Transcript Biochemistry of liver - Univerzita Karlova v Praze

Biochemistry of the liver
Magdaléna Fořtová
Department of Medical Chemistry and Clinical Biochemistry, 2nd Faculty
of Medicine, Charles University and University Hospital Motol,
Department of Nephrology, 1st Faculty of Medicine, Charles University
and General University Hospital
Central position in energy
and intermediary metabolism
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regulation of blood concentration of many metabolites
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regulation of storage and production of energy
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synthesis of molecules for other tissues
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interconversion of nutrients
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storage of some substances
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formation and secretion of bile
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detoxification function
Lobules of liver
• Portal lobulus
• Hepatic acinus
Zone 1 (periportal) - is nearest to the entering vascular supply and receives the most oxygenated
blood (and a lot of nutrients), making it least sensitive to ischemic injury while making it very
susceptible to viral hepatitis, hepatocytes (with more mitochondria, less ER) are specialized
for oxidative liver functions such as gluconeogenesis, β-oxidation of fatty acids and cholesterol
synthesis, CC, RCH, oxidative phosphorylation, urea synthesis, cholesterol synthesis, proteosynthesis
(cytochrome oxidase, CC enzymes, LD, AST, ALT, GMT, ALP), occurs in phosphorus poisoning,
hemochromatosis (deposition of hemosiderin) or eclampsia
Zone 2 (midzonal) - rare – is seen in yellow fever
Zone 3 (centrilobular, perivenous) - has the poorest oxygenation (and few nutriens), and will be
most affected during a time of ischemia, cells are more important for reductive reactions,
glycolysis, glycogen synthesis, ketogenesis, lipogenesis and cytochrome P-450-based drug detoxification,
biotransformation of xenobiotics (sm. ER), detoxification of NH3 (synthesis of Gln) (GMD, alcohol
dehydrogenase, isocitrate dehydrogenase), occurs with ischemic injury, toxic effects, carbon
tetrachloride exposure or chloroform ingestion, cells have the highest concentration of CYP2E1
and thus are most sensitive to NAPQI (N-acetyl-p-benzoquinone imine) production in acetaminophen
toxicity
Drugs such as acetaminophen may be metabolized in zone 1 to toxic compounds that cause
necrosis in zone 3
CHS, coagulations
factors, plasmat.proteins
DNA-ase
glucuronyltransferase,
detoxification
GMD, mAST, CC enzymes
hydrolases, kathepsin
ALP, GGT, NTS
ALT, cAST, LD
Cytoplasm
ALT, cAST
LD
mAST,GMD
kathepsin
CHS, coag.fact.
Alb., TTR
ALP, GGT, NTS
DIAGNOSTIC ENZYMES
Cytoplasm: ALT, cAST
, LD
permeability
dysfunction
Mitochondria: mAST, GMD (glutamate dehydrogenase) necrosis
(30 % of total liver AST)
Membranes of bile duct endothelium and sinusoids:
ALP, GGT, 5-NTS (5´-nukleotidase)
cholestasis
Lysosomes: hydrolytic enzymes:
proteinases (kathepsin) a β-glucuronidase
Rough endoplasmic reticulum: CHS
(Gaucher´s disease)
(cholinesterase),
coagulations factors, plasmat. proteines (albumin,
transthyretin, transferrin)
protein synthesis defect (decrease !)
Liver function tests
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Standard liver tests
Aspartate transaminase
Alanine transaminase
Alkaline phosphatase
Gamma glutamyl transpeptidase
Total, direct, and indirect bilirubin
Albumin, prealbumin, cholinesterase
INR
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Other tests
Other coagulation test
5´nucleotidase
Serum glucose
Lactate dehydrogenase
Albumin
• The main protein of human blood plasma, made specifically by the liver
• Its main function is to regulate the colloidal osmotic (oncotic)
pressure of blood.
• It also serves as a carrier for molecules of low water solubility, including
lipid soluble hormones (thyroxine), bile salts, unconjugated bilirubin,
free fatty acids, cations (Ca2+, Na+, K+), ions and some drugs like
warfarin, clofibrate, phenytoin. (Competition between drugs for albumin
binding sites may cause drug interaction by increasing the free fraction
of one of the drugs).
