Iron deficiency in pernicious anemia: Specific features of iron deficient patients and preliminary data on response to iron supplementation.

BACKGROUND & AIMS: While vitamin B12 (B12) deficiency is considered as the hallmark of pernicious anemia (PA), iron deficiency (ID) is also prevalent. Indeed, this auto immune gastritis is responsible for parietal cell atrophy and increase in gastric pH, leading to impaired iron absorption. We compared PA patients' features according to their iron status at PA diagnosis, and we assessed the iron status recovery after oral or intravenous iron supplementation. METHODS: We prospectively included patients presenting with a newly diagnosed PA in a tertiary referral hospital between November 2018 and October 2020. Iron status was assessed at PA diagnosis then regularly during a standardized follow-up. In case of ID, the decision of treatment with oral and/or intravenous iron supplementation was left to the clinician convenience. RESULTS: We included 28 patients with newly diagnosed PA. ID was observed in 21/28 (75.0%) patients: from the PA diagnosis in 13 patients, or during the follow-up in 8 patients. Iron deficient PA patients had higher plasma B12 (p = 0.04) and lower homocysteine levels (p = 0.04). Also, ID was independently associated with the 'APCA (anti-parietal cell antibodies) alone' immunological status (absence of anti-intrinsic factor antibodies) after adjustment for age, gender and B12 level (aOR 12.1 [1.1-141.8], p = 0.04). High level of APCA was associated with lower ferritin level. After 3 months of supplementation, 3/11 PA patients normalized the iron status with oral iron supplementation, versus 7/8 with intravenous iron supplementation (p = 0.02). CONCLUSION: The high frequency of iron deficiency in PA highlights the interest of regular assessment of iron status in this condition. ID was associated with a profile including APCA alone and less pronounced B12 deficiency. Intravenous iron supplementation seemed to be more efficient than an oral supplementation in these preliminary data.

A case report: subacute combined degeneration of the spinal cord and pernicious anemia caused by autoimmune gastritis.

INTRODUCTION: Autoimmune gastritis causing both subacute combined degeneration of the spinal cord and pernicious anemia is rare in clinical practice. Here, we report a case of subacute combined degeneration of the spinal cord and pernicious anemia resulting from vitamin B12 deficiency due to autoimmune gastritis. PATIENT CONCERNS: A 66-year-old woman presented with a 2-month history of numbness in her extremities. DIAGNOSES: The diagnoses were (1) autoimmune gastritis (2) subacute combined degeneration of the spinal cord (3) pernicious anemia (4) hypergastrinemia (5) chronic lymphocytic thyroiditis. INTERVENTIONS: The patient received intramuscular methylcobalamin treatment for 5 days, followed by oral methylcobalamin daily.Outcomes: Symptoms improved, and anemia recovered in the second month after discharge. She discontinued her medication afterward, and the neurological symptoms recurred. CONCLUSIONS: Autoimmune gastritis can lead to several diseases if not intervened in the early course. Neuropathy and hematopathy recur with treatment discontinuity. Methylcobalamin and adenosylcobalamin are unlikely to be more effective than vitamin B12.

Nutritional neuropathies.

Neuropathies associated with nutritional deficiencies are routinely encountered by the practicing neurologist. Although these neuropathies assume different patterns, most are length-dependent, sensory axonopathies. Cobalamin deficiency neuropathy is the exception, often presenting with a non-length-dependent sensory neuropathy. Patients with cobalamin and copper deficiency neuropathy characteristically have concomitant myelopathy, whereas vitamin E deficiency is uniquely associated with a spinocerebellar syndrome. In contrast to those nutrients for which deficiencies produce neuropathies, pyridoxine toxicity results in a non-length-dependent sensory neuronopathy. Deficiencies occur in the context of malnutrition, malabsorption, increased nutrient loss (such as with dialysis), autoimmune conditions such as pernicious anemia, and with certain drugs that inhibit nutrient absorption. When promptly identified, therapeutic nutrient supplementation may result in stabilization or improvement of these neuropathies.

