Test 2: Liver Function and Bilirubin Metabolism Flashcards
What are the functions of the liver?
-carbohydrate metabolism
-protein metabolism
-lipid metabolism
-storage (glycogen, fat, vit., iron)
-detoxification
-porphyrin synthesis
The liver is hematopoietic organ for ______ only.
fetus
The liver is ________g in normal adult.
1400-1600
The liver functions for metabolism and synthesis includes…
carbohydrates, proteins, lipids, porphyrins,
and bile acids (cholesterol)
The liver synthesizes most plasma proteins except ______________ and ____________.
immunoglobulins & hemoglobin
The liver is responsible for storage of….
Iron, glycogen, metabolic end products and xenobiotics to less/
non-toxic form.
*increases water solubility for excretion
The liver synthesizes most plasma proteins except _____________ and ___________.
immunoglobulins, hemoglobin
Stellate cells in stimulated state are transformed into ___________ producing cells.
collagen*
-Responsible for Fibrosis & eventually cirrhosis
What is the function of Stellate cells in the normal (Quiescent state)?
-Vit A storage
-Nitric oxide synthesis
The liver is Divided into 2 primary lobes (4 total) that are abundantly vascularized (~___ ml/min) from hepatic artery to hepatic vein
15
____________ is structural unit of the liver: cords of liver cells (hepatocytes radiate from
central vein.
Lobule
Each lobule contains a branch of ________, __________, _________.
hepatic artery, portal vein, and bile duct.
What is referred to as “Triot”
hepatic artery, portal vein, and bile duct.
The lobule boundary is formed by __________ made of connective tissue.
portal tract
Lobule:
Between cords are vascular spaces (sinusoids) lined by _____________ and __________ cells.
endothelial and Kupffer’s cell
Bile _____________ are channels located between hepatocytes that interconnect and
eventually drain into larger bile ducts.
canaliculi
phagocytic macrophages that are specific to the liver
Kupffer’s cells
(parenchymal) cells that are responsible for metabolic functions
Hepatocytes
Increased ALT and AST means that __________ are damaged.
hepatocytes
The liver process endogenous and exogenous compounds by ___________.
biotransformation
—> a series of chemical alteration by “ENZYME ACTIVITY”
Carbohydrate metabolism:
(storage of glucose in form of glycogen)
Glycogenesis
Carbohydrate metabolism:
(release of glucose from glycogen)
Glycogenolysis
Carbohydrate metabolism:
(synthesis of glucose from amino acid or lactic acid precursors)*
Gluconeogenesis
What is the primary source for blood glucose?
Glycogen
[Glycogen]liver fluctuates depending on usage
The synthesis and release of glycogen from the liver is controlled by what hormones?
Insulin, glucagon, glucocorticoids, T3/T4 (thyroid hormone)
Normal blood glucose: _________ mg/dl, (regardless of last meal time)
ATP and NADH are produced by what
70-110***
Required for normal brain and tissue function
ATP and NADH are produced from oxidation of glucose and fatty acids.
Fasting blood glucose levels should be less than _______.
100 mg/dl
After meal liver has ____ hrs of glycogen reserve.
** Depletion of reserve leads to increased lipolysis (increasing the FA) and gluconeogenesis
14
All plasma proteins (except Igs & Hb) are synthesized in the liver.
* Neonates retain some ___________ synthesis
hemoglobin
under normal conditions the rate of protein synthesis =
rate of protein degradation.
Excessive amino acids are converted to ______ and _______ for excretion
ammonia and urea
Amino acids can also be used for gluconeogenesis, ___________ or _________ reactions
transamination or deamination
What are transamination reactions catalyzed by?***
alanine aminotransferase (ALT) &
aspartate aminotransferase (AST)
-for amino acid metabolism
Alkaline phosphatase (ALP) & 5’-nucleotidase (NT) signifies what kind of damage?
Damaged canalicular membrane and biliary obstruction
γ-glutamyl transferase (GGT) signifies what kind of damage?
Hepatocellular and obstructive disorders
What is important for bone metabolism and is elevated in kids?
Alkaline phosphatase (ALP)
What will increase with damage to hepatobiliary cells?
AST and ALT!***
Increased GGT can be associated with…
alcoholism
List 4 functions of proteins synthesized in liver
-nutrition
-oncotic blood pressure
-coagulation
-transport
Some key proteins include…
-albumin
-alpha 1 antitrypsin
-HDL
-Thyroxine binding protein
-heptoglobin
with acute Hepatic Diseases, what changes in plasma protein concentrations are seen?
not much change
With severe liver diseases what proteins are decreased ?