• Hypoalbuminemia may be caused by chronic liver disease (such as
cirrhosis), nephrotic syndrome (where it is lost through the urine), burns,
protein-losing enteropathy, malabsorption, malnutrition, late pregnancy,
artefact, genetic variations and malignancy.
• The consequence of low albumin can be edema since the intravascular
oncotic pressure becomes lower than the extravascular space.
• Hyperalbuminemia is almost always caused by dehydration.
• Referenge range: 3.5 to 5 g/dL, FN Motol 35 to 53 g/L
Transthyretin (TTR)
• TTR was originally called prealbumin (or thyroxine-binding
prealbumin) because it ran faster than albumin on electrophoresis
gels.
• It is better at detecting acute changes than albumin (half-life of
albumin and prealbumin is 2-3 weeks and 2-4 days, respectively).
• It is a serum and cerebrospinal fluid carrier of thyroxine and retinolbinding protein bound to retinol (this is how transthyretin gained its
name, transports thyroxine and retinol).
• Nutritional status can be assessed by measuring its concentration
in the blood (other transport proteins such as albumin or transferrin
could be used, but transthyretin is preferred because of its shorter
half-life, although this means that its concentration more closely
reflects recent dietary intake rather than overall nutritional status).
• Referenge range: 15.7 to 29.6 mg/dL, FN Motol 0.18 to 0.40 g/L
Pseudocholinesterase
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RR: 67 – 190 μkat/l
FN Motol
also known as plasma cholinesterase, butyrylcholinesterase, or acylcholine
acylhydrolase, catalyzes the hydrolysis of butyrylthiocholin, benzoylcholin, sukcinylcholin
and other cholin or thiocholin esters
(x acetylcholinesterase, found primarily in the blood on red blood cell membranes, in neuromuscular
junctions, and in neural synapses, catalyzes the hydrolysis of the neurotransmitter acetylcholine into
choline and acetic acid entirely)
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is produced in the liver (marker of protein synthesis)
the half-life of pseudocholinesterase is approximately 8–16 hours
Its levels may be reduced in patients with advanced liver disease. The decrease
must be greater than 75 % before significant prolongation of neuromuscular blockade
occurs with succinylcholine.
Genetic variants: normal activity: U (usual),
reduced activity: A (atypical), F (fluoride), S (silent)….
Acute organophosphate insecticide poisoning
An absence or mutation of the pseudocholinesterase enzyme leads to
a medical condition known as pseudocholinesterase deficiency
People with pseudocholinesterase deficiency respond abnormally to
succinylcholine, experiencing substantial prolongation of muscle paralysis
with apnea rather than the usual 2-6 min
Dibucaine number = (1- (CHS inhibited/CHS uninhibited))*100
(normal > 80)
Alanine transaminase (ALT)
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also called serum glutamic-pyruvic transaminase or alanine aminotransferase
ALT is found predominantly in the liver (in cytoplasm of parenchymal
cells), with clinically negligible quantities found in the kidneys, heart, and
skeletal muscle
It catalyzes the transfer of an amino group from L-alanine to α-ketoglutarate,
the products of this reversible transamination reaction being pyruvate and
L-glutamate
L-glutamate + pyruvate ⇌ α-ketoglutarate + L-alanine
ALT (and all transaminases) require the coenzyme pyridoxal phosphate, which is converted into
pyridoxamine in the first phase of the reaction, when an amino acid is converted into a keto acid
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It is commonly measured clinically as a part of a diagnostic evaluation
of hepatocellular injury, to determine liver health.
Significantly elevated levels often suggest the existence of other medical
problems such as viral hepatitis, congestive heart failure, liver damage, bile
duct problems, infectious mononucleosis….
