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PHAR 255 > Liver > Flashcards

Liver Flashcards

1
Q

What are lobules?

A

They are the functional unit of the liver

  • Centered on a branch of the hepatic vein
  • Interconnected by small ducts
  • Contain hepatocytes, separated by sinusoids
  • Portal triads (contains vessels that connect to hepatic vein, artery, and bile ducts)
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2
Q

What is the hepatic duct?

A
  • Transports bile produced by liver cells to the gallbladder and duodenum
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3
Q

What does the blood flow to the liver look like?

A
  1. Venous flow from portal vein (from GI to liver)
  2. Arterial flow from hepatic artery (recieves 25% of the cardiac output)
  3. Venous and arterial flow mixes in the blood and leaves via the hepatic vein
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4
Q

What are the four categories of major liver functions?

A
  • Excretion (bile)
  • Metabolism (Bilirubin, drugs, nutrients, hormones)
  • Storage (vitamins/minerals (B12, iron), CHO
  • Synthesis (plasma proteins, coagulation factors, other transport proteins)
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5
Q

What is the function of the gallbladder?

A

Stores and concentrated bile

Gallbladder releases bile in response to stimulation by food (cholestatic kinase)

Bile helps emulsify fats and improve elimination of fat-soluble waste

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6
Q

Is bile returned to the body after it has been secreted, or is it all excreted?

A

95% of bile acids are reabsorbed (enterohepatic recirculation)

Liver disease can impact bile recycling due to reduced enterohepatic recirculation

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7
Q

What is bilirubin?

A

It is the end product of heme degradation

Insoluble bilirubin = bound to albumin

Direct bilirubin = glucoronidated in liver and is excreted in the bile

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8
Q

What is fulminant liver failure?

A

This occurs when an acute and severe form of liver injury results in insufficient residual hepatocytes to maintain minimal essential liver functions

This is an irreversible type of liver injury

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9
Q

Review slide 13 for the patterns of hepatocellular injury (appreciate bifurcation)

A
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10
Q

What are the etiologies of hepatic injury?

A
  • Viral
  • Drugs
  • Environmental toxins
  • Alcohol
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11
Q

What are the main types of hepatic injury?

A
  1. Cholestasis
  2. Hepatocellular
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12
Q

What is cholestasis?

A

A failure of normal amounts of bile to reach the duodenum

This results in an accumulation of bile in liver cells and biliary passages (Intra vs extrahepatic)

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13
Q

What are some causes for cholestasis?

A
  1. Primary biliary cholangitis (PBC)
  2. Primary sclerosing cholangitis (PSC)
  3. Cholelithiasis (gall stones)
  4. Tumour
  5. Alcohol or drug related causes
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14
Q

What is primary biliary cholangitis (PBC)?

A

It is caused by the slow, immune-mediated destruction of small bile ducts within the liver

Leading cause of liver transplant for women in Canada

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15
Q

What is primary sclerosing cholangitis (PSC)?

A

It involves progressive inflammation and fibrosis affecting any part of the biliary tree

Leads to progressive destruction of the bile ducts

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16
Q

What are some symptoms of cholestatic syndrome?

A
  • Pruritis
  • Jaundice
  • Dark Urine
  • Light coloured stools
  • Steatorrhea (Fatty stools)
  • Xanthoma and xanthelasma (growths under skin due to bile deposition under the surface)
  • Hepatomegaly
  • Features specific to disease
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17
Q

What is the main therapeutic option used to treat cholealithiasis?

A

Ursodiol (a naturally occurring bile acid)

Works by decreasing cholesterol saturation. Result in gradual dissolution of stones in 30-40% of patients

Can also be used in cholestasis such as PBC or PSC

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18
Q

What are some treatment options for pruritis in liver disease?

A
  1. Cholestyramine (benefit seen in 90% of patients, but needs to be continued as long as there is pruritis)
  2. Antihistamines (likely due to sedation)
  3. Naltrexone, rifampin, sertraline (if pruritis is refractory)`
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19
Q

What is hepatocellular damage?

A

Direct damage to hepatocytes

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20
Q

What are some causes of hepatocellular damage?

A
  • Toxic agents (alcohol, drugs, toxins)
  • Infections (hepatitis)
  • Longstanding cholestasis
  • Ischemic injury
  • Other diseases (autoimmune, iron overload)
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21
Q

What factors impact the severity of hepatocellular damage?

A
  1. Duration of assault
  2. Intensity of assault (ex. fulminant hepatic failure)
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22
Q

What are some indicators for hepatocellular damage and destruction?

A
  • Elevated AST and ALT because the contents of hepatocytes have been released into the blood
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23
Q

What is involved in liver enzyme measurement?

A

The enzymes tested in liver enzyme measurement are released into circulation after injury

ALP, AST, ALT, GGT

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24
Q

What enzymes are indicators for cholestatic injury?

A
  1. ALP
  2. GGT (non-specfic but confirms liver injury)

If ALP and GGT are both high, there is high certainty there is some type of cholestatic injury

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25
Q

What enzymes are indicators for hepatocellular injury?

