mercaptan formation
  5. Males have problem metabolizing estrogen => hyper-estrogenemia => palmar erythema, spider angiomata, hypogonadism*, and gynecomastia
  6. Portal HTN => ascites
  7. increased risk of developing hepatocellular carcinoma

* = can also occur in W

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59
Q

In men, what are the adverse effects of impaired estrogen metabolism and consequent hyperestrogenemia associated w/ chronic liver disease?

A

- Palmar erythema

- Spider angiomas

  • Hypogonadism and Gynecomastia
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60
Q

Portal HTN = Increased resistance to portal blood flow.

What 3 categories are causes of portal HTN?

A
    1. Prehepatic causes
    1. Intrahepatic causes
    1. Posthepatic causes
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61
Q

What are pre-hepatic causes of portal HTN?

A
  1. Obstructive thrombosis
  2. Narrowing of the portal vein before entering the liver
  3. Massive splenomegaly with increased splenic blood flow
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62
Q

What are the post-hepatic causes of portan HTN?

A
  1. Severe right heart failure
  2. Constrictive pericarditis
  3. Obstruction of hepatic vein outflow
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63
Q

What is the most common intrahepatic cause of portal HTN?

A

Cirrhosis

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64
Q

What are the mechanisms that Cirrhosis causes edema and ascites?

A

In cirrhosis,

    1. ↓ in albumin => ↓ in oncotic pressure => ↓ in effective circulating volume.
    1. ↑ in many vasodilators (NO) => splanchnic vasodilation => ↓ in SVR and BP => sympathetic + and ↓ in effective circulating volume
  • 3. ↓ in effective circulating volume => ↑ RAAS and ADH => ↑ in Na/H20 => ↑ in total body water.
    1. => acites and edema.
      *
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65
Q

MCC of portal HTN is cirrhosis.

What are other intrahepatic causes?

A
  1. Schistomiasis
  2. Massive fatty change
  3. Granulomatous disease (sarcoidosis)
  4. Nodular regenerative hyperplasia
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66
Q

The pathophysiology of portal HTN develops due to what 2 causes?

NL path of blood?

A

NL, blood froms from portal vein => liver => hepatic vein => systemic. Cirrohosis causes obstructed BF through liver.

  1. ↑ in blood flow via portal vein to the liver.
  2. ↑ pressure in portal vein at the level of the sinusoids due to cirrhosis causing obstructed BF in the liver.
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67
Q

What are the clinical consequences of portal HTN? (4)

A

↑ pressure in the portal veins => fluid leaks out

  1. Ascites
  2. Congestive splenomegaly

Circulatory system starts to dlvert blood away from the liver via a portosystemic shunt (bc blood flow follows the path of least resistance), shunting blood away from the portal system => to systemic system of circulation.

  1. Formation of a portosystemic venous shunt
  2. Hepatic encephalopathy = bc less functional

units = liver cannot detoxify

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68
Q
  • Ascites is collection of excess ____ fluid in the peritoneal cavity, clinically detectable when ______ has accumulated.
  • In 85% of cases, it is caused by _______.
  • Long-standing ascites can cause what?
A
  • Serous; 500mL
  • Cirrhosis
  • Hydrothorax: peritoneal fluid seeps through trans-diagphragmatic lymphatic channels, especially on the R.
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69
Q

What is the composition of fluid seen in ascites?

A
  1. Serous fluid w/ < 3g/dL of protein (mainly albumin);
  2. Little # of mesothelial cells and mononuclear leukocytes
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70
Q

_______ in the fluid in ascites can indicate an infection; while ______ can indicate disseminated intraabdominal cancer.

A
  • Neutrophils = ascites
  • Blood = disseminated intraabdominal cancer
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71
Q

What are the 3 mechanism which account for the pathogenesis of ascites?

A
  1. Sinusoidal HTN/portal HTN [+/-] hypoalbuminemia
  2. Percolation of hepatic lymph into the peritoneal cavity
  3. ↑ in many vasodilators (NO) => splanchnic vasodilation => ↓ in SVR and BP => ↓ in effective circulating volume & sympathetic (+) => triggers vasoconstriction & RAAS + => Na+ and H20 retention => increase in TBW
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72
Q

Q: Patient presents with cirrhosis, but not portal HTN, will they develop ascites, edema or both?

A

Only edema; portal HTN must be present for ascites to develop.

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73
Q

Q: If you see a patient presenting with ascites, you KNOW that they have ______.

A

Portal HTN

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74
Q

What do SAAG levels measure?

How does it measure it?

A

Whether ascites is due to portal HTN or malignancy, which causes leaky vasculature.

  1. Measure SAAG: paracentesis of fluid in ascites (serum albumin - ascites albumin = SAAG)
  2. SAAG >1.1 g/dL = portal HTN.
    1. Large difference between serum and ascites albumin because high pressure in portal system is driving fluid into the peritoneum, not albumin.
  3. SAAG <1.1 g/dL = malignany ascites.
    1. Levels of albumin levels are similar between the serum and ascites = leaky vasculature leads to fluid/albumin into peritoneum.
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75
Q

Portal HTN causes the formation of portosystemic shunts. What are these?

A
  • Pressure in portal vein is high, as a result, flow is reversed into the systemic circulation through venous collaterals (connections between venous and portal veins). = engorge in portal HTN.
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76
Q

What are the portosystemic shunts (key collaterals) that engorge in portal HTN and what do they result in?

A

Swelling of venous collaterals around the:

    1. BB & falciform L of the liver => caput medusae
    1. Esophagus => esophgeal varices => UGIB
    1. Stomach => gastric varices
    1. Rectum => internal hemorrhoids.
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77
Q

What is responsible for massive hematemesis and death in pts with advanced cirrhosis of the liver?

A
  • Esophageal varices, which occur in 40% of people with advanced cirrhosis.
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78
Q

Splenomegaly due to portal HTN may cause what?

A
  1. Thrombocytopenia –> ↓ platelet count
  2. Pancytopenia –> ↓ RBC/WBC + platelets
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79
Q

What are 2 other conditions that occur in Chronic Liver Failure?

