Vitamin B12 in health and disease: part I--inherited disorders of function, absorption, and transport.
Kapadia C R
All of vitamin B12 in nature is of microbial origin. Cobalamin, as vitamin B12 should correctly be termed, is a large polar molecule that must be bound to specialized transport proteins to gain entry into cells. Entry from the lumen of the intestine under physiological conditions occurs only in the ileum and only when bound to intrinsic factor. It is transported into all other cells only when bound to another transport protein, transcobalamin II. Congenital absence or defective synthesis of intrinsic factor or transcobalamin II result in megaloblastic anemia. The Immerslund-Graesbeck syndrome, a congenital defect in the transcellular transport of cobalamin through the ileal cell during absorption, also presents with megaloblastic anemia, but with accompanying albuminuria. In most bacteria and in all mammals, cobalamin regulates DNA synthesis indirectly through its effect on a step in folate metabolism, the conversion of N5-methyltetrahydrofolate to tetrahydrofolate, which in turn is linked to the conversion of homocysteine to methionine. This reaction occurs in the cytoplasm, and it is catalyzed by methionine synthase, which requires methyl cobalamin (MeCbl), one of the two coenzyme forms of the vitamin, as a cofactor. Defects in the generation of MeCbl (cobalamin E and G diseases) result in homocystinuria; affected infants present with megaloblastic anemia, retardation, and neurological and ocular defects. 5'-Deoxyadenosyl cobalamin (AdoCbl), the other coenzyme form of cobalamin, is present within mitochondria, and it is an essential cofactor for the enzyme Methylmalonyl-CoA mutase, which converts L-methylmalonyl CoA to succinyl CoA. This reaction is in the pathway for the metabolism of odd chain fatty acids via propionic acid, as well as that of the amino acids isoleucine, methionine, threonine, and valine. Impaired synthesis of AdoCbl (cobalamin A or B disease) results in infants with methylmalonic aciduria who are mentally retarded, hypotonic, and who present with metabolic acidosis, hypoglycemia, ketonemia, hyperglycinemia, and hyperammonemia. Megaloblastic anemia does not develop in these children because adequate amounts of MeCbl are present, but the effect of methylmalonic acid on marrow stem cells may give rise to pancytopenia. Congenital absence of reductases in the cytoplasm, which normally reduce the cobalt atom in cobalamin from its oxidized to its reduced state (cobalamin C and D diseases), results in impaired synthesis of both MeCbl and AdoCbl. Both methylmalonic aciduria and homocystinuria therefore develop in these children, and they present with megaloblastosis, mental retardation, a host of neurological and ocular disorders, and failure to thrive; however, they do not have hyperglycinemia or hyperammonemia. A similar biochemical profile and clinical presentation is also seen in cobalamin F disease, which results from a defect in the release of cobalamin from lysosomes, following receptor-mediated endocytosis of the transcobalamin II-cobalamin complex into cells. It is important to recognize these inborn errors of cobalamin absorption, transport, or function as soon after birth as possible, because most respond (in some patients more fully than others) to parenteral administration of cobalamin. Delays in diagnosis can lead to grave clinical consequences.
[Megaloblastic anemia in a psychogenic eating disorder].
Pohl J,Stremmel W
Deutsche medizinische Wochenschrift (1946)
HISTORY AND ADMISSION FINDINGS:A 68-year-old woman had progressively lost strength over the past 5 years and become bed-ridden. She reported gradually reducing her diet during the last few years, for the last two years restricting herself to oatmeal, biscuits and water. Acute exacerbation of dyspnoea, dizziness, tachycardia and cardiac arrhythmias for the last 3 month necessitated her emergency admission when she was found to have oedema of the limbs and definite jaundice, as well as predominantly distal sensory deficits in the legs, a slightly ataxic gait and poor reflexes in the limbs. INVESTIGATIONS:She was found to have pancytopenia with marked megaloblastic anaemia (haemoglobin 4.8 mg/dl, mean red cell volume 141.8 fl, leukocytopenia 41/nl), marked haemolysis (lactate dehydrogenase 1629 U/l, haptohaemoglobin < 0.1 g/l, total bilirubin concentration 4.5 mg/dl). Pernicious anaemia was excluded: no antibodies against parietal cells and intrinsic factor, and no atrophic gastritis in a gastric biopsy. DIAGNOSIS, TREATMENT AND COURSE:Megaloblastic anaemia due to dietary deficiencies with early funicular myelosis was suspected. After infusion of four erythrocyte concentrates and vitamin B12 administration the symptoms and blood picture improved within days. CONCLUSION:Although dietary causes of megaloblastic anaemia are rare in Central Europe, they must be considered in the differential diagnosis, especially in the elderly and those with psychogenic disorders.
Current hematological findings in cobalamin deficiency. A study of 201 consecutive patients with documented cobalamin deficiency.
Andrès E,Affenberger S,Zimmer J,Vinzio S,Grosu D,Pistol G,Maloisel F,Weitten T,Kaltenbach G,Blicklé J-F
Clinical and laboratory haematology
With the introduction of automated assays for measuring serum cobalamin levels over the last decades, the hematological manifestations related to cobalamin deficiency have been changed from the description reported in 'old' studies or textbooks. We studied the hematological manifestations or abnormalities in 201 patients (median age: 67 +/- 6 years) with well-documented cobalamin deficiency (mean serum vitamin B12 levels 125 +/- 47 pg/ml) extracted from an observational cohort study (1995-2003). Assessment included clinical features, blood count and morphological review. Hematological abnormalities were reported in at least two-third of the patients: anemia (37%), leukopenia (13.9%), thrombopenia (9.9%), macrocytosis (54%) and hypegmented neutrophils (32%). The mean hemoglobin level was 10.3 +/- 0.4 g/dl and the mean erythrocyte cell volume 98.9 +/- 25.6 fl. Approximately 10% of the patients have life-threatening hematological manifestations with documented symptomatic pancytopenia (5%), 'pseudo' thrombotic microangiopathy (Moschkowitz; 2.5%), severe anemia (defined as Hb levels <6 g/dl; 2.5%) and hemolytic anemia (1.5%). Correction of the hematological abnormalities was achieved in at least two-thirds of the patients, equally well in patients treated with either intramuscular or oral crystalline cyanocobalamin. This study, based on real data from a single institution with a large number of consecutive patients with well-documented cobalamin deficiency, confirms several 'older' findings that were previously reported before the 1990s in several studies and in textbooks.
[Update of clinical findings in cobalamin deficiency: personal data and review of the literature].
Federici L,Henoun Loukili N,Zimmer J,Affenberger S,Maloisel F,Andrès E
La Revue de medecine interne
PURPOSE:During last decades, several progresses have been made in the diagnosis of cobalamin (vitamin B12) deficiency. Routine used of cobalamin standardized assays have potentially modified the frequency and the type of hematologic abnormalities. CURRENT KNOWLEDGE AND KEY POINTS:Current studies on cobalamin deficiency, including more precise definitions and the description of new etiologies of cobalamin deficiency in adults, as the food-cobalamin malabsorption syndrome, show that hematological abnormalities are generally incomplete compared to historical descriptions of megaloblastic anemia. Nevertheless, they include severe manifestations in 10% of the patients: pancytopenia, severe anemia (hemoglobin < 6 g/dl) or hemolytic anemia and pseudo thrombotic microangiopathy related to cobalamin deficiency. These studies also show the efficacy of new treatment modalities including oral cobalamin administration. PROSPECTS AND PROJECTS:Future studies will confirm these data with the routine use of the new cobalamin assay: holotranscobalamin and validate the usefulness of oral cobalamin therapy.
[Clinical, biological and therapeutic profile of anemia by vitamin B12 deficiency in the department of hematology of Marrakech (Morocco)].
Nafil H,Tazi I,Sifessalam M,Bouchtia M,Mahmal L
Bulletin de la Societe de pathologie exotique (1990)
The aim of this study is to examine retrospectively the clinical, biological and treatment features of anemia by vitamin B12 deficiency in the Hematology department of CHU Mohamed VI Marrakech. We report the results of a retrospective study conducted during six years (2005-2010). It included all patients with anemia (with or without thrombocytopenia or leukopenia) associated with vitamin B12 levels <200 pg / ml. One hundred twenty one cases were analyzed. The average age of patients was 62 years (38-89 years) with a female predominance (sex ratio F/M: 1.3). The clinical symptomatology is dominated by pallor (97.5%), cardiovascular signs (46%) and digestive symptoms (34.7%). Neurological signs were noted in 17.3% of cases. The blood count showed anemia (hemoglobin: mean= 6.9 g/dl), macrocythemia (MCV: mean= 109 fl). Leukopenia was noted in 35 patients (29%), thrombocytopenia in 34 patients (28%) and pancytopenia in 21 patients (17,3%). The average vitamin B12 was 72 pg/ml. The causes of B12 deficiency are pernicious anemia (43%), food-cobalamin malabsorption (43%), and in 14% of cases no etiology was found. Gastritis was found in 82.7% of our patients and Helicobacter pylori (HP) infection in 72.7% of cases. Reticulocyte crisis was observed after parenteral administration of hydroxocobalamine within an average of 8 days and normalization of blood counts, in all patients, within an average of 51 days. In patients with HP infection, eradication therapy of HP was performed. The cure rate of the HP is 90%.
Vitamin B12 deficiency with combined hematological and neuropsychiatric derangements: a case report.
Rannelli Luke,Watterson Rita,Pandya Rupang,Leung Alexander A
Journal of medical case reports
INTRODUCTION:Although vitamin B12 deficiency is a well-known cause of hematological and neuropsychiatric illness, the presentation of combined severe pancytopenia, demyelination and prominent psychiatric impairment is rare. CASE PRESENTATION:We present a case of a previously healthy 55-year-old East African man with severe vitamin B12 deficiency (serum vitamin B12 22pmol/L) secondary to pernicious anemia. He had a severe hypoproliferative megaloblastic anemia with hemolysis (hemoglobin 61g/L, mean corpuscular volume 99fL, reticulocytes 0.8%, haptoglobin undetectable), leukopenia (2.7×109/L), thrombocytopenia (96×109/L), ataxia with central demyelination, and megaloblastic madness. The patient's anemia, myelopathy and psychiatric condition responded well to parenteral vitamin B12 replacement therapy, with significant improvement seen within weeks. CONCLUSION:Hematological manifestations of vitamin B12 deficiency are typically inversely correlated with the presence and severity of neuropsychiatric impairment. Although uncommon, a presentation with severe hematological and neuropsychiatric disease can occur, as illustrated by this case. Its presence may help guide diagnosis as well as provide clinically important prognostic information.
Biermer anemia: Hematologic characteristics of 66 patients in a Clinical Hematology Unit at Senegal.