A

Increases in Aminotransferases (ALT and AST)

  • ALT is more specific than AST
  • Often increase before symptoms manifest (can deal with hepatic injury at a less severe state)
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26
Q

What are some examples of liver function tests?

A

A. Albumin levels
B. Bilirubin
C. Clotting (prothrombin time)

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27
Q

What happens to albumin in patients with liver disease?

A
  • Edema or ascities (due to reduced oncotic pressure)
  • Effects on calcium and highly bound drugs like phenytoin
  • Reduction in albumin is delayed because it has a 20 day lifespan
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28
Q

What are some symptoms of bilirubin accumulation?

A
  1. Deposits in skin and tissues
  2. Dark urine, pale stools, yellow skin
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29
Q

What are some causes for bilirubin accumualtion in liver disease?

A
  1. Obstruction (cholestasis)
  2. Impaired metabolism (hepatocellular)
  3. Excessive production due to hemolytic anemia
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30
Q

What are some properties of unconjugated bilirubin?

A
  • Bound to albumin
  • Water-soluble
  • Indirect bilirubin
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31
Q

What are some properties of conjugated bilirubin?

A
  • Conjugated by liver (via glucoronidation)
  • Soluble in water
  • Direct bilirubin
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32
Q

What happens to prothrombin time in patients with liver disease?

A
  • Reduced production of clotting factors (increased PT)
  • Changes in INR are seen when patient has lost 80% of liver function
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33
Q

What are the main 7 liver laboratory tests?

A

Liver enzymes:
1. Hepatocellular enzymes
- AST
- ALT

  1. Cholestatic enzymes
    - ALP
    - GGT

Liver function:
- Bilirubin
- Albumin
- INR/PTT

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34
Q

Review slide 33 to 37 for practice with interpreting liver lab values

A

Probably will come on the exam

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35
Q

Is the magnitude of liver function and enzyme values associated with severity of disease?

A

The magnitude of the values may not be associated with liver disease severity

Trends in liver enzyme and function tests are more important vs single point values

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36
Q

What are the main six complications of cirrhosis?

A
  1. Portal HTN
  2. Ascites
  3. SBP
  4. Hepatorenal syndrome
  5. Varices
  6. Encephalopathy
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37
Q

What is cirrhosis?

A

A chronic diffuse disease characterized by fibrosis and nodular formation

ex. long-standing alcohol use results in a hard, shrinken, and nodular liver

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38
Q

What is the only cure for cirrhosis?

A

Liver transplant

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39
Q

What are some types of cirrhosis?

A
  1. Alcohol-related liver disease (ALD)
  2. Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), used to be known as NAFLD (often caused by insulin resistance and metabolic syndrome)
  3. Metabolic Dysfunction-Associated Steatohepatitis (MASH)
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40
Q

What is the current alcohol consumption reccomendations?

A

All levels of alcohol consumption are associated with some risk, so drinking less is better for everyone

There is a continuum of risk in healthy individuals

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41
Q

How is cirrhosis diagnosed?

A
  1. Biochemical markers (liver enzymes + ABCs)
  2. Scoring systems (FIB-4, uses age, platelet count, AST, and ALT to estimate amount of scarring)
  3. Abdominal ultrasound (first imaging modality recommended)
  4. Elastogrpahy (Fibroscan, non-invasive)
  5. Liver Biopsy (definitive diagnosis of underlying cause of cirrhosis, invasive)
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42
Q

What are the consequences of cirrhosis?

A
  • Reduced functioning liver tissue (impaired function and diminished reserve)
  • Portal HTN
  • Patients will die 5-15 years after diagnosis of cirrhosis
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43
Q

What are some treatment options for cirrhosis?

A
  • Treat underlying disease
  • Treat complications of cirrhosis
  • Liver transplantation
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44
Q

What does compensated cirrhosis look like?

A
  • Body functions fairly well despite scarring of the liver (may be asymptomatic)
  • Non-specific symptoms (anorexia, weight loss, weakness, NV, GI upset, muscle wasting)
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45
Q

What does decompensated cirrhosis look like?

A
  • Severe scarring and disruption of function
  • Symptoms: confusion, edema, fatigue, bleeding
  • Abnormal LFTs
  • Abnormal exam (signs of chronic liver disease)
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46
Q

What happens when the the portal system has obstructed blood flow?

A
  1. Opens detours between the portal and systemic circulation
  2. Blood is diverted around the liver rather than filtered through the liver
  3. Portal blood bypasses the liver and directly enters systemic circulation
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47
Q

What is portal HTN?

A

It results from increase in resistance to portal flow and increase in portal venous inflow

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48
Q

How does the body compenate for portal HTN?

A
  1. Splanchnic dilation (results in under-perfusion of renal system)
  2. To deal with this under-perfusion, RAAS is activated and causes fluid overload
  3. Fluid overload causes backflow and further widens the venous channels that connect the portal and systemic circulation
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49
Q

What is splenomegaly?

A

A consequence of portal HTN

The spleen will enlarge by 3-6 times its normal size caused by sequestration and destruction of RBCs (causes anemia)

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50
Q

What are the consequences of portal-to-systemic shunting?

