Liver Function Tests (LFTs)

• Liver function tests (LFTs) are being discussed in this lecture.

Liver Structure and Functions

• The liver is the largest and most vascular gland
• It is located in the upper right portion of the abdominal cavity
• The liver sits beneath the diaphragm
• The liver can still function even if three-quarters of its cells are non-functional
• The liver is the only organ capable of regeneration
• The liver has metabolic, synthetic, storage, excretory, and blood coagulation functions
• Metabolic functions include carbohydrate, lipid, amino acid, and protein metabolism, as well as homeostasis
• Synthetic functions include the production of bile acids and salts, cholesterol, phospholipids, and plasma proteins, excluding immunoglobulins and adult hemoglobin
• The liver stores glycogen, Vitamin D, Vitamin B12, and iron, using ferritin as storage protein
• Excretory functions include conjugated bilirubin, bile acids and salts, and cholesterol
• The liver produces fibrinogen, prothrombin, and other clotting factors, playing a vital role in blood coagulation
• Hepatocytes detoxify both endogenous substances like bilirubin and ammonia (endobiotics) and exogenous products such as poisons and drugs like phenobarbital (xenobiotics)

Liver Failure Symptoms

• Liver failure is severe deterioration of liver function
• It occurs when a large portion of the liver is damaged due to liver disorder
• Symptoms of liver failure includes:
• Jaundice caused by elevated bilirubin levels
• The tendency to bleed due to defects in blood coagulation factors
• Ascites which is fluid buildup in the abdominal cavity caused by decreased plasma proteins
• Impaired brain function due to high bilirubin and ammonia levels
• General failing health caused by metabolic disorders

Liver Function Tests (LFTs)

• LFTs assess the functional capacity of the liver and any cellular damage
• LFTs do not quantitatively assess the full capacity of the liver functions

Classification of Liver Function Tests

• LFTs are classified according to the function of the test, the type of variables, and the type of liver disease

Classification by Function

• Basic metabolic function tests measure serum levels of liver enzymes such as ammonia, ALT, and AST
• Excretory function tests measure serum levels of total and direct bilirubin
• Synthetic function tests estimate serum levels of albumin and cholesterol

Classification by Variable

• Hepatic anion transport tests check bilirubin conjugation and excretion
• Plasma protein abnormalities involve plasma albumin levels, coagulation factors, and ceruloplasmin
• Plasma enzyme tests detect enzymes from the cytoplasm (ALT), mitochondria (AST), and membranes (GGT & ALP), or due to the effects of liver damage on enzyme synthesis

Classification by Liver Disease

• Tests for hepatic fibrosis identify collagen deposits in the basement membrane, using N-terminal peptide measurements
• Liver cirrhosis diagnosis involves estimating desialated transferrin levels
• Cholestasis tests include estimating total and direct bilirubin, ALP, GGT, and 5'NT levels
• Liver tumor detection involves estimating alpha-fetoprotein levels

Importance of Liver Function Tests (LFTs)

• Used in the diagnoses liver diseases (LDs)
• Categorize liver diseases
• Monitor the progress of liver diseases

Blood Tests and Clinical Implications

• Bilirubin levels indicate excretory function
• Alkaline phosphatase (ALP) suggests cholestasis or biliary obstruction
• Gamma-glutamyl transferase (GGT) and 5'NT elevations also indicate cholestasis or biliary obstruction
• Alanine Transaminase (ALT) and Aspartate Transaminase (AST) indicate hepatocellular damage
• Albumin, prothrombin time (PT), and Cholesterol indicate the liver's synthetic function

Liver Dysfunction, Bilirubin and Jaundice

• Haem gives iron and bilirubin
• The normal range of bilirubin is:
  • Total Bilirubin: 0.2 to 1 mg/dl
  • Unconjugated bilirubin: 0.1 to 0.6 mg/dl
  • Conjugated bilirubin: 0.1 to 0.4 mg/dl
• Jaundice, also known as icterus, the yellowing of skin and sclera indicates excessive bilirubin
• Jaundice is clinically visible when serum total bilirubin is > 2 mg/dL

Bilirubin Metabolism

• Red blood cells are broken down into Iron and Protein
• Heme is converted to Bilirubin
• Bilirubin combines with Albumin
• Travels from liver to intestines and produces urobilinogen
• Urobilinogen is passed into feces or reabsorbed back into the liver

Types of Jaundice

• Types of jaundice include physiological (neonatal), pathological, congenital, pre-hepatic, hepatic, and post-hepatic (obstructive)

Physiological Jaundice

• Physiological jaundice is a transient condition in newborns, especially premature ones
• The liver contains very little UDP-glucuronyl transferase enzyme limiting bilirubin conjugation
• Accelerated hemolysis of RBCs and the presence of extra hemoglobin (fetal Hb) contribute
• High unconjugated bilirubin can cross the blood-brain barrier
• Causes Kernicterus which is toxic encephalopathy leading to mental retardation and death

Physiological Jaundice Treatment

• Phototherapy uses blue fluorescent light (around 450 nm) to transform bilirubin into water-soluble isomers for excretion without the need for conjugation
• The use of Phenobarbital and oral glucose aids or induces UDP-glucuronyl transferase
• Blood transfusions are necessary if bilirubin concentration is > 25 mg %

Pathological Jaundice (Pre-Hepatic)

• Characterized by increased unconjugated bilirubin due to hemolytic anemia (extensive destruction of RBCs
• The rise of unconjugated bilirubin surpasses the liver's processing
• Hemolytic disorders which are haemoglobin abnormalities, RBC membrane defects, RBC enzyme defects, malaria, and bacterial toxins all cause hemolysis
• Ineffective erythropoiesis causes megaloblastic anemias
• Blood group incompatibilities are mainly from Rh factor or ABO systems