Seynabou F,Fatou Samba Diago N,Oulimata Diop D,Abibatou Fall S,Nafissatou D
Medecine et sante tropicales
Hematological manifestations can lead to diagnosis of pernicious anemia, also known as Biermer disease and Biermer anemia. This disease has been little studied among black Africans. Our aim is to describe its diagnostic and therapeutic aspects and outcome in our practice. This descriptive study retrospectively examined the records of 66 patients with pernicious anemia seen at the Clinical Hematology Unit of Le Dantec Hospital in Senegal from January 1, 2000, to June 30, 2014. Symptoms were anemic syndrome (40 cases), hemolytic anemia (13), anemic heart failure (7), isolated pallor of the mucous membranes (5), and venous thrombosis (2). Their mean hemoglobin on diagnosis was 6.52 g/dL [1.3-15.2 g/dL], macrocytosis (52), normocytosis (14), hypochromia (4), thrombocytopenia (39), and leukopenia (28 cases). Cytopenia was associated with pancytopenia (25) and bicytopenia (18). Cytologic abnormalities were documented in 42 cases: megaloblastic erythrosis (37 cases) and hypersegmented neutrophils (24 cases). After vitamin B12 therapy - intramuscular (52) or oral (14) -, a reticulocyte crisis was noted on the 8th day and followed by correction of the blood count. Macrocytic anemia, frequently associated with thrombocytopenia and/or leukopenia, is the main hematologic sign evoking pernicious anemia. Venous thrombosis is a rare circumstance of diagnosis that must not be ignored. Intramuscular or oral vitamin B12 is recognized to be effective in these cases and reverses hematological manifestations.
Pancytopenia--a rare manifestation of folic acid deficiency.
Hansen P B,Jørgensen L M
Journal of internal medicine
In the western world folic acid deficiency is a relatively rare cause of anaemia in the elderly population. A 79-year-old woman presented with pancytopenia (haemoglobin 3.4 mmol l-1, leucocytes 1.2.10(9)l-1, thrombocytes 22.10(9)l-1) due to folic acid deficiency. The deficiency was caused by an extremely low dietary intake. The case was complicated with infection and haemorrhagic manifestations. Administration of folic acid increased the number of erythrocytes, leucocytes and thrombocytes markedly. Beside vitamin B12 deficiency folic acid deficiency must be borne in mind in megaloblastic anaemias complicated with leucopenia and/or thrombocytopenia. Since the body stores of folic acid are low, rapid diagnosis and treatment are important.
Pancytopenia in nutritional megaloblastic anaemia. A study from north-west India.
Sarode R,Garewal G,Marwaha N,Marwaha R K,Varma S,Ghosh K,Mohanty D,Das K C
Tropical and geographical medicine
We have analysed 139 consecutive cases (71 males and 68 females) of nutritional megaloblastic anaemia over a period of four and a half years. The majority of these patients belonged to the low socio-economic class and many of them were strict vegetarians. Sixty one percent were in the second and third decades of life. At the time of presentation, 46% had mild hepatomegaly, 42% fever, 34% mild splenomegaly and 20% bleeding manifestations. Of 102 cases in whom the biochemical parameters were available, vitamin B12 deficiency was detected in 76%, folate deficiency in 6.8%, combined B12 and folate deficiency in 8.8%; the remaining 7.8% had normal vitamin levels at presentation. All 139 patients had severe anaemia, 80.5% had thrombocytopenia and 43.8% had neutropenia as well as thrombocytopenia. It appears that during progression (in terms of duration) of megaloblastosis, anaemia is followed by thrombocytopenia and then neutropenia. Infection and bleeding in these patients may be aggravated by impaired functions of neutrophils and platelets, respectively.
[Differential diagnosis of a macrocytic, hyperchromic anemia following alcohol abuse and simultaneous therapy with triamterene and cotrimoxazole].
Kahl C,Freund M
Deutsche medizinische Wochenschrift (1946)
HISTORY AND ADMISSION FINDINGS:A 50-year-old woman was admitted to our emergency room because of progressive weakness. She collapsed the night before admission. Skin and mucosa were pale, she denied major infections or bleedings. An alcohol abuse was known for many years. Because of edema she received a therapy with triamteren, an infection of the urinary tract was treated with cotrimoxacol. INVESTIGATIONS:In addition to thrombocytopenia (50 Gpt/l) and leukocytopenia (1,51 10 (9)/l) we diagnosed a hyperchromic and macrocytic anemia (Hb 3,6 mmol/l [5,8 g/dl], Hk 0,17, MCH 2.52 fmol, 116,8 fl). Folic acid was decreased to 0.677 ng/ml, whereas levels of cobalamin, ferritin and iron were normal. Examination of bone marrow showed a hypercellular marrow with typical megaloblastic features of erythropoiesis and granulopoiesis. A systemic hematological disorder could be ruled out. The folic acid deficiency in our patient was the result of a long time alcohol abuse and a simultaneous therapy with mild folate antagonists (triamteren and cotrimoxacol). CLINICAL COURSE:The patient received folic acid (5 mg/d orally). Within one week the peripheral blood counts increased to normal, the follow up bone marrow examination showed a hyperplastic marrow with normal hematopoietic maturation. CONCLUSIONS:Folic acid deficiency can be aggravated because of simultaneous therapy with mild folate antagonists. In addition to megaloblastic anemia this can lead to thrombocytopenia and/or leukocytopenia. Therefore in patients with pancytopenia a deficiency of folic acid should be ruled out.
Pancytopenia in a patient receiving home intravenous nutrition.
Wagner S,Wood S,Amess J A
European journal of clinical nutrition
A patient is described who developed pancytopenia several months after home intravenous nutrition (IVN) was started following a major small bowel resection for volvulus. In the post-operative period his weight fell by about 15 kg to 45 kg. Bone marrow aspiration and leucokinetic studies were carried out which suggested that bone marrow failure was the cause of this patient's haematological abnormalities. Five of the 16 patients at St Mark's Hospital who are receiving home IVN were noted to have had transient neutropenia. In 3 of these patients significant weight loss was also noted in the few months preceding the development of neutropenia. It is suggested that there is an association between relative energy malnutrition and the development of the haematological abnormalities that have been observed. In the patient described here these abnormalities were prolonged.
[Vitamin deficiency-induced pancytopenia mimicking leukemia. Three cases].
Cacoub P,Gatfosse M,Derbel A,Chapelon C,Verny C,Godeau P
Presse medicale (Paris, France : 1983)
Folate and vitamin B12 are indispensable to normal cell division. High turnover tissues, therefore, are the first to be affected when these vitamins are deficient. Such deficiencies, which are known to result in megaloblastic anaemia at a late stage, may also influence the granulocyte and platelet lines, but pancytopenia rarely occurs. We report 3 cases of pancytopenia associated with folate and/or vitamin B12 deficiency in elderly patients. In two of these patients bone marrow examination showed a misleading "pseudo-leukaemia" due to a significant proportion of strongly dystrophic young cells. Cure was obtained within 30 to 45 days of vitamin therapy, with complete normalization of the haemogram.
[Vitamin deficiency pancytopenia].
Talarmin F,Hugard L,Mion M,Sellier P,Charles D
Annales de medecine interne
Eight patients with vitamin deficiency pancytopenia were admitted, within a year, in a department of internal medicine. Folic acid and vitamin B12 metabolism and the clinical and haematological symptoms are discussed. These vitamin deficiencies are frequent in underdeveloped countries and are responsible of megaloblastic anaemia. Such deficiencies may also influence the granulocyte and platelet lines and may be mistaken for leukaemia. A therapeutic test may be undertaken, giving rapid diagnosis and avoiding high mortality.
[Folic acid deficiency can cause severe anemia and pancytopenia].
Brinch L,Tjønnfjord G,Ly B
Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke
Pancytopenia is occasionally a consequence of folate deficiency. The most important differential diagnostic considerations are haematologic malignancies, aplastic anaemia and vitamin B12 deficiency. We discuss the problem as exemplified by three patients. Bone marrow examination and determination of blood concentrations of vitamin B12 and folate will give the correct diagnosis.
Bello-González S A,Bergés-García A
Boletin medico del Hospital Infantil de Mexico
Peripheral pancytopenia is a syndrome which allows for an early diagnosis, and although is may cover a large number of pathological entities, it can be clearly defined into three groups of illnesses which evolve with this syndromal manifestations. The first group includes non-neoplastic illnesses which include aplastic anemia, hemophagocytic syndrome associated to infection, immunological diseases and the deficiency of folates or vitamin B12. The second group includes neoplastic diseases as acute leukemia, non-Hodgkin lymphoma, and Hodgkin's lymphoma with myelofibrosis, malignant histiocytosis and non-hematological neoplasms, like the neuroblastoma and the embryonal rhabdomyosarcoma. The third group is formed by illnesses which have some similarity with neoplasms.
Sulphasalazine associated pancytopenia may be caused by acute folate deficiency.
Logan E C,Williamson L M,Ryrie D R
Agranulocytosis and aplastic anaemia associated with sulphasalazine are well recognised, but pancytopenia caused by acute megaloblastic arrest of haemopoiesis while taking sulphasalazine has not previously been described. We report three patients who, after taking sulphasalazine for over two years, suddenly developed severe pancytopenia with gross megaloblastic changes in the marrow. In two patients there was a good response to high dose oral folic acid but the third required folinic acid. The mechanism appears to be acute folate deficiency, and the requirement for folinic acid in one case suggests that the known inhibition of folate metabolism by sulphasalazine also contributes. The syndrome appears to be associated with high dosage and slow acetylator status. The drug has been successfully restarted at reduced dosage with folate supplements in two patients both of whom were slow acetylators. In the third case, whose acetylator status is not known, progression of her disease led to colectomy.
[Pernicious anemia in an adolescent with type 1 diabetes mellitus].
Carneiro M,Dumont C
Archives de pediatrie : organe officiel de la Societe francaise de pediatrie
The most frequent organ-specific autoimmune diseases associated with type 1 diabetes mellitus in children are hypothyroidism and celiac disease. Among adults, other associations exist, notably with pernicious anemia, which is extremely rare in children. We relate the observation of an adolescent with type 1 diabetes mellitus and hypothyroidism, admitted for severe anemia in addition to chronic anemia caused by autoimmune gastritis. Blood cell count showed severe aregenerative anemia with pancytopenia, with signs of non-autoimmune hemolysis. Vitamin B12 levels were low, bone marrow aspiration revealed erythroid hyperplasia, and anti-intrinsic factor antibodies were positive, providing the diagnosis of pernicious anemia. Treatment with intramuscular vitamin B12 produced brisk reticulosis after 6 days, with a subsequent rapid resolution of the anemia. Follow-up of type 1 diabetes mellitus in children requires screening for organ-specific autoimmune diseases; in case of unexplained anemia, autoimmune gastritis must be suggested. It can evolve into pernicious anemia.
Pancytopenia due to vitamin B12 deficiency associated with Graves' disease.
Burns R W,Burns T W
Pancytopenia has a broad differential diagnosis, which can be narrowed depending on the cellularity of the bone marrow. The authors describe a complex patient with a history of Graves' disease who presented with pancytopenia, initially suspected of being due to aplastic anemia. He was later diagnosed with Vitamin B12 deficiency as a result of pernicious anemia. The potentially striking hematologic effects of cobalamin deficiency and the autoimmune basis for concurrent Graves' disease and pernicious anemia are reviewed.
Megaloblastic anemia: back in focus.
Indian journal of pediatrics
Megaloblastic anemia (MA), in most instances in developing countries, results from deficiency of vitamin B(12) or folic acid. Over the last two to three decades, incidence of MA seems to be increasing. Of the two micronutrients, folic acid deficiency contributed to MA in a large majority of cases. Now deficiency of B(12) is far more common. In addition to anemia, occurrence of neutropenia and/or thrombocytopenia is increasingly being reported. Among cases presenting with pancytopenia, MA stands out as an important (commonest cause in some series) cause. This article focuses on these and certain other aspects of MA. Possible causes of increasing incidence of MA are discussed. Observations on other clinical features like neurocognitive dysfunction, associated hyperhomocysteinemeia and occurrence of tremors and thrombocytosis during treatment are highlighted.