A

Effectively portal blood is bypassing the liver
1. Metabolites/toxins in the blood have not been processed by the liver first
2. Increased sensitivity to noxious substances absorbed from the GI tract
3. Malabsorption of fat in the stool (reduction in bile flow)
4. Contributes to all complications as well (ascites, SBP, varices, hepatorenal sx)

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51
Q

What is ascites?

A

It is a collection of fluid in the peritoneal cavity

Can cause massive distention (very uncomfortable to patient)

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52
Q

What is the pathogenesis of ascites?

A
  • Hydrostatic pressure (due to fluid overload from RAAS activation)
  • Hypoalbuminemia (reduced oncotic pressure)
  • Renal retention of Na+ and water
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53
Q

What is the role of serum-ascites albumin gradient (SAAG) test in liver disease?

A

It is used in patients with ascites to determine cause of swelling

If greater than 11g/L = portal HTN

If lesser than 11g/L = other likely causes (non-liver disease)

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54
Q

What is the treatment goal in ascites?

A
  • Remove abdominal fluid
  • Prevent symptoms and maintain resonable quality of life
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55
Q

What are some treatment options for ascites?

A
  1. Salt restriction
  2. Diuresis
  3. Paracentesis (drawing fluid through needle)
  4. TIPS (shunt implant)
  5. Liver transplant
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56
Q

What does salt restriction in ascites look like?

A

Less than 2g/day, if Na+ is very high then fluid restriction can be considered

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57
Q

What are the diuretic choices in ascites treatment?

A
  • Spironolactone (1st line)
  • Furosemide (adjunct)
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58
Q

What is paracentesis?

A

Aspiraton of peritoneal flui with a needle (provides immediate relief, but it is temporary)

Albumin can also be given as adjunt to help improve oncotic pressure

There is a non-zero risk for abdominal perforation and infection

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59
Q

What is TIPS in ascites treatment?

A

Transjugular Intrahepatic Portosystemic Shunt

This implant helps reduce portal HTN by redirecting some of the portal flow to the hepatic vein

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60
Q

What dose of spironolactone used in cirrhosis (ascites management)?

A

A high dose is used (100mg)

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61
Q

What is the mechanism of action for spironolactone?

A

Inhibits effects of aldosterone (RAAS activity)

Watch for side effects (hyperkalemia, dehydration, gynecomastia)

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62
Q

How should a spironolactone-furosemide combo therapy be dosed for ascites management?

A

Usual regimen: spironolactone 100mg + furosemide 40mg

Maintain 100:40 ratio if dose needs to me increased to a max dose of spironolactone 400mg + furosemide 160mg

Metolazone (TZD) can be used if ascites is refractory to spironolactone and furosemide

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63
Q

What are some monitoring tips for diuretics use in ascites treatment?

A
  • Monitoring is important
  • SCr, Na, K
  • Weight and BP (helps track fluid overload)
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64
Q

What is refractory ascites?

A

Patient is unresponsive to sodium-restricted diet and high dose diuretic treatment (spirono+furo)

Ascites recurs rapidly after a therapeutic paracentesis and high-dose diuretics

AVOID NSAIDs (turns diuretic sensitve patients to refractory)

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65
Q

How is refractory ascites treated?

A
  1. Serial therapeutic paracentesis (+/- albumin)
  2. Transjugular intrahepatic portasystemic shunt (TIPS)
  3. Liver transplantation
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66
Q

What are the principles of therapy for ascites?

A
  1. Patients should monitor daily weights (gradual weight loss is the goal)
  2. If no response to diuretics, check urinary sodium
  3. Monitor SCr, Na+, K+
  4. Monitor other complications (ex. SBP)
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67
Q

What is spontaneous bacterial peritonitis (SBP)?

A

It is an infection in ascitic fluid without obvious cause

Caused by bacterial translocation from GI tract to bloodstream and other extraintestinal sites

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68
Q

Is spontaneous bacterial peritonitis a relatively benign condition?

A

No, mortality rates are high so diagnostic paracentesis and empiric antibiotic treatment is started

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69
Q

What are the most common pathogens found in spontaneous bacterial peritonitis infections?

A

E. Coli

Klebsiella pneumoniae

Streptococcus pneumoniae

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70
Q

How is spontaneous bacterial peritonitis treated?

A

Community acquired:
- Cefotaxime or Ceftriaxone x 5days

Nosocomial acquired:
- Piperacillin/tazobactam
- Meropenem+/-vancomycin

Albumin infusions may be adjunct

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71
Q

What patients groups should be given prophylaxis for spontaneous bacterial peritonitis?

A
  • Patients that have survived an episode of spontaneous bacterial peritonitis (secondary prophylaxis)
  • Patients at high risk (low protein ascites, variceal hemmorhage) (primary prophylaxis)
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72
Q

What are some prophylactic agents used for spontaneous bacterial peritonitis?

A

Norfloxacin, septra or ciprofloxacin

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73
Q

What is hepatorenal syndrome?

A

It is renal failure in patients with severe liver disease. They usually also have massive, tense ascites

Characterized by severe vascoconstriction of the renal circulation (no pathological changes to kidney itself)

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74
Q

What are some treatment options for hepatorenal syndrome?

A
  • Stop diuretics
  • Avoid all potential nephrotoxins such as NSAIDs and aminoglycosides
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75
Q

What are varices?

