Transcript Document

LIVER FUNCTION TESTS
Liver Functions
• General Metabolic Function:
– Glucose to Glycogen
– Glycogenolysis
– Gluconeogensis
– Carbon skeletons of fatty acids transported to adipose
tissue as very low-density lipoprotein (VLDL)
– Fatty acids reaching the liver from fat stores may be
metabolized in the tricarboxylic acid cycle, converted to
ketones or incorporated into triglycerides
Liver Functions
• Synthetic functions:
– Plasma proteins
– Most coagulation factors, Including fibrinogen, factor II
(prothrombin), V, VII, IX, X, XI, XII, and XIII
– Primary bile acids
– Lipoproteins: VLDL, HDL
Liver Functions
• Excretion and Detoxification:
– Cholesterol
• Unchanged
• Bile acids
– Amino Acids
• Deamination, amino group and the ammonia produced by
intestinal bacterial action converted to urea
– Steroid Hormones: Metabolized and inactivated by
conjugation with glucuronate and sulphate
– Many drugs which are metabolized and inactivated by
enzymes of the endoplasmic reticulum system
– Toxins: the reticuloendothelial Kupffer cells in the
hepatic sinusoids are well placed to extract toxic
substances
• Efficient excretion of the end products of metabolism and
of bilirubin depends on:
– Normally functioning liver cells
– Normal blood flow through the liver
– Patent biliary ducts
Liver Function Tests
• Are groups of Clinical Biochemistry Laboratory Blood Assays
Designed to Give Information About The State of a Patient’s
Liver
• Most Liver Diseases Cause Only Mild Symptoms Initially, But It
Is Vital That These Diseases be Detected Early
• This Testing Performed on a Patient’s Serum or Plasma Samples
Obtained by Phlebotomy
• Some of These Tests Are Associated with Functionality, Some
With Cellular Integrity and Some With Conditions Linked to
The Biliary Tract
• Liver function tests are used to aid in diagnosing, differential
diagnosis, evaluating severity, monitoring therapy and assessing
the prognosis of the liver disease and dysfunction
Liver Function Tests
– Total bilirubin (TBIL): Bilirubin is a breakdown product of heme. The
liver is responsible for clearing the blood of bilirubin (2-14 µmole/L). Total
bilirubin might be increased by the following drugs:
• Anabolic Steroids
• Antibiotics
• Antimalarials
• Ascorbic Acid
• Diabinese
• Codeine
• Diuretics
• Epinephrine
• Oral contraceptives
• Vitamin A
– Direct bilirubin: elevated in bile duct obstruction by gallstones or cancer
should be suspected (0-4 µmole/L).
– Alanine transaminase (ALT): is an enzyme necessary for energy
production. It is present in a number of tissues including the liver
(hepatocytes), heart and skeletal muscles it rises dramatically in
acute liver damage, such as viral hepatitis or paracetamol overdose
(5-40 IU/L). Drugs that may increase ALT levels:
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Acetaminophen
Ampicilline
Codeine
Dicumarole
Indomethacine
Methotrexate
Oral contraceptives
Tetracyclines
Verapamil
– Aspartate transaminase (AST): enzyme involves in energy
production. it is raised in acute liver damage, but is also present in
red cells, cardiac and skeletal muscle, and is therefore not specific
to the liver (10-40 IU/L).
• ALT in conjuction with AST helps to distinguish between heart
damage and liver tissue damage
– Alkaline phosphatase (ALP): It maily comes from liver,
bone and placenta. In the liver it is in the cells lining the
biliary ducts. ALP levels in plasma will rise with large
bile duct obstruction, intrahepatic cholestasis or
infiltrative diseases of the liver (30-120 IU/L).
