Liver function, jaundice and hepatitis Flashcards

1
Q

Liver storage

A
Lglycogen (5% weight)
lipids (temporary, until lipoprotein secretion)
B12 and folate
Vitamin A stored as retinyl palmitate
ferritin and hemosiderin
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2
Q

Liver - role in metabolism

A

carb
amino acids
lipids

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3
Q

Liver - synthesis

A

plasma proteins
porphyrins (precursor for heme)
bile
hematopoiesis (fetal)

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4
Q

Liver - detox

A

ammonia converted to urea

CYP450 hydroxylation and oxidation

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5
Q

Glycogen synthesis pathway

A
  1. Glucose into cell via GLUT2
  2. Glucokinase phosphorylation to G1P
  3. Glycogen synthase
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6
Q

Glycogenolysis pathway

A
  1. Glycogen phosphorylase breaks alpha 1-4 linkage
  2. G1P to G6P
  3. G6P –> glucose (liver), or glycolysis (liver and skeletal muscle)
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7
Q

Glycolysis pathway

A
  1. Glucose to pyruvate

2. Pyruvate to lactate in cytoplasm, or to acetyl-CoA and into mitochondria for TCA cycle

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8
Q

Gluconeogenesis

A

can use lactate, amino acids (pyruvate or oxaloacetate), or glycerol (to trioses)
only in the liver

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9
Q

Lactate clearance

A
  1. Glucose –> lactate in skeletal muscle
  2. Lactate –> glucose in liver

not energy-efficient

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10
Q

Bile acid content

A
bile salt
electrolyte
phospholipids
proteins
cholesterol
bilirubin
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11
Q

Bile acid function

A

digestion of dietary lipids –> micelles

excretion of waste products/drugs/toxins

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12
Q

Bile salt composition

A

derived from cholesterol, conjugated to glycine or taurine

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13
Q

Bilirubin production

A

In reticuloendothelial cells (spleen, liver):

  1. Heme –> biliverdin, CO, FE
  2. Biliverdin –> bilirubin
  3. Bilirubin (insoluble) binds albumin, transported to the liver
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14
Q

Bilirubin metabolism in the liver

A
  1. Hepatocytes take up bilirubin without albumin via carrier
  2. Bilirubin binds ligandin in cytosol
  3. ER conjugates bilirubin to glucoronic acid, catalyzed by UDPGT
  4. Conjugated bilirubin diffuses out of ER to canalicular membrane/bile canaliculus (energy-dependent)
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15
Q

Bilirubin metabolism in gut

A
  1. Bilirubin in bile drains into duodenum
  2. In distal ileum & colon: hydrolyzed to unconjugated bilirubin by bacterial glucuronidases
  3. UC bilirubin reduced to urobilinogens by gut bacteria (colourless)

80-90% excreted in feces as urobilins
10-20% reabsorbed, re-excreted
small portion escapes hepatic uptake, excreted in urine
UC bilirubin is bound to albumin and cannot be filtered - not found in urine

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16
Q

Bile enterohepatic circulation

A
  1. Hepatocytes synthesize bile acids using dietary cholesterol
  2. During interdigestive period, bile acids move down biliary tract, sequestered in gallbladder (sphincter of Oddi contracted, gallbladder wall relaxed)
  3. DUring digestion, intestinal mucosa simulated to secrete cholecystokinin –> contracts gallbladder wall, relaxes sphincter of Oddi –> bile acids flow into uodenum via ampulla of Vater
  4. Active transport systems in terminal ileum actively reabsorb bile acids into portal circulation (>90%)
  5. Bile acid lost replaced by hepatic biosynthesis using cholesterol
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17
Q

Vitamin B12 enterohepatic circulation

A
  1. Dietary vitamin B12 released by gastric acid
  2. B12 binds R-protein
  3. Pancreatic protease releases B12 from R-protein, binds IF secreted by parietal cells
  4. Terminal ilem actively takes up IF-B12 into portal circulation
  5. B12 complexed to transcobalamin
  6. Tissue takes up B12-TC complex; TC degraded in lysosome, B12 utilized

Primarily stored in the liver (50%) - excreted in bile but reabsorbed

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18
Q

Major transport proteins made by liver

A

Albumin
Transferrin
Ceruoplasmin

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19
Q

Major protease inhibitors made by liver

A

a1-antritrypsin

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20
Q

Major coagulation factors made by liver

A

fibrinogen, all clotting factors except VII

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21
Q

Major immunoproteins made by liver

A

IgG (plasma cells)