A
  • 1. Hepatopulmonary syndrome
  • 2. Portopulmonary HTN
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80
Q
  • Hepatopulmonary Syndrome occurs in 1/3 of patients w/ cirrhosis and portal HTN.
  • What is the pathogenesis?
A
  1. Patients develop intrapulmonary vasodilation =>
  2. ↑ blood flow =>
  3. ↓ O2 diffusion of blood =>
  4. V/Q mismatch =>
  5. Hypoxia (dyspnea that is worse when standing) and is best in recumbant position.
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81
Q

What are the 2 most common clinical manifestations of Portopulmonary HTN?

A

1) Dyspnea on exertion
2) Clubbing

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82
Q

What is acute-on-chronic liver failure?

A
  • Ppl with stable, well-compensated chronic liver failure develop sudden signs of acute liver failure.
    • Develops d/t large amounts of the liver having borderline vascular function and vulnerable to superimposed insults.
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83
Q

Viral hepatitis refers to

A

Infection by Hepatitis A-E.

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84
Q

All viral hepatitis are ____ viruses, except ______, which is _____.

A
  • RNA viruses
  • Except HepB => partial DNA
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85
Q

Which Hepatitis are transmitted fecal-orally?

A

Hep A and E

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86
Q

Fulminant hepatitis (acute liver failure) is unusual, but is seen primarily with which hepatitis viruses?

A
  1. A
  2. B
  3. D
  4. *HEV in pregnant women
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87
Q

Hepatitis A

  1. Type of virus:
  2. Viral family:
  3. Route of transmission:
  4. Mean incubation period:
  5. Frequency of chronic liver disease:
  6. Carrier state?
  7. Diagnosis:
A
  1. Small, naked +ssRNA
  2. Picornavirus
  3. Fecal-oral via contaminated water in developing countries; eating raw or steamed shellfish that was contamined in seawater with sewage in developed countries
  4. 2-6 weeks
  5. Never: benign, self-limited and rarely lethal.
  6. No carrier state
  7. Onset of sx =
    1. IgM Ab = acute infection
    2. Within a few months, as IgM Ab ↓ => IgG Ab ↑ and persist for years => confer immunity.
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88
Q

Which immune cell appears to play the key role in the hepatocellular injury caused during Hep A and B infection?

A

CD8+ cytotoxic T cells => kill virus infected cells.

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89
Q

Case: Travelor who goes to MX/ Central America

A

HepA

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90
Q

Hepatitis E

  1. Type of virus:
  2. Viral family:
  3. Route of transmission:
  4. Mean incubation period:
  5. Frequency of chronic liver disease:
  6. Carrier state?
  7. Diagnosis:
A
  1. Type of virus: naked (+) ssRNA
  2. Viral family: Hepevirus
  3. Route of transmission: Enterically via fecal-oral from contaminated water in young-middle aged adults.
  4. Mean incubation period: 4-5 weeks
  5. Frequency of chronic liver disease: NEVER; self-limited => virions are shed in shit during acute illness.
  6. Carrier state? -
  7. Diagnosis: Serum IgM and IgG; PCR for HEV RNA
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91
Q

What is the reservoir in Hep E?

A
  • Animals: increased risk with exposure to monkeys, cats, pigs, and dogs
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92
Q

What is a UNIQUE characteristic feature about HepE?

A
  • High mortality rate in pregnant women (20%)
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93
Q

Hepatitis B

  1. Type of virus:
  2. Viral family:
  3. Route of transmission:
  4. Mean incubation period:
  5. Frequency of chronic liver disease:
  6. Fulminant hepatitis?
  7. Diagnosis:
A
  1. Enveloped, partially dsDNA (circular)
  2. HepaDNAvirus
  3. Parenteral, sexual contact, perinatal
  4. 8 weeks
  5. 5-10%
  6. YES
  7. Detection of HBsAg, antiHBcAg; PCR for HBV DNA
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94
Q

Even in the absence of cirrhosis, chronic infection by which viral hepatitis is an important precursor for the development of hepatocellular carcinoma?

A

Hepatitis B

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95
Q

What are the 5 different forms of HBV illness?

A
  1. Acute hepatitis => recovery and clearance of the virus
  2. Non-progressive chronic hepatitis
  3. Progressive chronic disease resulting in cirrhosis & ↑ risk of HCC
  4. Fulminant hepatitis (acute LF) with massive liver necrosis
  5. Asymptomatic, ‘healthy’ carrier state
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96
Q

In high prevalence areas of HBV, like Africa & Asia, what is the major mode of transmission?

A

Transmission during childbirth

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97
Q

What is the most common mode of transmission for HepB in areas with intermediate prevalence and areas with low prevalence?

A
  • Intermediate: horizontal transmission in early childhood by minor breaks in skin or mucous membranes
  • Low (USA): unprotected sex and IV drug abuse (sharing needles)
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98
Q

Which mature hepatitis virus, when intact, is referred to as the “Dane particle?”

A

HepB Virus

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99
Q

What is unique about the replication cycle of HepB?

Mediated by what?

A
  • Contains Pol, which has both DNA polymerase and reverse transcriptase activity
  • Partial dsDNA —> dsDNA => mRNA —> makes proteins, such as reverse transcriptase, which converts it back into partial dsDNA => packaged into virions.
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100
Q

What is the structure of a HepB virus Dane Particle?

A

Virus has antigens (BAD):

  1. HBsAg (HepB surface antigen)
  2. Capsid is made up of
    1. HBcAg (HepB core antigen), which stays in hepatocytes and does not circulate in blood, to help with the assembly of complete virions
    2. HBeAgs (HepB e Antigen), which is released during viral replication
  3. Partially dsDNA in the center, with its own DNA polymerase to complete double-stranding of the genome once the molecule gets into the nucleus.
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101
Q

Each AB targets only a single type of antigen, proteins found on BAD SHIT: viruses, bacteria, funguses, cancer or even bodies own cells (in AI diseases).

Job of AB is to go hunt down antigen and attack it.

Which HepB antigens can be detected in the blood?

A

1. HBsAg

2. HBeAg

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102
Q

Which HepB antibodies can be measured in the blood?