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Referenge range: 10 to 45 IU/L, FN Motol: 0,17 to 0,78 μkat/L
Aspartate transaminase (AST)
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also called serum glutamic oxaloacetic transaminase or aspartate
aminotransferase
• a pyridoxal phosphate (PLP)-dependent transaminase enzyme
• It catalyzes the reversible transfer of an α-amino group between aspartate
and glutamate
Aspartate (Asp) + α-ketoglutarate ↔ oxaloacetate + glutamate (Glu)
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AST is found in the liver (parenchymal cells), heart, skeletal muscle, kidneys,
brain, and red blood cells, and it is commonly measured clinically as a a part
of diagnostic liver function tests, to determine liver health (but it is not specific
to the liver, it has also been used as a cardiac marker etc.), it is raised mainly
in acute liver damage
Two isoenzymes are present in humans:
– cAST, the cytosolic isoenzyme derives mainly from red blood cells and
heart (30 % of liver AST)
– mAST, the mitochondrial isoenzyme is present predominantly in liver
(70 % of liver AST)
Referenge range: 8 to 40 IU/L, FN Motol: 0,16 to 0,72 μkat/L
Transaminases
Alanine aminotransferase
(ALT)
Aspartate aminotransferase
(AST)
De Ritis Ratio
• The AST/ALT ratio is sometimes useful in differentiating
between causes of liver damage
• In healthy people ALT > AST; when AST > ALT, pathosis
is likely. Thus:
– AST/ALT is normally < 1.0 and is also < 1.0 in viral hepatitis
(albeit with extremely high levels of both AST and ALT).
– When AST/ALT > 1.0 but < 2.0, it is likely to be associated with
cirrhosis
– When AST/ALT > 2.0, it is more likely to be associated with
alcoholic hepatitis or hepatocellular carcinoma
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However, the AST/ALT ratio is less useful in scenarios where the liver
enzymes are not elevated, or where multiple conditions co-exist.
Transaminases
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AST is similar to ALT in that both enzymes are associated with liver
parenchymal cells (ALT occurs in cytoplasm, AST in cytoplasm, but also in
mitochondria).
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ALT is found predominantly in the liver, while AST is found in the liver and
the other organs (cardiac and skeletal muscle etc.)
ALT is a more
specific indicator of liver inflammation than AST.
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Many drugs may elevate ALT and AST levels, including anti-inflammatory
drugs, antibiotics, cholesterol medications, some antipsychotics such
as risperidone, and anticonvulsants.
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AST/ALT elevations instead of ALP elevations favor liver cell necrosis
as a mechanism over cholestasis.
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When AST and ALT are both over 1000 IU/L, the differential can include
acetaminophen (paracetamol) toxicity, shock, or fulminant liver failure.
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When AST and ALT are greater than three times normal but not greater
than 1000 IU/L, the differential can include alcohol toxicity, viral hepatitis, druginduced level, liver cancer, sepsis, Wilson's disease, post-transplant rejection of
liver, autoimmune hepatitis, and steatohepatitis (nonalcoholic).
Alkaline phosphatase (ALP)
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is a hydrolase enzyme responsible for removing phosphate groups from many
types of molecules, including nucleotides, proteins, and alkaloids. The process
of removing the phosphate group is called dephosphorylation
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is present in all tissues throughout the entire body, but is particularly
concentrated in liver, bile duct, kidney, bone, intestine and the placenta
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isoenzymes: ALPI – intestinal
ALPL – tissue-nonspecific (liver/bone/kidney)
ALPP – placental (Regan isozyme)
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in the liver occurs in the cells lining the biliary ducts
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ALP levels in plasma rise with cholestasis (bile duct obstruction, intrahepatic
cholestasis, primary biliary cirrhosis, cholecystitis, cholangitis, liver tumor, liver
metastases), or infiltrative diseases of the liver (cirrhosis, hepatitis, fatty liver,
sarcoidosis, drug intoxication - e.g. verapamil, carbamazepine, phenytoin,
erythromycin, allopurinol, ranitidine)
Alkaline phosphatase (ALP)
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ALP is also present in bone, and placental tissue, so it is higher in growing
children (as their bones are being remodelled), elderly patients with Paget's
disease and in many more causes (e.g. osteosarcoma, bone metastases of
prostatic cancer, other bone metastases, renal osteodystrophy, fractured
bone, multiple myeloma (only when associated with fractures), osteomalacia,
rickets, vitamin D deficiency). In the third trimester of pregnancy, ALP
is about two to three times higher.
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If it is unclear why alkaline phosphatase is elevated, isoenzyme studies using
electrophoresis can confirm the source of the ALP.
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ELFO: commonly only 2 fractions: α2 (liver -52%) a β1 (bone -48%),
after the 16th week of pregnancy placental
intestinal: only in blood group A or 0 in plasma, it binds to ery blood group A
RR: 20 to 140 IU/L, FN Motol 0,66 – 2,2 μkat/L
Gamma glutamyl transpeptidase (GGT)
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also called gamma-glutamyl transferase
it is an enzyme that transfers gamma-glutamyl functional groups
it catalyzes the transfer of the gamma-glutamyl moiety of glutathione to an
acceptor that may be an amino acid, a peptide or water (forming glutamate)
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this general reaction is:
(5-L-glutamyl)-peptide + an amino acid
acid
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peptide + 5-L-glutamyl amino
It plays a key role in the gamma-glutamyl cycle, a pathway for the synthesis
and degradation of glutathione and drug and xenobiotic detoxification.
