Hemoglobin Malmö Beta-97 (FG-4) histidine--glutamine: a cause of polycythemia.

A striking history of familial polycythemia led to a search for an abnormal hemoglobin. None could be demonstrated by routine electrophoretic methods, but the propositus' hemolysate had increased oxygen affinity. Manipulation of the conditions of electrophoresis, and chromatographic methods, permitted identification of hemoglobin Malmö. Studies of hemolysates demonstrated a normal Bohr effect, decreased heme-heme interaction (n=1.58), and a p50 of 1.3 mm Hg at 10 degrees C and pH 7.2. The amino acid substitution occurs in the same position (FG-4) as that of hemoglobin Chesapeake, but in the beta-chain rather than the alpha-chain. The two types of hemolysate have different pathophysiologic properties, and carriers of hemoglobin Malmö exhibit more striking hematologic abnormalities.

Lead neuropathy. 1) Morphometry, nerve conduction, and choline acetyltransferase transport: new finding of endoneurial edema associated with segmental demyelination.

Morphometric and pathologic studies along the length of the peripheral nervous system were obtained in groups of rats fed 4% lead carbonate for 3 and 6 months and in match-fed controls. The number and diameter histograms of L6 cytons of spinal ganglia and of myelinated fibers of proximal and distal portions of peroneal and sural nerve were not significantly different from the control groups. On the other hand, segmental demyelination occurred approximately as frequently in proximal as in distal parts of nerves. At 3 months approximately 1/3 of teased myelinated fibers showed changes of segmental demyelination (Condition C), or of remyelination after segmental demyelination (Condition F) or of both segmental demyelination and of remyelination (Condition D), while at 6 months more than 4/5ths of fibers showed these changes. As expected, regression lines of axonal area on number of lamellae of myelin, were less steep in nerves of rats fed on lead for 6 months as compared to controls. Axonal transport of choline acetyltransferase in lead neuropathy did not differ from that in control rats. As expected from the studies of others, conduction velocity of myelinated fibers of caudal nerve were low. A new finding was the often quite striking increase of transverse fascicular area of peripheral nerves. This was due to edema which appeared to develop at about the time of onset os segmental demyelination. Although the edema may be an epiphenomenon, it could be an important observation bearing on the development of lead neuropathy. It would be important to know next whether or not the blood nerve barrier is altered in lead neuropathy.

Radiation absorbed doses from iron-52, iron-55, and iron-59 used to study ferrokinetics.

Biological data obtained principally with Fe-59 citrate are used with physical data to calculate radiation absorbed doses for ionic or weak chelate forms of Fe-52, Fe-55, and Fe-59, administered by intravenous injection. Doses are calculated for normal subjects, primary hemochromatosis (also called idiopathic or hereditary hemochromatosis), pernicious anemia in relapse, iron-deficiency anemia, and polycythemia vera. The Fe-52 doses include the dose from the Mn-52m daughter generated after injection of Fe-52. Special attention has been given to the dose to the spleen, which has a relatively high concentration of RBCs and therefore of radioiron, and which varies significantly in size in both health and disease.

Blue gods, blue oil, and blue people.

Studies of the composition of coal tar, which began in Prussia in 1834, profoundly affected the economies of Germany, Great Britain, India, and the rest of the world, as well as medicine and surgery. Such effects include the collapse of the profits of the British indigo monopoly, the growth in economic power of Germany based on coal tar chemistry, and an economic crisis in India that led to more humane tax laws and, ultimately, the independence of India and the end of the British Empire. Additional consequences were the development of antiseptic surgery and the synthesis of a wide variety of useful drugs that have eradicated infections and alleviated pain. Many of these drugs, particularly the commonly used analgesics, sulfonamides, sulfones, and local anesthetics, are derivatives of aniline, originally called "blue oil" or "kyanol." Some of these aniline derivatives, however, have also caused aplastic anemia, agranulocytosis, and methemoglobinemia (that is, "blue people"). Exposure to aniline drugs, particularly when two or three aniline drugs are taken concurrently, seems to be the commonest cause of methemoglobinemia today.

Hereditary red blood cell disorders in middle eastern patients.