A
  1. Anti-HBsAg
  2. Anti HBeAg
  3. Anti-HBcAg
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103
Q
  • _______ ↑ in acute disease and ↓ as infections resolves.
  • _______ ↑ as acute infection resolves.
A
  • Antigens ↑ in acute disease and ↓ as infections resolves.
  • Antibodies ↑ as acute infection resolves.
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104
Q

In HepB, _______ appears in the blood before the onset of symptoms and tells that the person is infected (acute or chronic) or not.

A

HBsAg

  • (+): person is infected (acute, chronic or carrier)
  • (-): person is not infected
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105
Q

How do we know a ID a person who was vaccinated with HepB vaccine?

A

Vaccine => administer HBsAg to patient.

  1. + Anti HBsAg (antibodies to HBs antigen)
  2. All other AB (HBc, HBe) should be negative.
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106
Q

(+) anti-HBsAg antibodies

(-) HBsAg

Tells us what?

A

Increases when disease is over, about the dsame time that HBsAg goes away.

  1. Prior infection = no active disease
  2. Vaccination (IgG form = immunity)
107
Q

Generally, infection clears when:

  • Anti-HBsAg levels ____
  • HBsAg levels ____
A
  • anti-HBsAg ↑
  • HBsAg ↓
108
Q

+ HBeAg (HepB e antigen) indicates what?

What about if it is persistant?

A
  • Viral replication & VERY infectious.
  • If persistant => probably progression to chronic hepatitis.

*E antigen Escapes during rEEplication

109
Q

What marker helps to distinguish between acute, chronic or prior HepB infection?

A
  • IgM Ab to HBcAg => new, acute infection
  • IgG Ab to HBcAg => old, chronic infection or prior infection.
110
Q
  • (+) IgG Ab to HBcAg
  • (-) HBsAg

Indicates what?

A

Past infection

111
Q

What is the window period?

A
  • Window period= Brief period where HbsAg are undetectable, but Anti-HBsAg are not yet detected, giving people a false appearance of no infection.
  • During THIS period, the sole marker of infection is IgM anti-HBc .
112
Q

How do we detect HepB virus during window period?

A

Anti-HBc IgM Ab.

113
Q

If HBeAg is (-); but Anti-HBeAg is (+),

What does this mean?

A

Person went through a phase where the virus was replicating actively, but it has now stopped replicating and the person is less infectious.

114
Q

__________ is measured determine the viral load of HepB for treatment.

A

HepB DNA via PCR

115
Q

In a patient with acute HepB infection, what would you see?

A
    1. ↑ HBsAG, except during window period
    1. IgM Anti HBc, even during window period
    1. HBeAg, indicates infectivity
    1. HBV DNA
116
Q

What would you see in a person that recovered from an acute HepB infection?

A
  1. + IgG Anti-HBsAg/ Anti-HBeAg/ IgG Anti-HBcAg
  2. Undetectable HBsAg = bc marker of infection
  3. Absence of HBV DNA
117
Q

What do you see in a person with chronic Hep B infection?

A
  1. Persistant HBsAg +
  2. IgG Ab for HbcAg
  3. If HBeAg + => high infectivity
  4. Viral DNA may be high, low depending on viral load
118
Q

Which “core” protein of HBV stays within hepatocytes and participates in the assembly of complete virions?

A

HBcAg

119
Q

What is the course of Ab/Ag appearances in HepB Virus?

A
  1. One month after infection: HBsAg rises during incubation period, before patient develops acute illness and symptoms (anorexia, fever, jaundice). Peaks during overt disease if virus is cleared, declines over months. If patient converts to chronic HepB infection => HBsAg would not fall into low levels.
  2. ~2 months: HBeAg and HBV DNA appear after HBsAg, but before disease onset. HBeAg = viral replication but decreases in weeks. Persistance suggests progression to chronic hepatitis.
  3. IgM anti-HBcAg is the 1st antibody to appear: right before symptoms appear and same time aminotransferases ↑.
    • Followed shortly by Anti-HBeAg and IgG anti HBcAg.
  4. Anti-HBsAg => end of acute disease and persists for years; IgG form confers immunity
    *As you can see during window period, Anti-HBc levels are high => measured to detect virus
120
Q

What is the best predictor of chronicity in association with HBV infection?

A

Age when infected

*Younger = ↑ probability of chronicity

121
Q

What is the main determinant of the outcome of HepB infection?

A

Host immune response to the virus

  • Strong response by CD4+ and CD8+ IFN-γ producing cells => associated with the resolution of acute infection
122
Q

Appearance of which 3 serum markers in HBV infections indicate active viral replication?

A
  1. - HBeAg
  2. - HBV-DNA
  3. - DNA pol
123
Q

Histologically what is the diagnostic hallmark of chronic HepB infection?

A

“Ground-glass” hepatocytes due to accumulation of HBsAg in ER

124
Q

Hepatitis C

  1. Type of virus:
  2. Viral family:
  3. Route of transmission:
  4. Mean incubation period:
  5. Frequency of chronic liver disease:
  6. Fulminant hepatitis?
  7. Diagnosis:
A
  1. Enveloped ssRNA
  2. Flavi virus
  3. Parenteral; snorting cocaine is a risk factor
  4. 4-26 (avg 9)
  5. >80% *
  6. NO
  7. PCR for HepC RNA; ELISA to detect Ab
125
Q

What are the 2 hallmarks for HepC infection?

A

Persistent infection + chronic hepatitis

126
Q

80% of cases of HepC lead to chronic disease. Why?

A
  • No vaccine is availble because HepC has alot of genomic instability + antigenic variability
  • Anti-HepC IgG Abs do NOT offer effective immunity => reinfection can occur.
127
Q

How does the clinical course of acute HCV infection differ from that of HBV?

A
  • Acute HepC –> asymptomatic and much milder than HBV. However,
    • 80-90% => chronic infection
    • 20% => cirrhosis
128
Q

Chronic HepC infection is characterized by persistant ↑ in ____________.

How do the levels change?

A
  • Serum aminotransferases, whose levels wax and wane, but never become NL
129
Q

What unique characteristic is seen in 35% of people with chronic HepC infection?