Jaundice and anaemia as presenting features of an incomplete autoimmune polyglandular syndrome type II.

The coexistence of adrenal failure with either autoimmune thyroid disease and/or type 1 diabetes is defined as autoimmune polyglandular syndrome (APS) type 2 or Schmidt's syndrome. Vitiligo, hypergonadotropic hypogonadism, chronic autoimmune hepatitis, alopecia, pernicious anaemia and seronegative arthritis may also be present. We present a case of 45-year-old Indian man with progressive jaundice and asthenia for 3 months. He was also found to have pallor, icterus, dry coarse skin and delayed relaxation of ankle jerk. Investigations showed pancytopaenia with megaloblastic changes due to pernicious anaemia, autoimmune hypothyroidism and autoimmune adrenalitis with evolving adrenal insufficiency. Upper gastrointestinal endoscopy guided biopsy showed evidence of gastric mucosal atrophy. Patient responded well to hydroxocobalamin and thyroxine replacement. Detailed workup to check for evolving APS II is prudent in a hypothyroid patient presenting with pallor and jaundice. It may alert physicians to possible adrenal crisis in the future, especially after starting levothyroxine replacement in these patients.

[Successful treatment with mecobalamin in a pernicious anemia patient presenting with false-normal serum vitamin B12].

An 81-year-old woman presented to our hospital with anemia. Complete blood counts revealed macrocytic anemia; however, serum vitamin B12 and folate levels were normal. Bone marrow aspiration revealed multilineage dysplasia, and the patient was initially diagnosed with refractory cytopenia and multilineage dysplasia subtype of myelodysplastic syndrome. However, blood smear revealed hypersegmented neutrophils and bone marrow aspiration showed remarkable megaloblastic changes of erythroid cells. Based on these findings, the patient was administered 1,500 µg mecobalamin per day on a trial basis. Three weeks after initiating mecobalamin, macrocytic anemia improved. Her hemoglobin levels were also normalized along with immediate resolution of peripheral blood dysplasia. The final diagnosis was pernicious anemia (PA) based on anti-intrinsic factor positivity and the efficacy of mecobalamin. Use of automated analyzers may be associated with falsely normal or falsely elevated vitamin B12 levels in the presence of anti-intrinsic factor antibodies. Our case suggests that trial administration of mecobalamin may be an important step to correctly diagnose PA associated with falsely normal or falsely elevated vitamin B12 levels, particularly when typical morphological features of PA are present.

Reversal of isolated 20q deletion with vitamin B12 replacement in a patient with pernicious anaemia.

Severe vitamin B12 deficiency is well known to cause morphological alterations in bone marrow. In rare instances, these myelodysplastic and megaloblastic changes can coexist with cytogenetic abnormalities. Here, we report a case of a 38-year-old African-American woman with pernicious anaemia, who was found to have an isolated 20q deletion and which resolved after vitamin B12 replacement. We also discuss various mechanisms in which vitamin B12 deficiency can lead to chromosomal abnormalities. A literature review is also performed to evaluate various other chromosomal aberrations associated with B12 deficiency.

Pernicious anemia presenting as catatonia: correlating vitamin B12 levels and catatonic symptoms.

Pernicious anemia has been associated with various psychiatric manifestations, such as depression, mania and psychosis. Psychiatric symptoms can sometimes occur without hematological and neurological abnormalities and can be prodromal of vitamin B12 deficiency. We report a case of autoimmune B12 deficiency presenting as catatonia without signs of anemia or macrocytosis, in which a correlation was found between the patient's B12 blood levels and catatonic symptoms over time. This catatonic episode was successfully treated with only lorazepam and adequate doses of cyanocobalamin.

[History of the therapy of pernicious anemia]. / Az anaemia perniciosa terápiájának története.

