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PHAR123 > Liver > Flashcards

Liver Flashcards

1
Q

What is the largest parenchymal organ?

A

the liver

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2
Q

Where is the liver located?

A

below the diaphragm

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3
Q

Which lobe of the liver is larger?

A

the right lobe

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4
Q

Where is the hepatic portal vein bringing blood from?

A

the GI tract

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5
Q

What is the basic functional unit of the liver?

A

liver lobule
-hexagonal with central vein, corners contain portal triads

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6
Q

What makes up a portal triad?

A

portal vein
bile duct
hepatic artery

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7
Q

What are the functions of the liver?

A

metabolism of food substances and drugs
production of bile
cholesterol metabolism & lipoproteins; production of steroid hormones from cholesterol
glucose storage (glycogen) and release
iron storage
production of various other substances
-clotting factors, serum proteins, fat-soluble vitamins

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8
Q

What is the goal when a drug enters the liver?

A

elimination of foreign (ex: drug) substances

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9
Q

How does the liver metabolize drugs?

A

active drug to inactive drug
prodrug to active drug
increased solubility
increased lipophilicity
pathway depends on chemical structure, influence of pharmacogenomics in some cases (CYP450s)

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10
Q

What is the function of bile?

A

aid in digestion of fats in the duodenum

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11
Q

What is the composition of bile?

A

bile acid
salts
phospholipids
cholesterol
pigments
water
electrolytes that keep the total solution slightly alkaline
-pH of 7-8

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12
Q

How much bile is excreted each day?

A

500-1000ml
most (95%) of the bile that has entered the intestines is reabsorbed in the terminal ileum, and returned to the liver for reuse

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13
Q

Which organ secretes bile?

A

gallbladder

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14
Q

Describe normal bilirubin metabolism.

A
  1. Hb release and breakdown (spleen, bone marrow)
  2. heme enzymatically converted to bilirubin
  3. bilirubin enters the liver through the circulation
    (unconjugated)
  4. hepatocytes add additional functional groups to bilirubin to
    increase its solubility and excretion (conjugated)
  5. most of the conjugated bilirubin then is excreted in bile
  6. bile enters the GI tract
  7. a small fraction of the bilirubin is reabsorbed and sent back
    to the liver (enterohepatic circulation)
  8. most of the bilirubin (~90%) is excreted in feces after being
    enzymatically reduced by colon bacteria
  9. the breakdown products contribute to fecal colour
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15
Q

Describe the epidemiology of liver disease in Canada.

A

approximately 1/10 have liver disease (>3M people)
over 100 forms of liver disease affecting all age groups
95% of deaths from chronic liver disease are due to:
-chronic hepatitis B or C
-alcoholic liver disease
-NAFLD
-liver cancer

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16
Q

What are the risk factors for liver disease?

A

obesity/diabetes
chemicals or toxins (drugs, herbals, illegal drugs)
alcohol abuse
family history
hepatitis B or C

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17
Q

How does early-stage liver disease present itself?

A

asymptomatic

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18
Q

What are the symptoms that are experienced in advancer liver disease?

A

jaundice (yellowing of skin and eyes)
nausea, vomiting, loss of appetite
abdominal swelling (ascites) or tenderness in liver area
fatigue
pruritis
dark urine
pale stool
dementia-like confusion

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19
Q

What causes jaundice?

A

elevation of serum bilirubin

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20
Q

What does jaundice indicate?

A

problem with the livers processing of bile

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21
Q

What are the different causes of jaundice?

A

prehepatic: hemolysis
hepatic: cirrhosis, tumors, drugs, viral, hepatitis
posthepatic: carcinoma, gallstones

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22
Q

What is the only indicator of jaundice?

A

yellow colour to skin, nails, and sclera

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23
Q

What is hepatic jaundice?

A

the liver is unable to transform unconjugated bilirubin to the conjugated form or conditions in which the liver cannot transfer the conjugated bilirubin into bile ducts
-free bilirubin then escapes into blood

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24
Q

What are some disorders that cause hepatic jaundice?

A

hepatitis A, B, C
alcoholic liver disease
drug-induced liver disease
chronic hepatitis due to various causes
cirrhosis
liver metastases

