Liver function tests:-
The liver is a reddish brown organ with four lobes of unequal size and shape. A human liver normally weighs 1.44–1.66 kg. It is both the largest internal organ and the largest gland in the human. It is located in the right upper quadrant of the abdominal cavity, resting just below the diaphragm. The liver lies to the right of the stomach and overlies the gallbladder. It is connected to two large blood vessels, one called the hepatic artery and one called the portal vein.
- Architecture of hepatic tissue
The liver is covered with a connective tissue capsule that branches and extends throughout the substance of the liver as septae.
This connective tissue tree provides a scaffolding of support and the highway which along which afferent blood vessels, lymphatic vessels and bile ducts traverse the liver. Additionally, the sheets of connective tissue divide the parenchyma of the liver into very small units called lobules.
The hepatic lobule is the structural unit of the liver. It consists of a roughly hexagonal arrangement of plates of hepatocytes radiating outward from a central vein in the center. At the vertices of the lobule are regularly distributed portal triads, containing a bile duct and a terminal branch of the hepatic artery and portal vein..
- Blood flow
The liver receives a dual blood supply from the hepatic portal vein and hepatic arteries.
The hepatic portal vein carries venous blood drained from the spleen, gastrointestinal tract, and its associated organs.
The hepatic arteries carries blood from the aorta and supply arterial blood to the liver. These blood vessels subdivide into capillaries, which then lead to a lobule.
Terminal branches of the hepatic portal vein and hepatic artery empty together and mix as they enter sinusoids in the liver. Sinusoids are distensible vascular channels lined with highly fenestrated or “holey” endothelial cells and bounded circumferentially by hepatocytes.
As blood flows through the sinusoids, a considerable amount of plasma is filtered into the space between endothelium and hepatocytes (the “space of Disse.
Blood flows through the sinusoids and empties into the central vein of each lobule.
Central veins coalesce into hepatic veins, which leave the liver and empty into the vena cava.
Hepatocytes are metabolic super achievers in the body. They play critical roles in synthesizing molecules that are utilized elsewhere to support homeostasis, in converting molecules of one type to another, and in regulating energy balances.
- 1-Carbohydrate Metabolism
- Glycogenesis (the formation of glycogen from glucose)
- Glycogenolysis (the breakdown of glycogen into glucose)
- Gluconeogenesis (the synthesis of glucose from certain amino acids, lactate or glycerol)
- 2-Fat Metabolism
- The liver synthesizes large quantities of cholesterol, phospholipids and triglycerides
- The liver is extremely active in oxidizing triglycerides to produce energy.
- The liver produces and excretes bile (a yellowish liquid) required for emulsifying fats.
- 3-Protein Metabolism
- Deamination and transamination of amino acids, followed by conversion of the non-nitrogenous part of those molecules to glucose or lipids.
- Removal of ammonia from the body by synthesis of urea.
- The liver produces coagulation factors such as fibrinogen and prothrombin
- The liver is a major site of protein synthesis as albumin and globulins (except gamma globulin)
- The breakdown of hormones such as insulin.
- The liver breaks down or modifies toxic substances.
- The liver stores a multitude of substances, including glucose (in the form of glycogen), vitamin A (1–2 years’ supply), vitamin D (1–4 months’ supply), vitamin B12 (1-3 years’ supply), iron, and copper.
6-Excretory Function:- secretes bile secretion((mainly,Bilirubin,Bile acids,Cholesterol,Phosphlipids,and some salts.
Note:-there are 2 types of bile acids
-Primary bile acids:- Cholic acid & Chenodeoxy cholic acid.
Secondary bile acids:-Deoxy cholic acid & Litho deoxy choluc acid.
7-Protective Function:- The liver protects the body from foreign or harmful substances by phagocytic action or detoxification reactions.
(I)Phagocytic action:-the liver contains many phagocytic cells called (Kupffer cells) wich are active in removing of foreign substances.
Note:- Kupffer cells are part of reticuloendothelial system which include:- the bone marrow,and spleen.
(II)Detoxification Reactions:-There are many toxic or water insolube substances.
Note:-the liver converts water insolube substances into water solube by conjugation with glucuronic acid,which then can be excreted easily by the kidney.
Note:-Detoxification process include:-Esterfication,Oxidation,Reduction,acetylation,Methylation,or Conjugation,….etc
8-Circulatory Function:– the liver works as a storage for the blood,and this helps in the blood volume regulation.
9-Blood Coagulation:-blood clotting factors are protein in nature,and synthesized in the liver((all plasma protein are synthesized in the liver EXCEPT immunoglobulin,its synthesized in the immune system
Liver Function Panel
A liver (hepatic) function panel is a blood test to check how well the liver is working. This test measures the blood levels of albumin, and liver enzymes. High or low levels may mean that liver damage or disease is present.