Short lived hepatic proteins [Transthyretin (T4 carrier), Prothrombin]
What is the half life of transthyretin?
prothrombin?
24-48 hours
about 60 hours
In advanced cirrhosis, what plasma proteins are decreased?
-all liver-synthesized plasma proteins decreases
-increased Igs (to maintain oncotic pressure)
What lipids dose the liver synthesize?
-cholesterol (free & esters)
-free fatty acids
-triglycerides
-sphingolipids
-phospholipids
increased or decreased lipid synthesis with dietary intake?
increased
-lipids are repackaged by liver with specific proteins and transported as lipoproteins (VLDL, LDL)
What happens with increased carbohydrate intake?
Acetyl CoA —> fFA —-> TG
70% of synthesized cholesterol is esterified with FA from phosphatidyl
choline by…
LCAT (lecithin cholesterol acyltransferase)
cholesterol synthesis is necessary for…
1) Cell membrane fluidity
2) Bile acid formation (helps emulsify digested lipids for absorption)
What is the final excretory metabolite of cholesterol?
bile acids
80% of cholesterol is converted into what 4 major bile acids?***
-cholic acid
-chemodeoxycholate
-deoxycholic acid
-lithocholic acid
Bile acids are conjugated with amino acids (________ and ________) forming
conjugated bile salts.
glycine & taurine
Bile salts are released into intestinal lumen to emulsify and absorb ______ and ________ from diet.
TG, cholesterol
what is the cofactor for lipase to work?
colipase
What is it called when the liver breaks down FAs for energy? (occurs when glycogen is depleted)
lipolysis
FFA —> AcetylCoA —> CO2 +NADH
Excess acetyl-CoA formation (as might occur in Fasting, DM or Alcohol
intoxication) and limited amounts of NAD+/NADP+ results in hepatic
synthesis of ______ bodies
ketone
What substances does the liver store?
Iron, glycogen, amino acids(?), vitamins (A & B12), Lipid (transient).
How is iron stored in the liver?
as ferritin (and some hemosiderrin)
Only the ______ & _______ contains **glucose-6-phosphatase which converts glucose-6-phosphate to glucose.
liver and kidneys
Liver is primarily responsible for detoxification of…
poisons, drugs and toxic
metabolic end products
What converts heme to biliverdin?
heme oxygenase
What converts biliverdin to bilirubin?
biliverdin reductase
Two ways detoxification is done by the liver?
- Inactivation of agent by binding with serum protein (albumin binds bilirubin)
- Chemical modification of agent in liver to increase likelihood of excretion
Detoxification is the _______________ function of the liver.
excretory
Detoxification by chemical Modifications can also occur via ____________ system located in
microsomes
cytochrome P-450
Detoxification by chemical Modification includes…
hydroxylation, sulfation or conjugation (to make more water soluble) with a
carbohydrate or amino acid.
_______________ are chemical intermediates in the synthesis of hemoglobin,
myoglobin and Respiratory cytochromes
Porphyrins
▪ (Within the liver), heme synthesis is controlled by…
aminolevutinic acid
(ALA) Synthase
What is the rate-limiting enzyme that converts Succinyl CoA —-> d-aminoluevulic acid
ALA synthase***
What enzyme converts d-aminoluevulic acid —-> Porphobilinogen
ALA dehydrogenase
What are the types of accelerators for bilirubin testing?***
Methanol, DMSO, urea
Conjugated bilirubin: should be less than…
0.3 mg/dL (5.1 µmol/L)
Total bilirubin: _______mg/dL
0.1 to 1.2 mg/dL (1.71 to 20.5 µmol/L)
What causes jaundice?
hyperbilirubinemia (25-50 mg/L)
by Interference of bilirubin metabolism
Jaundice CANNOT be present in many individual with liver diseases such as…
chronic liver disease
How are conditions that interfere with bilirubin metabolism classified?
-Prehepatic (overproduction)
-Hepatic (impaired uptake by hepatocytes, conjugation defects, reduced excretion into bile)
-Posthepatic (obstruction of bile flow
Prehepatic, hepatic, or postherpetic?
▪ Over production: **Excessive hemolysis (e.g. chronic hemolytic
anemia, pernicious anemia) exceeds liver’s capacity to clear bilirubin
Pre-hepatic
Prehepatic:
-Serum bilirubin rarely exceeds _____ mg/L [almost entirely “Unconjugated”]
Chronic bilirubin production may lead to formation of bilirubin containing
gallstones.
50
Prehepatic, hepatic, or postherpetic?
Impaired hepatocyte uptake
HEPATIC
What are two things that can cause impaired hepatocyte uptake?