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25
What is cirrhosis?
liver becomes fibrotic after chronic injury such that the liver becomes nodular with regenerating hepatocytes surrounded by scar tissue
26
What is NAFLD associated with?
obesity Type II diabetes hypertension dyslipidemia excess caloric intake with macronutrient imbalance
27
What do 10% of cases of NAFLD progress to?
steatosis and cirrhosis
28
What are the symptoms of NAFLD?
may be silent or patients may have abdominal pain, fatigue, jaundice at more advanced stages
29
Is NAFLD reversible?
reversible with: -weight loss -exercise -dietary changes such as Mediterranean diet (limits red meat, sweets, and baked goods)
30
What are the main causes of posthepatic jaundice?
intrahepatic cholestasis (bile not moving out) extrahepatic obstruction of the biliary tract (prevents bilirubin from moving into the intestines)
31
What is cholestasis?
stagnation or a marked reduction in bile secretion and flow
32
What are examples of disorders that cause posthepatic jaundice?
inflammation, scar tissue, tumor, gallstones pancreatic or biliary disorders involving inflammation and obstruction carcinoma of pancreas head or common bile duct of gallbladder
33
What causes cholestasis?
functional impairment of the hepatocytes in the secretion of bile and/or due to an obstruction at any level of the excretory pathway of bile -intrahepatic or extrahepatic -leads to retention of constituents of bile in blood
34
What are the prominent features of cholestasis?
pruritis malabsorption of fat and fat-soluble vitamins
35
What is the pathogenesis of intrahepatic cholestasis?
failure to transport bile salts out in the bile=accumulation bile salts have strong detergent-like effect=membrane damage physical obstruction to bile flow at the extrahepatic biliary ducts
36
What is the treatment of intrahepatic cholestasis?
aimed at the primary problem and may be surgical pruritis managed with: -cholestyramine (reduces cholesterol) -ursodeoxycholic acid -antihistamines (sleep) -phenobarbitone or naloxone (investigational)
37
What is the most common drug used for gallstones?
ursodiol -solubilizes cholesterol in micelles and acts by dispersing cholesterol in aqueous media
38
How are gallstones formed?
solubility of cholesterol or bile pigments is exceeded in bile a nidus of precipitated salts forms more precipitate is added and the stone grows larger symptoms when they cause obstruction, irritation or infection
39
What are the causes of cirrhosis of the liver?
75%: hepatitis (B,C,D), NAFLD, alcohol 25%: others -hereditary metabolic diseases -autoimmune disease -biliary obstruction -drugs -idiopathic
40
What is the pathogenesis of cirrhosis?
cellular damage, fibrosis, nodule formation, impaired blood flow, bile obstruction-->liver failure
41
What does the surface of the liver with alcoholic cirrhosis look like?
hard, lumpy, shrunken impaired circulation and function
42
What is NASH?
non-alcoholic steatohepatitis -more severe form of NAFLD that involves inflammation
43
What are the stages of alcoholic liver disease?
fatty liver alcoholic hepatitis alcoholic cirrhosis
44
What is the pathogenesis of alcoholic hepatitis?
even moderate alcohol consumption creates fatty deposits in the liver -women more susceptible -alcoholic hepatitis can be proceeded by variable amounts of hepatic steatosis disease progression due to complex mechanisms -lipid peroxidation -dysregulated lipid metabolism -acetaldehyde protein adduct formation -disruption of cytoskeletal and membrane function reactive oxygen species formed during oxidation of ethanol -these free radicals react with membranes and proteins neutrophils generate reactive oxygen species excess TNF-a, IL8, IL6, IL18 (abnormal cytokine regulation concurrent hepatitis accelerates the disease activation of fibrotic processes
45
What does alcohol do to hepatocytes?
alcohol is a hepatotoxin that interferes with mitochondrial and microsomal function leading to accumulation of lipids
46
What are the distant and systemic complications of cirrhosis?
bleeding tendency: low clotting factors, thrombocytopenia hematemesis and exsanguination steroid hormones lacking due to reduced synthesis from cholesterol hepatic encephalopathy hepatorenal syndrome
47
What are the enzymes used in liver function tests?
ALT (alanine aminotransferase) AST (aspartate aminotransferase) *high values means acute injury* also: albumin, bilirubin, prothrombin time
48
What are the causes of elevated liver enzymes?
A: autoimmune hepatitis B: hepatitis B C: hepatitis C D: drugs or toxins E: ethanol F: fatty liver G: growths (tumors) H: hemodynamic disorder (HF) I: iron, copper, alpha1-antitrypsin deficiency M: muscle injury
49
What are the biggest risk factors for hepatocellular carcinoma?
hepatitis B and/or hepatitis C especially if also heavy alcohol use
50
Is hepatocellular carcinoma treatable?
curable by surgical resection -but surgery is the treatment of choice for only the small fraction of patients with localized disease other treatments: -radiofrequency ablation -transarterial chemoembolization
51
What are the benign liver tumors?
hemangioma hepatocellular adenoma
52
What are the malignant liver tumors?
hepatocellular carcinoma metastases -rare: cholangiocellular carcinoma of the liver carcinoma of extrahepatic bile ducts gallbladder carcinoma
53
Describe each class of the Child-Turcotte-Pugh Classification.
Class A: 5-6 points (least severe disease) Class B: 7-9 points (moderately severe disease) Class C: 10-15 points (most severe disease)
54