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22
Q

major complement protein made by liver

A

C3

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23
Q

Regulator of plasma protein synthesis

A

Low oncotic pressure
acute phase reaction (increase a1-AT, ceruloplasmin, C3, C4, decrease albumin and transferrin)
Estrogen (increase alpha1-AT, ceruloplasmin

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24
Q

Acetaminophen metabolism

A
  1. Oxidized by CYP 2E1 –> NAPQI
  2. Therapeutic> NAPQI –> glutathione, renally excreted
  3. High dose: binds cellular proteins

Toxicity: oxidative damage, mitochondrial dysfunction, inflammatory response –> injury/death of hepatocytes –> centrilobular liver necrosis

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25
Acetaminophen toxicity management
Most deaths due to cerebral edema (hepatic encephalopathy) 60% survival with liver transplant N-acetylcysteine infusion - >95% effective if started within 10 hours of ingestion
26
Jaundice definition
Yellowish pigmentation of the skin, conjunctival membranes over the sclerae and other mucous membranes due to hyperbilirubinemia
27
Pre-hepatic jaundice pathophys
Due to hemolysis | Conjugating enzyme becomes saturated, UC bilirubin causes yellow skin discolouration
28
Hepatic jaundice pathophys
Gilberts hepatitis: reduced activity of glucuronyltransferase (conjugates bilirubin) Viral: inflammation --> liver tissue destroyed and released Drug: disruption of hepatocyte, transport proteins, cytolytic T_cell activation, apoptosis of hepatocytes, mitochondrial disruption, bile duct injury Alcohol: hepatocyte death Cirrhosis: fibrosis - blocks blood flow, liver does not remove enough bilirubin from blood
29
Post-hepatic jaundice pathophys
Sex hormones Promazines: obstructive jaundice Cancer of the bile ducts/head of the pancreas, gallstones: intra/extrahepatic obstruction
30
Hepatocellular injury labs
ALT and AST ALT more specific to liver (look at creatinine kinase to differentiate with muscular cause) >1000 IU/L --> acute viral hepatitis/drug toxicity/ischemic liver injury Values may be smaller in fulminant due to death of hepatocytes 2) Biliary obstruction <200
31
Cholestasis labs
ALP and GGT - localized to the apical region of hepatocytes | Synthesized by impaired bile flow
32
Jaundice labs
increase UC bilirubin: prehaptic increase C bilirubin: hepatic/posthepatic dark urine: only C bilirubin
33
Chronic liver disease labs
albumin and INR | Hypoalbuminemia and coagulopathy seen when hepatic function impairment > 90%
34
Hep A epidemiology
principally in children and young adults worldwide common in daycare, summer camp, NICU, military
35
Hep A MOT
fecal-oral
36
Hep A natural history
acute only, usually abrupt onset complete recovery in 99% fulminant in 1% 2-3 weeks
37
Hep B epidemiology
high prevalence in SE asia, sub-Saharan Africa | high risk groups - MSM, IVDU, immigrants from endemic areas, etc
38
Hep B MOT
``` parenteral vertical transmission (almost 100%) ```
39
Hep B natural history
complete recovery to progression to chronic (1-5%) some progress to fulminant hepatitis 80-95% infected infants become chronic carriers (high risk for HCC)
40
Hep C pathophys
immune-mediated cytolysis of virus-infected hepatocytes | also: fibrosing cholestatic hep C causes direct cytopathic effect
41
Hep C epidemiology
worldwide high risk group: 70% cases in NA are IVDU/transfusion hemophiliacs treated <1987
42
Hep C MOT
parenteral vertical (2-5%) breast milk (rare)
43
Hep C natural history
Chronic hepatitis (70%) wide range in rate of progression - avg 20% cirrhosis in 25 years slower in younger, IVDU faster in elderly, immunosuppressed, HIV+, alcohol
44
HBsAg
acute and chronic infections | earliest indicator of acute hep B
45
anti-HBs
previous exposure to HBV or vaccination
46
anti-HBc, IgM
first antibody produced after infection with HBV | detects acute infection
47
anti-HBC, total
acute and chronic HBV infections | persists for life
48
HBeAg