Hemorrhagic manifestation of megaloblastic anemia: report of two cases and literature review.
Masoodi Ibrahim,Kakar Atul,Byotra Shrishti P,Sachdev Munish K,Hussain Shabnum
Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis
Megaloblastic anemia is not uncommon in developing countries. Its presentation as thrombocytopenia and hemorrhagic manifestation are, however, rare. We describe the clinical scenario in two young patients who presented to the emergency room of Sir Ganga Ram Hospital, a tertiary care center in New Delhi, India, with pancytopenia and bleeding diathesis. Both patients improved after B12 supplementation. Reports of two cases and a brief review is presented.
Autoimmune pernicious anaemia as a cause of collapse, heart failure and marked panyctopaenia in a young patient.
Carey Justin,Hack Ebru
BMJ case reports
A 35-year-old woman with a history of vitiligo, hypothyroidism and amenorrhoea presented with collapse and clinical features of cardiac failure. Laboratory investigations revealed pancytopaenia, the cause of which was found to be vitamin B12 deficiency due to pernicious anaemia. Treatment with intramuscular hydroxycobalamin was commenced and the patient improved steadily with concomitant improvement in her haematological indices. Clinical features of pernicious anaemia which can include marked pancytopaenia, diagnostic approach, associated conditions and approach to treatment are discussed. The importance of surveillance for gastrointestinal malignancy is emphasised.
Folate and Vitamin B(12) deficiency presenting as pancytopenia in pregnancy: a case report and review of the literature.
Van de Velde A,Van Droogenbroeck J,Tjalma W,Jorens Ph G,Schroyens W,Berneman Z
European journal of obstetrics, gynecology, and reproductive biology
We present a case of extreme pancytopenia in a 27-year-old pregnant woman. The initial picture was compatible with a severe hematological problem in the category of aplastic anemia, paroxysmal nocturnal hemoglobinuria or even acute leukemia. The further biochemical investigations revealed, however, a folate deficiency. Nowadays this is a very rare cause of pancytopenia. Next to this she also had a Vitamin B(12) deficiency due to intrinsic factor failure. The recent literature is discussed.
Protein-energy malnutrition halts hemopoietic progenitor cells in the G0/G1 cell cycle stage, thereby altering cell production rates.
Borelli P,Barros F E V,Nakajima K,Blatt S L,Beutler B,Pereira J,Tsujita M,Favero G M,Fock R A
Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas
Protein energy malnutrition (PEM) is a syndrome that often results in immunodeficiency coupled with pancytopenia. Hemopoietic tissue requires a high nutrient supply and the proliferation, differentiation and maturation of cells occur in a constant and balanced manner, sensitive to the demands of specific cell lineages and dependent on the stem cell population. In the present study, we evaluated the effect of PEM on some aspects of hemopoiesis, analyzing the cell cycle of bone marrow cells and the percentage of progenitor cells in the bone marrow. Two-month-old male Swiss mice (N = 7-9 per group) were submitted to PEM with a low-protein diet (4%) or were fed a control diet (20% protein) ad libitum. When the experimental group had lost about 20% of their original body weight after 14 days, we collected blood and bone marrow cells to determine the percentage of progenitor cells and the number of cells in each phase of the cell cycle. Animals of both groups were stimulated with 5-fluorouracil. Blood analysis, bone marrow cell composition and cell cycle evaluation was performed after 10 days. Malnourished animals presented anemia, reticulocytopenia and leukopenia. Their bone marrow was hypocellular and depleted of progenitor cells. Malnourished animals also presented more cells than normal in phases G0 and G1 of the cell cycle. Thus, we conclude that PEM leads to the depletion of progenitor hemopoietic populations and changes in cellular development. We suggest that these changes are some of the primary causes of pancytopenia in cases of PEM.
A child with vitamin B12 deficiency presenting with pancytopenia and hyperpigmentation.
Simşek Ozlem Pelin,Gönç Nazli,Gümrük Fatma,Cetin Mualla
Journal of pediatric hematology/oncology
The authors describe a 16-month-old infant presenting with neurologic developmental regression, severe pancytopenia, excessive skin pigmentation, and tremor resulting from nutritional vitamin B12 deficiency. She had been exclusively breast-fed and had refused to take any other food. Laboratory studies showed severe pancytopenia, a decrease in serum B12 levels, and an increase in urinary methylmalonic acid levels. Bone marrow aspiration was compatible with megaloblastic changes. Schilling test was normal. The serum B12 level of the mother was also low. Megaloblastic anemia resulting from inadequate B12 intake was diagnosed. Parenteral B12 therapy was initiated. The neurologic picture did not completely resolve, but pancytopenia, tremor, and hyperpigmentation of the extremities recovered completely.
[Role of vitamin deficiency in pancytopenia in Djibouti. Findings in a series of 81 consectutive patients].
Lavigne C,Lavigne E,Massenet D,Binet C,Brémond J L,Prigent D
Medecine tropicale : revue du Corps de sante colonial
The purpose of this study of patients with pancytopenia in Republic of Djibouti was to identify etiologic factors and attempt to define diagnostic and therapeutic strategies adapted to local conditions. Clinical, biological and radiological assessment was performed in 81 patients hospitalized for pancytopenia. There were 56 men and 25 women. Mean hemoglobin, leukocyte and platelet rates were 56,5 +/- 22,7 g/l, 2,1 +/- 0,7.g/l and 56,2 +/- 24,7 g/l respectively. Vitamin deficiency was the most common cause of pancytopenia (49%), followed by hypersplenism (9%), HIV infection (6%) and leishmaniasis (6%). Vitamin-deficient patients had significantly more severe anemia and thrombopenia and significantly higher mean corpuscular volume than patients with pancytopenia related to other causes. Hemoglobin rate lower than 40 g/L and platelet rate lower than 35 G/L showed a positive predictive values of 90% and 100% respectively for a vitamin deficient pancytopenia. Vitamin deficiency is the most frequent etiology of pancytopenia and causes the most severe cytopenia in Djibouti. Rapid vitamin supplementation after minimal etiologic assessment including a myelogram is an effective treatment strategy for this public health problem.
[Pancytopenia and hemolysis--diagnosis, differential diagnosis and therapy of pernicious anemia].
Meier N,Lipp E,Solenthaler M
Deutsche medizinische Wochenschrift (1946)
Pernicious anemia and Vitamin B12 deficiency have a wide range of symptoms and are a common finding in the elderly. A 73 year old female is admitted to the hospital because of dyspnea, fatigue and loss of appetite and weight. While previous medical history and physical examination are inconspicuous, laboratory findings show severe pancytopenia with macrocytosis, low reticulocyte count and marked signs of hemolysis. A very low serum level of vitamin B12 and chronic atrophic type A gastritis upon endoscopy with presence of parietal cell antibodies in the serum lead to the diagnosis of pernicious anemia. Complete restitution is achieved by parenteral vitamin B12 substitution. Nowadays, severe pernicious anemia is only rarely seen. The differential diagnosis of pancytopenia (with macrocytic anemia) combined with hemolysis and the essential hints to the diagnosis of pernicious anemia are discussed, and thereby practical aspects including therapy actualized.
Severe vitamin B12 deficiency resulting in pancytopenia, splenomegaly and leukoerythroblastosis.
Halfdanarson Thorvardur R,Walker James A,Litzow Mark R,Hanson Curtis A
European journal of haematology
Deficiency of vitamin B12 is a well known cause of megaloblastic anemia and pancytopenia. Splenomegaly and leukoerythroblastosis are much less well known manifestations of B12 deficiency. We report a B12 deficient female with severe pancytopenia including normocytic anemia who also had enlarged spleen and circulating nucleated red blood cells as well as circulating immature myeloid cells. Although these findings are reported in the earlier literature, more modern reviews of the subject often fail to mention this association. We review the literature on these unusual manifestations of B12 deficiency and remind clinicians that splenomegaly and erythroblastosis can serve as diagnostic clues in cases of severe megaloblastic anemia secondary to B12 deficiency.
Pancytopenia due to vitamin B12 deficiency in a breast-fed infant.
Pediatric hematology and oncology
Nutritional B12 deficiency in childhood is an uncommon disorder. Most cases are due to maternal insufficiency, resulting from deficient stores and intake, and is generally seen in exclusively breast fed infants. This report describes a breast-fed infant with megaloblastic anemia secondary to maternal vitamin B12 deficiency. We describe this patient to remind readers that B12 deficiency may cause severe pancytopenia and regression of motor functions. These patients can present with unexpected signs and symptoms, such as developmental delay and regression as in our patient. It is also important to take the nutritional history of both the child and the mother of early prevention and treatment. With early awareness and appropriate measures potentially irreversible neurologic damage can be prevented in the infant.
[Pancytopenia and folate deficiency: a case report].
Roche Céline,Roche Nicolas-Charles,Thefenne Hélène,Saidi Redouan,De Pina Jean-Jacques,Molinier Sylvain,Oliver Manuela
Annales de biologie clinique
Anemia is the most common pathology encountered in hematology. Etiologies are numerous, so it is important to adopt a rigorous approach. Complementary examinations must be specific to the clinical situation in order to determine the mechanisms on the one hand and decide the therapeutic management on the other. We report the observation of a case of sudden onset of profound pancytopenia. Investigation led to the diagnosis of major folic acid deficiency with favorable evolution. Through this case, we describe the diagnostic approach towards anemia and the mechanisms involved in the formation of folate deficiency.
Vitamin B(12)-responsive pancytopenia mimicking myelodysplastic syndrome.
Kim Myungshin,Lee Sung-Eun,Park Joonhong,Lim Jihyang,Cho Byung-Sik,Kim Yoo-Jin,Kim Hee-Je,Lee Seok,Min Chang-Ki,Kim Yonggoo,Cho Seok-Goo
This study presents 12 patients (7 women and 5 men) with vitamin B(12)-responsive pancytopenia who had discordant laboratory findings and were misdiagnosed as having myelodysplastic syndrome (MDS). The median hemoglobin level was 6.5 g/dl, and the leukocyte and platelet counts were 2.85 × 10(9)/l and 55.5 × 10(9)/l, respectively. The median serum lactate dehydrogenase level was high (3,204.5 IU/l). The serum vitamin B(12) levels were within normal limits at the initial evaluation, but a serial follow-up of the vitamin B(12) levels revealed either fluctuations or a gradual decrease. The patients were initially diagnosed with MDS and responded rapidly to a 7-day parenteral B(12) treatment with normal complete blood counts (CBCs). We propose that patients suspected to have MDS may suffer from vitamin B(12) deficiency and that this can be revealed by a normalization of CBCs following 7 days of treatment with parental vitamin B(12).
Severe folate-deficiency pancytopenia.
Clarke Viktoriya,Weston-Smith Simon
BMJ case reports
Folate-deficiency anaemia occurs in about 4 per 100 000 people, although severe cases causing moderate pancytopenia are rarer. We present the case of a significant folate deficiency in a 50-year-old alcoholic with a background of mild liver impairment and recurrent nasal and rectal bleeding. Her blood tests showed profound macrocytic anaemia with haemoglobin 2.6 g/dl, leucopoenia with white cell count 3.2 × 10(9)/litre and thrombocytopenia with platelets 17 × 10(9)/litre. Serum folate was 0.8 ng/ml (normal 2.5-13.5 ng/ml) confirming severe deficiency. Despite these life-threatening results, the patient was stable, alert and was keen to avoid admission. Medical management of the anaemia included slow transfusion of red cells and one unit of platelets in view of haemorrhagic symptoms, two injections of vitamin B12 while awaiting assays and oral folic acid. A rapid improvement in the leucopoenia and thrombocytopenia resulted and no additional complications were encountered.
