Sickle-cell disease is an inherited mutation that produces a hemoglobinopathy: the glutamate at the number 6 amino acid in the 146-amino acid b chain of hemoglobin (Hb) is replaced by valine. This mutation results from a single base-pair substitution in the gene encoding for the b chain. The resulting Hb in sickle-cell patients is denoted HbS. In sickle-cell disease, when the HbS encounters regions where there is a low O2 tension (like venous blood arising from an exercising muscle), the HbS polymerizes, forming long strands within the RBC that distorts its shape (see figure, right). The distorted RBCs lose there normal flexibility and pile up, blocking blood flow through capillaries and small vessels. One can enter a positive feedback situation whereby the local ischemia (reduced blood flow) causes further drops in the O2 levels, which causes still further sickling, and the patient is said to be in sickle-cell crisis. Patients also suffer from severe hemolytic anemia—a reduction of the number of circulating RBCs due to hemolysis of the fragile sickle cells. Most patients with sickle-cell disease have a reduced life span—especially in poor third-world countries where the disorder is most prevalent.
Sickle-cell disease is found only in individuals who are homozygous for the mutation—i.e., they have two copies of the mutation, one inherited from their father and one from their mother. Individuals who are heterozygous for the trait (i.e., have only one copy of the mutation) do not exhibit symptoms, since they have adequate levels of HbA (normal hemoglobin). But, individuals exhibiting the sickle-cell trait can pass the trait on to their offspring.
In the African-American population, the incidence of sickle-cell trait (heterozygous) is ~8% in the general population. In Equatorial Africa, the incidence of the trait can reach levels >50% in local populations. This high incidence posed a mystery for many years. Why would such a seemingly lethal gene remain at such high incidence in a general population? If the individuals who contract the disorder die before they reproduce, then should not the mutation die with them since it would not have been passed on to their offspring? The mystery was solved when epidemiologists looked also at the incidence of malaria in the population.
Malaria is a mosquito borne parasite (Plasmodium falciparum) that invades RBCs. Persons who have the sickle-cell trait have an unusually high resistance to infection by the parasites: the HbS in their RBCs interferes with the ability of the parasite to reproduce. Thus, in tropical regions of the world where malaria is endemic, the benefit of surviving untreated malaria outweighs the detriment of the chance of producing offspring that have sickle-cell disease. Of course, in the United States, the trait serves no benefit to the individual: malaria is rare in the U.S., and effective drug treatments are readily available (e.g., quinine and its derivatives). Thus, the relatively high incidence of the trait in African Americans is a remnant of a trait that greatly benefited their ancestors.
An aside (for your interest only)… a popular summer libation evolved from a prophylactic treatment. British soldiers who were supervising construction of the Suez Canal were issued daily doses of quinine to guard against malaria infection. Quinine is an extremely bitter substance, and as such, the soldiers found it more palatable to dissolve the tablets in bottled soda water sweetened with sugar. Somebody had the bright idea to add gin, also issued in daily allotments, and voilà: the Gin and Tonic is invented!
Pernicious anemia is caused by a lack of sufficient quantities of vitamin B12. As discussed in lecture, the disorder is rare: one needs only small dietary quantities of the vitamin on a daily basis, and the liver stores up to a two-year supply of the vitamin. Thus only strict vegetarians must take care to acquire the vitamin by taking oral supplements.
Prior to the advent of effective anti-ulcer drugs, for example H2-type antihistamines like cimetidine (Tagamet®), one of the sole effective treatments of ulcers was the surgical removal of the stomach (gastrectomy); note that the stomach secretes into its lumen vast quantities of HCl, which combined with other factors can cause gastric (stomach) or duodenal (intestinal) ulcers. It was observed that virtually all gastrectomy patients developed pernicious anemia typically six months to two years after surgery. Thus, gastroenterologists postulated that the stomach must secrete some intrinsic factor that is necessary for the absorption of dietary vitamin B12, and that factor was later identified and is termed intrinsic factor.
Intrinsic factor is secreted into the stomach lumen by gastric parietal cells, the same cells that make the HCl. Intrinsic factor tightly binds to B12 and subsequently serves two functions: it prevents the denaturation and destruction of the vitamin by intestinal digestive processes, and the bound form of the vitamin specifically binds to a site on the mucosal cells of the ileum (the lowest portion of the small intestines). Once bound to the mucosal cells, a specific transport process takes up the vitamin (combined with the intrinsic factor) into the mucosal cells, and the vitamin is subsequently released into the interstitial fluid where it can then enter the blood.
Gastrectomies as a treatment for ulcers are rarely today. However, in patients suffering from gastric secretory diseases, or patients who must undergo gastric resection (e.g., for stomach cancer) or intestinal resection of the ileum (e.g., intestinal cancer), or patients with intestinal mucosal disease (e.g., Crohn’s disease), pernicious anemia will develop unless the patient receives 1000 mg per month of vitamin B12 via injections.
Recall that platelets (thrombocytes) are cell fragments released from megakaryocytes that rupture in the bone marrow. The existence of sufficient quantities of circulating platelets is absolutely essential to stopping bleeding for a period of time sufficient for wound healing. Thrombocytopenia is the term that describes a low blood platelet count (defined as <>mL, with normal values typically ~250,000 per mL). Patients suffering from severe thrombocytopenia (<>mL) present with excessive nose and gum bleeding, easy bruising (n.b., a bruise is a hemorrhage under the skin), blood in the feces, petechiae (pinpoint skin hemorrhages), and in women, excessive uterine bleeding during menstrual periods. Causes of thrombocytopenia include increased uptake of platelets by the spleen (frequently associated with autoimmune disorders), decreased production rate of platelets (most commonly caused by chemotherapy and/or radiation therapy in cancer patients), and increased destruction of platelets (e.g., due to autoimmune disease, drug toxicity to platelets). In severe cases of thrombocytopenia, the only immediate recourse is to transfuse the patient with platelets derived from pooled donated blood. Note that in severe cases, even a simple dental procedure can produce bleeding that is life threatening. Finally, the common pain reliever aspirin inhibits the function of circulating platelets (see below), but it does not decrease the platelet count, so patients who are using aspirin can exhibit increased bleeding times.