Hereditary disorders of erythrocytes are common in many areas of the world, including the Middle East. In some regions of the Middle East more than 10% of the population are carriers of a gene for one of these conditions. When patients from the Middle East seek medical care in the West, an unrecognized but clinically important erythrocyte disorder can result in serious complications during routine medical care, such as a drug-induced hemolytic crisis. This article reviews the most important and most common inherited red blood cell disorders in Middle Eastern patients, including glucose-6-phosphate dehydrogenase deficiency, the thalassemias, and sickle cell disorders. We discuss when to suspect such conditions, how to determine their presence, and how to avoid potential complications related to them. Although a detailed discussion of treatment of erythrocyte disorders is beyond the scope of this article, some general management principles are described.

Methemoglobinemia from topically applied anesthetic spray.

Topically applied anesthetic spray is commonly used as part of premedication for general anesthesia and for endoscopic procedures; it is rarely associated with side effects. In this report, we describe two cases of toxic methemoglobinemia that resulted from topically applied anesthetic spray used before endoscopy. In both cases, standard doses were used; however, methemoglobin levels of 45% and 38% developed within 1 hour of the procedure. Both patients had normal levels of erythrocyte methemoglobin reductase, an indication that this rare but potentially fatal side effect can occur in persons who have no predisposing factors. Because toxic methemoglobinemia is easily treated, our report emphasizes the need to recognize this problem when topically applied anesthetic sprays are used.

Effect on hemoglobin A1 of rapid normalization of glycemia with an artificial endocrine pancreas.

Six insulin-requiring chronically hyperglycemic diabetic patients underwent glucose control for 72 hours with an artificial endocrine pancreas, the Biostator Glucose Controller. Euglycemia was within 4 hours and was maintained (110 leads to 2 mg/dl) thereafter. The concentration of hemoglobin A (HbA) was elevated, at 12.5 leads to 0.6%, at the initiation of Biostator treatment. Decreases in HbA, of 0.5 leads to 0.1% (P less than 0.01) were observed within 4 hours of Biostator therapy. Over the first 16 hours, the slope was less steep, -0.018 leads to 0.004% per hour (P less than 0.01). After 72 hours, decreases in HbA of 1.8 leads to 0.4% (P less than 0.01) were observed. The current concept of HbA as an indication of integrated glycemia over weeks and months requires modification to account for a small, rapidly reversible component. Interpretation of the value of HbA when measured by a kit method must take into consideration that small changes in HbA may occur over a few hours as a result of a large and persistent change in glycemia.

Hemoglobin Columbia Missouri or alpha 2[88 (F9) Ala----Val]beta 2: a new high-oxygen-affinity hemoglobin that causes erythrocytosis.

A previously undescribed hemoglobin variant, hemoglobin Columbia Missouri, alpha 88 (F9) Ala----Val, was detected in a 22-year-old white man who was undergoing assessment for erythrocytosis. This new hemoglobin variant does not separate from hemoglobin A by electrophoresis in conventional media, by isoelectric focusing, or by electrophoresis of purified globin chains in 8 M urea. It exhibits a high oxygen affinity, with a P50 (oxygen tension at 50% saturation) of 19.3 torr for the patient's whole blood. The substitution of hemoglobin Columbia Missouri is an internal residue near the end of the F helix of the alpha chain. Hemoglobin Okazaki has an arginyl residue substitution for a cysteinyl residue at F9 (beta 93) in the beta chain. In comparison with hemoglobin Okazaki, the substitution in hemoglobin Columbia Missouri has a more pronounced effect on oxygen affinity. Consequently, hemoglobin Columbia Missouri is associated with erythrocytosis, whereas hemoglobin Okazaki is not.

Update on hereditary hemochromatosis and the HFE gene.

Hereditary hemochromatosis (HHC) is the most common inherited single gene disorder in people of northern European descent. Hereditary hemochromatosis is characterized by increased intestinal absorption of iron leading to its deposition into multiple organs. The classic description of HHC is bronze diabetes in a patient with cirrhosis. Hereditary hemochromatosis is increasingly being diagnosed at an earlier, less symptomatic stage. Diagnosis is based on an elevated fasting early morning transferrin saturation. Treatment is by phlebotomy, which, if initiated before the development of cirrhosis or diabetes, is associated with a normal life expectancy. Recently, a gene associated with HHC was discovered and named HFE. Two point mutations of this gene have been referred to as C282Y and H63D. Several US and European studies have found that 60% to 93% of patients with suspected HHC are homozygous for C282Y. Positive results of HFE gene testing may eliminate the need for a liver biopsy in selected cases. The greatest utility of HFE gene testing will likely be in screening family members of an identified proband and in helping to resolve ambiguous cases.