A

Cryoglobulinemia

130
Q

Which testing must be performed to assess viral replication and to confirm the diagnosis of HCV infection?

A

PCR for HCV RNA

131
Q

HepC RNA is detected in blood for ___________ & __________ levels increase at the same time.

A
  • 13 weeks during active infection
  • Aminotransferase levels
132
Q

Infection with HepC genotype 3 can cause what?

A

Metabolic syndrome => can cause insulin resistance and non-alcoholic fatty liver disease

133
Q

Polymorphisms in ______ are associated with better response to treatment of HepC infection w/ IFN-α and ribavarin?

A

IL-28B gene

134
Q

In 90% of individuals with chronic HCV infection, circulating _________ persists despite the presence of antibodies

A

HCV RNA

135
Q

What is characteristic of the morphology seen in Chronic Hep C?

A
  1. Lymphoid aggregates or fully formed lymphoid follicles
  2. Fatty change of scattered hepatocytes
136
Q

What is Hepatitis D Virus?

A

A circular defective ssRNA virus that can replicate and cause infection ONLY when there is a HepB infection.

**Bc HepD does not have genes for envelope proteins and uses HBsAg for envelop protein**

137
Q

Hepatitis D

  1. Type of virus:
  2. Viral family:
  3. Route of transmission:
  4. Mean incubation period:
  5. Frequency of chronic liver disease:
  6. Fulminant hepatitis?
  7. Diagnosis:
A
  1. Type of virus: circular defective ssRNA
  2. Viral family: Deltavirus
  3. Route of transmission: Parenteral
  4. Mean incubation period: Same as HBV
  5. Frequency of chronic liver disease: 10% (coinfection); 90-100% for superinfection
  6. Fulminant hepatitis? YES
  7. Diagnosis: IgM and IgG Ab; HepD RNA in serum; HepD Ag in liver
138
Q

What are the 2 ways you can get HepD?

A
  • 1. Co-infection with HepD and HepB
    1. Superinfection of HepD, in patient who ALREADY has HepB
139
Q

How does co-infection with HepB/D occur?

A
  1. Serum is exposed to both HDV and HBV.
  2. HBV infect 1st to provide the HBsAg required for HepD to mature
  3. Results in acute hepatits that is usually self-limited and followed by clearance of both viruses. Thus, chronicity rarely occurs.
140
Q

_________ have higher rate of acute liver failure after co-infection by HepD/HepB virus.

A

IV drug users

141
Q

How does superinfection of HepD occur?

A
  • Chronic carrier of HBV is exposed to HDV => severe hepatitis around 30-50 days later
142
Q

What are the 2 phases of HBV- HDV superinfection and what occurs in each?

A

1) Acute: active HDV replication and suppression of HBV w/ ↑ transaminase levels
2) Chronic: HDV replication decreases, HBV replication increases, transferase levels fluctuate, and disease progresses => cirrhosis and sometimes hepatocellular carcinoma

143
Q
  • Right before and in the beginning of acute symptomatic HepD infection, _______ is detectable in the blood and liver.
A

HDV RNA

144
Q
  • ________ is the most reliable indicator of recent HepD exposure
A
  • IgM anti-HDV
145
Q
  • _____ = acute HepB/D coinfection
  • _____= superinfection
A
  • IgM anti-HbcAg = coinfection
  • HBsAg = superinfection
146
Q

_______ vaccine prevents a person from contracting HepD

A

HepB vaccination

147
Q

Where is HepE infection most likely to occur?

A
  • Asia, Mexico, Africa
  • India (30-60% of acute Hep are due to HepE)
148
Q

Which viral Hepatitis undergoes immune reconstitution?

A

If HIV is treated without treating HepB, it can cause severe liver damage. Thus, HepB testing is usually done BEFORE HIV therapy.

149
Q

Patient has [polyarteritis nodosa] + [nephrotic glomerular disease that causes proteinuria].

Which viral hep do they have?

A

Hep B

150
Q

Which viral hepatitis infections are most often acute asymptomatic infections that recover, only ID’d by serologic evidence.

A

HepA and HepB infection are often subclinical events in childhood, discovered in adulthood by the presence of anti-HAV or anti-HBV antibodies

151
Q

________ = viral hepatitises that are the MCC of acute liver failure in the world.

_________ = viral hepatitis that is the MCC of acute liver failure in Asia.

A
  • World = HepA and E
  • Asia = HepB
152
Q

In some patients with Chronic Hepatitis the only signs are persistent elevations of?

A

Serum transaminases

153
Q

What is the leading cause of morbidity and mortality for patients with HIV?

A

Chronic HBV or HCV** infection

154
Q

Most of the parenchymal injury seen in acute hepatitis is seen how morphologically?

A
    • Scant mononuclear infiltrate in the portal tract
    • “Spotty necrosis” or lobular hepatitis throughout the lobule
  3. Injured cells are eosinophillic and round with shrunken or fragmented nuclei (apoptosis) or swollen (ballooning degeneration)
155
Q

What is the defining histological feature of severe acute viral hepatitis?

A
  1. Confluent necrosis around central veins
  2. Increasing severity => central-portal bridging necrosis => parenchymal collapse.
156
Q

What is the defining histological feature of chronic viral hepatitis?

A
  1. DENSE mononuclear infiltration in the portal triad
  2. Progressive => extension of chronic inflammation from portal tracts with interface hepatitis
  3. Bridging necrosis
  4. Continued loss of hepatocytes => formation of fibrous septum
157
Q

What SPECIFIC histologic changes suggest HepB and HepC?

A
  • HepB: Ground glass hepatocytes whose ER is swollen with HBsAg
  • HepC: Hepatocytes that have lymphoid aggregates or fully formed lymphoid follicles; scattered fatty change of hepatocytes
158
Q

Bile duct injury, potentially mimicing primary biliary cirrhosis is prominent in some pts with what type of viral hepatitis?

A

Hepatitis C

159
Q

Which organisms most commonly found is SE Asia is notorious for causing a very high rate of cholangiocarcinoma?

A

Liver flukes (trematodes)

160
Q

Which bacteria can affect the liver directly?