– Gamma glutamyl transpeptidase (GGT): Although
reasonably specific to the liver and a more sensitive
marker for cholestatic damage than ALP, it may be
elevated with even minor, sub-clinical levels of liver
dysfunction. It is raised in alcohol toxicity acute and
chronic (2-30 IU/L). Drugs that may cause increased
GGT levels:
• Alcohol
• Phenytoin
• Phenobarbital
– GGT level is compared with ALP level to distinguish between
skeletal disease and liver disease
• Lactate Dehydrogenase (LDH): is an
enzyme found in many body tissues,
including liver. Elevated levels of LDH may
indicate liver damage
• Coagulation Tests (prothrombin time, PT):
It is not a sensitive measure of liver function
• Albumin (Alb): it is made specifically by the
liver, Its levels are decreased in chronic liver
diseases such as cirrhosis (3.2-5.4 g/L).
– Ammonia: a breakdown product of protein that
is normally converted into urea by the liver.
Analysis of blood ammonia aids in the diagnosis
of sever liver diseases and helps to monitor the
course of these diseases. Increasing ammonia
signals end-stage liver disease and a high risk of
hepatic coma (10-70 µg/dl). Drugs that may
cause increased levels of ammonia are:
• Alcohol
• Barbiturates
• Narcotics
• Diuretics
• 5’Nucleotidase (5’NTD): is specific for cholestasis or
damage to the intra or extrahepatic biliary system
• Serum Glucose
• Cholesterol
• Serological Tests: to demonstrate antibodies
• DNA tests: hepatitis and other viruses
• Tests for antimitochondrial antibodies
• Test for transthyretin (prealbumin)
• Protein Electrophoresis
• Bile Acids
• Alpha-fetoprotein
• Carcinoembryonic antigen
• Total protein
• Fibronogen
• Serum Protein Electrophoresis:
– Abnormal in both necrotic and obstructive liver
diseases
– In the acute stages of hepatitis, the albumin will be low
and the gamma globulin fraction will be elevated. The
alpha-1 globulin and alpha-2 globulin fractions will be
elevated
– In biliary cirrhosis the beta globulin may be elevated
owing to an increase in beta lipoprotein
– In hepatic cirrhosis the albumin will be greatly
decreased
• Liver function tests performed individually do not give the
physician very much information, but used in combination
with a careful history, physical examination and imaging
studies, they contribute to making an accurate diagnosis of
the specific liver disorder
• Differentiation of acute and chronic forms of
hepatocellular injury is aided by examining the ratio of
ALT to AST, called the DeRitis ratio. In acute hepatitis,
Reye’s syndrome and infectious mononucleosis the ALT
predominates. However, in alcoholic liver disease, chronic
hepatitis and cirrhosis, the AST predominates
• The most prevalent liver disease is viral hepatitis. Tests for
this condition include a variety of antigen and antibody
markers and nucleic acid tests.
• Acute viral hepatitis is associated initially with 20 to 100
fold increases in transaminases and is followed shortly by
bilirubin elevation. Such patients should be tested for
hepatitis B surface antigen (HbsAg) and IgM antibodies to
hepatitis B core antigen (anti-HBc IgM) and anti-hepatitis
C virus (anti-HVC) to identify these causes. In addition to
hepatitis A-E, viral hepatitis may be caused by EpsteinBarr virus (EBV) and cytomegalovirus (CMV) infections
of the liver. Tests for these viruses such as the infectious
mononucleosis antibody test, anti-viral capsid antigen test
(anti-VCA), and anti-CMV tests are useful in diagnosing
these infection
• ALT values are significantly increased in cases of hepatitis and
moderately increased in cirrhosis, liver tumors, obstructive
jaundice
• AST values are increased in liver damage, hepatitis
• ALP values are increased in diseases that impair bile formation
(cholestasis)
• GGT values are elevated in hepatitis, cirrhosis, liver tumors or
metastasis, toxic injury to the liver mainly by alcohol
• LDH levels are elevated in viral hepatitis
• Bilirubin levels: increased indirect or total bilirubin levels in
hemolytic disease and transfusion reaction. Increased direct
bilirubin levels can be diagnostic of bile duct obstruction,
gallstones, cirrhosis, or hepatitis
Glycogen Storage diseases
GSDs
Glycogen Storage Disease Type-I
• Von Gierke’s disease, is the most common of the glycogen
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storage disease
It is a genetic disease results from deficiency of the glucose6-phosphatase
Glucose-6-phosphatase is an enzyme located on the inner
membrane of the endoplasmic reticulum
The catalytic unit is associated with a calcium binding
protein, and three transporter proteins (T1,T2,T3) that
facilitate movement of glucose-6-phosphate, phosphate and
glucose respectively, into and out of the enzyme
The ability of the liver to produce free glucose from
glycogen and from gluconeogenesis is impaired
Affects Liver, Kidney and Intestine
Types of GSD-I and molecular Biology
• The most common forms of GSD-I are
– GSD-Ia (80%) and GSD-Ib (20%)
– GSD-Ia; an autosomal recessive disease results from
mutations of G6PC, the gene for glucose-6-phosphatase
– GSD-Ib results from mutations of the gene for T1, the
G6P transporter.