List all the clinical and lab criteria with their points of the Child-Turcotte-Pugh Classification.
encephalopathy: -1 point: none -2 points: mild to moderate (grade 1 or 2) -3 points: severe (grade 3 or 4) ascites: -1 point: none -2 points: mild to moderate (diuretic responsive) -3 points: severe (diuretic refractory) bilirubin (mg/dL): -1 point: <2 -2 points: 2-3 -3 points: >3 albumin (g/dL): -1 point: >3.5 -2 points: 2.8-3.5 -3 points: <2.8 prothrombin time: -1 point: <4s prolonged, <1.7 INR -2 points: 4-6s prolonged, 1.7-2.3 INR -3 points: >6s prolonged, >2.3 INR
55
What is drug induced liver injury?
hepatic inflammation, hepatocellular necrosis, or jaundice due to exposure to a medication or toxin
56
What is the most common cause of drug induced liver injury?
overdose of acetaminophen
57
What is idiosyncratic drug metabolism?
when medication causes DILI at therapeutic doses, not overdose
58
When is DILI more likely?
when there are multiple drugs being used that are hepatically metabolized -some drugs are more likely than others to cause DILI
59
Which drugs make up the biggest percentage of DILI?
antimicrobials (46.52%)
60
What are the many factors that predispose or increase the risk of DILI?
drug properties -lipophilicity, dose, chronic exposure, structure, weight host factors -race, age, sex, lifestyle, comorbidities, etc genetic factors -polymorphisms metabolic factors -reactive metabolites, alterations in metabolism, etc immunological factors -viral co-infection, immunomodulators, mitochondrial stress
61
What is the predictable pattern of DILI? What is the unpredictable pattern of DILI?
predictable: dose-related unpredictable: not related to dose or risk factors (idiosyncratic) -genetic effects on drug metabolism -immune related reactions
62
True or false: there is a test available to predict DILI
false
63
Describe the histological patterns of DILI.
zonal hepatocellular necrosis: -acetaminophen, mushrooms cholestasis: -estrogens, SMX acute hepatitis: -isoniazid, antibiotics (typically resolves upon dc) chronic hepatitis fatty liver: -ethanol, mushrooms, corticosteroids, methotrexate vascular disease: -contraceptives, anabolic steroids, tamoxifen neoplastic lesions: -hepatic adenomas, contraceptives, anabolic steroids
64
What does the fat droplet accumulation reflect in fatty liver?
underlying damage to liver cell mitochondrial metabolism and integrity
65
What is Reyes syndrome?
severe liver failure with aspirin in children with influenza or chicken pox
66
Where is ALT found?
hepatocyte cytosol, more liver specific also found in kidney, heart, muscle *normal range: 12-37U/L*
67
Where is AST found?
hepatocyte mitochondria and cytosol, less specific as well as skeletal muscle, heart, brain, pancreas *normal range: 15-65U/L*
68
When do AST/ALT leak?
when there is damage to hepatocytes
69
When will AST levels be greater than ALT levels?
chronic alcohol use and cirrhosis
70
True or false: the degree of elevation of liver enzymes reflects the extent of liver injury
false serial measurements better reflect severity and prognosis than dose a single measurement
71
Describe mild increases in liver enzymes.
<300U/L may be nonspecific and often presents in disorders like: -cirrhosis due to viral hepatitis -NAFLD -cholestasis -hepatocellular carcinoma -alcohol related liver disease -alcoholic hepatitis
72
Describe very high increases in liver enzymes.
>500U/L may occur in: -acute hepatitis -drug toxicity
73
When would a fall of liver enzymes to normal not indicate liver recovery?
fall to normal but accompanied by an increase in bilirubin and PT or INR -may indicate liver failure, also called "fulminant liver failure"
74
What are the liver enzymes indicating cholestasis?
alkaline phosphatase (Alk.Phos.) -found also in bone gamma-glutaryl transpeptidase (GGT) -also elevated with alcohol toxicity
75
What are drugs that may elevate Alk.phos and GGT?
some antibiotics anabolic steroids oral contraceptives NSAIDs antihypertensives antidiabetic agents anticonvulsants lipid-lowering agents psychotropic drugs
76
What are the major proteins made by the liver?
albumin and globulins
77
What does albumin do?
oncotic pressure binds many substances for transport binds drugs *acidic (-) and neutral drugs, as well as steroid hormones*
78
What is alpha-1 acid glycoprotein (AAG)?
serum protein that binds drugs -carrier of basic (+) and neutrally charged lipophilic compounds represents 1-3% of total serum protein
79
What is globulin?
made up of different proteins: alpha, beta, gamma certain globulins bind with Hb others transport metals such as iron to fight infection
80
What is direct bilirubin?
bilirubin conjugated by the liver cells to form bilirubin diglucuronide which is water-soluble and excreted in urine
81
What is indirect bilirubin?
free (unconjugated) bilirubin, not water soluble, converted in the liver to the soluble conjugated form
82
True or false: bilirubin is never elevated in drug induced liver injury
false bilirubin may be elevated in drug induced liver injury
83
What is prothrombin time?
test that tells you how long it takes the blood to clot
84
What is the INR?
international normalized ratio -compares patient to normal population and indexes to the sensitivity of the thromboplastin reagent (ISI) used in the lab test -commonly used in monitoring warfarin therapy -INR=(patient PT/mean normal PT) to the power of ISI
85
What is a normal INR? What is the desired INR of a warfarin patient?
normal: <1.1 warfarin: 2.0-3.0

PHAR123 (15 decks)

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