A
  • 1. Staph. aureus, in toxic shock syndrome
  • 2. Salmonella typhi in typhoid fever
  • 3. Treponema pallidum in secondary or tertiary syphilis
161
Q

What is autoimmune hepatitis?

Triggered by?

Who is most at risk?

A
  • Chronic, progressive AI inflammation of the liver that is ID’d by the prescene of autoantibodies (2 types)
  • Viral infections or drugs/toxins
  • White F 40s-50s, espcially if they have DRB1 allele
162
Q

Type 1 autoimmune hepatitis is most often seen in which age group/sex?

Characteristically associated with what 2 antibodies?

A

- Middle-aged woman

  • Antinuclear (ANA) and Anti-smooth muscle actin (ASMA)
163
Q

Type 2 autoimmune hepatitis is most often seen in which age group/sex?

Characteristically associated with what _____ antibody, which attacks ____.

A
  • Children and teens
  • Anti-liver kidney microsome-1 (anti-LKM1) –> attack CYP2D6
164
Q

Inflammatory infiltrate seen in Autoimmune Hepatitis?

A

Plasma cells

165
Q

How is the histologic progression of viral hepatitis and AI hepatitis different?

A

Viral hepatitis = fibrosis takes years to develop in chronic viral hepatitis

AI hepatitis = Early phase of severe parenchymal destruction followed rapidly by scarring

166
Q

Hepatocyte “rosettes” in areas of marked activity are a characteristic of which disease?

A

Autoimmune Hepatitis

167
Q

AI Hepatitis can develop as a rapidly progressive acute disease or follow a more indolent path. If untreated, which can lead to liver failure?

A

Both

168
Q

What is the first sign of AI disease?

Chronic?

A
  • REAL bad injury to hepatocytes with widespread confluent necrosis, but little scarring.
  • Chronic: burned out cirrhosis with little necroinflammatory activity; likely due to years of subclinical disease
169
Q

In general, prognosis of Autoimmune Hepatitis is better in which age group?

A

adults

170
Q

Treatment of AI Hep

A

Steroids and immunosupression = 80% of patients respond

171
Q

What is the most common cause of acute liver failure necessitating transplantation in the US?

A

Acetaminophen toxicity

172
Q

What is the most common hepatoxin causing chronic liver disease?

A

Alcohol

173
Q

What kind of damage does acetominophen toxicity cause?

A
  • Coagulative necrosis around the central/hepatic vein (acinus zone 3) caused by toxic metabolite from the breakdown of CYP450.
174
Q

Describe the progression to acute hepatic failure due to acetominophin toxicity, what is the last zone to be injured?

A
  1. Coagulative necrosis of zone 3
  2. Zone 2 tries to compensate and become injured.
  3. Severe ODs => zone 1 (periportal hepatocytes) => acute hepatic failure
175
Q

This pattern of hepatocyte injury is characteristic of which toxicity?

A
  • Acetaminophen toxicity
  • Confluent/coagulative necrosis in perivenular region (zone 3)
176
Q

“Microvesicular steatosis” (diffuse small droplet fat) is a morphological finding associated with toxicity by which agent?

A

Aspirin (in Reye syndrome)

177
Q

Bland hepatocellular cholestasis, without inflammation, is can be caused by which drugs?

A
  1. Anabolic streroids
  2. *OC’s
  3. ABX
  4. HARRT
178
Q

Blood-filled cavities, not lined by endothelial cells, knows as Peliosis hepatitis is associated with toxicitiy by which agent?

A

Anabolic steroids

179
Q

Which 2 agents are associated with Hepatocellular Adenoma?

A
  1. OCPs
  2. Anabolic steroids
180
Q

Which 2 agents are assoicated witn Angiosarcoma of the liver?

A

1. Thorotrast

2. Vinyl Choride

181
Q

Which 2 agents are associated with Hepatocellular Carcinoma?

A
  1. Alcohol
  2. Thorotrast
182
Q

Which agent is associated with Cholangiocarcinoma?

A

Thorotrast

183
Q

What are the 3 ways alcohol can damage the liver?

A
  • 1. Alcoholic fatty liver disease
  • 2. Acute hepatitis
  • 3. Cirrhosis
184
Q
  • Name the 3 types of liver injury caused by alcohol.
  • All changes in alcoholic liver disease begins in ________.
    *
A
  1. Hepatocellular steatosis (Fatty liver disease)
  2. Alcoholic (Steato-) Hepatitis
  3. Steatofibrosis (scarring typical for all fatty liver diseases including alcohol)

Zone 3

185
Q

What is hepatic steatosis (fatty liver)?

  • Histo:
  • Gross:
A

Moderate alcohol intake causes FA to accumulate in the liver (hepatic steatosis), increasing risk of cirrhosis. However, it is reversible is alcohol consumption is ↓.

  • Histo:
    • Fatty change: Lipid drops build up inside of the hepatocytes & coalesce and push nucleus aside. Reversible if you stop drinking.
    • Perivenular fibrosis
  • Gross: Large, soft, greasy yellow liver.
186
Q

Can Hepatic Steatosis (Fatty Liver Disease) associated with alcohol intake be reversed?

A

Completely reversible with abstinence from alcohol

187
Q

What is Alcoholic Hepatitis (steatohepatitis)?

Histological characteristics (3).

A

Classically occurs after heavy, binge drinking (d/t ↑ in acetaldehyde) on top of long history of alcoholic consumption.

  1. Ballooned/swollen hepatocytes (fat, H20, proteins) + necrosis
  2. Mallory-Denk bodies: eosinophilic cytoplasmic inclusions of damaged intermediate filaments (keratin 8/18 and ubiquiton) in ballooned hepatocytes (pink twisty structure that looks like rope)
  3. Neutrophilic rxn: neutrophils surround dying hepatocytes
188
Q

What are Mallory-Denk bodies made up of?

Are they specific for Alcoholic Hepatitis?