Prevalence of anemia in medical practice: community versus referral patients.

OBJECTIVE: To compare the prevalence of anemia among community and referral patients. DESIGN: A Mayo Clinic laboratory database was searched for hemoglobin determinations between Jan. 1, 1985, and Dec. 31, 1989, in residents and nonresidents of Olmsted County, Minnesota, who were 20 years of age or older (a more restricted period within this interval was used for those 70 years of age or older). MATERIAL AND METHODS: Using the World Health Organization criteria for anemia, we estimated the prevalence of anemia as of July 1, 1987, among Olmsted County residents 20 years of age or older (community patients) and compared this finding with the prevalence among non-Olmsted County patients of the same age registered at the Mayo Clinic during the same year (referral patients). RESULTS: The crude prevalence of anemia among Olmsted County men was less than that among male referral patients, but this difference was decreased by adjusting for the older mean age of referral patients (6.6% versus 7.0%; P = 0.01). Even after age-adjustment, the prevalence of anemia was greater among community women than among female referral patients (12.4% versus 8.2%; P < 0.001). Before age 55 years, the prevalence of anemia was lower among men than among women, but after that age, anemia became more frequent in men, reaching a 44.4% prevalence among community men 85 years of age or older. The overall prevalence rate was sensitive to the criteria used to define a low hemoglobin level, however. CONCLUSION: Clinicians should be aware of the high prevalence of anemia, especially among elderly community patients. This precaution should help minimize the overlooked diagnosis of anemia and the failure to identify and treat its underlying cause.

Deferoxamine-chelatable iron in hemochromatosis and other disorders of iron overload.

Deferoxamine-chelatable iron was measured in 103 patients with known or suspected iron overload. All of 34 patients with untreated hemochromatosis had distinctly elevated values for deferoxamine-chelatable iron. The mean value in these cases was significantly greater than that in patients with cirrhosis, who had little or no stainable hepatic iron. In 15 patients with hemochromatosis who were tested sequentially during the course of phlebotomy therapy, deferoxamine-chelatable iron proved a reliable index of the degree of reduction of storage iron. In 22 additional patients with partially treated hemochromatosis and 14 with iron overload accompanying chronic anemia, this test correlated well with the magnitude of iron deposits in liver or bone marrow. In patients with unexplained elevations of serum iron, normal or only slightly elevated deferoxamine-chelatable iron correctly indicated that storage (hepatic) iron was not excessive. The test was more reliable than determination of serum iron or transferrin saturation as an indicator of increased storage iron. Elevated values could not be attributed to disturbed liver function. Determination of deferoxamine-chelatable iron is a safe, practical, and useful procedure for identifying persons with increased iron stores and for assessing the effect of phlebotomy therapy.

Hemosiderosis in a dialysis patient: treatment with hemofiltration and deferoxamine chelation therapy.

Although the highly permeable membranes utilized in hemofiltration are theoretically more permeable to deferoxamine-chelated iron than the standard cuprophan membranes used in conventional hemodialysis, no clinical data support this contention. Ours are the first published results of a preliminary short-term trial of combined therapy with deferoxamine and hemofiltration in a dialysis patient with hemosiderosis. An average of 15.3 mg of iron was mobilized with a 19.5-liter exchange over only 4 1/2 hours of postdilution hemofiltration. This compares favorable with previous reports in which 8 to 12 hours of dialysis were performed with Kiil dialyzers, and also with the 24-hour urinary excretion of chelated iron in iron-overloaded patients with normal renal function. We conclude that combined therapy with deferoxamine and hemofiltration offers promises as an effective means of iron mobilization in dialysis patients with hemosiderosis.

Hemoglobin Denver [alpha 2 beta 2(41) (C7) Phe-->Ser]: a low-O2-affinity variant associated with chronic cyanosis and anemia.

