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
2
Q
Liver - role in metabolism
A
carb
amino acids
lipids
3
Q
Liver - synthesis
A
plasma proteins
porphyrins (precursor for heme)
bile
hematopoiesis (fetal)
4
Q
Liver - detox
A
ammonia converted to urea
CYP450 hydroxylation and oxidation
5
Q
Glycogen synthesis pathway
A
- Glucose into cell via GLUT2
- Glucokinase phosphorylation to G1P
- Glycogen synthase
6
Q
Glycogenolysis pathway
A
- Glycogen phosphorylase breaks alpha 1-4 linkage
- G1P to G6P
- G6P –> glucose (liver), or glycolysis (liver and skeletal muscle)
7
Q
Glycolysis pathway
A
- Glucose to pyruvate
2. Pyruvate to lactate in cytoplasm, or to acetyl-CoA and into mitochondria for TCA cycle
8
Q
Gluconeogenesis
A
can use lactate, amino acids (pyruvate or oxaloacetate), or glycerol (to trioses)
only in the liver
9
Q
Lactate clearance
A
- Glucose –> lactate in skeletal muscle
- Lactate –> glucose in liver
not energy-efficient
10
Q
Bile acid content
A
bile salt electrolyte phospholipids proteins cholesterol bilirubin
11
Q
Bile acid function
A
digestion of dietary lipids –> micelles
excretion of waste products/drugs/toxins
12
Q
Bile salt composition
A
derived from cholesterol, conjugated to glycine or taurine
13
Q
Bilirubin production
A
In reticuloendothelial cells (spleen, liver):
- Heme –> biliverdin, CO, FE
- Biliverdin –> bilirubin
- Bilirubin (insoluble) binds albumin, transported to the liver
14
Q
Bilirubin metabolism in the liver
A
- Hepatocytes take up bilirubin without albumin via carrier
- Bilirubin binds ligandin in cytosol
- ER conjugates bilirubin to glucoronic acid, catalyzed by UDPGT
- Conjugated bilirubin diffuses out of ER to canalicular membrane/bile canaliculus (energy-dependent)
15
Q
Bilirubin metabolism in gut
A
- Bilirubin in bile drains into duodenum
- In distal ileum & colon: hydrolyzed to unconjugated bilirubin by bacterial glucuronidases
- 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
16
Q
Bile enterohepatic circulation
A
- Hepatocytes synthesize bile acids using dietary cholesterol
- During interdigestive period, bile acids move down biliary tract, sequestered in gallbladder (sphincter of Oddi contracted, gallbladder wall relaxed)
- DUring digestion, intestinal mucosa simulated to secrete cholecystokinin –> contracts gallbladder wall, relaxes sphincter of Oddi –> bile acids flow into uodenum via ampulla of Vater
- Active transport systems in terminal ileum actively reabsorb bile acids into portal circulation (>90%)
- Bile acid lost replaced by hepatic biosynthesis using cholesterol
17
Q
Vitamin B12 enterohepatic circulation
A
- Dietary vitamin B12 released by gastric acid
- B12 binds R-protein
- Pancreatic protease releases B12 from R-protein, binds IF secreted by parietal cells
- Terminal ilem actively takes up IF-B12 into portal circulation
- B12 complexed to transcobalamin
- Tissue takes up B12-TC complex; TC degraded in lysosome, B12 utilized
Primarily stored in the liver (50%) - excreted in bile but reabsorbed
18
Q
Major transport proteins made by liver
A
Albumin
Transferrin
Ceruoplasmin
19
Q
Major protease inhibitors made by liver
A
a1-antritrypsin
20
Q
Major coagulation factors made by liver
A
fibrinogen, all clotting factors except VII
21
Q
Major immunoproteins made by liver
A
IgG (plasma cells)
22
Q
major complement protein made by liver
A
C3
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
24
Q
Acetaminophen metabolism
A
- Oxidized by CYP 2E1 –> NAPQI
- Therapeutic> NAPQI –> glutathione, renally excreted
- High dose: binds cellular proteins
Toxicity: oxidative damage, mitochondrial dysfunction, inflammatory response –> injury/death of hepatocytes –> centrilobular liver necrosis
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
