Chapter 1 Cell Physiology
Clinical note: In I-cell disease, the process of post-translational modification is impaired. The Golgi apparatus is unable to tag proteins with M6P because of a deficiency of a phosphorylating enzyme. Lysosomal enzyme precursors are therefore secreted from the cell instead of being taken up by lysosomes, resulting in impaired lysosomal function. The characteristic pathologic finding is the presence of inclusions within the cytoplasm. Death commonly results from cardiopulmonary complications (as a result of inclusions in heart valves) during childhood.
Clinical note: There are more than 45 lysosomal storage diseases, caused by impairment of lysosomal function, usually secondary to an inherited deficiency in a hydrolytic enzyme (Table 1-3). The resulting lipid accumulation within lysosomes eventually hinders the activity of cells in many organs, including the liver, heart, and brain. As with I-cell disease, clinical symptoms are severe, and average life expectancy across the entire group of diseases is approximately 15 years, reflecting the importance of normal lysosomal function.
Clinical note: When mitochondrial dysfunction is inherited through mitochondrial DNA, all offspring are equally affected, but only female offspring pass on the disorder. However, other types of mitochondrial dysfunction result from defects in specific proteins that are coded by nuclear DNA but function in the mitochondria, such as Leber hereditary optic neuropathy (LHON), which is characterized by loss of vision in the center of the visual field. LHON is believed to be a result of decreased mitochondrial function and resulting lack of energy in the optic nerve and retina. Disorders resulting from mutations in nuclear genes encoding mitochondrial proteins can be passed on from both male and female offspring.
Clinical note: In hereditary spherocytosis, a form of hemolytic anemia, most patients have mutations in the ankyrin gene, which causes impaired function of the membrane protein spectrin in red blood cells (RBCs). The characteristically spherical, mechanically unstable, and relatively inflexible RBCs tend to rupture within blood vessels and, because of their inflexibility, become lodged and subsequently scavenged within the splenic cords, resulting in a decrease in the number of circulating RBCs. The classic presentation is jaundice, splenomegaly, and anemia that typically resolves after splenectomy.
Clinical note: In Kartagener syndrome (immotile cilia syndrome), ciliary dysmotility results in the clinical triad of bronchiectasis, chronic sinusitis, and situs inversus. Respiratory tract infections occur as a result of impaired mucociliary clearance. The reason for situs inversus is unknown, although normal ciliary function is postulated to be a requirement for visceral rotation during embryogenesis. Deafness and male infertility may also result from the impaired ciliary function.
Clinical note: The integrin GPIIb/IIIa is present on the surfaces of platelets and plays an important role in binding of platelets to fibrinogen. The drug eptifibatide (Integrilin) inhibits the GPIIb/IIIa receptor on platelets, thereby preventing platelet aggregation and thrombus formation. Integrilin is commonly used during angioplasty in high-risk cardiac patients.
Clinical note: Gas exchange in the lungs normally occurs very efficiently across the thin, lipid-rich pulmonary capillary and alveolar walls. However, in pathologic states such as pneumonia, gas exchange becomes less efficient because the accumulation of fluid increases the distance over which oxygen must diffuse.
Pharmacology note: Cardiac glycosides such as ouabain and digitalis inhibit the Na+,K+-ATPase (sodium) pump in the myocardium (see Fig. 1-6). This increases the amount of sodium inside the cell, triggering the Ca2+-Na+ countertransporter. More calcium is brought into the cell, which increases the contraction of atrial and ventricular myocardium and increases cardiac output.
Clinical note: Familial hypercholesterolemia is caused by a variety of mutations in the LDL receptor protein. The result is that plasma LDL particles cannot be effectively taken up by cells and therefore accumulate in the blood at high levels. Patients who are homozygous for these mutations typically die at an early age from atherosclerosis-induced myocardial infarction.