A
  • Damaged intermediate filaments (keratin)
  • Characteristic, but not specific: also found in
    • NAFLD
    • Wilson’s
    • Chronic biliary tract disease
189
Q
  • What is Alcoholic steatofibrosis?
A
  • Chronic, progressive liver disease characterized by thickening and scarring (fibrosis) of the liver as well as possible death (necrosis) of the liver tissue, d/t excessive, prolonged alcohol use.
  • Stellate cells and portal fibroblasts are (+) => fibrosis that begins with sclerosis around central vein (zone 3) in a chicken-wire fence pattern.
190
Q

Describe the chicken wire fence pattern of fibrosis seen in alcoholic steatofibrosis.

A
  • Fibrosis spreads out and encircles individual or small clusters of hepatocytes
191
Q
  • If a patient with Alcoholic steatofibrosis continues alcohol use with out interuption, what do they develop?
  • Associated with what stage of alcoholic liver disease?
A
  • Lannec cirrhosis (classic cirrhosis w small nodules) = continued subdivision of established nodules by new webs of perisinusoidal scarring
  • *First described for end-stage alcoholic liver disease
192
Q

10-15% of alcoholics develop cirrhosis.

What are risk factors for developing alcoholic cirrhosis?

A
  1. F
  2. AA
  3. Iron overload
  4. HepB/C
193
Q

Which variant of ALDH is found in 50% of Asians, has a very low activity?

Those homozygous for this variant develop what?

A
  • Asians homozygous for ALDH*2 develop alcohol intolerance because they cannot oxidize acetylaldehyde.
  • Sx: flushing, N, lethargy
194
Q

Which serum liver enzyme elevations are unique to alcoholic liver disease and can be helpful in a diff. dx of chronic liver injury when adequate hx is not available?

A

AST > ALT (2:1 ratio)

195
Q
  • Hepatocellular steatosis pathogenesis
A
  1. Impaired assembly and secretion of lipoprotein
  2. ↑ catabolism of fat –> release FFA into the circulation
  3. Instead of breaking down substrates, shunt them to form lipids due to ↑ NADH made by enzymes of metabolism)
    • alcohol dehydrogenase and acetaldehyde dehydrogenase –> increased NADH production
196
Q
  • Alcoholic hepatitis pathogenesis
A
  1. Acetaldehyde causes lipid peroxidation and protein adduct formation (carcinogen)
  2. Induced CYP450 => ROS and toxic metabolites.
  3. Impaired methionine metabolism = decreases glutathione levels which usually protect
  4. Release of endothelin => contract stellate cells
  5. Decreased perfusion of hepatic sinusoid
197
Q

Clinically, what is characterstic of Hepatic Steatosis (fatty liver)?

A
  1. Hepatomegaly
  2. Mild ↑ of serum bilirubin and ALP
198
Q

Classic patient: Goes out binge drinking and presents with fever, jaundice, RUQ pain due to a build up of acetaldehyde in the liver bc of too much alcohol consumption.

What is this and what changes do we see in blood?

A

Alcoholic hepatitis.

  • Tender hepatomegaly
  • AST/ALT levels will be 2:1
  • Hyperbilirubinemia + high ALP
    *
199
Q

↑ AST/ALT, ↑ ALP, hyperbilirubinemia, hypoproteinemia, and anemia, are common findings in which form/phase of alcoholic liver disease?

A

Alcoholic cirrhosis

  1. - hepatic dysfuntion (all liver enzymes increase)
  2. - Hypoproteinemia
  3. - Coag problems
  4. - Anemia
200
Q

Outcome of people with alcoholic hepatitis

A
  • Treatment: cessation of alcohol + adequate nutrition may slowly clear disease
  • Cirrhosis?
    • Some patients progress to cirrhosis despite complete abstinence
    • 1/3 progress to cirrhosis without treatment
201
Q

In the end-stage alcoholic, what are the MCC of death?

A
  1. Hepatic coma
  2. Massive GI hemorrhage
  3. Intercurrent infection (predisposed to infection)
  4. Hepatorenal syndrome after bout with hepatitis
  5. Hepatocellular carcinoma
202
Q

Metabolic Liver Diseases (4)

A
  1. NAFLD (aq)
  2. Hemochromatosis (in)
  3. Wilsons Disease
  4. A1-AT deficiency
203
Q

The WHO criteria for Metabolic Syndrome requires at least one of which 4 conditions?

And at least two of which 4 conditions?

A

One of:

  • DM
  • Impaired glucose tolerance
  • Impaired fasting glucose
  • Insulin resistance

Two of:

  • BP >140/90
  • Dyslipidemia
  • Central obesity
  • Microalbuminuria
204
Q

The most common acquired metabolic disorder of the liver is?

A

Non-alcoholic fatty liver disease (NAFLD)

205
Q

What is the most common cause of chronic liver disease in the US?

A

NAFLD

Spectrum of diseases with fatty infiltration (hepatic steatosis) of the liver in ppl who do not drink alcohol or drink very little (< 20g/week)

206
Q

NAFLD

  1. Occurs in people who:
  2. Increases risk of:
  3. More common in who:
A
  1. Obesity and have metabolic syndrome
  2. Hepatocellular carcinoma (even w/o significant scarring)
  3. Hispanics > AA > Caucasians.
207
Q

What is NASH?

A

Steatosis (fat) + hepatocyte damage due to inflammation

208
Q

What is the 2 hit model for the pathogenesis of NAFLD and how do insulin resistance and oxidative injury play a role?

A
    1. Insulin resistance –> hepatic steatosis
    1. Hepatocellular oxidative injury —> necrosis of liver cell and inflammatory rxns
209
Q

The level of activity in which pathway correlates with the stage of fibrosis in NAFLD?

This pathway activates which cells?

A

Hedgehog signaling pathway –> activates Stellate cells

210
Q

NASH vs. Alcoholic Hepaitis almost completely overlap histologically, how can they be differentiated

A
  • NASH = MORE prominent mononuclear cells; LESS prominent Mallory-Denk bodies
  • AH = more neutrophils
211
Q

>90% of previously described “cryptogenic cirrhosis” (i.e., cirrhosis of unknown cause) is now thought to represent what?

