Thursday 20 March 2014

Drug Induced Liver Disease (Hepatotoxicity)-Chapter 4-PHYSIOLOGY & Chapter 5-SYMPTOMS OF LIVER DISEASE



PHYSIOLOGY

       The various functions of the liver are carried out by the liver cells or hepatocytes. Currently, there is no artificial organ or device capable of emulating all the functions of the liver. Some functions can be emulated by liver dialysis, an experimental treatment for liver failure.



Metabolism of Carbohydrates

The liver breaks down complex carbohydrates (example: fructose, lactose) into simpler carbohydrates like glucose, which can the be utilized by the body for energy production. Excess glucose which is not needed immediately by the body is stored in the liver as glycogen.

In the event of low blood sugar levels, the liver then releases the stored glucose to regulate the sugar levels. This is known as the glucose buffer function. In the absence of carbohydrates, especially with high protein, no carbohydrate diets, the liver will use protein and fats to produce glucose.

§  The liver performs several roles in carbohydrate metabolism:

§  Gluconeogenesis (the synthesis of glucose from certain amino acids, lactate or or glycerol)

§  Glycogenolysis (the breakdown of glycogen into glucose)

§  Glycogenesis (the formation of glycogen from glucose) (muscle tissues can also do this)



Metabolism of Protein

The liver breaks down amino acids by removing the functional group (NH2) which allows it to be used for energy production or converted into carbohydrates and/or fat. This process is known as deamination. During the deamination process, ammoniais formed. The liver is able to remove ammonia by converting it into urea and excreting it mainly via the kidneys as urine.

Apart from breaking down proteins, the liver can also produce amino acids. It does this by converting existing amino acids into other types of amino acids (interconversion). 



Plasma proteins, which are an integral part of blood, are also produced by the liver.
Proteins produced and secreted by the liver:-
§  A large part of amino acid synthesis
§  The liver is responsible for the mainstay of protein metabolism, synthesis as well as degradation

Metabolism of Fats
The liver breaks down fats into acetyl-CoA (acetyl coenzyme A) to for energy production. Conversely, fat may be synthesized by carbohydrates and proteins as it is the more efficient form of nutrient storage. Certain types of lipids like cholesterol, phospholipids and lipoproteins are also produced within the liver.

Filtration and Storage of Blood
The liver plays an important role in filtering the blood and storing blood so that it is not in circulation. Approximately 1.5 liters of blood pass through the liver every minute. This blood enters through the portal vein and hepatic artery. Excess nutrients are removed and processed as described above or stored, toxins are neutralized and secreted and specialized liver cells also play a part in removing pathogens. Calcium and the body’s own hormones are also neutralized and/or removed from the body by the liver.
Up to 500 milliliters of blood is stored within the liver in the hepatic sinuses and hepatic vein. This excess blood can be released into the circulation should the body require it. In the event of any congestion that results in backflow of blood, the liver may hold up to 1 liter of blood or more before it becomes damaged. This can significantly increase the weight of the liver (normal weight in adults is approximately 1.5 kg).

Production of Bile
Bile is an important compound for the emulsification of fats in the gastrointestinal tract. It is also a means for the body to get rid of bilirubin from the bloodstream as well as cholesterol produced by the liver.


Formation of Blood Clotting Factors
The liver produces essential clotting factors which are crucial for the coagulation of blood. This  includes :
  • Factor I (fibrinogen)
  • Factor II (prothrombin) 
  • Factor V (accelerator globulin)
  • Factor VII (antihemophilic factor A) 
  • Factor IX (plasma thromboplastin component / antihemophilic factor B) 
  • Factor X (Stuart-Prower factor) 
  • Factor XI (plasma thromboplastin antecedent)
  • Factor XII (Hageman factor)
  • Factor XIII (fibrin-stabilizing factor)
* The liver requires vitamin K to produces these factors.

Storage of Vitamins and Minerals
The liver stores many micronutrients including vitamins AD and B12 and minerals like iron (stored as ferritin). The storage capacity of the liver is so large that it has enough of some of these vitamins to sustain the body from a few months to several years should there be no further nutrient intake.

Breakdown
§  The breakdown of insulin and other hormones
§  The liver breaks down hemoglobin, creating metabolites that are added to bile as pigment (bilirubin and biliverdin).
§  The liver breaks down or modifies toxic substances (e.g., methylation) and most medicinal products in a process called drug metabolism. This sometimes results in toxication, when the metabolite is more toxic than its precursor. Preferably, the toxins are conjugated to avail excretion in bile or urine.
§  The liver converts ammonia to urea.

Other functions
§  The liver is responsible for immunological effects- the reticuloendothelial system of the liver contains many immunologically active cells, acting as a 'sieve' for antigens carried to it via the portal system.
§  The liver produces albumin, the major osmolar component of blood serum.
§  The liver synthesizes angiotensinogen, a hormone that is responsible for raising the blood pressure when activated by renin, an enzyme that is released when the kidney senses low blood pressure



SYMPTOMS OF LIVER DISEASE

Patients with mild liver disease may have few or no symptoms or signs. Patients with more serious disease develop symptoms and signs that may be nonspecific or specific.
Nonspecific symptoms, that is, symptoms that don't suggest that the liver is their cause, include:
·         Fatigue,
·         Weakness,
·         Vague abdominal pain, and
·         Loss of appetite.
Symptoms and signs that are specific for liver disease include:
·         Yellowing of the skin (jaundice) due to the accumulation of bilirubin in the blood,
·         Itching, and
·         Easy bruising due to decreased production of blood clotting factors by the diseased liver.
Severe, advanced liver disease with cirrhosis can produce symptoms and signs related to cirrhosis; these symptoms include:
·         Fluid accumulation in the legs (edema) and abdomen (ascites),
·         Mental confusion or coma,
·         Kidney failure,
·         Vulnerability to bacterial infections, and
·         Gastrointestinal bleeding.

The first sign of damage to the liver is an increase in liver enzyme levels in the blood. When the liver is damaged, its enzymes are released into the bloodstream, where the levels can be measured by blood tests. These are called liver function tests (LFTs). Enzyme levels that are routinely checked as part of LFTs include:

·         alanine aminotransferase (ALT)
·         aspartate aminotransferase (AST)
·         gamma-glutamyltransferase (GGT)



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