Why liver function tests are required?
- detect the presence of liver disease (useful in the evaluation of patients having symptoms of liver disease asfever, vomiting, abdominal pain, yellowing of your eyes or skin (jaundice), dark yellow urine, and feeling tired).
- distinguish among different types of liver disorders,
- gauge the extent of known liver damage,
- follow the response to treatment of liver disease.
- assess the effect of hepatotoxic drugs
- Alanine transaminase (ALT)
Also called Serum Glutamic Pyruvate Transaminase (SGPT) is an enzyme present in hepatocytes.
Found mainly in cytoplasm of cells.
It is widely distributed in tissues but highest levels is found in the liver
It catalyzes the transfer of an amino group from alanine to a-ketoglutarate, the products of this reversible transamination reaction being pyruvate and glutamate (it provide a source of pyruvate for gluconeogensis).
- Aspartate transaminase (AST)
Also called Serum Glutamic Oxaloacetic Transaminase (SGOT) is similar to ALT in that it is another enzyme associated with liver parenchymal cells.
Two isoenzymes are present
- GOT1/cAST, the cytosolic isoenzyme
- GOT2/mAST, the mitochondrial isoenzyme.
It is widely distributed in tissues but highest levels is found in liver , heart , skeletal muscles and RBCs
AST catalyzes the reversible transfer of an α-amino group between aspartate and glutamate and, as such, is an important enzyme in amino acid metabolism (it provide a source of oxaloacetate for krebs cycle).
Why ALT is a more specific indicator of liver damage?
The difference is that ALT is found predominantly in the liver, with clinically negligible quantities found in the kidneys, heart, and skeletal muscle, while AST is found in the liver, heart, skeletal muscle, kidneys, brain, and red blood cells. As a result, ALT is a more specific indicator of liver damage than AST
- Elevation of only GPT
ALT levels can increase in response to strenuous physical exercise. Remain elevated for about two days
- Elevation of only GOT
- myocardial infarction
During myocardial infarction only AST increase and ALT is normal or marginal elevated. It starts to increase 4-6h after onset of infarction peaks16-48h then return to normal 3-5 days later.
Note: There duration and extent of increase being related to the size of infraction
Note: high value donate bad prognosis (values 10-15 times ULN considered fatal)
Note: GPT may also be increased in cases of severe infarction due to liveer hypoxia
- Skeletal muscle disease
Skeletal muscle trauma (AST is moderately increase
Duchenne muscular dystrophy.
Note: AST and ALT is normal in muscle disease of neurogenic origin as mysthenia gravies.
Note: In muscle disease AST and CK increase but AST has a longer half life so increase in AST persists for longer than increase in CK.
- Hemolytic anemia
such as that caused by sickle cell anemia
- Elevation of both GOT & GPT
- Acute hepatitis
Liver enzymes are elevated in acute hepatitis due to cell necrosis and membrane damage . In this disease AST and ALT increase even before the clinical sign and symptoms of disease appear.
Very high levels of liver enzymes are usually due to acute hepatitis, often due to a virus infection.
Liver enzymes starts to rise (30 times ) before jaundice ,peaks (100 times ) 6-10 days after jaundice then return to normal 2-6 weeks after jaundice
ALT is higher than AST in mild cases
AST is higher than ALT in severe cases due to mitochondrial affection
Extent of rise reflects the degree of hepatocellular damage
AST return to normal faster than ALT so AST is used to follow up
- Chronic hepatitis
During chronic hepatitis
AST and ALT levels remain elevated (but not very high)
In advanced cirrhosis
The increase in liver enzymes is less marked and the liberation of enzymes from liver cells is now much reduced but failure of function is very marked (albumin and PT decreased)
- Liver carcinoma
Moderate elevation of AST and ALT is found in individuals with primary and metastatic hepatoma
In liver carcinoma AST is usually higher than ALT
- Toxic hepatitis
Elevation of AST and ALT is found in toxic hepatitis
- Highest level with drugs that acts on liver cells causing acute liver necrosis as paracetamol overdose
- Moderate level with drugs that cause intra-hepatic cholestasis as oral contraceptives
- Alcoholic hepatitis
When liver damage is due to alcohol, both AST and ALT is moderately elevated
AST often increases much more than ALT.
- De-Ritis ratio
It is the ALT / AST ratio, normally less than 1
- Elevated level : mild liver disease
- Decreased level : chronic liver disease
Alkaline phosphatase (ALP)
Alkaline phosphatase (ALP) is an enzyme in the cells lining the biliary ducts of the liver. ALP is also present in bone , intestine and placental tissue
Functions of phosphatase
Alkaline phosphatase 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. As the name suggests, alkaline phosphatases are most effective in an alkaline environment.