A

“Burned out” NAFLD

212
Q

How does the morphology of pediatric NAFLD differ significantly from the adult version?

i.e., type of steatosis, fibrosis, and inflammatory infiltrate

A

More DIFFUSE steatosis + PORTAL fibrosis

  • Portal and parenchymal mononuclear infiltration, rather than parenchymal neutrophils
213
Q

What is the clinical presentation of NAFLD/NASH most often related to?

A

Signs and symptoms of the underlying metabolic syndrome, like insulin resistance and DM

214
Q

Due to the association of NASH w/ metabolic syndrome what is a frequent cause of death in these patients?

A

Cardiovascular disease

215
Q

Pathologic steatosis is defined as involving _____ of hepatocytes.

A

> 5%

216
Q

80% of NAFLD is isolated fatty liver, which has 0- very minimal progression to cirrhosis and no increased death. What happens to the other 20%?

A

20% => NASH, which shows increased overall mortality and increased risk for cirrhosis and hepatocellular carcinoma.

217
Q

What are the clinical symptoms of NAFLD?

Diagnosis is confirmed by ________.

A
  • Asymptomatic or nonspecific symptoms with RUQ pain.
  • ↑ ALT>AST (different from alcoholic FLD)
  • Diagnosis is confirmed by biopsy.
218
Q
  • UTAH: “A 45-year-old man has had a fever and a productive cough for the past 3 days. On physical examination there is dullness to percussion over the right upper lung. His temperature is 37.9°C. A chest radiograph reveals right upper lobe consolidation. Laboratory findings include serum total protein of 6.0 g/dL, albumin 2.7 g/dL, AST 185 U/L, ALT 98 U/L, total bilirubin 1.0 mg/dL, alkaline phosphatase 31 U/L, and prothrombin time 20 sec. An abdominal CT scan shows hepatomegaly with decreased hepatic attenuation. Which of the following conditions is the most likely underlying cause of death?”
A
  • ANSWER: Diabetes Mellitus
  • Big fatty liver without alcohol abuse => NAFLD
  • “Big fatty livers with decreased attenuation on CT scans are often seen in conjunction with chronic alcoholism. In the absence of a history of chronic alcohol abuse, non-alcoholic fatty liver (NAFL) is the likely cause, and NAFL can be associated with obesity and diabetes mellitus. Microscopically, the pattern will be macrovesicular steatosis, with large lipid vacuoles filling hepatocytes”
219
Q

How to treat NAFLD?

A
  • Address underlying metabolic problem
    • Correct obesity, hyperlipidemia, insulin resistance
220
Q

What is hemochromatosis?

A

Excess iron deposits in tissue, creates free radicals that damages organs (liver and pancreas => heart, joints and endocrine organs)

221
Q

Which 3 characteristics/findings are common to fully developed cases of severe iron overload (hematochromatosis)?

A

1) Micronodular cirrhosis in ALL patients
2) DM in 75-80% of pts
3) Abnormal skin pigmentation (bronze) in 75-80% of pts

222
Q

When do symptoms of hereditary hemochromatosis usually appear?

More often affects which sex?

A

Presents late in adulthood

  • 40-50s in M
  • LATER in women bleed out iron during period

Men

223
Q

What are the 3 mechanisms that Hemochromatosis causes liver damage?

A

1) Iron overload creates free radicals => lipid peroxidation
2) ROS interact with DNA => lethal cell injury, which predisposes to HCC
3) Stimulates of collagen formation by (+) stellate cells

224
Q

What are the types of hemochromatosis?

A
  1. Primary (heriditary)
  2. Secondary (acquired)
225
Q

What is Primary Hemochromatosis?

A

Inherited mutation of HFE C282Y gene (=> inactivates HEF => inactivation/deficiency of hepcidin => hemochromatosis) on Chr6 that causes abnormal intestinal absorption of iron.

226
Q

Main regulator of iron absorption is the protein ________, encoded by the gene ________ and secreted by the _________

A
  • Hepcidin
  • HAMP gene
  • liver
227
Q

The C282Y mutation of the HFE gene causing hemochromatosis is largely confined to which population of people?

A

White populations of European origin

228
Q

Is the direct toxic injury produced by iron on hepatocytes and other cells reversible?

A

Yes, if removed before they are fatally injured

229
Q

What is seen morphologically in both the early and late stages of the deposition of hemosiderin in the liver associated with severe hemochromatosis?

How does the size of the liver change as well?

A
  • Early:
  • Deposition of golden-brown hemosiderin pigments in cytoplasm of periportal hepatocytes (> pancreas > myocardium > pit gland), which stain with Prussian blue to distinguish from lipofuscin
  • Hepatomegaly due to accumulation
  • Late:
  • Liver parenchyma turns dark brown to black due to too much iron
  • Liver gets small and shrunks as fibrous septa develops
230
Q

Is there inflammation involved in hemochromatosis?

A

No, because iron is directly hepatoxic.

231
Q

What is seen morphologically in the heart of severe hemochromatosis?

A
  • Big
  • Myocardium is brown because hemosiderin in myocardial fibers
232
Q

What is the characteristic color of the skin in someone with severe hemochromatosis?

This color is due to increased what?

A

Slate/gray due to ↑ melanin production

233
Q

What are 2 complications of the joints that can arise with severe hemochromatosis?

Cause of each?

A
  1. Acute synovitis => Hemosiderin deposits in synovial joints
  2. Pseudogut (disabling polyarthritis) => Calcium pyrophosphate damages articular cartilage
234
Q

What is this?

A
  • Either lipfuscin or iron.
  • If blue on Prussian stain => iron.
235
Q

What is this?

A

Prussian blue stain indicating iron

236
Q

What is the classic tetrad of clinical findings associated w/ hemochromatosis?

A
  1. Cirrhosis w/ hepatomegaly –> abdominal pain
  2. Gray/slate skin
  3. DM from fucked up glucose homeostasis
  4. Cardiac dysfunction (arrhythmias, cardiomyopathy)
  • will also see gonadal dysfunction (small and atrophic testes)
237
Q

Patients with what metabolic liver disease have a 200-fold greater risk of developing hepatocellular carcinoma?

A

Hemochromatosis

238
Q

Does treatment of the iron overload in hemochromatosis remove the risk of cancer?