Hematologic Manifestations of Nutritional Deficiencies: Early Recognition is Essential to Prevent Serious Complications.
Yu Jennifer C,Shliakhtsitsava Ksenya,Wang YunZu M,Paul Megan,Farnaes Lauge,Wong Victor,Kim Jenny,Thornburg Courtney D
Journal of pediatric hematology/oncology
Nutritional deficiencies, including deficiencies of vitamin B12, copper, and vitamin C, may result in cytopenias and hematologic symptoms. Early recognition of these deficiencies is imperative for prompt treatment and improvement in hematologic and other manifestations. We describe 5 cases which illustrate the hematologic manifestations of nutritional deficiencies and challenges to initial diagnosis and management. Supplementation of the deficient vitamin or micronutrient in all of these cases resulted in rapid resolution of cytopenias, hemorrhage, and other associated hematologic symptoms. We also review other nutritional deficiencies that manifest with hematologic symptoms and compile recommendations on treatment and expected time to response.
Severe vitamin B12 deficiency in a breast fed infant with pancytopenia.
Citak Funda Erkasar,Citak Elvan Caglar
Journal of tropical pediatrics
We report the case of a 7-month-old breast fed infant who presented with a nose bleed and bruises. Investigation showed severe nutritional B12 deficiency anemia with a pancytopenia. It is important to take the nutritional history of both the infant and the mother for early prevention and treatment.
Subacute combined spinal cord degeneration and pancytopenia secondary to severe vitamin B12 deficiency.
Cabrerizo-García José Luis,Sebastián-Royo Mariano,Montes Nerea,Zalba-Etayo Begoña
Sao Paulo medical journal = Revista paulista de medicina
CONTEXT:Decreased vitamin B12 concentration does not usually result in clinical or hematological abnormalities. Subacute combined spinal cord degeneration and pancytopenia are two serious and rarely displayed consequences that appear in severe deficits. CASE REPORT:We present the case of a patient with subacute combined spinal cord degeneration and pancytopenia secondary to severe and sustained vitamin B12 deficiency. Such cases are rare nowadays and have potentially fatal consequences. CONCLUSIONS:Vitamin B12 deficiency should be taken into consideration in the differential diagnosis in cases of blood disorders or severe neurological symptoms. Early diagnosis and treatment can avoid irreversible consequences.
Another cause of pancytopenia in a patient receiving temozolomide.
Pehlivan Yavuz,Sevinc Alper,Turkbeyler Ibrahim Halil,Dirier Ahmet,Kalender Mehmet Emin,Camci Celalettin
Medical principles and practice : international journal of the Kuwait University, Health Science Centre
OBJECTIVE:To report pancytopenia caused by temozolomide, a second-generation alkylating agent. CLINICAL PRESENTATION AND INTERVENTION:A 22-year-old patient presenting with seizures and confusion was seen in the emergency room. Cranial magnetic resonance imaging revealed a mass. After surgery, the patient was diagnosed with glioblastoma multiforme and was given temozolomide at 150 mg/m(2) on days 1 through 5 every 4 weeks. During the last cycle of temozolomide, grade 3 thrombocytopenia persisted. Possible causes of pancytopenia including vitamin B(12) deficiency were investigated. CONCLUSION:This case report shows that vitamin B(12) deficiency can be a potential cause of pancytopenia and it should be kept in mind for patients receiving chemotherapy.
Reversible pancytopenia and immunodeficiency in a patient with hereditary folate malabsorption.
Erlacher Miriam,Grünert Sarah Catharina,Cseh Annamaria,Steinfeld Robert,Salzer Ulrich,Lausch Ekkehart,Nosswitz Ulrike,Dückers Gregor,Niehues Tim,Ehl Stephan,Niemeyer Charlotte Marie,Speckmann Carsten
Pediatric blood & cancer
Mutations in SLC46A1 result in a defect of the proton coupled folate transporter (PCFT) and are the basis of hereditary folate malabsorption (HFM). Patients with HFM frequently present with neurodevelopmental delay and megaloblastic anemia. Some cases may be complicated by additional lymphopenia and immunodeficiency. We report a patient with a new homozygous mutation in the SLC46A1 gene. The boy presented with early-onset pancytopenia and secondary immunodeficiency. We provide clinical and molecular observations that extend the phenotypic description of HFM and highlight diagnostic as well as therapeutic pitfalls in this rare condition.
Severe vitamin B₁₂ deficiency in a 15-year-old boy: presentation with haemolysis and pancytopenia.
Keskin Ebru Yılmaz,Keskin Mahmut
BMJ case reports
A 15-year-old boy on a vegetarian diet presented with severe macrocytic anaemia (haemoglobin, 5.1 g/dL; mean corpuscular volume, 116 fL) in addition to leucopenia and thrombocytopaenia (pancytopenia), icterus secondary to haemolysis and splenomegaly. Laboratory investigations revealed severe vitamin B12 (cobalamin) deficiency. Following cobalamin replacement therapy, the patient reported increased well-being, including appetite and weight gain, and his icterus resolved. In the follow-up laboratory examinations, leucocyte and platelet counts in addition to serum bilirubin and lactate dehydrogenase levels normalised. At the end of 2 months, laboratory findings, including haemoglobin level, were all within the normal range. We present this case as a reminder that severe vitamin B12 deficiency may present with findings mimicking acute leukaemia (pancytopenia and splenomegaly) and findings suggestive of pseudothrombotic microangiopathy.
Isolated folate deficiency causing profound pancytopenia in pregnancy.
Obaji Samya Gwen,Al-Ismail Saad
BMJ case reports
New-onset pancytopenia in pregnancy is challenging in the clinical setting particularly as the management and outcome of pregnancy are entirely dependent on the underlying aetiology. In the absence of increased peripheral destruction, for example, hypersplenism, bone marrow (BM) failure should be considered as the cause of pancytopenia. Profound folate or B12 deficiency may result in BM failure and are relatively easy to diagnose and manage. Other causes include aplastic anaemia (AA), infiltration by a haematological malignancy and other non-haematological disorders. We report a 26-year-old woman presenting with severe pancytopenia due to folate deficiency with complete recovery observed after folic acid replacement. This case highlights the importance of recognising folate deficiency as a reversible cause of pancytopenia, since prompt replacement can lead to rapid normalisation of counts with no subsequent clinical sequelae. We also consider the indications for measuring serum folate in pregnancy.
Severe pancytopenia due to acute folate deficiency despite normal folate erythrocyte level.
Huguenin Antoine,Barraud Sara,Daliphard Sylvie,Marot Didier,Garnotel Roselyne,Bani-Sadr Firouzé
Annales de biologie clinique
We report the case of an alcoholic patient with severe pancytopenia with low plasma folate level but normal erythrocyte folates and cobalamin levels. The bone marrow smear concluded to a pancytopenia due to folates and/or cobalamin deficiency. Severe pancytopenia due to acute plasma folate deficiency can be observed despite normal erythrocyte folates level which reflects the organism's folates store.
Hypocobalaminaemia as a cause of bone marrow failure and pancytopenia in a cat.
Stanley E L,Eatroff A E
Australian veterinary journal
CASE REPORT:A male Domestic Short-hair cat was presented for chronic weight loss, lethargy and hyporexia. Complete haematological examination revealed non-regenerative anaemia, neutropenia and thrombocytopenia, as well as Howell-Jolly bodies, anisocytosis, polychromasia and macrocytosis on blood smear evaluation. Histopathological evaluation of bone marrow biopsy disclosed hypocellularity consistent with bone marrow failure. Concurrent hypocobalaminaemia was identified and treated with parenteral cyanocobalamin supplementation. Other differential diagnoses for pancytopenia, including infectious, toxic, immune-mediated and neoplastic causes, were ruled out. CONCLUSION:The cat's erythrocyte, leucocyte and platelet counts normalised after 2 months of cyanocobalamin supplementation, suggesting that pancytopenia may be a rare manifestation of feline cobalamin deficiency.
Anorexia nervosa-associated pancytopenia mimicking idiopathic aplastic anemia: a case report.
Takeshima Masahiro,Ishikawa Hiroyasu,Kitadate Akihiro,Sasaki Ryo,Kobayashi Takahiro,Nanjyo Hiroshi,Kanbayashi Takashi,Shimizu Tetsuo
BACKGROUND:Patients with anorexia nervosa (AN) often present with pancytopenia. In most cases described in the literature, AN with pancytopenia demonstrates gelatinous marrow transformation (GMT), which is a typical bone marrow feature of malnutrition. Differentiation of AN-associated pancytopenia from other types of pancytopenia, especially idiopathic aplastic anemia (IAA), has not been studied. We encountered a case of pancytopenia in a patient with AN and relatively poor nutritional status, whose hematological findings mimicked those of IAA, specifically fatty bone marrow and absence of GMT. CASE PRESENTATION:The patient was a 32-year-old woman with poorly controlled AN. At 31 years of age, her body mass index (BMI) had fallen from 17.0 kg/m to below 13.8 kg/m. The patient presented with ongoing fatigue and thus was examined by a hematologist. Hematological findings were consistent with IAA: peripheral blood tests revealed pancytopenia, whereas the bone marrow displayed fatty replacement without GMT. Despite the absence of bone marrow features typically seen in malnutrition, the patient's hematological abnormalities had manifested after a decrease in body weight. Thus, although the bone marrow findings indicated IAA, we considered that the nutritional etiology of pancytopenia could not be thoroughly ruled out. Using nutritional therapy alone, the hematological abnormalities improved as BMI increased to 16.5 kg/m. The final diagnosis was pancytopenia secondary to malnutrition because pancytopenia and fatty bone marrow improved after implementation of nutritional therapy alone. CONCLUSIONS:The present case is the first documented case of AN with pancytopenia for which bone marrow examination confirmed fatty marrow without any evidence of GMT. IAA and pancytopenia secondary to malnutrition can present the same clinical findings. This case is significant because it suggests a need to differentiate between malnutrition and IAA.
Effect of protein deprivation on hematopoietic stem cells and on peripheral blood counts.
Fried W,Barone S J,Anagnostou A
The Journal of laboratory and clinical medicine
Experiments were performed to determined the effect of protein deprivation on CFU-S in the spleen and femoral marrow, on the peripheral blood counts, and on the rate at which these parameters regenerate following radiation. Splenic CFU-S decrease in number after only 3 days on diets containing 5% protein or less. Marrow CFU-S, on the other hand, decrease only after mice are fed a protein-free diet for 4 weeks or more. The hematocrits, platelet counts, and WBC counts fall in the latter group. Marrow CFU-S regenerate more slowly in irradiated mice fed diets containing 5% protein or less. Also, the hemocrits, WBC counts, and platelet counts of irradiated mice fed diets containing 5% protein regenerate more slowly than do those of irradiated mice fed normal diets. The effect of protein deprivation on erythropoietin production, erythropoiesis, granulocyte function, and immunocompetence is well known. The studies reported here indicate, in addition, that protein deprivation also causes the numbers of CFU-S and the platelet counts to decline.