found only when HBV is actively replicating marker for infectivity monitor treatment efficacy some strains do not make e-antigen
49
Anti-HBe
recovery from acute hep B | monitoring in chronic hep B
50
HBV DNA
active HBV infection | monitor antiviral therapy in chronic patients
51
HCV lab
RT-PCR for HCV-RNA | presence indicates active infection
52
Hep A symptoms
often asymptomatic flu like to fulminant hepatitis Prodrome: anorexia, nausea/vomiting, headache, malaise, fatigue, diarrhea overt hep A: sx for classic hepatitis, >2x in 6-10 wks cholestaic hep A (10% symptomatic cases): prolonged pruritus, persistant jaundice fulminant: rapid deterioration with signs of hepatic encephalopathy
53
Hep A vaccination
pre-exposure: HAV | Post-exposure: HAV vaccine + optional co-adminstration of ISG
54
Hep B vaccination
pre-exposure: recombinant HBsAg - very effective
55
Hep B treatment
interferon alpha - chance of seroconversion entecavir (NRTI) tenofovir (NRTI)
56
Interferon alpha MOA
- cell becomes more resistant to viral infections - slows growth of rapidly proliferating cells - modulates immune system - inhibits viral replication
57
Entecavir MOA
competes with the natural substrate to inhibit HBV polymerase
58
Tenofovir MOA
inhibits HIV reverse transcriptase by competing with the natural substrate, terminates DNA chain
59
Hep C medications
PEG-interferon, ribavirin
60
Ribavirin MOA
nucleoside RNA-dependent RNA polymerase inhibitor inhibits RNA-dependent RNA polymerase RNA substrate analogue
61
Interface hepatitis features
Inflammation and erosion of the hepatic parenchyma at its junction with portal tracts/fibrous septa Cell death occurs at the interface between liver parenchyma and stroma = limiting plate Inflammatory infiltrate composed of lymphocytes and accompanied by fibrosis of the affected areas Common in chronic viral hepatitis
62
Lobular hepatitis features
portal and periportal inflammation, with/without fibrosis Sinusoids filled with lymphocytes Kupffer cells serve as scavengers
63
Hepatic fibrosis histo features
Consequence of the host immunological response Loss of hepatocytes, microarchitecture, proliferation of hepatic fibroblasts, excess deposition of ECM Activation and proliferation of hepatic stellate cells (Lipocyte/Ito cells) due to chornic liver injury - contractile, produces ECM, secretes chemokines & cytokines
64
Important steps in glycolysis
Initial: Glucokinase --> G6P (liver) (energy-requiring) | Phosphofructokinase (energy-requiring, unidirectional)
65
Causes of lactic acidosis
Lack of oxygen in muscle tissue Excessive muscle glycolysis Impaired gluconeogenesis ETC disorder
66
Hep A incubation period
28-30 days
67
Hep A communicability
maximum infectivity in latter half of incubation period to few days after onset of jaundice
68
Hep A labs
Marked elevation in ALT >1000, before rise in bilirubin
69
Hep B diagnosis
HBsAg 1-10 weeks after acute exposure then appearance of anti-HBs and anti-HBc HBe for replication and infectivity
70
Vertical transmission of hep B clinical cours
1) Immune tolerant: ALT normal, HBe positive, high HBV DNA 2) Immune clearance: ~30yo. ALT elevation/inflammation, HBV DNA drops, observe variable flares 3) Inactive carrier: no inflammation, low HBV DNA. anti-HBe appears. Can stay in this forever, or 4) Reactivation: flares of disease. ALT goes up, virus level goes up, but anti-HBe always positive and HBeAg always negative
71
Hepatitis D
RNA, needs HBV | High occurrence in eastern Europe and the middle east
72
Types of hep D infection
co-infection with HBV - anti HDV IgM, HDV RNA, anti-HBc IgM positive superinfection in HBV carrier - anti HBc IgM negative worse prognosis and higher risk of HCC
73
HDV treatment
PEG-interferon
74
Intrinsic DILI
cause liver injury predictably in humans at a high dose
75
Idiosyncratic DILI
affects susceptible individuals, variable presentations, less consistent relationship to dose
76
R-value
ALT/ULN divided by ALK/ULN (upper limit normal) | Hepatocellular: R>5, cholestatic R<2