A

Not fully due to alterations in DNA that occur before dx and tx

239
Q

Screening of whom for hemachromatosis is important?

A

Family members of probands (the 1st person in a family to have the disease)

240
Q

What is the treatment for hemochromatosis?

A

Phlebotomy: depletes tissues of iron and gives pt NL life expectancy.

241
Q

Neonatal hemochromatosis (aka congenital hemochromatosis) manifests how and when does it occur?

Which biopsy is needed for the correct diagnosis?

A

- Severe liver disease occuring in utero

  • Extrahepatic hemosiderin deposition, detected by buccal biopsy
242
Q

What is the most common cause of secondary (or acquired) hemochromatosis?

Disorders associated with this?

A
  1. Disorders associated w/ ineffective erythropoiesis
    1. i.e., β-thalassemia, Sideroblastic Anemia, and Pyruvate kinase deficiency
  2. *Excess iron results from transfusions, and increased absorption
243
Q

What is Wilson Disease?

Which gene is mutated and on what chromosome?

A
  • AR mutation of ATP7B gene on Chr13, resulting in an accumulation of toxic levels of copper in the [liver, kidney and eye] because excretion into is impaired and it cannot be incorperated into ceruloplasm (binds copper).
244
Q

Deficiency in the ATPB7 protein associated with Wilson Disease causes what 3 changes that lead to the accumulation of copper?

A

Copper absorption and delivery to liver is NL, but

  • 1) Excretion into bile is ↓
  • 2) Not incorperated into ceruloplasmin
  • 3) Ceruloplasmin secretion into blood is inhibited
245
Q

By which 3 mechanisms does the accumulated copper in Wilson Disease cause toxic liver injury?

A

1) Undergoes fenton rxn and makes free radicals
2) Binds to sulfhydryl groups of cellular proteins
3) Displaces other metals from hepatic metalloenzymes

246
Q

Excess copper in Wilson Disease can often be demonstrated by using what special stains?

A
    • Rhodamine stain = copper
    • Orcein stain = copper-associated protein
247
Q

How does Wilsons disease affect the morphology of the liver?

A
  1. Fatty change (steatosis) w/ focal necrosis
  2. Acute, fulminant hepatitis (mimics viral form)
  3. Chronic hepatitis: inflammation, hepatocyte necrosis, and steatohepatitis (hepatocyte ballooning and Mallory-Denk bodies)
  4. Eventually Cirrhosis
248
Q

CNS toxicity associated with Wilson Disease primarily affects which area?

A

Basal ganglia, mainly the putamen: atrophy and cavitation

249
Q

What is a clinical case of a patient with Wilsons Disease?

A

11 YO child (but can be 6-40 YO), who presents with

  1. Cirrhosis
  2. Neurlogic manifestations that mimic Parkinsons (movement problems and rigid dystonia)
  3. Psychiatric symptoms
  4. Kayser-Fleisher rings: green-brown deposits in the cornea
  5. Hemolytic anemia because cooper damaged RBC
  6. Increased risk of HCC (bc ROS are made)
250
Q

Due to the toxicity of copper to RBC membranes what complication may arise in Wilson Disease?

How does this trascend on labs?

A

Hemolytic anemia

  • ↑ direct bilirubin
251
Q

The biochemical diagnosis of Wilson Disease is based on which 3 criteria?

Which is the most sensitive and accurate?

Which is the most specific?

A

1) ↓ serum Ceruloplasmin
2) ↑ copper in hepatocytes = MOST sensitive/accurate
3) ↑ urinary excretion of Cu = MOST specific

252
Q

What is the treatment for Wilsons Disease?

A
  1. Long term chelation therapy (D-pencillamine) or zinc based therapy
  2. If unmanageable cirrhosis develops => liver transplant is curative
253
Q

What is the most commonly diagnosed inherited liver disorder in infants and children?

A

α1​-antitrypsin deficiency

254
Q

What is α1-antitrypsin deficiency?

A

AR mutation on Chr 14, causing misfolded A1-AT => impaired secretion into serum.

255
Q

What is the normal function of α1-antitrypsin?

Normally acts on?

A

Inhibits proteases, which destroy tissue:

    • Neutrophil elastase
    • Cathepsin G
    • Proteinase 3
256
Q

α1​-antitrypsin deficiency leads to the development of what 2 main disorders?

A
  1. Emphysema: ↑ elastase activity
  2. Liver disease (cholestasis or cirrhosis): accumulation of abnormal a1-AT
257
Q

Which genotype of α1AT is the most common type seen in normal individuals (aka the “wild type”)?

A
  • PiMM == wild-type; 90% of people
258
Q

Which is the most common clinically significant mutation/genotype in a1-AT deficiency?

A
  • Most common mutated genotype = PiZ
  • Homozygous => α1AT levels only 10% of normal
259
Q

Pathogenesis of α1AT deficiency

A
  • Mutation prevents migration of the misfolded protein from the ER => golgi, leading to accumulation of the protein in the liver
    • All patients with PiZZ genotype accumulate protein but only 10-25% develop liver disease
260
Q

How do we diagnose A1 AT deficiency?

______ does not determine the severity.

A
  • Cytoplasmic globular inclusions of AAT in hepatocytes that stain magenta on PAS stain + diastase
  • Number of globules
261
Q

Which % of adults with the PiZZ genotype will develop hepatocellular carcinoma?

A

2-3%; usually, but not always, in the setting of cirrhosis

262
Q

What are the clinical features of α1AT deficiency in some neonates?

Adolescence?

A
  • Neonates: hepatitis w/ cholestatic jaundice (10-20% of affected)
  • Adolescence = cholestasis/ hepatitis /cirrhosis or emphysema
263
Q

Treatment for a1 antitrypsin deficiency

A
    1. Orthotopic liver transplant = cure
    1. If emphysema = prevent by avoiding smoking
264
Q

What are functions of bile?

A
  1. Emulsify dietary fat in the lumen of the gut via bile salts
  2. Gets rid of bilirubin, excess cholesterol, xenobiotics, and other wastes that cannot be removed in urine.

GI II Exam II (10 decks)

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