Hepatic physiology

Introduction

The kidney modifies the contents of the plasma by filtering its components into the urine, whereas the liver modifies the blood contents by metabolically transforming them. The liver is where drugs, hormones, and toxic waste products, such as ammonia, are metabolized to inactive forms.

The liver also plays an important role in carbohydrate metabolism. Specifically, the liver is involved in:

• Glycogen storage.

• Gluconeogenesis.

• Formation of many biochemical compounds from products of carbohydrate digestion and absorption.

The liver also synthesizes:

• Cholesterol, phospholipids, and most of the lipoproteins required by the body (see Ch. 24 ).

• Nonessential amino acids and major plasma proteins, including albumin and clotting factor.

This brief chapter will focus on the liver’s role in detoxification and the synthesis of blood proteins.

System structure

The liver is situated in the right upper quadrant of the abdomen. It has a dual blood supply from the hepatic artery and the portal vein.

• The hepatic artery, which branches off the celiac trunk, is oxygen-rich but nutrient-poor and provides the liver with 20% to 30% of its blood supply.

• The portal vein, which carries blood from the digestive tract, pancreas, and spleen, is oxygen-poor but nutrient-rich and provides the liver with 70% to 80% of its blood supply.

Both of these vessels enter the liver at the porta hepatis, which is also the site at which the common hepatic bile duct leaves the liver. These three vessels—artery, portal vein, and bile duct—form the portal triad. The three vessels of the portal triad divide and subdivide together through the hepatic parenchyma, separating the liver into functional segments called lobules.

Lobules are hexagonal groups of hepatocytes bounded by portal triads at each corner. In the center of each hexagon is a central vein.

• The arterial and portal venous blood mix as they flow toward the center of the lobule in the spaces between hepatocytes called sinusoids ( Fig. 26.1 ).

  

• The sinusoids empty into the lobular central vein(s), which join together in collecting veins, which coalesce into hepatic veins.

• Hepatic veins leave the liver and empty into the vena cava.

The plates of hepatocytes in the lobule are one or two cells thick, with sinusoids on either side.

• Bile canaliculi, into which bile is secreted, run between hepatocytes and ferry bile away from the center of the lobule and out to the bile duct at the hexagonal corners ( Fig. 26.2 ).

  

• The endothelium of hepatocytes lacks a basement membrane, which facilitates the exchange between hepatocytes and the blood.

• Specialized macrophages, called Kupffer cells, line the sinusoidal epithelium on the bloodstream side and are involved in host defense and recycling body iron.

The location in the liver between a hepatocyte and a sinusoid is called the space of Disse or the perisinusoidal space.

• Fenestrations and endothelial discontinuity makes this region highly permeable to the exchange of solutes between the hepatocytes and sinusoidal blood plasma.

• The space of Disse contains hepatic stellate cells, which play an important role in storing fat soluble vitamins, such as vitamin A.

• Inflammation to these cells, such as following liver injury, results in collagen production in the space of Disse, fibrosis, and impaired hepatic function.

The functions of the liver are performed by the various hepatocyte organelles.

• The mitochondria of hepatocytes have enzymes that take part in the urea cycle.

• The smooth endoplasmic reticulum (ER) is the site of glycogen synthesis, the conjugation of bilirubin, and the detoxification of foreign substances.

• The rough ER is the site of the synthesis of plasma proteins, such as albumin, fibrinogen, and prothrombin.

• Lysosomes take part in the receptor-mediated endocytosis of lipoproteins, such as low-density lipoprotein (LDL) and high-density lipoprotein (HDL), as well as chylomicrons.

• Hepatocyte peroxisomes remove peroxide generated by oxidases, and they are the site of long-chain fatty acid oxidation.

• The Golgi apparatus is responsible for the glycosylation and secretion of plasma proteins, such as transferrin, and lipoproteins, such as very-low-density lipoprotein (VLDL).

System function

As stated earlier, this chapter will focus on just a few of the liver functions that have not been detailed in other chapters. Particular aspects of liver physiology are helpful not only in predicting the consequences of disease, but also in understanding the clinical signs and symptoms by which liver disease is diagnosed.

Detoxifying actions of the liver

We will focus on three significant detoxifying mechanisms within the liver:

• Drug metabolism

• Ammonia metabolism

• Metabolism of bilirubin (a breakdown product of heme from red blood cells and the cause of jaundice)

These processes are not hormonally controlled; they are governed by the kinetics of hepatic enzyme-substrate interactions.

• In other words, when more toxic substrate is present in the blood, the rate of enzymatic reactions in the liver increases.

• When the enzymes are saturated, which does not occur under physiologic circumstances, the toxic substrates accumulate in the blood and can have adverse effects.

Drug metabolism

The liver plays a critical role in the transformation of drugs and xenobiotic compounds into inactive and hydrophilic (water-soluble) substances that are readily eliminated from the body through bile or urine.

Two sets of enzymatic reactions take place in hepatocytes to serve these purposes ( Fig. 26.3 ).

• Phase I reactions are slow, energy-consuming reactions catalyzed by the heme-containing cytochrome P-450 enzymes.

  • These reactions result in oxidation, reduction, or hydrolysis of the parent compound.

  • Three gene superfamilies (I, II, III) encode different cytochrome P-450 enzymes, each with different substrate specificities.

  • Sometimes a phase I reaction alone is adequate to inactivate a drug and prepare it for elimination. Often, however, the phase I product is a toxic intermediate such as a free radical that must be inactivated by a phase II conjugation reaction.

• Phase II reactions, which are much faster and less energy-dependent than phase I reactions, add bulky polar groups to the metabolites of the phase I reactions, inactivating them and rendering them even more water-soluble.

Most of the enzymes involved in phase I and phase II reactions are located in the smooth ER of hepatocytes, so that toxic metabolites cannot interact with the rest of the cell.

Recall from renal physiology that the clearance of a compound from the blood by an organ is the volume of plasma rid of the substance by that organ per unit time. Drug clearance varies in different contexts.

• Newborns, whose cytochrome P-450 enzymes are poorly developed, clear drugs more slowly, as do older adults.

• Genetic cytochrome P-450 polymorphisms have been identified in members of different ethnic groups, which may contribute to altered metabolism of certain drugs.

• The presence of a second drug in the plasma may also affect the metabolism of the first drug (e.g., by inducing the expression of cytochrome P-450 enzymes, thereby increasing clearance of the first drug).

• Certain foods have also been found to interact with medications as a result of interference with the hepatic and intestinal cytochrome P-450 enzymes (see Fast Fact Box 26.1 ).

Fast Fact 26.1

Grapefruit and grapefruit juices contain furanocoumarin derivatives that inhibit cytochrome P450 enzymes and subsequently increase the bioavailability of certain drugs.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here