Role inside the body
Its role is not fully known but its attachment to cell membrane suggesting an association between ALP activity and membrane transport so its function may be:
- Facilitate the transferee of metabolites across cell membrane
- Calcification process in bone synthesis
Four isoenzymes are found liver isoenzyme , bone isoenzyme , Intestinal isoenzyme , Placental isoenzyme.
- High activity of serum ALP in infant is due to the predominance of BAP bone isoenzyme
- LAP liver isoenzyme accounts for most of the activity in healthy adults
- Placental isoenzyme present in second and third trimester so ALP is elevated during normal pregnancy
- Increased ALP level
- Age: children usually have much higher ALP levels than adults because rapid bone growth is normal in children.
- Pregnancy: women in the third trimester of pregnancy have high ALP levels because the placenta produces ALP.
- Bone healing: normal healing of a bone fracture can raise ALP levels.
- Liver disease
- Liver disease without jaundice:
That affect the paranchymal cells as fatty liver and liver cirrhosis show only moderate or even normal ALP
- Liver disease with jaundice
- Intra-hepatic cholestasis
This is due to suppression of bile flow due to hepatocellular failure as in hepatocellular carcinoma or metastatic neoplasia (cancer that has spread (metastasized) to the liver from another location in the body.).
- Extra-hepatic cholestasis
This is due to suppression of bile flow due to mechanical obstruction as gall bladder stone and pancreatic head cancer
Note: elevation is more marked in case of extra-hepatic than in intra-hepatic and the degree of obstruction is parallel to increased elevation
- Bone disease
High ALP levels can be caused by bone diseases:
- Paget’s disease
- osteosarcoma (so it can be used as a tumor marker for bone cancer)
- Bone metastases of prostatic cancer (High / very high ALP values)
- Fractured bone(active bone formation occurring as ALP is a byproduct of osteoblast activity)
- Due to drugs
- That cause cholestasis: as antidepressants and immunosuppressant
- That cause cell toxicity: as paracitamol and antiepileptic
- Decreased ALP level
Hypothyroidism in infancy leads to failure of physiological and mental growth
- Congenital hypophsphatesia
The metabolic basis of hypophosphatasia stems from a molecular defect in the gene encoding tissue non-specific alkaline phosphatase (TNSALP). TNSALP is an enzyme found in the outer surface of osteoblast and chondrocyte cell membranes. This enzyme normally hydrolyzes several substances, including inorganic pyrophosphate (PPi). The enzyme defect leads to inorganic pyrophosphate (PPi) accumulates extracellularly and potently inhibits formation of hydroxyapatite (mineralization) causing rickets in infants and children and osteomalacia (soft bones) in adults.
Gamma glutamyl transpeptidase (GGT)
gamma-glutamyl transpeptidase (also γ-glutamyltransferase, GGT, GGTP, gamma-GT) is an enzyme that transfers gamma-glutamyl functional groups. It is found in many tissues, the most notable one being the liver. Small fraction of the enzymes present in cytosol , but the larger fraction is located in the cell membrane.
It is also involved in glutathione metabolism by transferring the gamma-glutamyl moiety to a variety of acceptor molecules including water (forming glutamate), certain L-amino acids, and peptides, leaving the cysteine product to preserve intracellular homeostasis of oxidative stress.
Elevated serum GGT activity can be found in diseases of the liver, biliary system, and pancreas.
- Liver disease
- Acute hepatitis
GGT is moderately elevated in acute hepatitis it starts to rise in the first week, peaks second week and return to normal after 3 weeks
AST and ALT are more sensitive than GGT in cases of acute hepatitis
- Alcoholic liver disease (Alcoholism)
GGT is elevated by large quantities of alcohol ingestion. Alcohol may increase GGT production by inducing hepatic microsomal production, or it may cause the leakage of GGT from hepatocytes.
Isolated elevation or disproportionate elevation compared to other liver enzymes can be used to screen for chronic alcohol abuse (it will be elevated in about 75% of chronic drinkers)
GGT level is correlated with the duration of alcohol intake or dose
- Hepatic malignancies
GGT is elevated in hepatic cancer and primary has higher levels than secondary.
- Toxic hepatitis
Antiepileptic drugs as Phenobarbital cause GGT elevation due to that drugs stimulate excess proteins synthesis.
- Biliary disease
GGT is similar to alkaline phosphatase (ALP) in detecting disease of the biliary tract (intra and extra hepatic cholestasis). Indeed, the two markers correlate well. In general, ALP is still the first test for biliary disease. The main value of GGT over ALP is in verifying that ALP elevations are, in fact, due to biliary disease.
ALP can also be increased in certain bone diseases, but GGT is not.
- Pancreatic disease
GGT is moderately elevated in acute pancreatitis and pancreatic malignancy which associated with hepatobiliary obstruction.