A

They are associated with high pressure in portal vein (due to constriction due to cirrhosis)

Shunting around the liver causes small veins to become engorged with an excess of blood

76
Q

What are the principle sites for varices to form in cirrhosis?

A
  • Esophageal varices (most common presentation)
  • Abdominal wall
  • Veins in rectal area (hemmorrhoids)
77
Q

At what portal vein pressure does the risk of varices bursting significantly increase?

A

At 12mmHg, varices can burst and cause major bleeds (in liver disease there is a shortage of clotting factors, so hard to stop bleeding)

78
Q

How many patients with advanced cirrhosis have esophageal varices?

A

65% of patients with advanced cirrhosis

79
Q

What are the treatment goals for acute management of variceal bleeds?

A
  • Adequate blood volume resuscitation
  • Prevent aspiration of blood into lungs
  • Prophylaxis for SBP
  • Control bleeding and prevent re-bleeding
  • Preservation of liver function
  • Prevent hepatic encephalopathy
  • Prevention of AKI
80
Q

What are some treatment options for variceal bleeds?

A
  1. Packed RBCs
    - Resuscitate blood volume (taget HgB of 70-90g/L)
    - Antibiotic prophylaxis for SBP (ceftriaxone, cipro, septra, norfloxacin)
    - Octreotide or somatostatin IV (vasconstrictors that decrease splanchic blood flow, d/c after 24h of stopped bleeding)
    - Endoscopic therapies (band ligation and sclerotherapy)
    - TIPS (used in patients that fail to maintain hemostasis despite combo endoscopic and pharmacological therapy)
81
Q

What patient groups should recieve prophylaxis for variceal bleeding?

A

Patients with high risk of bleeding +small varicies
- Cirrhosis, portal pressure above 12mmHg, continued alcohol use

Patients with medium/large varicies

82
Q

What drugs are used for prophylaxis in variceal bleeding?

A

Propranolol and Nadolol (non-selective beta-blockers)

MOA:
- decreased portal HTN by reduce CO and splanchic vasoconstriction

Reduced bleeding incidence by 50%

83
Q

What treatment options (drug & non-drug) are used in primary prophylaxis of variceal bleeds?

A
  • Non-selective beta-blockers (Propranolol and Nadolol)
  • Band ligation (endoscopic variceal ligations), preferred in high risk of bleed, refractory ascities, or SBP
84
Q

What treatment options (drug & non-drug) are used in secondary prevention of variceal bleeding?

A
  • Non-selective beta blocker and band ligation
  • TIPS for patients that have re-bleeding despite therapy
85
Q

What is hepatic encephalopathy?

A

It is CNS dysfunction in late-stage cirrhosis

Often caused by accumulatuon of neurotoxic substances that would be normally removed by the liver

86
Q

What are the potential pathways by which hepatic encephalopathy develops?

A

The following are not properly metabolized in cirrhosis, so they following may accumulate and cause hepatic encephalopathy

  • Ammonia (most treatments target this pathway)
  • Tryptophan
  • GABA’ergic compounds
87
Q

What is the presentation of hepatic encephalopathy?

A
  • Drowsiness, personality changes, confusion, motor symptoms
  • Many symptoms are reversible with appropriate therapy
88
Q

What are the four grades of hepatic encephalopathy?

A

Grade 1: changes in behaviour, mild confusion, mild tremor

Grade 2: Lethargy, moderate confusion, ataxia, personality changes

Grade 3: Marked confusion, incoherent speech, sleeping but arousable, siezures, delirium

Grade 4: Coma, unresponsive to pain

89
Q

What are the preciptating factors for hepatic encephalopathy?

A
  • Protein intake (increased ammonia) or GI bleeds
  • Drugs (diuretics and sedatives/CNS depressants)
  • Continued alcohol use
  • Hypokalemia (can increase renal ammonia production)
90
Q

How can hepatic encephalopathy be managed?

A
  • Be alert for changes in focus, drowsiness, asterixis
  • Treatment should start ASAP if symptoms appear
  • Identify and correct precipitant
  • Restrict dietary protein
  • Most therapies are aimed at lowering blood ammonia (lactulose and some antibiotics)
91
Q

What is the mechanism of action for lactulose in hepatic encephalopathy?

A

First line option for hepatic encephalopathy

  • Lactulose is degraded into acids in the GI tract by bacteria
  • Reduced pH = reduced ammonia absorption
92
Q

How is lactulose dosed for hepatic encephalopathy?

A

According to bowel movement (no more than 2-3 bowel movements per days)

Very sweet (can be off-putting to some patients)

GI adverse effects (nausea, bloating)

93
Q

What is the role of Metronidazole in treatment of hepatic encephalopathy?

A

It sterilizes the GI tract and reduces the activity of urease-producing bacteria (decreasing production of ammonia)

Limited use due to peripheral neuropathy with long-term use

94
Q

What is the general approach to cirrhosis management?

A
  • Discontinue alcohol
  • Avoid NSAIDs (hepatorenal syndrome, ascites, increased GI bleed risk)
  • Avoid sedatives/narcotics
  • Adequate nutritional intake
  • Deficiencies are common
95
Q

Why do patients with cirrhosis have nutritional deficiencies?