OBJECTIVE: To report a previously undescribed low-O2-affinity hemoglobin variant that is associated with chronic cyanosis. DESIGN: Pertinent laboratory and historical data for the index case (from Denver, Colorado) and certain family members were recorded, and the hemoglobin variant was characterized. MATERIAL AND METHODS: Electrophoresis, high-performance liquid chromatography (HPLC), and isoelectric focusing were used to examine blood specimens for the presence of hemoglobin variants, and the O2 affinity of whole blood was determined. The abnormal peptide detected on reverse-phase HPLC of separated globin chains was analyzed for its amino acid composition and sequence. RESULTS: Although no abnormal hemoglobin band separated from hemoglobin A on electrophoresis, HPLC, and isoelectric focusing, a heat test showed hemoglobin instability, and O2 affinity studies disclosed an appreciably right-shifted dissociation curve. On chromatography, the new variant--hemoglobin Denver--was found to be due to a substitution of serine for phenylalanine at position 41 (C7) in the beta chain. In addition to substantial reduction in O2 affinity, hemoglobin Denver is accompanied by moderate reticulocytosis and mild anemia. CONCLUSION: Hemoglobin Denver causes no clinical symptoms other than cyanosis, which is attributable to the low O2 affinity.

Liver biopsy diagnosis of homozygous hemochromatosis: a diagnostic algorithm.

The diagnosis of homozygous hemochromatosis (HH) should be based on appropriate findings on liver biopsy specimens. In cases with equivocal morphologic features, quantitative tissue iron determination and calculation of the hepatic iron index generally enable one to distinguish HH from other types of hepatic iron overload. In this article, we describe a diagnostic algorithm that is designed to avoid diagnostic errors because of histologic misinterpretation or erroneous, usually false-negative, chemical iron studies. The algorithm also delineates a cost-effective method of using quantitative tissue iron analysis. Diagnostic biopsy features of uncomplicated HH include (1) hemosiderosis that involves primarily hepatocytes, with or without inactive cirrhosis, and (2) a tissue iron index of 1.9 or higher. Findings such as prominent fatty changes or lymphocytic piecemeal necrosis indicate the presence of HH in conjunction with another complicating condition or secondary iron overload in the absence of HH.

Hemoccult stool tests: false-negative results due to storage of specimens.

Stoll samples mixed with 0 to 38 mg of hemoglobin per gram of stool were tested for occult blood by the Hemoccult (HO) method when fresh and after storage for 1 to 14 days. The intensity of the HO reaction in fresh stool samples was directly related to the hemoglobin concentration, and approximately 8 mg/g was required for a positive reaction. After samples had been stored on HO cards for 4 days, the intensity of the HO reaction was decidedly less in all. Except at the highest concentrations studied, all became HO-negative or trace within 8 days. In contrast, samples of most concentrations that were stored in tightly capped containers prior to preparation of HO cards maintained a positive reaction intensity for 1 week. Nevertheless, the intensity of the HO reaction decreased significantly (P less than 0.01) with each method of storage. No false-positives were induced by storage during this portion of our study. Samples from 100 stool specimens sent to the clinical laboratory for determination of occult blood were also smeared on separate HO cards for testing immediately and after 4, 7, or 10 days of storage. Only one positive HO reaction was observed on an HO card prepared from a specimen initially classified as HO-negative. In contrast, up to 40% of the stored HO cards prepared from specimens initially classified as HO-positive were HO-negative when analyzed 4 days later.

Two families with hemoglobin Sogn, beta(A11)14 Leu----Arg, in Minnesota and Indiana: hematologic, functional, and biosynthetic features.

Sogn hemoglobinopathy was identified in a young American woman and in a young American man of apparently unrelated families of Norwegian ancestry. Both persons were asymptomatic and without clinical or hematologic manifestations. Hemoglobin Sogn, beta(A11)14 Leu----Arg, is an unstable hemoglobin that may easily be mistaken for hemoglobin S, G, or D by alkaline hemoglobin electrophoresis. These are the first known instances of hemoglobin Sogn outside of Norway. Oxygen affinity is normal. Sogn hemoglobinopathy is an incidental finding that has no adverse implication for the health of heterozygotes.

Intra-abdominal, angiofollicular lymph node hyperplasia (plasma-cell variant) with an antierythropoietic factor.

An 11-year-old girl presented with a refractory hypochromic microcytic anemia, hypoferremia, normoblastic hyperplastic bone marrow, hypergammaglobulinemia, and growth retardation. Many varied treatments failed to produce any improvement. Ferrokinetic studies revealed rapid plasma clearance and increased plasma iron turnover, but impaired incorporation of 59Fe. Excretion of 57Co after an oral dose indicated an increased iron absorption. A (99M)Tc-sulfur colloid scintigram of the abdomen failed to demonstrate abnormal uptake. A nodal mass showing the plasma-cell variant of angiofollicular hyperplasia was removed from the gastrolienal ligament. Follow-up studies at 3 and 6 months revealed complete correction of the anemia, a 4.8-cm increase in height, and normal serum gamma-globulin levels. Serum obtained before operation inhibited the incorporation of 59Fe that was induced by a standard dose of erthyropoietin in the exhypoxic mouse system, and this inhibition persisted in serum obtained 3 days after surgery but disappeared by 6 days. The data suggest that the hyperplastic angiofollicular lymph node (plasma-cell variant) secreted a substance the inhibited erythropoiesis.