A case of asymptomatic pancytopenia with clinical features of hemolysis as a presentation of pernicious anemia.
Kollipara Venkateswara K,Brine Patrick L,Gemmel David,Ingnam Sisham
Journal of community hospital internal medicine perspectives
Pernicious anemia is an autoimmune disease with a variety of clinical presentations. We describe a case of pernicious anemia presenting with pancytopenia with hemolytic features. Further workup revealed very low vitamin B12 levels and elevated methylmalonic acid. It is important for a general internist to identify pernicious anemia as one of the cause of pancytopenia and hemolytic anemia to avoid extensive workup. Pernicious anemia can present strictly with hematological abnormalities without neurological problems or vice versa as in our case.
Pathophysiology and laboratory diagnosis of pernicious anemia.
Pernicious anemia is the hematologic manifestation of chronic atrophic gastritis affecting the corpus of the stomach that denudes the gastric mucosa of gastric parietal cells. Asymptomatic autoimmune gastritis, a chronic inflammatory disease of the gastric mucosa, precedes the onset of corpus atrophy by 10-20 years. The gastritis arises from activation of pathologic Th1 CD4 T cells to gastric H/K ATPase that is normally resident on gastric mucosal secretory membranes. The onset of autoimmune gastritis is marked by circulating parietal cell antibody to gastric H/K ATPase. Gastric parietal cells produce two essential biologics: intrinsic factor and HCl acid. Pernicious anemia is a consequence of intrinsic factor loss and neutralizing intrinsic factor antibody that impairs cobalamin absorption. Acid loss leads to iron deficiency anemia that precedes cobalamin-deficient pernicious anemia by 20 years. Laboratory diagnosis rests on parietal cell antibody with or without intrinsic factor antibody, cobalamin-deficient megaloblastic anemia and elevated serum gastrin from loss of acid secretion. Autoimmune gastritis is associated with autoimmune thyroiditis and type 1 diabetes mellitus.
Challenging clinical presentations of pernicious anemia.
Oo Thein Hlaing,Rojas-Hernandez Cristhiam Mauricio
Pernicious anemia (PA) is an autoimmune disease of multifactorial etiologies characterized by autoimmune chronic atrophic gastritis, cobalamin deficiency (CD) due to defective absorption of dietary cobalamin from the terminal ileum, and by the presence of intrinsic factor and parietal cell antibodies. PA is a very common cause of CD-related anemia worldwide. Despite advances in the understanding molecular biology and pathophysiology of PA, the diagnosis of PA remains challenging in many circumstances for many clinicians because of its diverse clinical manifestations and the limitations of currently available diagnostic tools. Diagnostic dilemmas could occur when patients with PA present with spuriously normal or high cobalamin levels, normocytic or microcytic anemia, non-anemic macrocytosis, autoimmune hemolytic anemia, pseudo-thrombotic microangiopathy, hyperhomocysteinemia-associated thromboembolism, pseudoleu-kemia, bone marrow failure, bone marrow ring sideroblasts, and neurologic manifestations without anemia or macrocytosis. Herein, we provide an overview of the challenging clinical presentations of PA, diagnostic approach, and management.
Defective in vitro granulopoiesis in patients with anorexia nervosa.
Vaisman N,Barak Y,Hahn T,Karov Y,Malach L,Barak V
Patients with anorexia nervosa (AN) frequently suffer from a mild degree of anemia and from moderate leukopenia on top of their undernourished state and metabolic disarrangements. To evaluate in vitro granulopoiesis and its relationship to cytokine production and undernutrition, we have studied 10 adolescent girls with moderate AN (age range, 13.5-18.0). Study methods included assessment of peripheral blood (PB) granulocyte-macrophage colony-forming cells (GM-CFC) of the patients and age-matched controls, and determination of plasma and conditioned medium (CM) of mononuclear cells levels of IL-1, IL-3, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF), all of which may play a role in GM-CFC growth regulation. GM-CFC numbers were significantly lower in AN patients compared with the normal controls (13.09 +/- 11.15 versus 39.33 +/- 26.61 colonies/5 x 10(5) cells, p < 0.01). No inhibitory effect was found in either plasma or CM of patients with AN. However, when CM were applied to non-recombinant human GM-CSF-stimulated normal bone marrow GM-CFC targets, the number of colonies stimulated by the CM of patients with AN was significantly lower than those stimulated by the CM of the controls (73.5 +/- 20.1 versus 113.0 +/- 11.6, p < 0.025). GM-CSF concentrations in CM were significantly lower in patients with AN compared with normal controls, but no such differences were found in IL-1, IL-3, IL-6, or TNF concentrations. These results indicate defective in vitro granulopoiesis in AN patients, manifested by a reduction of both GM-CFC and GM-CSF. It has to be determined whether these changes are the result of the basic disease process or are they due to malnutrition.
[Influenza-virus associated hemophagocytic syndrome in a patient with pernicious anemia].
Shirono K,Tsuda H,Akahoshi I
[Rinsho ketsueki] The Japanese journal of clinical hematology
A 59-year-old man with pernicious anemia (vitamin B12 deficiency) was admitted because of rapidly developing pancytopenia with the symptoms of influenza. Laboratory data indicated that the pancytopenia was manifested by influenza virus-associated hemophagocytic syndrome. In the patients with pernicious anemia, it is known that there are immunologic disturbances in either humoral and cellular immunity and increased hematopoiesis due to ineffective hematopoiesis. This patient was thought to have developed influenza virus-associated hemophagocytic syndrome due to the immunologic and hematopoietic abnormality in the pernicious anemia.
Kinetics of mobilization of neutrophils and their marrow pool in protein-calorie deficiency.
Suda A K,Mathur M,Deo K,Deo M G
Migration of marrow neutrophils under basal conditions and their mobilization, following subcutaneous implantation of cover slips, were investigated in groups of protein-deficient rats, using 3HTdR with sequential autoradiography of the peripheral blood smears. Animals fed a protein-rich diet served as controls. The pattern of appearance of labeled neutrophils in the blood was identical in the two groups under basal conditions. However, a higher percentag of labeled neutrophils appeared earlier in the blood following cover slip implantation in the deficient rats as compared to controls. The inflammatory exudate on the cover slips was low throughout the period of observation in deficient animals, with a delay in the appearance of monocytes. A pool of mature neutrophils resides in the bone marrow. It is proposed that in PCM there is atrophy of all neutrophil compartments, including that of the marrow pool, associated with a proportionate reduction in the efflux of cells from one compartment to another. This proportionate reduction in efflux would explain the normal kinetics of migration of neutrophils under basal conditions in the deficient rats in spite of a reduction in the marrow pool. On the other hand, in cover slip-implanted deficient rats, appearance of larger numbers of labeled neutrophils in the blood is attributed to a reduction in size of the marrow pool. This hypothesis is substantiated by the experiments in protein-deficient monkeys in which estimation of the marrow pool of neutrophils revealed a marked reduction in the deficient animals. It is further proposed that a diminuation of the marrow pool of neutrophils and retarded mobilization of cells at the site of inflammation are important mechanism responsible for the increased susceptibility of the malnourished host to infections.
Vitamin D and anemia: insights into an emerging association.
Smith Ellen M,Tangpricha Vin
Current opinion in endocrinology, diabetes, and obesity
PURPOSE OF REVIEW:The current review highlights recent findings in the emerging association between vitamin D and anemia through discussion of mechanistic studies, epidemiologic studies, and clinical trials. RECENT FINDINGS:Vitamin D has previously been found to be associated with anemia in various healthy and diseased populations. Recent studies indicate that the association may differ between race and ethnic groups and is likely specific to anemia of inflammation. The mechanism underlying this association involves the reduction of proinflammatory cytokines by vitamin D and the direct suppression of hepcidin mRNA transcription. There is also evidence that vitamin D may be protective against anemia by supporting erythropoiesis. Other calciotropic hormones including fibroblast growth factor 23, and parathyroid hormone have also been found to be associated with iron homeostasis and erythropoiesis. SUMMARY:Recent advances in our understanding of the association between vitamin D and anemia suggest that maintenance of sufficient vitamin D status may be important in preventing anemia, particularly in diseases characterized by inflammation. Early clinical trials have been promising, but further research is needed to define the efficacy of vitamin D as a future approach for the treatment of anemia.
Assessment of DNA damage in spleen, bone marrow, and peripheral blood from malnourished rats by single cell gel electrophoresis assay.
Cortés E,González C,Betancourt M,Ortiz R
Teratogenesis, carcinogenesis, and mutagenesis
Severe malnutrition is widely distributed throughout the world and exhibits a high prevalence in developing countries. Experimental malnutrition models have been useful to study the effects of malnutrition at early ages. The purpose of this study was to determine if severe malnutrition induced during lactation in rats increases DNA damage in spleen, peripheral blood, and bone marrow cells, as well as in isolated lymphocytes or lymphoid cells from the same tissues. These cells were obtained from malnourished rats at weaning (21 days of age). DNA damage was estimated by using the alkaline single cell electrophoresis assay. The results obtained in this study indicate that malnutrition is associated with a significant increase in DNA damage in all cell types that were studied in malnourished rats. The analysis of the length of DNA migration and dispersion coefficient showed that some cell types were more susceptible to DNA damage related with malnutrition. The damage observed could be due to the deficiency of several essential nutrients required for protein synthesis that are associated with DNA integrity, impaired DNA repair mechanisms, and/or to the unavailability of molecules necessary to protect the cells against DNA oxidative damage. This damage may produce negative effects for the further development of the organism, since bone marrow is the main site of hematopoiesis and spleen is an important lymphopoietic organ. Also, the increased level of DNA damage in peripheral blood lymphocytes and leukocytes could be related to negative effects such as a deficient immune response.
Serum immunoreactive erythropoietin and erythropoiesis in protein-energy malnutrition.
Wickramasinghe S N,Cotes P M,Gill D S,Tam R C,Grange A,Akinyanju O O
British journal of haematology
Immunoreactive erythropoietin was estimated in the sera of 23 Nigerian children with protein-energy malnutrition (PEM) and 14 healthy Nigerian children of similar age attending a well baby clinic. The geometric mean estimate for this parameter was 262 mIU/ml (observed range 39-1340 mIU/ml; 95% confidence range 25-1738 mIU/ml) in the children with PEM and 80 mIU/ml (observed range 43-257 mIU/ml; 95% confidence range 27-241 mIU/ml) in the health children. Erythropoietin levels were above the 95% confidence range for the healthy children in 14 of the cases of PEM. There was a statistically significant inverse correlation between the haemoglobin levels of the children with PEM and the logarithm of immunoreactive serum erythropoietin estimates (r = -0.73; P less than 0.001). By contrast, statistically significant correlations were not found between the logarithm of erythropoietin estimates and either the percentage of erythroblasts in the marrow, the M/E ratio or the logarithm of the absolute blood reticulocyte count. These data suggest that there is no abnormality of erythropoietin production in PEM and that the anaemia seen in this condition results from an impairment of erythropoiesis. A stepwise multiple regression analysis revealed a positive correlation between the logarithm of the erythropoietin level and the logarithm of the concentration of circulating neutrophil metamyelocytes plus myelocytes and we speculate on the aetiology of this finding.
Ultrastructure and cell cycle distribution of bone marrow cells in protein-energy malnutrition.