A
  • Decreased dietary intake
  • Malabsorption/digestion
  • Overall loss of protein
  • No bile, therefore reduced absorption of fat-soluble vitamins
96
Q

What are some examples of B vitamin deficiencies in cirrhosis?

A

B1 (thiamine)
B6 (pyridoxine)
B9 (folate)

97
Q

What causes B1 (thiamine) deficiencies in cirrhosis?

A

People with alcohol-related liver disease at risk for deficiency due to the following factors:
- Inadequate intake
- Impaired absorption and utilization
- Increased requirements

Deficiency can cause Wernicke’s Encephalopathy

Take 200mg/day for prevention

98
Q

What causes B6 (pyridoxine) deficiencies in patients with cirrhosis?

A

Alcohol use

2mg od supplementation

99
Q

How common is folate (vitamin B9) deficiency among patients that binge drink alcohol?

A

2/3 of binge drinkers

400mcg od supplementation

100
Q

What are the various presentations of hepatitis (liver inflammation)?

A
  • Asymptomatic (infection without disease)
  • Acute Hepatitis (non-specific & liver specific symptoms)
  • Acute Fulminant Hepatitis (rare, but fatal)
  • Chronic Persistent Hepatitis (delayed recovery with limited liver damage)
  • Chronic Active Hepatitis (progressive liver damage, may be asymptomatic)
101
Q

What are some characteristics of the Hepatitis A virus?

A

RNA Virus

Tranmission via fecal-oral route (more common in 3rd world countries)

Vaccines available (ex. Havrix)

102
Q

What are some symptoms of Hepatitis A viral infection?

A

70% of patients are symptomatic with fever, jaundice, and scleral icterus

Usually manifests 30 days after exposure

Symptoms last 3 months

103
Q

Is Hepatitis A viral infection life-threatening?

A

No, very low mortality (0.1%)

Plus Hepatitis A infection is not chronic (once it is cured, it is cured)

104
Q

What are some treatment options for Hepatitis A viral infection?

A

No clear role for pharmacology

Healthy diet, maintaining fluid balance, avoiding hepatotoxic

105
Q

What is the best prophylactic for a Hepatitis A infection?

A

Vaccine for high-risk individuals (2 doses, 6 months apart)

The vaccines are still effective post-exposure is given within 14 days of exposure

106
Q

What are some characteristics of the Hepatitis B virus?

A

DNA Virus

Transmission via sexual contact or sharing used needles

Vaccines available (ex. Twinrix)

107
Q

What are some symptoms of a Hepatitis B viral infection?

A

Approximately 70% of patients are anicteric (no symptoms of jaundice) or subclinical

In the 30% of patients that develop symptoms, jaundice, dark urine, abdominal pain

108
Q

Is a Hepatitis B infection in most cases chronic?

A

It depends on age range

90% chronic in neonatal infection
25-50% chronic in children aged 1-5
10% chronic in adults

109
Q

What are the important serological markers to look out for in patients with a Hepatitis B viral infection?

A
  • HBsAg (HBV surface antigen): indicated HBV infection (acute or chronic)
  • Anti-HBs (HBV surface antigen antibody): marker of HBV immunity
  • Anti-HBc IgM (IgM antibodies to HBV core antigen): positive represents acute infection or flare-up of chronic infection
  • HBV-DNA (marker of viral replication/infectivity): used to assess and monitor the treatment of chronic HBV infection
110
Q

How often is universal screening for Hepatitis B virus?

A

At least once for all patients over 18

111
Q

When is treatment for chronic Hep B warranted?

A

Treat during immune active HBV (increased HBV-DNA and ALT; liver inflammation)

112
Q

What is the traditional approach to treatment of Chronic Hep B?

A

Interferons were used commonly until a few years ago

ex. Peginterferon alfa-2a

113
Q

What is the newer approach to treatment of Chronic Hep B?

A

Nucleoside analogues

ex. lamuvidine, Tenofovir, Adefovir

114
Q

What are the treatment goals for Chronic Hep B?

A
  • Permanent suppression or elimination of thr virus (elimination defined as undectectable HBV DNA is not always possible)
  • Prevent cirrhosis, liver failure, and hepatocellular carcinoma
115
Q

What is considered to be the functional cure of hepatitis B?

A

HBsAg loss with or without the appearance of antibodies to HBsAg (anti-HBs)

116
Q

What is the role of interferons in Hepatitis B treatment?

A

Cytokines with direct antiviral and immunomodulatory properties

16-48 week course (30% successful in developing immunity)

Used in patients in lower HBV DNA levels and higher serum aminotransferase

117
Q

What are some advantages of interferons?

A
  • Shorter course of therapy
  • Absence of resistance
  • A chance at full seroconversion
118
Q

What are the disadvantages of interferons?

A
  • Contraindicated in decompressed cirrhosis (increased risk of life-threatening infections and worsening of hepatic function)
  • Subcutaneous injection
  • Many side effects (flu-like symptoms, emotional labilirt, myleosuppresive, hyper/hypothyroidism)
119
Q

What are the advantages of nucleoside analogues

A
  • Safer
  • Fewer side effects
  • oral administration
120
Q

What are the disadvantages of nucleoside analogues?

