Chapter 34: Role of the Liver in Metabolism

Helpfulness: 0
Set Details Share
created 3 weeks ago by ryankutz
3 views
updated 3 weeks ago by ryankutz
show moreless
Page to share:
Embed this setcancel
COPY
code changes based on your size selection
Size:
X
Show:
1

The liver is the largest solid organ in the body. What are the clinical sequelae of severe liver disease? (4)

card image
  1. jaundice
  2. profuse bleeding
  3. ascites
  4. hepatic encephalopathy
2

The structure of the liver facilitates exchange of metabolites between hepatocytes and plasma. What is the microscopic organization of the liver?

card image

It is composed of hepatocytes arranged in polyhedral lobules.

3

Portal tracts are located at the “corners” of the polyhedral lobules of the liver. What three structures are found in a portal tract?

card image
  1. portal vein
  2. hepatic artery
  3. interlobular bile ducts
4

Sinusoids of the liver are lined by two cell types. What are they?

  1. vascular endothelial cells
  2. Kupffer cells (phagocytes)
5

The liver plays a central role in glucose metabolism. What two functions of the liver function in maintaining blood glucose concentration?

  1. glycogenesis (stores glucose)
  2. gluconeogenesis (synthesizes glucose)
6

Depending on metabolic conditions, the liver can either take up or produce glucose. What enzyme in the liver allows the release of free glucose?

glucose-6-phosphatase

7

Most plasma proteins are synthesized in the liver. What is the most abundant protein in the blood?

albumin

8

Which coagulation factors are produced by the liver?

  1. factors II
  2. factor VII (shortest half-life)
  3. factor IX
  4. factor X
9

What test assesses the functional concentration of coagulation factors are produced by the liver?

prothrombin time (PT)

10

(...) is a term encompassing all the systemic changes that occur in response to infection or inflammation.

acute-phase response

11

The liver synthesizes a number of acute-phase proteins. What defines an acute-phase protein?

A protein whose plasma concentrations change by more than 25% within a week of the onset of an inflammatory or infective process.

12

What are three types of acute-phase proteins produced by the liver?

  1. binding proteins (e.g. CRP)
  2. complement factors
  3. protease inhibitors (e.g. α1AT)
13

Hepatic protein turnover is highly regulated. What protein marks intracellular proteins for proteasomal degradation?

ubiquitin

14

What by-product of amino acid metabolism is highly toxic to the central nervous system?

ammonia (NH3)

15

What is the major route by which waste nitrogen is excreted?

urea cycle

16

How is ammonia detoxified in the liver?

It is converted to urea.

17

What results from inhe­rited defects of any of the enzymes of the urea cycle?

hyperammonemia

18

What results form hyperammonemia?

encephalopathy

19

Heme is a constituent of hemoglobin, myoglobin, and cytochromes. What is the the main nonerythrocyte source of its synthesis?

liver

20

Heme is synthesized from glycine and succinyl-coenzyme A. What do these condense to form?

card image

5-aminolevulinate (5-ALA)

21

Condensation of glycine and succinyl-coenzyme A is the rate-limiting step of heme synthesis. What enzyme catalyses this reaction?

card image

5-ALA synthase

22

Glycine and succinyl-coenzyme A condense to form 5-ALA. What is formed by condensation of two molecules of 5-ALA?

card image

porphobilinogen (PBG)

23

What enzyme catalyses the condensation of two molecules of 5-ALA to form PBG?

card image

porphobilinogen synthase

24

Four PBG molecules combine to form a linear tetrapyrrole compound. What is formed by cyclization of this compound?

card image

coproporphyrinogen III

25

Coproporphyrinogen III is formed by cyclization of a tetrapyrrole. What is formed by decarboxylation and oxidation of side chains in coproporphyrinogen III?

card image

protoporphyrin IX

26

Protoporphyrin IX is formed by decarboxylation and oxidation of coproporphyrinogen III What is formed by addition of iron (Fe2+) to protoporphyrin IX?

card image

heme

27

What enzyme catalyses the addition of iron (Fe2+) to protoporphyrin IX to form heme?

card image

ferrochelatase

28

Defects in the heme synthetic pathway lead to rare disorders known as (...).

porphyrias

29

Three porphyrias are known as acute porphyrias and can be a cause of emergency admissions to hospital with abdominal pain. What are the acute porphyrias?

