Intracellular accumulations
represent the buildup of substances that cells cannot immediately use or
eliminate. The substances may accumulate in the cytoplasm (frequently in the
lysosomes) or in the nucleus. In some cases the accumulation may be an abnormal
substance that the cell has produced, and in other cases the cell may be
storing exogenous materials or products of pathologic processes occurring
elsewhere in the body. An example would be the accumulation of beta amyloid
fragments, which progress to a skeletal muscle disorder called myositis. These
substances may accumulate transiently
or permanently, and they may be
harmless or, in some cases, toxic.
These substances can be grouped
into three categories:
• Normal
body substances, such as lipids, proteins, carbohydrates, melanin, and
bilirubin, that are present in abnormally large amounts
• Abnormal
endogenous products, such as those resulting from inborn errors of metabolism
• Exogenous products,
such as environmental agents and pigments, that cannot be broken down by the
cell.
The accumulation of normal cellular
constituents occurs when a substance is produced at a rate that exceeds its
metabolism or removal. An example of this type of process is fatty changes in
the liver due to intracellular accumulation of triglycerides. Liver cells
normally contain some fat, which is either oxidized and used for
energy or converted to triglycerides. This fat is derived from free fatty acids released from adipose tissue.
Abnormal accumulation occurs when the delivery of free fatty acids to the liver
is increased, as in starvation and diabetes mellitus, or when the intrahepatic
metabolism of lipids is disturbed, as in alcoholism.
Intracellular accumulation can
result from genetic disorders that disrupt the metabolism of selected
substances. A normal enzyme may be replaced with an abnormal one, resulting in
the formation of a substance that cannot be used or eliminated from the cell,
or an enzyme may be missing, so that an intermediate product accumulates in the
cell. For example, there are at least 10 genetic disorders that affect glycogen
metabolism, most of which lead to the accumulation of intracellular glycogen
stores. In the most common form of this disorder, von Gierke disease, large
amounts of glycogen accumulate in the liver and kidneys because of a deficiency
of the enzyme glucose-6-phosphatase. Without this enzyme, glycogen cannot be
broken down to form glucose. The disorder leads not only to an accumulation of
glycogen but also to a reduction in blood glucose levels. In Tay-Sachs disease,
another genetic disorder, abnormal lipids accumulate in the brain and other
tissues, causing motor and mental deterioration beginning at approximately 6
months of age, followed by death at 2 to 5 years of age. In a similar manner,
other enzyme defects lead to the accumulation of other substances.
Pigments are colored substances
that may accumulate in cells. They can be endogenous (i.e., arising from
within the body) or exogenous (i.e., arising from outside the body).
Icterus, also called jaundice, is characterized by a yellow discoloration
of tissue due to the retention of bilirubin, an endogenous bile pigment. This
condition may result from increased bilirubin production from red blood cell
destruction, obstruction of bile passage into the intestine, or toxic diseases
that affect the liver’s ability to remove bilirubin from the blood. Lipofuscin
is a yellow-brown pigment that results from the accumulation of the indigestible
residues produced during normal turnover of cell structures (Fig. 5.3). The
accumulation of lipofuscin
increases with age, and it is sometimes referred to as the wear-and-tear pigment. It is more common in heart,
nerve, and liver cells than other tissues and is seen more often in conditions
associated with atrophy of an organ.
One of the most common exogenous
pigments is carbon in the form of coal dust. In coal miners or people exposed
to heavily polluted environments, the accumulation of carbon dust blackens the
lung tissue and may cause serious lung disease. The formation of a blue lead
line along the margins of the gum is one of the diagnostic features of lead
poisoning. Tattoos are the result of insoluble pigments introduced into the
skin, where they are engulfed by macrophages and persist for a lifetime.
The significance of intracellular
accumulations depends on the cause and severity of the condition. Many
accumulations, such as lipofuscin and mild fatty change, have no effect on cell
function. Some conditions, such as the hyperbilirubinemia that causes jaundice,
are reversible. Other disorders, such as glycogen storage diseases, produce
accumulations that result in organ dysfunction
and other alterations in physiologic function.