A
  • Chronic therapy (seroconversion doesn’t happen in most patients and can take years and some may require treatment indefinitely)
  • Drug resistance
  • Renal adjustment required
121
Q

What are some characteristics of lamivudine?

A

Also known as Heptovir

It is a pryimidine nucleoside analogue inhibitor of Hep B

Well tolerated and effective, but resistance develops after a few years of use

Not DOC for HepB patient in most patients, but is useful for Hep B prophylaxis in patients on immunosuppressants and are safe in pregnant women

122
Q

What is the role of adefovir in Hep B treatment?

A

It is often an adjunct to lamivudine resistance

123
Q

What is tenofovir?

A

It is a DOC agent for Hep B treatment

two different formulations are available (TAF and TDF)

It is the most potent with a low chance of resistance

124
Q

What is entecavir?

A

Second DOC for Hep B treatment

Selective guanosine analogue and potent inhibitor of HBV DNA replication

More effective than lamivudine, but should not be used to rescue in lamivudine resistance (need to use tenofivir instead)

125
Q

When is adjunct antiviral treatment in Hep B patients warranted?

A
  • People with cirrhosis who have resistance may have a flare which could be fatal

Ex. lamivudine + tenofivir or tenofivir + entecavir

126
Q

What are some characteristics of a Hepatitis C infection?

A
  • Trasmuitted via perinatal, sexual, and blood contact (parenteral transmission is the most effective)
  • Low prevalence
127
Q

What are some symptoms associated with Hepatitis C infection?

A

70% of patients are asymptomatic

If symptoms occur (jaundice, dark urine, white stool, abdominal pain, loss of appetite)

128
Q

What are the effects of a hepatitis C infection on human health?

A
  • Chronic disease (75% of patients)
  • Cirrhosis
  • Hepatocellular cancer
129
Q

How long can a Hepatitis C infection take to manifest a clinical presentation?

A

Can be as late as 20-30 years post-exposure (accelerated in patients with HIV/HCV coinfection)

130
Q

What are the most common genotypes of Hepatitis C?

A

Globally: Genotypes 1-6

Canada: Genotypes 1a, 1b, 2, & 3

131
Q

What are the important serological markers to look out for in patients with a Hepatitis C viral infection?

A
  • Anti-HCV (antibody to HCV): indicates infection, either acute or chronic
  • HCV RNA by PCR: indicates virus replication activity (appears at the start of an acute infection, if negative then no active infection)
132
Q

How often do high-risk individuals need to be screened for the Hepatitis C virus?

A

Annually with an Anti-HCV (antibody to HCV) to determine whether or not an infection is present

If previously treated or spontaneously cleared the infection, HCV RNA should be performed

133
Q

What does contemporary treatment of Hepatitis C look like?

A

Complete elimination of virus defined by undectectble HCV RNA is now possible with newer drugs in 8-12 weeks

134
Q

What was the traditional treatment combination for Hepatitis C?

A

Interferon and Ribavirin

135
Q

What were the cons of interferon-ribavirin therapy for Hepatitis C?

A

Poor ADR profile + could not use in patients with decompensated cirrhosis

Common:
- Flu-like symptoms
- Decreased blood counts (required therapy)
- Weight loss and anorexia

Infrequent:
- Diarrhea
- Depression
- Vasculitis
- Retinopathy
- Autoimmune disease

136
Q

What are the main antiviral agents used in the treatment of Hepatitis C?

A
  • Harvoni (Ledipasvir and Sofosbuvir)
  • Zepatier (Grazoprevir and Elbasavir)
  • Epclusa (Sofosbuvir and Velpatasvir)
  • Mavriet (Glecaprevir and Pibrentasvir)
  • Vosevi (Sofosbuvir + Velpatasvir + Voxilaprevir)
137
Q

What are some characteristics of Harvoni (ledipasvir and sofosbuvir) for treatment of Hepatitis C?

A
  • Indicated for pediatric use

-Useful against (g1, 4, 5, 6)

  • Oral preparation (no need to inject)
  • Mild to moderate in severity, fatugue, headache, insomnia, nausea (relatively less severe compared to legacy antiviral combination products)
  • Decreased absorption if taken with acid-suppressing drugs (Ex. PPI)
138
Q

What are some characteristics of Zepatier (grazoprevir and elbasavir) for treatment of Hepatitis C?

A
  • Studied to show benefit in patients who are difficult to treat or have a lack of data in literature (ex. PWIDs, renally impaired patients)
  • Works against all genotypes, except g6 (need to add sofosbuvir)
  • Avoid in decompensated cirrhosis
139
Q

What are some characteristics of Epclusa (sofosbuvir and velpatasvir) for the treatment of Hepatitis C?

A
  • Pan-genomic, some exceptions with cirrhotic patients with g3
  • 99-100% cure rates
  • Monitor closely when acid-suppressing drugs (ex. PPI) are used
140
Q

What are some characteristics of Maviret (glecaprevir and pibrentasvir) in treatment of Hepatitis C?

