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
Q

What is cirrhosis?

A

liver becomes fibrotic after chronic injury such that the liver becomes nodular with regenerating hepatocytes surrounded by scar tissue

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26
Q

What is NAFLD associated with?

A

obesity
Type II diabetes
hypertension
dyslipidemia
excess caloric intake with macronutrient imbalance

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27
Q

What do 10% of cases of NAFLD progress to?

A

steatosis and cirrhosis

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28
Q

What are the symptoms of NAFLD?

A

may be silent or patients may have abdominal pain, fatigue, jaundice at more advanced stages

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29
Q

Is NAFLD reversible?

A

reversible with:
-weight loss
-exercise
-dietary changes such as Mediterranean diet (limits red meat,
sweets, and baked goods)

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30
Q

What are the main causes of posthepatic jaundice?

A

intrahepatic cholestasis (bile not moving out)
extrahepatic obstruction of the biliary tract (prevents bilirubin from moving into the intestines)

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31
Q

What is cholestasis?

A

stagnation or a marked reduction in bile secretion and flow

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32
Q

What are examples of disorders that cause posthepatic jaundice?

A

inflammation, scar tissue, tumor, gallstones
pancreatic or biliary disorders involving inflammation and obstruction
carcinoma of pancreas head or common bile duct of gallbladder

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33
Q

What causes cholestasis?

A

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

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34
Q

What are the prominent features of cholestasis?

A

pruritis
malabsorption of fat and fat-soluble vitamins

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35
Q

What is the pathogenesis of intrahepatic cholestasis?

A

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
Q

What is the treatment of intrahepatic cholestasis?

A

aimed at the primary problem and may be surgical
pruritis managed with:
-cholestyramine (reduces cholesterol)
-ursodeoxycholic acid
-antihistamines (sleep)
-phenobarbitone or naloxone (investigational)

37
Q

What is the most common drug used for gallstones?

A

ursodiol
-solubilizes cholesterol in micelles and acts by dispersing
cholesterol in aqueous media

38
Q

How are gallstones formed?

A

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
Q

What are the causes of cirrhosis of the liver?

A

75%: hepatitis (B,C,D), NAFLD, alcohol
25%: others
-hereditary metabolic diseases
-autoimmune disease
-biliary obstruction
-drugs
-idiopathic

40
Q

What is the pathogenesis of cirrhosis?

A

cellular damage, fibrosis, nodule formation, impaired blood flow, bile obstruction–>liver failure

41
Q

What does the surface of the liver with alcoholic cirrhosis look like?

A

hard, lumpy, shrunken
impaired circulation and function

42
Q

What is NASH?

A

non-alcoholic steatohepatitis
-more severe form of NAFLD that involves inflammation

43
Q

What are the stages of alcoholic liver disease?

A

fatty liver
alcoholic hepatitis
alcoholic cirrhosis

44
Q

What is the pathogenesis of alcoholic hepatitis?

A

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
Q

What does alcohol do to hepatocytes?

A

alcohol is a hepatotoxin that interferes with mitochondrial and microsomal function leading to accumulation of lipids

46
Q

What are the distant and systemic complications of cirrhosis?

A

bleeding tendency: low clotting factors, thrombocytopenia
hematemesis and exsanguination
steroid hormones lacking due to reduced synthesis from cholesterol
hepatic encephalopathy
hepatorenal syndrome

47
Q

What are the enzymes used in liver function tests?

A

ALT (alanine aminotransferase)
AST (aspartate aminotransferase)
high values means acute injury
also: albumin, bilirubin, prothrombin time

48
Q

What are the causes of elevated liver enzymes?

A

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
Q

What are the biggest risk factors for hepatocellular carcinoma?

A

hepatitis B and/or hepatitis C
especially if also heavy alcohol use

50
Q

Is hepatocellular carcinoma treatable?

A

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
Q

What are the benign liver tumors?

A

hemangioma
hepatocellular adenoma

52
Q

What are the malignant liver tumors?

A

hepatocellular carcinoma
metastases
-rare: cholangiocellular carcinoma of the liver
carcinoma of extrahepatic bile ducts
gallbladder carcinoma

53
Q

Describe each class of the Child-Turcotte-Pugh Classification.