It can also exert a prooxidant role, with regulatory effects at various levels
in cellular signal transduction and cellular pathophysiology.
It is found in the cell membranes of many tissues, the most notable are
the liver and bile duct, other tissues are: the kidneys, pancreas, gallbladder,
spleen, heart, brain, and seminal vesicles.
It is involved in the transfer of amino acids across the cellular membrane
and leukotriene metabolism.
Gamma glutamyl transpeptidase (GGT)
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GGT is predominantly used as a diagnostic marker for liver disease, latent
elevations in GGT are typically seen in patients with chronic viral hepatitis infections often
taking 12 months or more to present
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Elevated GGT can be found in diseases of the liver, biliary system, and
pancreas. It is similar to ALP in detecting disease of the biliary tract (these
two markers correlate well, the main value of GGT over ALP is in verifying that
ALP can also be increased in certain bone diseases)
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More recently, slightly elevated serum GGT has also been found to correlate with
cardiovascular diseases and is under active investigation as a cardiovascular risk marker.
GGT in fact accumulates in atherosclerotic plaques.
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GGT is elevated by large quantities of alcohol ingestion. Isolated elevation
or disproportionate elevation compared to other liver enzymes (such as ALP or
ALT) may indicate alcohol abuse or alcoholic liver disease (it may indicate excess
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alcohol consumption up to 3 or 4 weeks prior to the test).
Numerous drugs can raise GGT levels, including barbiturates, phenytoin, NSAIDs, and
aspirin. Elevated levels of GGT may also be due to congestive heart failure.
RR: 15-85 IU/L for men, and 5-55 IU/L for women, FN Motol: M 0,14 – 0,84 μkat/L, Ž 0,14 – 0,64 μkat/L
5' Nucleotidase
• 5' Nucleotidase (5'NTD) is another test specific for cholestasis
or damage to the intra- or extrahepatic biliary system.
• In some laboratories, is used as a substitute for GGT for
ascertaining whether an elevated ALP is of biliary or extrabiliary
origin.
Lactate dehydrogenase (LD, LDH)
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LDH is found extensively in body tissues, such as blood cells, liver and heart
muscle etc.
it is released during tissue damage
a marker of common injuries and disease
A dehydrogenase is an enzyme that transfers a hydride from one molecule to
another. LDH catalyzes the conversion of pyruvate to lactate and back, as it
converts NADH to NAD+ and back
LD is a protein that normally appears throughout the body in small amounts.
Many cancers can raise LD levels, so LD may be used as a tumor marker, but it
is not useful in identifying a specific kind of cancer. Measuring LD levels can be
helpful in monitoring treatment for cancer.
Noncancerous conditions that can raise LD levels include heart failure, anemia,
lung or liver disease…
LD is often used as a marker of tissue breakdown as LD is abundant in red blood
cells and can function as a marker for hemolysis.
A blood sample that has been handled incorrectly can show false-positively
high levels of LD due to erythrocyte damage.
Lactate dehydrogenase
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homo or hetero tetramers composed of M and H protein subunits
The five isoenzymes, each contain four subunits
The major isoenzymes of skeletal muscle and liver, M4, has four muscle (M)
subunits, H4 is the main isoenzymes for heart muscle, containing four heart (H)
subunits. The other variants contain both types of subunits.
H (heart) ● M (muscle) ●
isoenzymes
LD1
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LD2
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LD3
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LD4
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LD5
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occurence
heart, red blood cells, kidney
heart, red blood cells, kidney, reticuloendothelial system
lungs, striated muscle, kidney, reticuloendoth.system, leukocytes
liver, striated muscle, kidney, pancreas, placenta
liver, striated muscle, placenta
Usually LD-2 is the predominant form in the serum. A LD-1 level higher than the
LD-2 level suggests myocardial infarction (damage to heart tissues releases
heart LD, which is rich in LD-1, into the bloodstream).