A
  • Pan-genomic (no need to genotype patients)
  • Can also be used in patients with severe kidney failure (even dialysis
  • Can be used in patients who have recieved a Hepatitis C kidney transplant
141
Q

What are some characteristics of Vosevi (sofosbuvir and velpatasvir) in treatment of Hepatitis C?

A
  • Pan-genomic (no need to genotype patient)
  • Used in treatment failure
  • Avoid in decompensated cirrhosis
142
Q

What are the two most common antiviral treatment options for Hepatitis C treatment?

A
  • Epclusa (sofosbuvir and velpatasvir)
  • Maviret (glecaprevir and pibrentasvir)
143
Q

Do all Hepatitis C patients recieving antiviral therapy need to be treated by a specialist?

A

Not neccessarily, uncomplicated patients can be treated by a GP if they are registered as a prescriber

144
Q

What are some requirements for Hepatitis C testing?

A
  • 40-45% of patients who live with a Hepatitis C infection, are undiagnosed

THe CDD reccomends everyone over 18 atleast once and during each pregnancy

145
Q

What are some at-risk groups for Hepatitis C infection?

A
  • PWIDs
  • Prior incarceration
  • Remote blood transfusion
  • Immigrants from endemic countries
146
Q

What are the three tests involved in screening for Hepatitis C infections?

A
  1. Hepatitis C antibody
  2. If above positive, Hepatitis C antigen
  3. If above positive, Hepatitis C RNA (HCV RNA)
147
Q

What are some characteristics of the Hepatitis D virus?

A

RNA virus that occurs simultaneously with HBV

Therefore the Hepatitis B vaccine indirectly protects against Hepatitis D

148
Q

How is Hepatitis D transmitted?

A

Perinatal, sexual, blood

149
Q

How is Hepatitis D treated?

A

PEG interferon at standard dosing x minimum of 12 months

Mortality is between 2-20%

150
Q

What are some characteristics of the Hepatitis E virus?

A

RNA virus (less common in Canada, more common in poor regions)

151
Q

How is Hepatitis E transmitted?

A

Via the fecal-oral route

152
Q

What are the consequences of Hepatitis E on human health?

A

Most recover unscathed, but there is a higher mortality rate for pregnant women that contract Hepatits E

153
Q

How can any type of Hepatitis infection be prevented?

A
  • Risk reduction (participate in more safer activities)
  • Education
  • Active immunization (vaccination)
  • Passive immunization (immune globulins)
154
Q

What are some lifestyle modifactions for all viral hepatitis patients?

A
  • All household members and sexual contacts should be vaccinated anf anti-HBs levels
  • Alcohol (Abstain)
  • Use acetaminophen (less than 2g/day), avoid NSAIDs
  • Do not share toothbrushes, nail clippers, or razors
  • Cover all cuts & scrapes
  • Maintain/achieve ideal body weight
  • Use two forms of contraception while on RBV
155
Q

What is the most common reason for drug recall?

A

Drug-induced liver injury (DILI)

1000 drugs have been pulled off the market due to DILI. Often impacts to liver are not caught in clinical trials, but are identified in post-marketing

156
Q

Is drug-induced liver injury always an acute condition?

A

No, it can be acute or chronic

157
Q

What are some types of drug-induced liver injury?

A
  • Hepatocellular
  • Steatonecrosis
  • Fibrosis
  • Cholestatic
158
Q

What are some characteristics of hepatocellular damage caused by DILI?

A
  • Increased AST and ALT (preceded increases in bilirubin and ALP)
  • Usually occurs within 1 year of starting drug
  • Can result in fulminant hepatitis

ex. Allopurinol

159
Q

What are some characteristics of steatonecrosis caused by DILI?

A
  • Increased synthesis of FA in hepatocytes which can cause cell to burst open
  • Inflammation

ex. Valproic Acid

160
Q

What are some characteristics of fibrosis caused by DILI?

A
  • Mild
  • Chronic hepatitis can progress to fibrosis, which can further progress to cirrhosis if drug is not d/c

ex. Methotrexate

161
Q

What are some characteristics of cholestatic damage due to DILI?

A
  • Prevents proper elimination of bile by liver (accumulation of bile)
  • Increased ALP

ex. Carbemazepine

162
Q

What is the definition of hepatotoxicity?

A

Clinically significant abnormalities of liver tests

  • ALT is more than 3x the upper normal limit
    AND
  • Total bilirubin is more than 2x the upper normal limit
163
Q

How can the pattern of injury in DILI be determined?

A

Determine an R value

R = Measured ALT/Upper Normal Limit of ALT
or
Measured ALP/Upper Normal Limit of ALP

If R is greater than 5 = hepatocellular injury

If R is between 2 and 5 = mixed (hepatocellular and cholestatic)

If R is below 2 = cholestatic injury

164
Q

What are the two mechanisms of DILI?

A
  • Intrinsic (predictable)
  • Idiosyncratic (unpredictable)
165
Q

What are the characteristics of an intrinsic DILI?

A

An intrinsic DILI is caused by a direct hepatotoxin which has inherent propensity to induce injury to all individuals (dose dependent or time dependent and reproducible)

ex. Acetaminophen overdose (extremely high AST/ALT)

166
Q

What are the characteristics of an idiosyncratic DILI?