Wickramasinghe S N,Akinyanju O O,Grange A
Clinical and laboratory haematology
Bone marrow aspirates from four children with kwashiorkor and three with marasmus were studied using the techniques of electron microscopy and combined Feulgen microspectrophotometry and 3H-thymidine autoradiography. The majority of the erythroblasts were ultrastructurally normal, the distribution of the early polychromatic erythroblasts between the various stages of the cell cycle was normal or almost normal, and the macrophages did not contain ingested erythroblasts. Since erythropoietin production has been shown to be normal in protein-energy malnutrition, these findings suggest that at least in some cases of PEM the impairment of erythropoiesis results primarily from an abnormality in the erythroid progenitor cell pool rather than from dyserythropoiesis and ineffective erythropoiesis. In one afebrile and apparently uninfected patient with marasmus, a substantial proportion of the neutrophil granulocytes and their more mature precursors contained electron-dense, myelin-containing intracytoplasmic structures which were presumed to be abnormal primary granules. In four of the patients, the 3H-thymidine labelling index of the neutrophil promyelocyte-myelocyte pool was increased. In addition, in all of the cases, neutrophils at various stages of degradation were readily found within the cytoplasm of some of the macrophages. Thus, whereas the techniques employed did not reveal a major disturbance in the morphologically recognizable precursor cells of the erythroid series in PEM, they demonstrated some abnormalities in such cells of the neutrophil series.
Folate levels and deoxyuridine suppression tests in protein-energy malnutrition.
Wickramasinghe S N,Akinyanju O O,Grange A,Litwinczuk R A
British journal of haematology
A group of 39 Nigerian infants and pre-school children with protein-energy malnutrition (PEM) have been studied. Red cell folate levels were within the range observed in 19 age-matched healthy Nigerian children. Serum vitamin B12 levels were either normal or raised. Deoxyuridine (dU) suppression tests were performed on the bone marrow cells of 30 of the patients and were abnormal in 13. It is proposed that the abnormal dU-suppressed values were not caused by vitamin B12 or folate deficiency and were probably a consequence of the protein deficiency. A few megaloblasts and several giant metamyelocytes were found in four of the cases of PEM; the remaining 35 cases had normoblastic erythropoiesis, sometimes with small to moderate numbers of giant metamyelocytes. All four marrow samples containing megaloblasts gave abnormal dU-suppressed values. However, in the marrows showing normoblastic erythropoiesis there was no correlation between the presence or absence of giant metamyelocytes and the dU-suppressed value.
Alterations in proteins of bone marrow extracellular matrix in undernourished mice.
Vituri C L,Alvarez-Silva M,Trentin A G,Borelli P
Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas
The objective of the present study was to determine the effect of protein malnutrition on the glycoprotein content of bone marrow extracellular matrix (ECM). Two-month-old male Swiss mice were submitted to protein malnutrition with a low-protein diet containing 4% casein as compared to 20% casein in the control diet. When the experimental group had attained a 20% loss of their original body weight, we extracted the ECM proteins from bone marrow with PBS buffer, and analyzed ECM samples by SDS-PAGE (7.5%) and ECL Western blotting. Quantitative differences were observed between control and experimental groups. Bone marrow ECM from undernourished mice had greater amounts of extractable fibronectin (1.6-fold increase) and laminin (4.8-fold increase) when compared to the control group. These results suggest an association between fluctuations in the composition of the hematopoietic microenvironment and altered hematopoiesis observed in undernourished mice.
[Hematopoietic changes in states of severe malnutrition in anorexia nervosa].
Jarrige A,Marinof C,Moron P
This work, studying the effects of severe caloric deficiency on the medullary activity, shows that, in anorexia nervosa, there are some modifications of the stem cells, in particular in the granulocyte line and that its rarefaction is proportional to the intensity of denutrition. The reduction of the stock of stem cells, for which two hypotheses have been raised, could be a factor of vulnerability to infections in these patients in case of severe denutrition.
Pancytopenia in an adult patient with thiamine-responsive megaloblastic anaemia.
Moulin Virginie,Grandoni Francesco,Castioni Julien,Lu Henri
BMJ case reports
Thiamine-responsive megaloblastic anaemia (TRMA) is a syndrome associated with megaloblastic anaemia, diabetes mellitus and sensorineural deafness, due to mutations in the gene, which codes for a thiamine carrier protein. Oral thiamine supplementation is the main treatment. We report the case of a 25-year-old woman known for TRMA, who presented with pancytopenia (haemoglobin 7.6 g/dL, leucocytes 2.9×10/L, thrombocytes 6×10/L) revealed by dyspnoea. Investigations excluded coagulopathy, a recent viral infection, vitamin and iron deficiencies, and a malignant process. We later found out that thiamine treatment had been discontinued 5 weeks before, due to prescription error. Parenteral thiamine administration resulted in the recovery of haematopoiesis within 3 weeks. Pancytopenia is uncommon in patients with TRMA. Pre-existing medullary impairment caused by the patient's daily antipsychotic medications or the natural course of the syndrome may explain the severity of the laboratory findings in our patient.
Ineffective hematopoiesis in folate-deficient mice.
Bills N D,Koury M J,Clifford A J,Dessypris E N
A folate-free amino acid-based diet provided an opportunity to characterize the effects of folate depletion on growth, tissue folate levels, and hematopoiesis of mice under well-standardized conditions. Weanling mice were fed a folate-free, amino acid-based diet supplemented with either 0 or 2 mg folic acid/kg diet for 35 to 48 days. Folate concentrations were decreased in liver, kidney, serum, and erythrocytes in mice fed the folate-free diet. The folate-deficient mice had anemia, reticulocytopenia, thrombocytopenia, and leukopenia, all of which reverted to normal after folic acid was reintroduced to the diet. Hematopoietic organs of folate-deficient mice had alterations that were similar to those seen in folate-deficient humans except that in mice, the hyperplasia of hematopoietic tissue occurred in the spleen rather than in the marrow. Ferrokinetic studies showed a normal 59Fe-transferrin half-life, but the percentage of 59Fe-incorporation into red blood cells at 48 hours was markedly subnormal. The number of committed hematopoietic progenitors at the stages of erythroid colony-forming units (CFUs), megakaryocyte CFUs, and granulocyte-macrophage CFUs were all increased in folate-deficient mice. However, the progeny of these progenitors was markedly decreased in folate-deficient mice. Thus, the folate-deficient mice had "ineffective hematopoiesis" leading to pancytopenia, and they therefore provide a murine model of megaloblastic anemia.
The correctability of the nutritional, immune, and hematopoietic manifestations of protein calorie malnutrition in the elderly.
Lipschitz D A,Mitchell C O
Journal of the American College of Nutrition
Protein calorie malnutrition is being recognized with greater frequency in the hospitalized patient. This report describes the clinical presentation and response to nutritional therapy in nine elderly malnourished patients ranging from 73 to 95 years. Clinical features of malnutrition include weight loss, confusion, hypoalbuminemia (mean 2.8 gm/dl), a low total iron binding capacity (TIBC) (mean 192 micrograms/dl), anergy, lymphocytopenia (mean 1 X 10(3) cells/microliter) and an anemia (mean 9.0 gm/dl). Our subjects were followed for 42 days. In two, hyperalimentation was achieved by voluntary food intake and polymeric dietary supplements. In seven, feeding for 21 days via nasogastric tube was required. After three weeks, weight gain, decreased confusion, improved appetite and mobility, and significant increases in serum albumin and TIBC were seen. At that time, no subject was anergic and lymphocyte counts increased significantly. Increase in the serum iron and percent saturation was noted, and by day 42, a significant elevation in the hemoglobin occurred. As a measure of stem cell function, the committed granulocyte/macrophage progenitor cell (CFU-C) was quantitated in four subjects prior to and following 21 days of nutritional support. A marked increase in CFU-C number from a mean of 0.1 X 10(7) cells/kg to a normal value of 0.85 X 10(7) cells/kg was seen. Thus in addition to correcting the nutritional deficit, hyperalimentation returned immune and hematopoietic abnormalities to near normal levels. While improvement could reflect recovery from an associated disease, it is just as likely that correction of malnutrition, a well-recognized cause of these immunologic and hematopoietic abnormalities, accounted for the response. These observations emphasize the importance of recognizing malnutrition in the elderly and highlight the need for a careful nutritional assessment prior to ascribing hematologic and immunologic abnormalities to the aging process.
Dietary supplementation with Lactobacilli improves emergency granulopoiesis in protein-malnourished mice and enhances respiratory innate immune response.
Herrera Matias,Salva Susana,Villena Julio,Barbieri Natalia,Marranzino Gabriela,Alvarez Susana
This work studied the effect of protein malnutrition on the hemato-immune response to the respiratory challenge with Streptococcus pneumoniae and evaluated whether the dietary recovery with a probiotic strain has a beneficial effect in that response. Three important conclusions can be inferred from the results presented in this work: a) protein-malnutrition significantly impairs the emergency myelopoiesis induced by the generation of the innate immune response against pneumococcal infection; b) repletion of malnourished mice with treatments including nasally or orally administered Lactobacillus rhamnosus CRL1505 are able to significantly accelerate the recovery of granulopoiesis and improve innate immunity and; c) the immunological mechanisms involved in the protective effect of immunobiotics vary according to the route of administration. The study demonstrated that dietary recovery of malnourished mice with oral or nasal administration of L. rhamnosus CRL1505 improves emergency granulopoiesis and that CXCR4/CXCR12 signaling would be involved in this effect. Then, the results summarized here are a starting point for future research and open up broad prospects for future applications of probiotics in the recovery of immunocompromised malnourished hosts.
Evaluation of erythropoiesis in protein energy malnutrition.
el-Nawawy A,Barakat S,Elwalily T,Abdel-Moneim Deghady A,Hussein M
Eastern Mediterranean health journal = La revue de sante de la Mediterranee orientale = al-Majallah al-sihhiyah li-sharq al-mutawassit
This study evaluated erythropoiesis in 50 infants hospitalized with protein energy malnutrition and in 50 control infants. The red cell count, mean corpuscular haemoglobin and reticulocyte index were significantly lower, while the white blood cell count, median corpuscular fragility and red cell distribution width were significantly higher on admission than in controls. Total serum protein, albumin, fasting blood glucose, and serum folate were significantly lower on admission than in controls. Serum ferritin was significantly higher and total iron-binding capacity was significantly lower on discharge compared to controls. The serum erythropoietin was significantly higher on admission and discharge than in controls. The anaemia of protein energy malnutrition is due to mixed deficiencies resulting in ineffective erythropoiesis despite an increased level of erythropoietin.
Protein-energy malnutrition decreases the expression of TLR-4/MD-2 and CD14 receptors in peritoneal macrophages and reduces the synthesis of TNF-alpha in response to lipopolysaccharide (LPS) in mice.