FN Motol RR: 3,5 – 7,0 μkat/l
Lactate dehydrogenase
Tissues:
A - myocard
B - kidney
C - erythrocytes
D - lien
E - liver
F - striated muscle
Isoenzymes
1 - LD1
2 - LD2
3 - LD3
4 - LD4
5 - LD5
Bilirubin
heme
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formerly referred to as hematoidin
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it is the yellow breakdown product of normal heme catabolism
it consists of an open chain of four pyrrole-like rings (tetrapyrrole); in heme,
these four rings are connected into a larger ring, called a porphyrin ring
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heme is found in hemoglobin, a principal component of red blood cells
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heme can also come from myoglobin, found mostly in muscle,
cytochromes, found mostly in mitochondria, catalase, peroxidase, and
nitric oxide synthase
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bilirubin is excreted in bile and urine, and elevated levels may indicate
certain diseases
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it is responsible for the yellow color of bruises, the background straw-yellow
color of urine (via its reduced breakdown product, urobilin), the brown color
of feces (via its conversion to stercobilin), and the yellow discoloration
in jaundice
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bilirubin's main physiologic role is as a cellular antioxidant
FN Motol RR: 2 – 17 μmol/L
M methyl
P propionyl
V vinyl
Unconjugated ("Indirect") bilirubin
• Erythrocytes generated in the bone marrow are disposed
of in the spleen when they get old or damaged.
• This releases hemoglobin, which is broken down to heme
as the globin parts are turned into amino acids.
• The heme is then turned into unconjugated bilirubin in the
reticuloendothelial cells of the spleen. This unconjugated bilirubin
is not soluble in water, due to intramolecular hydrogen bonding.
It is then bound to albumin and sent to the liver.
Conjugated ("Direct") bilirubin
• In the liver, bilirubin is conjugated with glucuronic acid by the
enzyme UDP-glucuronyltransferase (making it soluble in water)
and secreted into the bile by canalicular multispecific organic
anion transporter CMOAT (multidrug resistance-associated protein
2 MRP2). Then it goes into the small intestine.
• However, 95% of the secreted bilirubin is reabsorbed by
the intestines (terminal Ileum) and reaches the liver by portal
circulation and then resecreted by the liver into the small intestine.
This process is known as enterohepatic circulation.
FN Motol RR: 0 – 5 μmol/L
Conjugated ("Direct") bilirubin
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Conjugated bilirubin is than metabolised in the large intestine by colonic
bacteria to form urobilinogen, which may be further oxidized to urobilin.
Urobilinogen can be directly reduced to stercobilin. Urobilinogen can also be
reduced to stercobilinogen, and further oxidized to stercobilin.
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Urobilin, stercobilin and their degradation products give feces its brown
color. Thus, having white or clay-colored stool is an indicator for a
blockage in bilirubin processing and thus potential liver dysfunction or
cholestasis.
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However, just like bile, some of the urobilinogen is reabsorbed and 95%
of what is reabsorbed is resecreted in the bile which is also part
of enterohepatic circulation.
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A small amount of the reabsorbed urobilinogen (about 5%) is excreted
in the urine following further oxidation to urobilin which gives urine its
characteristic yellow color.
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This whole process results in only 1–20% of secreted bile being lost in the
feces. The amount lost depends on the secretion rate of bile.
Bilirubin
• Although the terms direct and indirect bilirubin are used equivalently
with conjugated and unconjugated bilirubin, this is not
quantitatively correct.
• The direct fraction includes both conjugated bilirubin
and δ bilirubin (bilirubin covalently bound to albumin, which
appears in serum when hepatic excretion of conjugated bilirubin is
impaired in patients with hepatobiliary disease- cholestasis).
• Measurement of total bilirubin includes both unconjugated and
conjugated bilirubin.
• Addition of high-concentration hydrophobic drugs (certain
antibiotics, diuretics) and high free fatty acids can cause elevated
unconjugated bilirubin.
Increased total bilirubin (TBIL)
causes jaundice, and can indicate a number
of problems:
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Prehepatic: increased bilirubin production can be due to a number
of causes, including hemolytic anemias and internal hemorrhage
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Hepatic: problems with the liver are reflected as deficiencies
in bilirubin metabolism (reduced hepatocyte uptake, impaired conjugation
of bilirubin, and reduced hepatocyte secretion of bilirubin)
Some examples would be cirrhosis and viral hepatitis.