A

An idiosyncratic DILI only occurs in a small number of uniquely susceptible patients (injury does not occur in most patients)

Further classified into allergic and non-allergic type

167
Q

What happens in acetaminophen toxicity?

A

Acetaminophen is 90% (glucoronidated or sulfonated) and 10% metabolized by CYP450 normallly

If glucoronidation and sulfonation pathways are saturated, CYP becomes the major metabolic pathway

Acetaminophen metabolized by CYP450 produces NAPQI which is detoxified by glutathione. But glutathione is is quickly depleted

NAPQI accumulates and binds to and modifies critical hepatic cell proteins (causes hepatic necrosis and possiblly death to patient)

168
Q

What does Stage 1 of an acetaminophen overdose look like?

A

Within 24h
- GI symptims (NV, abd pain, malaise, sweating)

169
Q

What does Stage 2 of an acetaminophen overdose look like?

A

Within 24-72h
- Resolution of stage 1 symptoms
- Onset of right-upper quadrant pain, increased bilirubin, PT, and transaminases

170
Q

What does Stage 3 of an acetaminophen look like?

A

Depends on liver damage (72-96h)
- Recovery to fulminant hepatic failure (wide range of possibilities)
- AST and ALT peak (up to 100x normal)
- Death (at 3 to 5 days, if toxicity is bad enough)

171
Q

What does Stage 4 of an acetaminophen look like?

A

Recovery stage, if patient survives stage 3
- Symptoms subside and transaminases normalize
- Survivors do not have chronic hepatic dysfunction

172
Q

What is the role of acetylcysteine in acetaminophen overdose?

A

It is the antidote of choice for acetaminophen overdoses

Enhances glutathione stores

173
Q

What resource is used to determine if a patient should get acetylcysteine for an acetaminophen overdose?

A

Rumack-Matthew nomogram

Administer acetylcysteine if serum concentration exceeds the “treatment line” on the Rumack-Matthew nomogram

174
Q

What are some symptoms associated with allergic-type idiosyncratic DILI?

A
  • Fever, rash, eosinophilia
  • May have extrahepatic involvement as well

Symptoms may occur with increasing intensity with repeat exposure (sensitization)

175
Q

What are some drugs that are associated with allergic-type idiosyncratic DILI?

A
  • Anticonvulsants
  • Sulfonamide antibiotics
  • Allopurinol
  • Dapsone, Minocycline, PTU
176
Q

What is the cause of non-allergic idiosyncratic DILI?

A

LIkely due to the accumulation of toxic metabolites

Drugs associated:
- Isoniazid, valproic acid, ketoconazole, methyldopa

177
Q

What should pharmacists do when DILI is suspected?

A
  1. Take a detailed med history
    - Consider Rx, OTC, herbs, recreational use, environmental exposures to other hepatoxins
  2. Examine LETs and identify type of liver injury
    - AST/ALT elevations, more than 3x upper normal limit
    - Increase monitoring
  3. What symptoms are present?
    - Symptoms of liver injury (malaise, jaundice, dark urine, pale stool, pain)
  4. Is there a possible alternate cause?
    - Investigations for othe causes of hepatocellular, cholestatic, or mixed liver patterns (blood tests, imaging, liver biopsy)
  5. Consider onset of symptoms with relation to administration
    - Short = 3-30 days
    - Moderate = 30-90 days
    - Long = more than 90 days
  6. Did symptoms subside after drug d/c
  7. Consult your references
    - LiverTox, Local Gastroenterologist, MedSask
178
Q

How are DILIs managed?

A
  1. Immediate d/c of all potential hepatoxins
  2. Supportive care as needed
    - Acetylcysteine if acetaminophen poisioning
    - Corticosteroids can be considered for allergic idiosyncratic DILI
    - No other antidotes exist
  3. Serial biocehmical measurements until the liver enzymes return to normal
179
Q

What is the Child-Pugh Score?

A

It is a test that is commonly used to stage liver dysfunction by clinical presentation

180
Q

What are the variables that contribute to the Child-Pugh score?

A
  • Encephalopathy
  • Ascites
  • Bilirubin
  • Albumin
  • PT time
181
Q

What are the score ranges for the Child-Pugh scoring system?

A

Child Pugh A (less severe): 5-6 points

Child Pugh B: 7-9 points

Child Pugh C (most severe): 10-15 points

182
Q

Review slide 175 for the Child Pugh score

183
Q

Do patients with hepatic dysfunction, are they are a higher risk of DILI?

A

Generally NOT at increased risk for drug induced liver toxicity, but likelihood for recovery is lower if a reaction does occur

184
Q

Why should nephrotoxic drugs be used with caution in hepatic dysfunction?

A

Because renal blood blow may be impaired already, these drugs can worsen kidney perfusion

185
Q

What are some issues experienced in clinical practice for managing liver disease?

A
  • Accurately quantifying liver dysfunction
  • Accurate quantification of metabolism dysfunction
  • Data regarding drug adjustment
  • Relative effects of different liver diseases (cholestatic vs. hepatocellular)
  • Comorbid diseases
  • Plasma protein binding often not considered

PHAR 255 (15 decks)

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