Fock Ricardo Ambrósio,Vinolo Marco Aurélio Ramirez,de Moura Sá Rocha Vanessa,de Sá Rocha Luiz Carlos,Borelli Primavera
Protein-energy malnutrition (PEM) modifies resistance to infection, impairing a number of physiological processes, including hematopoiesis. In this study, we examined a few aspects of the inflammatory response to LPS in a model of PEM. We evaluated the cellularity of the blood, bone marrow and spleen, as well as phagocytic, fungicidal and spreading activity, the production in vivo and in vitro of TNF-alpha, IL-1alpha and IL-6, and the expression of CD14 and TLR-4/MD-2 receptors in macrophages. Two-month-old male Swiss mice were submitted to PEM with a low-protein diet containing 4% protein as compared to 20% protein in the control diet. When the experimental group had attained about 20% loss of their original body weight, they were used in the experiments. Malnourished animals presented anemia, leucopenia and severe reduction in bone marrow, spleen and peritoneal cavity cellularity. The production of TNF-alpha, IL-1alpha and IL-6 stimulated in vivo with LPS and the production of IL-6 in bone marrow cells cultured with LPS and the production of TNF-alpha in bone marrow, spleen and peritoneal cells cultured with LPS were significantly lower in malnourished animals. The expression of CD14 and TLR-4/MD-2 receptors was found to be significantly lower in macrophages of malnourished animals. These findings suggest that malnourished animals present a deficient response to LPS. The lower expression of the CD14 and TLR-4/MD-2 receptors may be partly responsible for the immunodeficiency observed in the malnourished mice. These data lead us to infer that the nutritional state interferes with the activation of macrophages and with the capacity to mount an immune response.
Reduction of erythroid progenitors in protein-energy malnutrition.
Borelli Primavera,Blatt Solange,Pereira Juliana,de Maurino Beatriz Beutler,Tsujita Maristela,de Souza Ana Cristina,Xavier José Guilherme,Fock Ricardo Ambrósio
The British journal of nutrition
Protein-energy malnutrition is a syndrome in which anaemia together with multivitamin and mineral deficiency may be present. The pathophysiological mechanisms involved have not, however, yet been completely elucidated. The aim of the present study was to evaluate the pathophysiological processes that occur in this anaemia in animals that were submitted to protein-energy malnutrition, in particular with respect to Fe concentration and the proliferative activity of haemopoietic cells. For this, histological, histochemical, cell culture and immunophenotyping techniques were used. Two-month-old male Swiss mice were submitted to protein-energy malnutrition with a low-protein diet (20 g/kg) compared with control diet (400 g/kg). When the experimental group had attained a 20 % loss of their original body weight, the animals from both groups received, intravenously, 20 IU erythropoietin every other day for 14 d. Malnourished animals showed a decrease in red blood cells, Hb concentration and reticulocytopenia, as well as severe bone marrow and splenic atrophy. The results for serum Fe, total Fe-binding capacity, transferrin and erythropoietin in malnourished animals were no different from those of the control animals. Fe reserves in the spleen, liver and bone marrow were found to be greater in the malnourished animals. The mixed colony-forming unit assays revealed a smaller production of granulocyte-macrophage colony-forming units, erythroid burst-forming units, erythroid colony-forming units and CD45, CD117, CD119 and CD71 expression in the bone marrow and spleen cells of malnourished animals. These findings suggest that, in this protein-energy malnutrition model, anaemia is not caused by Fe deficiency or erythropoietin deficiency, but is a result of ineffective erythropoiesis.
Hematopoiesis and retinoids: development and disease.
Oren Tal,Sher Justin A,Evans Todd
Leukemia & lymphoma
Retinoids function as activating ligands for a class of nuclear receptors that control gene expression programs for a wide range of tissues and organs during embryogenesis and throughout life. Over the years, three sets of observations have spurred interest in the function of retinoids with respect to development and disease of hematopoietic cells. Since the 1920s, epidemiological studies indicated altered hematopoiesis in vitamin A-deficient (VAD) human populations. More recently, the ability of retinoids to affect various aspects of hematopoietic development has been demonstrated in vitro. Finally, it was discovered that the gene encoding a retinoid receptor is a key target for chromosomal translocations that cause acute promyelocytic leukemia (APL). More recent investigations using targeted gene disruptions, VAD animal models, and mouse models of leukemia have continued to shed light on the function of the retinoid pathway in blood cells. It is now clear that retinoids are required for normal hematopoiesis during both yolk sac and fetal liver stages of hematopoiesis, while the pathway has at least modulatory functions for bone marrow derived progenitors. Studies of normal development and APL have provided complementary insight into the molecular control of blood cell differentiation. Here we review the evidence for retinoid requirements in hematopoiesis and also summarize current ideas regarding how this pathway is subverted in leukemia.
Malnutrition suppresses cell cycle progression of hematopoietic progenitor cells in mice via cyclin D1 down-regulation.
Nakajima Karina,Crisma Amanda R,Silva Graziela B,Rogero Marcelo M,Fock Ricardo A,Borelli Primavera
Nutrition (Burbank, Los Angeles County, Calif.)
OBJECTIVE:Protein malnutrition (PM) often is associated with changes in bone marrow (BM) microenvironment leading to an impaired hematopoiesis; however, the mechanism involved is poorly understood. The aim of this study was to compare the cell cycle progression of hematopoietic stem cells (HSC) and hematopoietic progenitor cells (HPC) and evaluate the cell cycle signaling in malnourished mice to assess the mechanism of cell cycle arrest. METHODS:C57Bl/6J mice were randomly assigned in control and malnourished groups receiving normoproteic and hypoproteic diets (12% and 2% protein, respectively) over a 5-wk period. Nutritional and hematologic parameters were assessed and BM immunophenotypic analysis was performed. Cell cycle of HPC (Lin(-)) and HSC (Lin(-)Sca-1(+)c-Kit(+)) were evaluated after 6 h of in vivo 5-bromo-2'-deoxyuridine (BrDU) incorporation. Cell cycle regulatory protein expression of HPC was assessed by Western blot. RESULTS:Malnourished mice showed lower levels of serum protein, albumin, glucose, insulin-like growth factor-1, insulin, and higher levels of serum corticosterone. PM also caused a reduction of BM myeloid compartment resulting in anemia and leukopenia. After 6 h of BrDU incorporation, malnourished mice showed G0-G1 arrest of HPC without changes of HSC proliferation kinetics. HPC of malnourished mice showed reduced expression of proteins that induce cell cycle (cyclin D1, cyclin E, pRb, PCNA, Cdc25a, Cdk2, and Cdk4) and increased expression of inhibitory proteins (p21 and p27) with no significant difference in p53 expression. CONCLUSION:PM suppressed cell cycle progression mainly of HPC. This occurred via cyclin D1 down-regulation and p21/p27 overexpression attesting that BM microenvironment commitment observed in PM is affecting cell interactions compromising cell proliferation.
Impairment of G-CSF receptor on granulocytic progenitor cells causes neutropenia in protein malnutrition.
Hastreiter Araceli Aparecida,Makiyama Edson Naoto,Borelli Primavera,Fock Ricardo Ambrósio
Nutrition (Burbank, Los Angeles County, Calif.)
OBJECTIVE:It is well known that protein malnutrition (PM) states can affect hematopoiesis, leading to severe leukopenia and reduced number of granulocytes, which act as the first line of defense, and are important to the innate immune response. The aim of this study was to elucidate some of the mechanisms involved in the impairment of granulopoiesis in PM. METHODS:Male C57BL/6 mice were submitted to PM with a low-protein diet containing 2% protein. Control mice were fed a 12% protein-containing diet. Bone marrow histology and the percentage of granulocytic progenitors were evaluated after in vivo granulocyte-colony stimulating factor (G-CSF) stimulus. Cell proliferation, STAT3 signaling, and the expression of G-CSF receptor were evaluated in hematopoietic progenitor cells. RESULTS:Malnourished animals presented with leukopenia associated with reduced number of granulocytes and reduced percentage of granulocytic progenitors; however, no differences were observed in the regulatory granulopoietic cytokine G-CSF. Additionally, the malnourished group presented with impaired response to in vivo G-CSF stimulus compared with control animals. PM was implicated in decreased ability of c-Kit cells to differentiate into myeloid progenitor cells and downregulated STAT3 signaling. Furthermore, the malnourished group exhibited reduced expression of G-CSF receptor on granule-monocytic progenitors. This reduced expression was not completely reversible with G-CSF treatment. CONCLUSIONS:This study implies that PM promotes intrinsic alterations to hematopoietic precursors, which result in hematologic changes, mainly neutropenia, observed in peripheral blood in PM states.
A review of select minerals influencing the haematopoietic process.
Oliveira Dalila Cunha,Nogueira-Pedro Amanda,Santos Ed Wilson,Hastreiter Araceli,Silva Graziela Batista,Borelli Primavera,Fock Ricardo Ambrósio
Nutrition research reviews
Micronutrients are indispensable for adequate metabolism, such as biochemical function and cell production. The production of blood cells is named haematopoiesis and this process is highly consuming due to the rapid turnover of the haematopoietic system and consequent demand for nutrients. It is well established that micronutrients are relevant to blood cell production, although some of the mechanisms of how micronutrients modulate haematopoiesis remain unknown. The aim of the present review is to summarise the effect of Fe, Mn, Ca, Mg, Na, K, Co, iodine, P, Se, Cu, Li and Zn on haematopoiesis. This review deals specifically with the physiological requirements of selected micronutrients to haematopoiesis, showing various studies related to the physiological requirements, deficiency or excess of these minerals on haematopoiesis. The literature selected includes studies in animal models and human subjects. In circumstances where these minerals have not been studied for a given condition, no information was used. All the selected minerals have an important role in haematopoiesis by influencing the quality and quantity of blood cell production. In addition, it is highly recommended that the established nutrition recommendations for these minerals be followed, because cases of excess or deficient mineral intake can affect the haematopoiesis process.
Dietary supplementation with probiotics improves hematopoiesis in malnourished mice.
Salva Susana,Merino María Cecilia,Agüero Graciela,Gruppi Adriana,Alvarez Susana
BACKGROUND:Lactobacillus rhamnosus CRL1505 (Lr) administered during the repletion of immunocompromised-malnourished mice improves the resistance against intestinal and respiratory infections. This effect is associated with an increase in the number and functionality of immune cells, indicating that Lr could have some influence on myeloid and lymphoid cell production and maturation. OBJECTIVE:This study analyzed the extent of the damage caused by malnutrition on myeloid and lymphoid cell development in the spleen and bone marrow (BM). We also evaluated the impact of immunobiotics on the recovery of hematopoiesis affected in malnourished mice. METHODS:Protein malnourished mice were fed on a balanced conventional diet for 7 or 14 consecutive d with or without supplemental Lr or fermented goat's milk (FGM). Malnourished mice and well-nourished mice were used as controls. Histological and flow cytometry studies were carried out in BM and spleen to study myeloid and lymphoid cells. RESULTS:Malnutrition induced quantitative alterations in spleen B and T cells; however, no alteration was observed in the ability of splenic B cells to produce immunoglobulins after challenge with LPS or CpG. The analysis of BM B cell subsets based on B220, CD24, IgM and IgD expression showed that malnutrition affected B cell development. In addition, BM myeloid cells decreased in malnourished mice. On the contrary, protein deprivation increased BM T cell number. These alterations were reverted with Lr or FGM repletion treatments since normal numbers of BM myeloid, T and B cells were observed in these groups. CONCLUSIONS:Protein malnutrition significantly alters B cell development in BM. The treatment of malnourished mice with L. rhamnosus CRL1505 was able to induce a recovery of B cells that would explain its ability to increase immunity against infections. This work highlights the possibility of using immunobiotics to accelerate the recovery of lymphopoyesis in immunocompromised-malnourished hosts.
Protein-energy malnutrition alters histological and ultrastructural characteristics of the bone marrow and decreases haematopoiesis in adult mice.