1) drugs (competition for ligand binding)
2) a hereditary disorder (**Gilbert’s syndrome: GS)
____________ syndrome:
✴ Degree of hyperbilirubinemia is variable but is made worse with fasting.
✴ No other apparent symptoms.
Gilbert’s syndrome: GS**
What syndromes has Lack/defect of conjugating enzyme (glucuronysltransferase)
Crigler-Najjar Syndrome (type I / II) & Neonates
What is type 1 Crigler-Najjar Syndrome?
inherited, complete lack of enzyme, leads to infant mortality by 1 year
What is type 2 Crigler-Najjar Syndrome?
inherited, partial deficiency: bilirubin levels not as high as with type I
caused by immaturity of glucuronysltransferase enzyme
Neonatal physiologic jaundice
What are the risks of Neonatal physiologic jaundice?
-Decreased albumin and incomplete blood-brain barrier (BBB) place infant at great risk of encephalopathy.
-Increased deposition of bilirubin in the Brain can result in kernicterus.
How is neonatal jaundice treated?
UV radiation (phototherapy) or exchange transfusion
Crigler-Najjar Syndrome (type I / II) & Neonates lead to increased _________ bilirubin.
unconjugated
glucuronysltransferase is also known as…
UDP-glucuronidase
What are the four types of “hepatic” jaundice?
-Impaired hepatocyte uptake
-Lack/defect of conjugating enzyme
-.Defective excretion to the bile
-Hepatocellular damage & necrosis
Excretion of bile is rate-limiting step of metabolism, what are two rare hereditary disorders of excretion?
Dubin-johnson & Rotor syndromes***
What type of bilirubin is increased with “hepatic” jaundice?
**Serum conjugated bilirubin
Dubin-Johnson syndrome is distinguished by ___________ in hepatocytes
dark pigment
What causes “post hepatic” jaundice?
Obstruction of bile flow by gallstones or tumors which increase conjugated serum bilirubin.
Memorize liver disease chart
!!!
Bilirubin + glucuronic acid —> conjugated bilirubin + bile is done by what enzyme?
Glucuronyl Transferase
What is the bacterial enzyme that deconjugated bilirubin in the intestines to make urobilinogen?
B-glucuronidase
What type of bilirubin is increased in hemolytic diseases?
unconjugated bilirubin
(think pre-hepatic)
What type of bilirubin is increased with parenchymal liver disease?
Unconjugated and conjugated bilirubin
(think “hepatic”)
What type of bilirubin is increased with liver obstruction?
Conjugated bilirubin
(think post-hepatic)
What is the carrier for unconjugated bilirubin?
albumin
Why is bilirubin seen in urine with liver obstruction?
conjugated bilirubin is increased and it is water soluble
What is the ratio seen with Non-alcoholic fatty liver disease?
less than 1 but AST and ALT are both increased
Inflammation of the liver may be _____ or _____ origin.
viral, drug
What are the most common causes of viral hepatitis?
A,B,C,D,E, cytomegalovirus, coxsackie virus B and
Epstein-Barr virus
How is viral hepatitis diagnosed?
1) antibodies directed toward virus or 2) patient specific antibodies
produced by viral antigens.
What are the lab findings for acute hepatitis infections?
Liver initially retains ability to excrete bilirubin, but analyte enzyme levels AST and ALT will be increased.
What are the lab findings for chronic hepatitis infections?
elevate serum bilirubin, ALP, and ALT/AST (ALT>AST).
(ALT has a longer half life)
What is a normal AST:ALT ratio?
less than 1
Increased ALP could indicate…
bile duct obstruction
The most common drug induced hepatic damage is alcohol, what is the most significant laboratory finding?
induction of GGT (γ-glutamyl transferase)
Other drugs that can cause drug induced hepatic damage?
Barbituates, tricyclic antidepressants, antiepileptics, acetaminophen,
chemotherapeutics
True of false:
Drug induced hepatic damage is usually reversed with removal of drug?
True
AST:ALT ratio greater than 2:1 with increased GGT could indicate…
Alcoholic liver damage***
-Typically occurs in children between the age of 2-13 years
-after recovery from Virus Infection such as flu and chickenpox.
REYE’S SYNDROME (CNS disorder)
What are the effects of Reye’s syndrome?
-Associated with increased fatty infiltration, necrosis and **cholestasis (blockage of bile flow)
-Encephalopathy develops with increased NH3.
caused by congenital deficiencies in porphyrin
synthesis pathway
How many types are there?