Hemoglobin Old Dominion/Burton-upon-Trent, beta 143 (H21) His-->Tyr, codon 143 CAC-->TAC--a variant with altered oxygen affinity that compromises measurement of glycated hemoglobin in diabetes mellitus: structure, function, and DNA sequence.

OBJECTIVE: To determine the nature and characteristics of a unique hemoglobin variant that causes a spurious increase in glycated hemoglobin (HbA1c). MATERIAL AND METHODS: Blood specimens from four unrelated persons with this hemoglobin variant were examined by conventional laboratory methods, including electrophoresis, high-performance ion-exchange chromatography, and isoelectric focusing; by amino acid sequence analysis, polymerase chain reaction-based DNA sequence analysis, and electrospray ionization mass spectrometry, to establish the molecular structure; and by studies of oxygen affinity under varied conditions, to define the functional characteristics of the hemoglobin variant. RESULTS: The unique hemoglobin variant observed in these four cases is due to the mutation CAC-->TAC, at beta-globin gene codon 143, corresponding to beta 143 (H21) His-->Tyr. This amino acid substitution affects an important 2,3-diphosphoglycerate binding site and slightly increases the oxygen affinity of the hemoglobin variant. CONCLUSION: A hitherto unrecognized hemoglobin variant, encountered in four unrelated persons of Irish or Scots-Irish ancestry, hemoglobin Old Dominion/Burton-upon-Trent, beta 143 (H21) His-->Tyr, has now been characterized at the molecular, structural, and functional levels. Although it is associated with a slight increase in oxygen affinity, it is without hematologic effect, and its only clinical significance is that it coelutes with HbA1c on ion-exchange chromatography and thereby causes a spurious increase in HbA1c and compromises the use of this analyte to monitor the treatment of diabetes mellitus.

Methemoglobinemia induced by a topical anesthetic spray (cetacaine).

In two seriously ill patients, cyanosis developed shortly after a topical anesthetic spray (Cetacaine) was used. In both cases the presence of methemoglobinemia was suggested by a discrepancy between the arterial oxygen tension and the oxygen saturation of hemoglobin, as measured spectrophotometrically. The characteristic responses of the spectrophotometric oximeter to blood containing different concentrations of methemoglobin are described. Physicians administering this topical anesthetic spray (Cetacaine) should be aware of the possible development of methemoglobinemia.

Incidence of anemia in older people: an epidemiologic study in a well defined population.

OBJECTIVE: To assess the incidence and clinical spectrum of anemia among older people. DESIGN: Inception cohort assembled and followed by medical records linkage until death or last clinical contact through January 1994. SETTING: Population-based study in Olmsted County, Minnesota. PARTICIPANTS: All 618 Olmsted County men and women aged 65 years or more with anemia by World Health Organization criteria that was first recognized in 1986. MEASUREMENTS: Age- and sex-adjusted incidence rates, corrected for prevalent anemia, and survival estimates using the Kaplan-Meier method, with calculation of standardized mortality ratios for specific causes of death. RESULTS: The corrected annual incidence of anemia rose with age, and rates were higher in men (90.3 per 1000; 95% CI, 79.2-101.4) than women (69.1 per 1000; 95% CI, 62.3-75.8). In 465 cases (75%), anemia was detected in conjunction with a hospitalization, but admission was due to anemia in only 57 instances. Half of the cases were caused by blood loss, two-thirds of these as a result of surgery. The cause of anemia was uncertain in 102 cases (16%). One-third of the patients were transfused with a median of 3 units each. Overall survival was worse than expected but was better among those with anemia caused by blood loss. Mortality attributable to malignancy, mental disorders, circulatory and respiratory diseases, ill-defined conditions, and injuries was significantly increased among these older patients with anemia. CONCLUSIONS: The incidence of anemia among older people is 4 to 6 times greater than that suspected clinically, rises with age, and is higher in men than in women. The apparent cause in half the cases is blood loss. Even mild anemia is associated with reduced survival, especially during the first year, but this could relate to underlying comorbid conditions.