  1. acute intermittent porphyria (AIC)
  2. hereditary coproporphyria
  3. variegate porphyria
30

What enzyme is deficient in acute intermittent porphyria (AIC)?

hydroxymethylbilane synthase (converts PBG to a linear tetrapyrrole)

31

What enzyme is deficient in acute intermittent porphyria (AIC)?

coprooxidase (converts coproporphyrinogen III to protoporphyrinogen III)

32

What enzyme is deficient in variegate porphyria?

protoporphyrinogen oxidase (converts protoporphyrinogen III to protoporphyrin IX)

33

What complication of porphyrias causes sensitivity of skin to light, disfiguration, and scarring?

photosensitivity

34

What is the catabolic product of heme?

bilirubin

35

Where is the majority (75%) of all bilirubin is derived from?

The breakdown of hemoglobin from senescent red blood cells.

36

What product is produced by cleavage of heme by heme oxygenase?

card image

biliverdin

37

What product is produced by cleavage of biliverdin by biliverdin reducase?

card image

bilirubin

38

What is the normal plasma concentration of bilirubin?

< 1.2 mg/dL

39

What results from excess bilibubin?

jaundice

40

At what concentration of bilibubin does jaundice become apparent as yellowing of the skin?

3 mg/dL

41

Bilirubin is metabolized by the hepatocytes and excreted in bile. Why must bilirubin be metabolized before excretion?

Because unlike biliverdin, bilirubin is not water soluble.

42

Bilirubin is not water soluble. What protein transports bilirubin in the blood?

albumin

43

How is the hydrophilicity of bilirubin increased in the liver?

card image

conjugation (esterification)

44

The hydrophilicity of bilirubin is increased by esterification of its carboxylic acid side chains. What are the three main conjugates?

card image
  1. glucuronic acid (major conjugate)
  2. xylose
  3. ribose
45

Conjugated bilirubin is water soluble and may be secreted by the hepatocyte into the biliary canaliculi. Why does biliary obstruction lead to dark urine?

card image

If the excretory process is impaired, conjugated bilirubin may be excreted in the urine.

46

What colorless compound is formed from conjugated bilirubin by gut bacteria?

card image

urobilinogen (stercobilinogen)

47

What colored compound is formed by oxidation of urobilinogen (stercobilinogen)?

card image

urobilin (stercobilin)

48

Some stercobilin may be reabsorbed from the gut and can then be reexcreted by either the liver or the kidneys. Why does biliary obstruction lead to pale feces?

card image

If the biliary excretion is impaired by a disease, no stercoblinogen/stercobilin is formed.

49

What is the function of bile acids?

They have a detergent-like effect in the intestinal lumen, emulsifying dietary fat to facilitate its digestion.

50

What is the only route by which cholesterol can be eliminated from the body?

biliary excretion

51

What explains the wide-ranging capability of hepatic enzymes for drug metabolism?

low substrate specificity

52

Drug metabolism proceeds in two phases. What is Phase I?

The polarity of the drug is increased by its oxidation or hydroxylation.

53

Phase I drug metabolism is the addition of a polar group. What type of enzymes catalyze this reaction?

microsomal enzymes (cytochrome P-450)

54

Drug metabolism proceeds in two phases. What is Phase II?

Conjugation of the functional groups, most often by glucuronidation or sulfation.

55

Phase II drug metabolism is the conjugation of functional groups. What type of enzymes catalyze this reaction?

cytoplasmic enzymes

56

Three of the 18 cytochrome P-450 gene families share the responsibility for drug metabolism. What are they?

card image
  1. CYP1
  2. CYP2
  3. CYP3
57

CYP1, CYP2, and CYP3, are responsible for most of the phase I drug metabolism. Of these, which seven are responsible for approximately 90% of drug metabolism?

  1. CYP1A2
  2. CYP3A4
  3. CYP2B6
  4. CYP2C9
  5. CYP2C19
  6. CYP2D6
  7. CYP2E1
58

What underpins mechanisms of drug interactions?

Induction and competitive inhibition of cytochrome P-450 enzymes.

59

CYP1A2 metabolizes, among others, caffeine and theophylline. What substance found in grapefruit juice inhibits CYP1A2?

naringin

60

CYP1A2 metabolizes, among others, caffeine and theophylline. What antibiotic inhibits CYP1A2?

ciprofloxacin

61

What is the mechanism of drugs that that induce induction or repression of CYP3A enzymes?

They combine with nuclear receptors, forming complexes that modulate CYP3 synthesis by binding to response elements in the gene promoter.

62

What determines much of the individual variations in the response to drugs?

Gene polymorphisms that affect the catalytic activity of a cytochrome P-450 enzymes.

