Chapter 099. Disorders of Hemoglobin (Part 9)

Unstable hemoglobins occur sporadically, often by spontaneous new mutations. Heterozygotes are often symptomatic because a significant Heinz body burden can develop even when the unstable variant accounts for a portion of the total hemoglobin. Symptomatic unstable hemoglobins tend to be β-globin variants, because sporadic mutations affecting only one of the four α-globins would generate only 20–30% abnormal hemoglobin.Hemoglobins with Altered Oxygen Affinity High-affinity hemoglobins [e.g., Hb Yakima (β99Asp- His)] bind oxygenmore readily but deliver less O2 to tissues at normal capillary PO2 levels (Fig. 992). Mild tissue hypoxia ensues, stimulating RBC production and erythrocytosis(Table 99-3). ...
Nội dung trích xuất từ tài liệu:
Chapter 099. Disorders of Hemoglobin (Part 9) Chapter 099. Disorders of Hemoglobin (Part 9) Unstable hemoglobins occur sporadically, often by spontaneous newmutations. Heterozygotes are often symptomatic because a significant Heinz bodyburden can develop even when the unstable variant accounts for a portion of thetotal hemoglobin. Symptomatic unstable hemoglobins tend to be β-globin variants,because sporadic mutations affecting only one of the four α-globins wouldgenerate only 20–30% abnormal hemoglobin. Hemoglobins with Altered Oxygen Affinity High-affinity hemoglobins [e.g., Hb Yakima (β99Asp -> His )] bind oxygenmore readily but deliver less O2 to tissues at normal capillary PO2 levels (Fig. 99-2). Mild tissue hypoxia ensues, stimulating RBC production and erythrocytosis(Table 99-3). In extreme cases, the hematocrits can rise to 60–65%, increasingblood viscosity and producing typical symptoms (headache, somnolence, ordizziness). Phlebotomy may be required. Typical mutations alter interactionswithin the heme pocket or disrupt the Bohr effect or salt-bond site. Mutations thatimpair the interaction of HbA with 2,3-BPG can increase O2 affinity because 2,3-BPG binding lowers O2 affinity. Low-affinity hemoglobins [e.g., Hb Kansas (β102Asn -> Lys )] bind sufficientoxygen in the lungs, despite their lower oxygen affinity, to achieve nearly fullsaturation. At capillary oxygen tensions, they lose sufficient amounts of oxygen tomaintain homeostasis at a low hematocrit (Fig. 99-2) (pseudoanemia). Capillaryhemoglobin desaturation can also be sufficient to produce clinically apparentcyanosis. Despite these findings, patients usually require no specific treatment. Methemoglobinemias Methemoglobin is generated by oxidation of the heme iron moieties to theferric state, causing a characteristic bluish-brown muddy color resemblingcyanosis. Methemoglobin has such high oxygen affinity that virtually no oxygen isdelivered. Levels >50–60% are often fatal. Congenital methemoglobinemia arises from globin mutations that stabilizeiron in the ferric state [e.g., HbM Iwata (α87His -> Tyr ), Table 99-3] or frommutations that impair the enzymes that reduce methemoglobin to hemoglobin(e.g., methemoglobin reductase, NADP diaphorase). Acquiredmethemoglobinemia is caused by toxins that oxidize heme iron, notably nitrateand nitrite-containing compounds. Diagnosis and Management of Patients with Unstable Hemoglobins,High-Affinity Hemoglobins, and Methemoglobinemia Unstable hemoglobin variants should be suspected in patients withnonimmune hemolytic anemia, jaundice, splenomegaly, or premature biliary tractdisease. Severe hemolysis usually presents during infancy as neonatal jaundice oranemia. Milder cases may present in adult life with anemia or only as unexplainedreticulocytosis, hepatosplenomegaly, premature biliary tract disease, or leg ulcers.Because spontaneous mutation is common, family history of anemia may beabsent. The peripheral blood smear often shows anisocytosis, abundant cells withpunctate inclusions, and irregular shapes (i.e., poikilocytosis). The two best tests for diagnosing unstable hemoglobins are the Heinz bodypreparation and the isopropanol or heat stability test. Many unstable Hb variantsare electrophoretically silent. A normal electrophoresis does not rule out thediagnosis. Severely affected patients may require transfusion support for the first 3years of life, because splenectomy before age 3 is associated with a significantlyhigher immune deficit. Splenectomy is usually effective thereafter, but occasionalpatients may require lifelong transfusion support. Even after splenectomy, patientscan develop cholelithiasis and leg ulcers. Splenectomy can also be considered inpatients exhibiting severe secondary complications of chronic hemolysis, even ifanemia is absent. Precipitation of unstable hemoglobins is aggravated by oxidativestress, e.g., infection, antimalarial drugs. High-O2 affinity hemoglobin variants should be suspected in patients witherythrocytosis. The best test for confirmation is measurement of the P50. A high-O2affinity Hb causes a significant left shift (i.e., lower numeric value of the P 50);confounding conditions, e.g., tobacco smoking or carbon monoxide exposure, canalso lower the P50. High-affinity hemoglobins are often asymptomatic; rubor or plethora maybe telltale signs. When the hematocrit reaches to 55–60%, s ...