Drugs Causing Hyperbilirubinemia

• Salicylates and sulphonamides increase the risk of kernicterus
• Novobiocin inhibits UDP-glucuronyl transferase enzyme
• Drugs that cause hemolysis increase bilirubin

Pathological Jaundice

• Intrahepatic jaundice involves liver cell damage from cirrhosis, viral or bacterial hepatitis, toxins like CCl4, or paracetamol poisoning
• Increased levels of both direct and indirect bilirubin and high levels of liver enzymes ALT and AST characterize it

Pathological Jaundice

• Post-hepatic jaundice is caused by mechanical obstruction of the biliary tree, such as gallstones in the common bile duct or and head of pancreatic
• Mostly conjugated bilirubin type
• Bile Flow Stoppage
• If complete blockage occurs both bilirubin and ALP are elevated
• Incomplete blockage causes elevation in ALP while bilirubin is normal
• Obstructive jaundice causes bilirubin and bile salts returns to blood
• High bile salts irritate sensory nerves causing itching and Bradycardia due to toxic effects on cardiac muscles

Non-Functional Plasma Enzymes

• Not all liver enzymes are specific which limits the use as markers for liver disease
• Consider all liver parameters
• Liver enzyme activities in plasma show liver cell membrane damage

Enzymes Reflecting Liver Cell Damage

• These are released from damaged cells
• They are caused by cell membrane permeability or cell necrosis from hepatitis A, B, & C, paracetamol toxicity, hypoxia, and congestive heart failure (CHF).

Transaminases

• AST is widespread in tissues (liver, RBCs, skeletal muscle and cardiac muscle)
• AST is a cytosolic and mitochondrial enzyme
• Normal is serum 8 to 40 IU/L
• ALT is more liver-specific and cytosolic
• Normal is serum 7 to 40 IU/L
• ALT increases in viral, infectious, and toxic hepatitis, with levels reaching 30-50 times the normal value
• Facilitate formation of non-essential amino acids, and ketones
• Convert amino acids into ketone bodies or glucose during starvation

ALT/AST Ratio

• Normal value:1
• If ALT/AST > 1, ALT is a liver-specific enzyme
• An increase occurs under infectious hepatitis or liver cirrhosis
• If ALT/AST < 1, AST is a heart-specific enzyme
• This increase occurs under heart disease such as myocardial infraction and ischemic heart disease
• If ALT/AST = 1, both AST and AST have increased mainly in viral hepatitis

Non-Functional Plasma Enzymes

• Lactate Dehydrogenase (LD or LDH) is a non-specific marker
• Used for liver cell damage
• Tissue-specific isoenzymes are used for differential diagnosis
• Can be separated by electrophoresis

Enzymes Reflecting Cholestasis

• Alkaline phosphatase (ALP) normal 45 to 115 IU/L
• Widespread tissue distribution and includes, liver, bone, placenta and GIT
• Ecto-enzyme, on the outside of the cell membrane/side of liver cell
• Marker of extrahepatic biliary obstruction, like a stone in the common bile duct, or intrahepatic cholestasis, such as primary biliary cirrhosis.

Plasma Enzymes II

• Gamma-glutamyl transpeptidase (GGT) Normal is 0 to 42 IU/L, making it more liver-specific.
• Body uses it synthesizes glutathione tripeptide
• Derived from the endoplasmic reticulum of the hepatobiliary tract.
• Involved in the transport of amino acids across the liver cell plasma membrane.
• Serum level increased by cholestasis or chronic ingestion of alcohol,
• Barbiturates, phenytoin which induce the enzyme.

5' Nucleotidase test (5'NT)

• 5'NT is a phosphatase that catalyzes the hydrolysis of neucleoside-5-phosphate esters.
• Although 5'NT can be found in a variety of cells, liver disease increases serum levels
• No bone source making it distinguishing elevations due to conditions from the liver

Plasma Proteins

• The liver synthesizes almost all plasma proteins excluding immunoglobulins
• Albumin levels range from 3.5-5 gm/dl
• It is decreased in chronic or severe liver disease
• Albumin ratio is not useful in acute or minimal liver dysfunction due to its long half-life(18 days.)
• Ascites caused by liver problems
• The normal range for an albumin to globulin ratio is between 1.2 to 1.5
• Hepatic dysfunction cause the ratio decrease under 1

Plasma Proteins II

• An albumin/globulin value below 1 is an ominous sign
• It marks an rise in serum globulin indicating liver damage
• Ferritin stores iron in which the level is influenced by liver conditions
• Growth Hormone is needed for synthesis Alpha-1 antitrypsin deficiency which occurs in childhood cirrhosis with neonatal jaundice, leading to severe emphysema
• Clotting factors have short half-lives which can indicates liver disease
• Alpha-foetoprotein (AFP) is measured during LFTs as a result of reversion of tumors when a liver cell experiences carcinoma

Plasma Proteins III

• Immunoglobulins: Normal plasma level is 2-2.5 gm/dL, they increase during increase liver disease
• Ceruloplasmin: Copper enzyme associated with chronic hepatitis and Wilson's disease

Liver Function

• Ammonia levels normal below 40, most useful in consciousness
• Liver encephalopathy occurs from elevated levels of neurologic signs

Hyperammonemia:

• Generalised liver disease/ hepatic failure, transient in newborns, deficiency in urea cycle all can experience such symptoms

Liver Ammonia Testing

• Must be done quickly/ on ice; CSF Glutamine indicated encephalopathy

Fatty Liver II

• Results in blood abnormalities, deficiencies and increased alcohol synthesis
• Lipotropic factors are nutritional
• Essential Polyunsaturated FAs must be available
• B12 an folate can be available