63

(...) is the phenomenon that one drug may be toxic in some individuals at concentrations normally tolerated by most other patients.

idiosyncratic drug toxicity

64

What commonly used analgesic is hepatotoxic in excess?

acetaminophen (paracetamol)

65

What are the three pathways of acetaminophen metabolism?

card image
  1. glucuronidation
  2. sulfation
  3. oxidation
66

Which metabolic pathway predominates in acetaminophen overdose?

card image

In acetaminophen overdose, the normal conjugation pathways are overwhelmed, and acetaminophen is largely oxidized.

67

What product is formed by oxidation of acetaminophen by CYP3A4?

card image

N-acetyl benzoquinoneimine (NABQI)

68

NABQI is formed by oxidation of acetaminophen. Why is formation of NABQI concerning?

card image

It causes free radical–mediated peroxidation of membrane lipids and hepatocellular damage.

69

How is NABQI normally detoxified by the liver?

card image

It is conjugated with glutathione.

70

Why does NABQI accumulate to toxic levels in acetaminophen overdose?

card image

In acetaminophen overdose glutathione stores become depleted and normal detoxification cannot occur.

71

What sulfhydryl compound can be given in cases of acetaminophen overdose?

card image

N-acetylcysteine (NAC)

72

What is the mechanism of action of N-acetylcysteine in acetaminophen overdose?

card image

It promotes detoxification of NABQI by the glutathione pathway and scavenges free radicals.

73

Alcohol excess is a major cause of liver disease. What are the three manifastations of alcoholic liver disease?

  1. steatosis
  2. hepatitis
  3. cirrhosis
74

What enzyme oxidizes ethanol in the liver to form acetaldehyde?

alcohol dehydrogenase (ADH)

75

What enzyme oxidizes acetaldehyde in the liver to form acetate?

aldehyde dehydrogenase (ALDH)

76

How does ethanol oxidation alter the redox potential of the hepatocyte?

It results in the increased ratio of NADH to NAD+ within the hepatic parenchymal cells.

77

How can alcohol consumption lead to lactic acidosis?

The increased NADH/NAD+ ratio promotes the reduction of pyruvate to lactate.

78

How can alcohol consumption lead to fatty liver?

card image

The increased NADH/NAD+ ratio inhibits β-oxidation of fatty acids and promotes triglyceride synthesis.

79

What affect does alcohol consumption affect proteasome activity?

It decreases proteasome activity, leading to increased apoptosis, a feature of alcoholic liver disease (ALD).

80

How does alcohol consumption lead to hepatomegaly?

The alcohol-induced decrease in proteasome activity may lead to the accumulation of protein in the liver.

81

What drug exploits symptoms of alcohol intolerance (i.e. flushing, sweating, nausea) to discourages alcohol abuse?

disulfiram

82

What is the mechanism of action of disulfiram?

It inhibits ALDH, leading to increased concentrations acetaldehyde after the ingestion of alcohol.

83

(...) describes the kinetic properties of a drug.

pharmacokinetics

84

(...) describes the pharmacologic effects of a drug.

pharmacodynamics

85

(...) studies the effects of genetic heterogeneity on drug responsiveness.

pharmacogenomics

86

Although plasma activities of liver enzymes are markers of liver disease, they do not exactly reflect the function of the liver. What is a a better indicator of liver synthetic function?

prothrombin time (PT)

87

What five laboratory tests used to access liver function?

  1. bilirubin
  2. albumin
  3. aminotransferase (ALT and AST)
  4. alkaline phosphatase (ALP)
  5. γ-glutamyl transpeptidase (GGT)
88

Which transaminase is more sensitive to liver function due to its cytoplasmic location?

ALT

89

What whould be the expected result of prothrombin time in a paitent with liver disease?

If synthetic functions of hepatocytes are impared, the patient would be expected to have a prolonged PT.

90

What are the two major sources of ALP?

It is synthesized both by the biliary tract and by bone.

91

What test may be measured to confirm the hepatic origin for a raised serum ALP?

GGT

92

What would be the expected findings for the following tests in a case of prehepatic jandice?

  1. bilirubin
  2. conjugated bilirubin
  3. AST and ALT
  4. ALP
  5. urine bilirubin
  6. urine urobilinogen
  1. () bilirubin
  2. (−) conjugated bilirubin
  3. normal AST and ALT
  4. normal ALP
  5. (−) urine bilirubin
  6. (+) urine urobilinogen
93

What would be the expected findings for the following tests in a case of intrahepatic jandice?

  1. bilirubin
  2. conjugated bilirubin
  3. AST and ALT
  4. ALP
  5. urine bilirubin
  6. urine urobilinogen
  1. () bilirubin
  2. () conjugated bilirubin
  3. () AST and ALT
  4. normal ALP
  5. (+) urine bilirubin
  6. (+) urine urobilinogen
94

What would be the expected findings for the following tests in a case of posthepatic jandice?