Porphyrias (six types)
hereditary disorder leads to accumulation of copper in liver —> jaundice —> cirrhosis
Wilson’s disease
congenital deficiency: Decreased ceruloplasmin, increased urinary copper excretion, glycosuria, phosphaturia, and
aminoaciduria.
Wilson’s disease
genetic disorder leading to accumulation of iron —> cirrhosis
Hemohromatosis
What are the clinical manifestations of Hemohromatosis?
increased serum iron and ferritin, decreased iron binding capacity.
How can Hemohromatosis lead to diabetes?
from the iron accumulation in the pancreas (causes damage)
How is Hemochromatosis monitored?
What is the treatment?
Phlebotomy treatment. 2-6 units/year
Monitoring with ferritin level
To make less then blank***
The term for iron induced cell death?
Ferroptosis
Hemochromatosis:
At what ferritin levels is treatment needed?
At what level is the treatment stopped?
-more than 200 mg/ml ferritin
-20-50ng/ml
Wilsons disease:
copper is elevated in ________ but not in _______.
tissues and urine but not in the blood
What three lab values will be elevated with bile duct obstruction and Hepatomas?
Increased serum alkaline phosphatase (ALP), 5’ nucleotidase & GGT
What is a good marker for liver cancer?
Increased α-fetoprotein (AFP) (yolk sac and liver in fetal development, should not be seen in adults otherwise)
Protein that reduces “PROTEASE ACTIVITY”
α1-ANTITRYPSIN
α1-ANTITRYPSIN makes up ____% of α1 fraction of serum proteins.
80
What causes lack of α1-antitrypsin?
a genetic disorder
How does α1-ANTITRYPSIN DEFICIENCY manifest itself?
as Emphysema and Liver Cirrhosis
pH at which particular molecule carries no NET electrical charge
Isoelectric point
How is phenotyping performed for α1-ANTITRYPSIN DEFICIENCY?
using Isoelectric Focusing
- Run samples on polyacrylamide gel/Immobilized pH gradient Strip
- Individual proteins are immobilized in the pH gradient as they approached
its own specific isoelectric point (IP)
*electrical flow is (-) to (+)
What converts Bilirubin – glucuronides to unconjugated bilirubin?
What converts unconjugated bilirubin to urobilinogen?
β-glucuronidase
Reduction by anaerobic
bacteria
Urobilinogen (serum and urine) is increased in…
hemolysis (hereditary
spherocytosis) and hepatocellular injury without cholestasis
Urobilinogen is decreased with…
1) with cholestasis and 2) when there is a lack
of intestinal bacteria (i.e. after antibiotic therapy).
True or flase:
urobilinogen is useful in the detection of liver disease.
False. of little use in the detection of liver disease.
What hepatitis type is most likely to become chronic?
Hepatitis C
How is hepatitis A virus measured?
(1) Total Ab ! persist forever with natural infection to HAV
(2) IgM anti-HAV ! Rapidly develop with acute exposure (detectable: 3-6 mo)
What is the most common chronic viral infection
Transmitted through body fluid (parenteral or sexual contact)
From mom to baby at birth or after birth
hepatitis B virus
42nm DNA virus (hepadna virus family)
Made from RNA template [Reverse transcriptase] –> prone to mutation
HBV
most common cause of chronic hepatitis in north America, Europe,
Japan
Primarily occur through plasma: drug injection, transfusion 80% ↓ over the past decade
HCV
Witch hepatitis virus is associated with increased cancer risk?
HCV
HBV mutant is resistant to…
RT inhibitor
What is the problem with Mutation with HBsAg?
not detected by routine lab test
Cf. HBsAg: used as a routine test Anti HBcAg is also commonly detected Ab
against HBV
Post hepatic bilirubin levels
Increased total bilirubin
Increased conjugated
Positive bilirubin In urine
Decreased urobilinogen
Pigment is brown
Neonatal bilirubin
Increased total bilirubin
Increased uncojugated bilirubin
Negative urine Bilirubin
Dubin Johnson bilirubin
Increased total and conjunction bilirubin
Positive bilirubin in urine
Decrease urobilinogen
Criglers syndrome bilirubin
Gilbert syndrome
Increased total and unconjugated bilirubin
Decreased conjugation bilirubin normal in Gilbert syndrome
Decreased urobilinogen
Hepatocellular bilirubin
Increased total bilirubin conjugated and unconjugated bilirubin
Positive bilirubin in urine
Decreased urobilinogen
Pre-hepatic bilirubin
Increased total and unconjugated and urobilinogen levels
Negative bilirubin in urine
Emphysema
A lung disease that causes shortness of breath
A1 anyitrypsin deficiency effects lungs by
Not removing over reactive immunoglobulins that will eventually cause emphysema