A

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
Q

List all the clinical and lab criteria with their points of the Child-Turcotte-Pugh Classification.

A

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
Q

What is drug induced liver injury?

A

hepatic inflammation, hepatocellular necrosis, or jaundice due to exposure to a medication or toxin

56
Q

What is the most common cause of drug induced liver injury?

A

overdose of acetaminophen

57
Q

What is idiosyncratic drug metabolism?

A

when medication causes DILI at therapeutic doses, not overdose

58
Q

When is DILI more likely?

A

when there are multiple drugs being used that are hepatically metabolized
-some drugs are more likely than others to cause DILI

59
Q

Which drugs make up the biggest percentage of DILI?

A

antimicrobials (46.52%)

60
Q

What are the many factors that predispose or increase the risk of DILI?

A

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
Q

What is the predictable pattern of DILI? What is the unpredictable pattern of DILI?

A

predictable: dose-related
unpredictable: not related to dose or risk factors (idiosyncratic)
-genetic effects on drug metabolism
-immune related reactions

62
Q

True or false: there is a test available to predict DILI

A

false

63
Q

Describe the histological patterns of DILI.

A

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
Q

What does the fat droplet accumulation reflect in fatty liver?

A

underlying damage to liver cell mitochondrial metabolism and integrity

65
Q

What is Reyes syndrome?

A

severe liver failure with aspirin in children with influenza or chicken pox

66
Q

Where is ALT found?

A

hepatocyte cytosol, more liver specific
also found in kidney, heart, muscle
normal range: 12-37U/L

67
Q

Where is AST found?

A

hepatocyte mitochondria and cytosol, less specific
as well as skeletal muscle, heart, brain, pancreas
normal range: 15-65U/L

68
Q

When do AST/ALT leak?

A

when there is damage to hepatocytes

69
Q

When will AST levels be greater than ALT levels?

A

chronic alcohol use and cirrhosis

70
Q

True or false: the degree of elevation of liver enzymes reflects the extent of liver injury

A

false
serial measurements better reflect severity and prognosis than dose a single measurement

71
Q

Describe mild increases in liver enzymes.

A

<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
Q

Describe very high increases in liver enzymes.

A

> 500U/L
may occur in:
-acute hepatitis
-drug toxicity

73
Q

When would a fall of liver enzymes to normal not indicate liver recovery?

A

fall to normal but accompanied by an increase in bilirubin and PT or INR
-may indicate liver failure, also called “fulminant liver failure”

74
Q

What are the liver enzymes indicating cholestasis?

A

alkaline phosphatase (Alk.Phos.)
-found also in bone
gamma-glutaryl transpeptidase (GGT)
-also elevated with alcohol toxicity

75
Q

What are drugs that may elevate Alk.phos and GGT?

A

some antibiotics
anabolic steroids
oral contraceptives
NSAIDs
antihypertensives
antidiabetic agents
anticonvulsants
lipid-lowering agents
psychotropic drugs

76
Q

What are the major proteins made by the liver?

A

albumin and globulins

77
Q

What does albumin do?

A

oncotic pressure
binds many substances for transport
binds drugs
acidic (-) and neutral drugs, as well as steroid hormones

78
Q

What is alpha-1 acid glycoprotein (AAG)?

A

serum protein that binds drugs
-carrier of basic (+) and neutrally charged lipophilic compounds
represents 1-3% of total serum protein

79
Q

What is globulin?

A

made up of different proteins: alpha, beta, gamma
certain globulins bind with Hb
others transport metals such as iron to fight infection

80
Q

What is direct bilirubin?

A

bilirubin conjugated by the liver cells to form bilirubin diglucuronide which is water-soluble and excreted in urine

81
Q

What is indirect bilirubin?

A

free (unconjugated) bilirubin, not water soluble, converted in the liver to the soluble conjugated form

82
Q

True or false: bilirubin is never elevated in drug induced liver injury

A

false
bilirubin may be elevated in drug induced liver injury

83
Q

What is prothrombin time?

A

test that tells you how long it takes the blood to clot

84
Q

What is the INR?

A

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
Q

What is a normal INR? What is the desired INR of a warfarin patient?

A

normal: <1.1
warfarin: 2.0-3.0