– The metabolic charateristics of both GSD-Ia and -Ib are
quite similar
– Prenatal diagnosis: fetal liver biopsy, DNA analysis
using chorionic villus sampling
Metabolic effects of G6P deficiency
• Hypoglycemia: fasting
– Chronic hypoglycemia produces secondary metabolic adaptations
• Low insulin levels
• High glucagon levels
• High cortisol levels
• Lactic acidosis:
– Arises from impairment of gluconeogenesis
– Accumulation of G6P inhibits conversion of lactate to pyruvate
– Uric acid, ketoacids and free fatty acids increase the anion gap
• Hypertriglyceridemia: resulting from increased triglyceride
production caused by chronically low insulin levels
• Hyperuricemia:
– Results from a combination of increased generation and decreased
excretion of uric acid, which is generated when increased amount
of G6P are metabolized via the pentose phosphate pathway
– Purine degradation
– Diminished urinary excretion , uric acid competes with lactic acid
for renal excretion and lactic acid is high
• Hepatomegaly and Liver problem: due to accumulation of glycogen
– Liver enzymes and bilirubin are usually normal
– Risk of developing liver tumors
• Growth failure: due to
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Chronically low insulin levels
Persistent acidosis
Chronic elevation of catabolic hormones
Calories insufficiency
Malabsorption
• Kidney effect:
– They are enlarged due to accumulation of glycogen
– Uric acid nephropathy
– Chronic glomerular damage similar to diabetic nephropathy lead to renal
failure
• Others; mild malabsorption, infection risk, bleeding, developmental
delay
Glycogen Storage Disease Type-II
• Pompe’s Disease, Lysosomal alpha(1-4)-glucosidase deficiency
• Inborn lysosomal enzyme defect
• Affects Liver, Heart, Muscle
• Excessive glycogen concentrations found in abnormal vacoules in the
cytosol
• Normal blood sugar levels
• Massive cardiomegaly
• Normal glycogen structure
• Early death usually occurs from heart failure
Glycogen Storage Disease Type III
• Cori’s disease, genetic disorder characterized by a
deficiency in glycogen debranching enzymes (amylo-1,6
glucosidase)
• Inherited as autosomal recessive
• Abnormal glycogen deposits in the liver, muscle and some
cases the heart
• Divided into four classes:
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– GSD IIIa; muscle and liver involvement
– GSD IIIb; liver involvement only
– GSD IIIc and GSD IIId; are rare phenotypes
The disease usually presents during infancy with:
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Hypoglycemia
Failure to thrive
Hepatomegaly
Hypotonia
Cardiomyopathy
Cirrhosis
Glycogen Storage Disease Type IV
• Anderson’s disease, is a very rare hereditary metabolic
disorder
• It is due to the absence of the glycogen branching enzyme
(amylo-1,4-1,6 transglucosidase) which is critical in the
production of glycogen
• Production of a very long un-branched glucose chains
(amylopectin), insoluble leads to glycogen precipitation in
the liver and the heart
• Liver failure
Glycogen Storage Disease Type VI
• Hers’s disease
• Caused by a deficiency in liver glycogen phosphorylase
• Presented with;
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Hepatomegaly
Growth retardation
Mild hypoglycemia
Hyperlipidemia
Hyperketosis