INTRACELLULAR ACCUMULATIONS

Intracellular accumulations represent the buildup of sub­stances that cells cannot immediately use or dispose of. 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. These substances can be grouped into three categories: (1) normal body substances, such as lipids, proteins, carbohydrates, melanin, and biliru-bin, that are present in abnormally large amounts; (2) ab­normal endogenous products, such as those resulting from inborn errors of metabolism; and (3) exogenous products, such as environmental agents and pigments that cannot be broken down by the cell.² These substances may accumu­late transiently or permanently, and they may be harmless or, in some cases, toxic.

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 intra-hepatic 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's 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 3 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 bili-rubin, 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 pig-

ment 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 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 persons 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.