Xavier J G,Favero M E,Vinolo M A R,Rogero M M,Dagli M L Z,Arana-Chavez V E,Borojevic R,Borelli P
Histology and histopathology
Protein-energy malnutrition (PEM) decreases resistance to infection by impairing a number of physiological processes, including haematopoiesis. The aim of this study was to evaluate the microanatomical aspects of bone marrow (BM) in mice that were subjected to PEM, in particular, with respect to the components of the local extracellular matrix and the proliferative activity of haematopoietic cells. For this, histological, histochemical, immunohistochemical and ultrastructural techniques were used. Two-month old male Swiss mice were fed with a low-protein diet containing 4% protein and control mice fed a 20% protein diet. When the experimental group had attained a 25% loss of their original body weight, we collected the different biological samples. Malnourished mice had presented severe BM atrophy as well as a reduction in proliferating cell nuclear antigen and gelatinous degeneration. The malnourished mice had more fibronectin accretion in paratrabecular and endosteal regions and more laminin deposition in perisinusal sites than controls. Endosteal cell activation and hyperplasia were found, suggesting their participation in the process. Additionally, we have observed a decrease in the capacity of malnourished haematopoietic stroma to support the growth of haematopoietic stem cells (CD34+) in vitro. These findings point to a structural impairment of the haematopoietic microenvironments in mice with PEM, possibly hampering the interactions between cells and cellular signalling.
Hematological alterations in protein malnutrition.
Santos Ed W,Oliveira Dalila C,Silva Graziela B,Tsujita Maristela,Beltran Jackeline O,Hastreiter Araceli,Fock Ricardo A,Borelli Primavera
Protein malnutrition is one of the most serious nutritional problems worldwide, affecting 794 million people and costing up to $3.5 trillion annually in the global economy. Protein malnutrition primarily affects children, the elderly, and hospitalized patients. Different degrees of protein deficiency lead to a broad spectrum of signs and symptoms of protein malnutrition, especially in organs in which the hematopoietic system is characterized by a high rate of protein turnover and, consequently, a high rate of protein renewal and cellular proliferation. Here, the current scientific information about protein malnutrition and its effects on the hematopoietic process is reviewed. The production of hematopoietic cells is described, with special attention given to the hematopoietic microenvironment and the development of stem cells. Advances in the study of hematopoiesis in protein malnutrition are also summarized. Studies of protein malnutrition in vitro, in animal models, and in humans demonstrate several alterations that impair hematopoiesis, such as structural changes in the extracellular matrix, the hematopoietic stem cell niche, the spleen, the thymus, and bone marrow stromal cells; changes in mesenchymal and hematopoietic stem cells; increased autophagy; G0/G1 cell-cycle arrest of progenitor hematopoietic cells; and functional alterations in leukocytes. Structural and cellular changes of the hematopoietic microenvironment in protein malnutrition contribute to bone marrow atrophy and nonestablishment of hematopoietic stem cells, resulting in impaired homeostasis and an impaired immune response.
Protein malnutrition impairs bone marrow endothelial cells affecting hematopoiesis.
Hastreiter Araceli Aparecida,Galvão Dos Santos Guilherme,Cavalcante Santos Ed Wilson,Makiyama Edson Naoto,Borelli Primavera,Fock Ricardo Ambrósio
Clinical nutrition (Edinburgh, Scotland)
BACKGROUND & AIMS:Protein malnutrition (PM) affects hematopoiesis leading to bone marrow (BM) hypoplasia and arrests hematopoietic stem cells (HSC) in G/G cell cycle phases, which cause anemia and leukopenia. Hematopoiesis is mainly regulated by BM niches where endothelial cells (EC) present a key regulatory role. Thus, our objective is to evaluate whether PM affects the modulatory capacity of EC on hematopoiesis. METHODS:C57BL/6 male mice received for 5 weeks a normal protein diet (12% casein) or a low protein diet (2% casein). MSC were isolated and differentiated in vitro into EC and the synthesis of SCF, Ang-1, CXCL-12, IL-11, TGF-β and G-CSF were evaluated. The HSC and hematopoietic progenitors were quantified and the EC capacity to modulate the hematopoietic system was also evaluated. Moreover, the ability of PM bone marrow to support hematopoieisis was assessed by proliferation of infused leukemic myelo-monoblasts cells. RESULTS:PM decreases HSC and hematopoietic progenitor pool and promotes cell cycle arrest and a lower proliferation rate of leukemic myelo-monoblasts. PM also committed hematopoietic regulatory characteristics from EC, resulting in the modification of both cell cycle pattern and hematopoietic differentiation. CONCLUSION:BM microenvironment is compromised in PM, and since PM disturbs EC, it becomes one of the factors responsible for the hematopoietic cell cycle arrest and impairment of HSC differentiation.
The Role of Bone Marrow Microenvironment in Governing the Balance between Osteoblastogenesis and Adipogenesis.
Li Jiao,Liu Xingyu,Zuo Bin,Zhang Li
Aging and disease
In the adult bone marrow, osteoblasts and adipocytes share a common precursor called mesenchymal stem cells (MSCs). The plasticity between the two lineages has been confirmed over the past decades, and has important implications in the etiology of bone diseases such as osteoporosis, which involves an imbalance between osteoblasts and adipocytes. The commitment and differentiation of bone marrow (BM) MSCs is tightly controlled by the local environment that maintains a balance between osteoblast lineage and adipocyte. However, pathological conditions linked to osteoporosis can change the BM microenvironment and shift the MSC fate to favor adipocytes over osteoblasts, and consequently decrease bone mass with marrow fat accumulation. This review discusses the changes that occur in the BM microenvironment under pathological conditions, and how these changes affect MSC fate. We suggest that manipulating local environments could have therapeutic implications to avoid bone loss in diseases like osteoporosis.
The influence of protein malnutrition on biological and immunomodulatory aspects of bone marrow mesenchymal stem cells.
Dos Santos Guilherme Galvão,Batool Shafqat,Hastreiter Araceli,Sartori Talita,Nogueira-Pedro Amanda,Borelli Primavera,Fock Ricardo Ambrosio
Clinical nutrition (Edinburgh, Scotland)
Tissues that require a great supply of nutrients and possess high metabolic demands, such as lympho-hemopoietics tissues, are the first to be affected by protein malnutrition (PM). Thus, PM directly affects hemopoiesis and the production and function of immune cells. Consequently, malnourished individuals are more susceptible to infections. Mesenchymal stem cells (MSCs) have immunomodulatory properties and are important in the formation of lympho-hemopoietic stroma. Since an adequate supply of nutrients is essential to sustain stroma formation, which is mainly constituted of MSCs and differentiated cells originated from them, this study investigated whether PM would influence some biological and immunomodulatory aspects of MSCs. Two-month-old Balb/c mice were divided into control and malnourished groups receiving normoproteic or hypoproteic diets, respectively (12% and 2% of protein) for 28 days. MSCs obtained from control (MSCct) and malnourished (MSCmaln) animals were characterized. In addition, the proliferation rate and cell cycle protein expression were determined, but no differences in these parameters were observed. In order to evaluate whether PM affects the immunomodulatory properties of MSCs, the expression of NFκB and STAT-3, and the production of IL-1α, IL-1β, IL-6, IL-10, TGF-β and TNF-α by MSCs were assessed. MSCmaln expressed lower levels of NF-κB and the production of IL-1β, IL-6 and TGF-β was significantly influenced by PM. Furthermore, MSCct and MSCmaln culture supernatants affected lymphocyte and macrophage proliferation. However, MSCmaln did not reduce the production of IFN-γ nor stimulate the production of IL-10 in lymphocytes in the same manner as observed in MSCct. Overall, this study implied that PM modifies immunosuppressive properties of MSCs.
Obesity modifies bone marrow microenvironment and directs bone marrow mesenchymal cells to adipogenesis.
da Silva Simone Vargas,Renovato-Martins Mariana,Ribeiro-Pereira Cristiane,Citelli Marta,Barja-Fidalgo Christina
Obesity (Silver Spring, Md.)
OBJECTIVE:To investigate the role of obesity on the bone marrow microenvironment and evaluate its possible impact on the adipogenic potential of mesenchymal stem cells (MSC). METHODS:C57BL/6 male mice were fed with a high-fat diet (HFD) for 10 weeks. Femurs and tibiae were collected, and bone marrow mesenchymal stem cells (BM-MSC) were isolated and analyzed for proliferative potential, immunophenotype, and expression of adipogenesis markers. Their capacity to produce extracellular matrix proteins and proinflammatory cytokines in vitro was also evaluated. RESULTS:HFD mice presented a significant increase in bone marrow cellularity and higher tumor necrosis factor-α production in vitro. BM-MSC from HFD mice had higher proliferative capacity, produced more extracellular matrix proteins associated with adipogenesis, collagen I, and collagen IV, and showed increased constitutive expression of adipogenic markers, peroxisome proliferator-activated receptor-γ, and CCAAT/enhanced binding protein family-α, without changes in preadipocyte factor-1 expression. Incubation with adipocyte-differentiation medium induced further increase in CCAAT/enhanced binding protein family-α and augmented adiponectin expression in obese BM-MSC. These alterations did not result in increased adipogenic differentiation within the bone marrow. Moreover, BM-HSC from HFD mice, co-cultivated with BM-MSCs from lean mice, exerted paracrine effects on these cells, inducing augment of peroxisome proliferator-activated receptor-γ. CONCLUSIONS:The data suggest that obesity promotes an inflammatory microenvironment in bone marrow that commits BM-MSC to adipogenesis.
Protein malnutrition induces bone marrow mesenchymal stem cells commitment to adipogenic differentiation leading to hematopoietic failure.
Cunha Mayara Caldas Ramos,Lima Fabiana da Silva,Vinolo Marco Aurélio Ramirez,Hastreiter Araceli,Curi Rui,Borelli Primavera,Fock Ricardo Ambrósio
Protein malnutrition (PM) results in pathological changes that are associated with peripheral leukopenia, bone marrow (BM) hypoplasia and alterations in the BM microenvironment leading to hematopoietic failure; however, the mechanisms involved are poorly understood. In this context, the BM mesenchymal stem cells (MSCs) are cells intimately related to the formation of the BM microenvironment, and their differentiation into adipocytes is important because adipocytes are cells that have the capability to negatively modulate hematopoiesis. Two-month-old male Balb/c mice were subjected to protein-energy malnutrition with a low-protein diet containing 2% protein, whereas control animals were fed a diet containing 12% protein. The hematopoietic parameters and the expression of CD45 and CD117 positive cells in the BM were evaluated. MSCs were isolated from BM, and their capability to produce SCF, IL-3, G-CSF and GM-CSF were analyzed. The expression of PPAR-γ and C/EBP-α as well as the expression of PPAR-γ and SREBP mRNAs were evaluated in MSCs together with their capability to differentiate into adipocytes in vitro. The malnourished animals had anemia and leukopenia as well as spleen and bone marrow hypoplasia and a reduction in the expression of CD45 and CD117 positive cells from BM. The MSCs of the malnourished mice presented an increased capability to produce SCF and reduced production of G-CSF and GM-CSF. The MSCs from the malnourished animals showed increased expression of PPAR-γ protein and PPAR-γ mRNA associated with an increased capability to differentiate into adipocytes. The alterations found in the malnourished animals allowed us to conclude that malnutrition committed MSC differentiation leading to adipocyte decision and compromised their capacity for cytokine production, contributing to an impaired hematopoietic microenvironment and inducing the bone marrow failure commonly observed in protein malnutrition states.