  1. bilirubin
  2. conjugated bilirubin
  3. AST and ALT
  4. ALP
  5. urine bilirubin
  6. urine urobilinogen
  1. () bilirubin
  2. () conjugated bilirubin
  3. normal AST and ALT
  4. () ALP
  5. (+) urine bilirubin
  6. (−) urine urobilinogen
95

Inflammatory disease of the liver is termed (...) and may be of short (acute) or long (chronic) duration.

hepatitis

96

What are the most common infectious causes of acute hepatitis?

viral infections

97

What are the most common toxicologic causes of acute hepatitis? (2)

  1. alcohol
  2. acetaminophen
98

Chronic hepatitis is defined as inflammation persisting for more than (...).

6 months

99

(...) is the result of chronic hepatitis and is characterized microscopically by fibrosis of the hepatic lobules.

cirrhosis

100

The term (...) denotes a clinical condition in which the biochemical function of the liver is severely compromised.

hepatic failure

101

(...) is the clinical term for biliary obstruction, which may occur in intrahepetic or extrahepatic ducts.

cholestasis

102

The causes of jaundice are conventionally classified into three categorys. What are they?

  1. prehepatic
  2. intrahepatic
  3. posthepatic
103

What is prehapatic jaundice the result of?

card image

Increased production or impaired hepatic uptake of bilirubin.

104

What might cause prehapatic jaundice?

  1. hemolysis
  2. impaired hepatic uptake of unconjugated bilirubin
105

What is intrahapatic jaundice the result of?

card image

Impaired hepatic metabolism or secretion of bilirubin.

106

What might cause intrahapatic jaundice? (3)

  1. infection (e.g. hepatitis)
  2. toxicity (e.g. acetaminophen, alcohol)
  3. genetic disease (e.g. Wilson disease)
107

What is posthepatic jaundice the result of?

card image
  1. intrahepatic bile ducts blockage
  2. extrahepatic bile ducts blockage
108

What might cause posthepatic jaundice?

biliary obstruction

109

Why is transient jaundice common neonates, particularly premature infants?

Because of the immaturity of the enzymes involved in bilirubin conjugation.

110

Unconjugated bilirubin is toxic to the immature brain and causes a condition known as (...).

kernicterus

111

Why are infants with severe neonatal jaundice exposed to phototherapy with blue-white light?

Blue light isomerizes bilirubin to more soluble pigments that might be excreted with bile.

112

(...) is a genetic disorder of iron metabolism that can lead to multiorgan dysfunction, including cirrhosis of the liver.

hemochromatosis

113

What gene is the most frequently mutated in hereditary hemochromatosis?

HFE gene

114

The most frequently seen mutation in hemochromatosis is in the HFE gene. What protein does this impair the synthesis of?

hepcidin

115

Mutations in the HFE gene and some others can impair the synthesis of hepcidin. This lead to excessive expression of what cell surface protein?

ferroportin

116

In hemochromatosis, impaired synthesis of hepcidin and excessive expression of ferroportin leads to iron egress. What does this cause?

Excess iron is deposited tissues, causing damage by catalyzing production of reactive oxygen species.

117

(...) is a condition associated with liver and CNS damage resulting from abnormal tissue copper disposition.

Wilson's disease

118

Wilson’s disease is a monogenic, autosomal recessive inhe­rited condition. What is the causative gene?

ATP7B

119

(...) presents in infancy as liver disease or in adulthood as lung disease caused by elastase-mediated tissue destruction - early-onset lung disease and liver cirrhosis.

α1-antitrypsin (α1AT) deficiency

120

α1AT is a member of the serpin family of serine protease inhibitors. What is the predominant target of α1AT?

elastase

121

Why is liver cancer associated with particularly high plasma concentrations of α-fetoprotein?

AFP in the fetus is largely replaced by albumin in the adult, during hepatic regeneration and proliferation, AFP is again synthesized.

122

(...) caused by a dinucleotide polymorphism in the TATA box promoter of the bilirubin UDP-glucuronyl transferase gene that impairs the hepatic uptake of unconjugated bilirubin.

Gilbert's syndrome

123

(...) is the result of a complete absence or marked reduction in bilirubin conjugation, causesing severe unconjugated hyperbilirubinemia that presents at birth.

Crigler–Najjar syndrome

124

(...) and (...) syndromes impair biliary secretion of conjugated bilirubin and therefore cause conjugated hyperbilirubinemia, which is usually mild.

Dubin–Johnson; Rotor's