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Posthepatic: obstruction of the bile ducts is reflected as deficiencies
in bilirubin excretion
(Obstruction can be located either within the liver or in the bile duct)
Jaundice may be noticeable in the sclera of the eyes at levels
of about 2 to 3 mg/dL (34 to 51 μmol/L), and in the skin at higher levels.
1 mg/dL = 17.1 µmol/L
Direct bilirubin
• The diagnosis is narrowed down further by evaluating the levels
of direct bilirubin.
• If direct (conjugated) bilirubin is normal, then the problem is an
excess of unconjugated bilirubin (indirect bilirubin), and the location
of the problem is upstream of bilirubin conjugation in the liver.
Hemolysis, viral hepatitis, or cirrhosis can be suspected.
• If direct bilirubin is elevated, then the liver is conjugating bilirubin
normally, but is not able to excrete it. Bile duct obstruction by
gallstones or cancer should be suspected.
Congenital bilirubin disorders
• About 5% of the population has Gilbert's syndrome,
a mutation (or variation) in the UDP-glucuronyl-transferase that
manifests itself as jaundice when the individual is stressed
(i.e. starves).
• Autosomal recessive knockouts of UDP-glucuronyl-transferase
can lead to Crigler-Najjar syndrome (often leads to brain
damage in infants) and elevations of unconjugated bilirubin.
• Defects in CMOAT (MRP2) results in Dubin-Johnson syndrome
(autosomal recesive disorder, it is usually asymptomatic but may
be diagnosed in early infancy based on laboratory tests) and
elevations of conjugated bilirubin.
• Rotor syndrome is a rare, relatively benign autosomal recessive
bilirubin disorder. It is a distinct, yet similar disorder to Dubin–
Johnson syndrome — both diseases cause an increase in
conjugated bilirubin.
High bilirubin in neonates
• Neonates are especially vulnerable to high unconjugated bilirubin
levels due to an immature blood-brain barrier that predisposes them
to kernicterus/bilirubin encephalopathy (bilirubin accumulates
particularly in the basal nuclei), which can result in permanent
neurological damage with seizures, abnormal reflexes and eye
movements etc.
• Neonates also have a low amount of functional UDP-glucuronyltransferase and can have elevated unconjugated bilirubin, since
conjugated is limited.
• Neonates in general are at increased risk since they lack the
intestinal bacteria that facilitate the breakdown and excretion of
conjugated bilirubin in the feces (this is largely why the feces of a
neonate are paler than those of an adult). Instead the conjugated
bilirubin is converted back into the unconjugated form by the enzyme
β-glucuronidase (in the gut, this enzyme is located in the brush border
of the lining intestinal cells) and a large proportion is reabsorbed
through the enterohepatic circulation.
High bilirubin in neonates
• So, newborns are often treated with UV light to turn the
hydrophobic, albumin-binding unconjugated bilirubin
into a form that is more hydrophilic and able to be
secreted in urine, sparing the neonate's brain.
• Some of the double-bonds in bilirubin isomerize when
exposed to light. This is used in the phototherapy of jaundiced
newborns: the E,Z-isomers of bilirubin formed upon light
exposure are more soluble than the unilluminated Z,Z-isomer,
as the possibility of intramolecular hydrogen bonding is
removed. This allows the excretion of unconjugated bilirubin
in bile.
Coagulation test
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The liver is responsible for the production of coagulation factors.
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INR (international normalized ratio) measures the speed of the extrinsic
pathway of coagulation, comparing it to normal.
Increased levels of INR means blood is taking more time than usual to clot.
The INR increases only if the liver is so damaged that synthesis of vitamin
K-dependent coagulation factors has been impaired; it is not a sensitive
measure of liver function.
It is used to determine the clotting tendency of blood, in the measure of
warfarin dosage, liver damage, and vitamin K status.
It measures factors I (fibrinogen), II (prothrombin), V, VII, and X.
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APTT (activated partial thromboplastin time) is a performance indicator
measuring the efficacy of both the "intrinsic" and the common
coagulation pathways. Apart from detecting abnormalities in blood clotting,
it is also used to monitor the treatment effects with heparin, a major
anticoagulant.
Coagulation cascade
Serum glucose
• The serum glucose test measures the liver's ability to produce
glucose (gluconeogenesis).
• It is usually the last function to be lost in the setting of fulminant
liver failure.
Metabolism of saccharides
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glucostatic function of the liver
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glycogen synthesis, glycolysis
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glycogen degradation, gluconeogenesis
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glucokinase, glc-6-phosphatase
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pentose cycle
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Cori cycle and glucose-alanine cycle
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excess of glucose FFA  TAG
transformation of saccharides to glucose
metabolism of fructose (fructokinase)
synthesis of amino saccharides
synthesis of uronic acids
degradation of insulin and glucagon
Metabolism of lipids
• liver controls blood FFA concentration
• energy is produced mainly by b-oxidation
• synthesis of ketone bodies
• synthesis of TAG (from FFA, glc, AA)
• synthesis of cholesterol
• synthesis of bile acids
• synthesis of phospholipids
• synthesis of VLDL and HDL
• degradation of plasma lipoproteins
Metabolism of N-containing compounds
• synthesis of plasma proteins (except Ig)
• synthesis of coagulation factors
• synthesis of acute phase reactants
• degradation of amino „N“ (urea, Gln)
• synthesis of nonessential amino acids
• metabolism of aromatic AAs
• degradation of purines to uric acid
• synthesis of creatine
• conjugation and excretion of bilirubin
Urea (ornithine) cycle
Metabolism of vitamins
• provitamins  vitamins, storage of vitamins
• carotenes  vitamin A
• 25-hydroxylation of provitamin D ( calcidiol)
• cleavage of side chain of vitamin K
• storage of vitamin B12 and folate
• synthesis of nicotinic acid from Trp
• formation of coenzymes from B vitamins
Metabolism of minerals
• storage of iron (ferritin)
• storage and metabolism of other trace elements
(Cu, Mn, Co, Mo, Zn,..)
• synthesis of transport proteins (transferrin, ceruloplasmin)
• deiodation of thyroidal hormones  I- (iodide)
Detoxification function
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breaking down or transforming substances like ammonia, metabolic waste, drugs,
alcohol and chemicals, so that they can be excreted
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The liver is a filter designed to remove toxic matter such as dead cells,
microorganisms, chemicals, drugs and particulate debris from the
bloodstream. The liver filter is called the sinusoidal system, and contains
specialized cells known as Kupffer cells that are part of the white blood cell
immune function.
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Filtration of toxins is absolutely critical as the blood from the intestines contains high
levels of bacterial waste, antigen-antibody complexes, and various toxic
pollutants. When working properly, the liver clears 99% of the bacterial toxins
during the first pass.
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The liver neutralizes a wide range of toxic chemicals, both those produced
internally and those coming from the environment.
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The liver enzymatically disassembles unwanted chemicals. This enzymatic
process usually occurs in two steps referred to as phase I and phase II. Phase I
either directly neutralizes a toxin, or modifies the toxic chemical to form activated
intermediates that are then neutralized by one of more of the several phase II
enzyme systems.
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Proper functioning of the liver's detoxification systems is especially important for the
prevention of cancer, since phase II detoxification deactivates carcinogens.
Hormones of the liver
• Insulin-like growth factor-1 (IGF-1, somatomedin)
• Angiotensinogen
• Thrombopoietin
• Hepcidin
• Betatrophin
α-fetoprotein (AFP)
• a major plasma protein produced by the yolk sac and the liver during
fetal development
• It is thought to be the fetal form of serum albumin. AFP binds to
copper, nickel, fatty acids and bilirubin.
• Plasma levels decrease rapidly after birth but begin decreasing
prenatally starting at the end of the first trimester. Normal adult
levels are usually achieved by the age of 8 to 12 months.
• Elevated AFP:
– Omphalocele
– Neural tube defects: ↑ AFP in amniotic fluid and maternal serum
– Nonseminomatous germ cell tumors
– Yolk sac tumor
– Ataxia telangiectasia: elevation of AFP is used as one factor
in the diagnosis of ataxia telangiectasia
– Tumors: hepatocellular carcinoma/hepatoma, germ
cell tumors, and metastatic cancers of the liver
Liver tests
• total bilirubin (2 – 17 μmol/L)
• ALT (0.17 – 0.78 μkat/L)
• AST (0.16 – 0.72 μkat/L)
• ALP (0.66 – 2.2 μkat/L)
• GMT (men: 0.14 – 0.84, women: 0.14 – 0.64 μkat/L)
ÚLCHKB FN Motol