Increased blood cell regeneration in exsanguinated experimental animals treated either with liver or with aqueous liver extracts was reported by Whipple and by Jeney and Jobling, respectively. These findings stimulated Minot and Murphy to provide evidence for the efficacy of liver against anaemia in clinical studies. After oral administration of liver (45-50 g per day) for 45 patients with anaemia perniciosa improvement of the hematological status was demonstrated. Consequently, for proving the therapeutic value of liver therapy Whipple, Minot and Murphy received Nobel price in 1934. The isolation of the antianemic factor from the liver has been succeeded in 1948 and designated as vitamin B12. At the same time Lucy Wills applied yeast for the treatment of pregnant women with anemia related to undernourishment. The conclusions of this study inspired the discovery of folate. The detailed investigation of the mode of action of vitamin B12 and folate enriched our knowledge in the area of pathophysiology and extended the clinical application of these two drugs.

The discovery of vitamin B(12).

The discovery of vitamin B(12), the elucidation of its role in metabolism, and the effects and treatment of its deficiency occurred in distinct phases over more than 100 years, and it was the subject of two separate Nobel Prizes. The valuable contribution of clinical reports and studies of patients with pernicious anemia throughout the 19th century resulted in enough clinical definition to allow Minot and Murphy to put together the first hallmark study on treatment of the condition, leading them to a Nobel Prize. These researchers were not the first to suggest that an inadequacy of nutrients was the cause of pernicious anemia, but their particular input was a carefully designed intervention in well-characterized pernicious anemia patients, of a special diet containing large amounts of liver. They found consistent improvement in the clinical and blood status of all subjects, most of whom remained on remission indefinitely. After the successful intervention studies, the next advance was made by Castle who discovered that a gastric component, which he called intrinsic factor, was missing in pernicious anemia. Many years later, intrinsic factor was found to be a glycoprotein that formed a complex with vitamin B(12), promoting its absorption through ileal receptors. The vitamin was isolated by two groups simultaneously and was crystallized and characterized in the laboratory of Dorothy Hodgkin, contributing to her Nobel Prize in 1964. Subsequently, the various biochemical roles of vitamin B(12) were elucidated, including its important interaction with folate and their common link with megaloblastic anemia. Many of the early clinical studies recognized that vitamin B(12) deficiency also caused a severe neuropathy leading to paralysis and death, while post mortem analysis demonstrated spinal cord demyelination. Vitamin B(12) is still the subject of intense research and, in particular, its role in preventing these irreversible neurological lesions remains unclear.

Autoimmune pernicious anaemia as a cause of collapse, heart failure and marked panyctopaenia in a young patient.

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.

Diagnosis and management of pernicious anemia.

Pernicious anemia is a macrocytic anemia due to cobalamin deficiency, which is the result of intrinsic factor deficiency. Pernicious anemia is associated with atrophic body gastritis, whose diagnostic criteria are based on the histologic evidence of gastric body atrophy associated with hypochlorhydria. Serological markers suggesting the presence of oxyntic mucosa damage are increased levels of fasting gastrin and decreased levels of Pepsinogen I. Without the now obsolete Schilling's test, intrinsic factor deficiency may not be proven, and gastric intrinsic factor output after pentagastric stimulation has been proposed. Intrinsic factor autoantibodies are useful surrogate markers of pernicious anemia. The management of patients with pernicious anemia should focus on the life-long replacement treatment with cobalamin and the monitoring to early diagnose an eventual onset of iron deficiency. Moreover, these patients should be advised about possible gastrointestinal long-term consequences, such as gastric cancer and carcinoids.

Pernicious anaemia presenting as catatonia without signs of anaemia or macrocytosis.

Pernicious anaemia can present with psychiatric symptoms before haematological or neurological manifestations appear. We describe a young woman who presented with insidious onset catatonia without evidence of psychosis or depression. Blood count and mean cell volume were normal and neurological findings were equivocal. Low B(12) levels and intrinsic factor antibodies were found only by chance when they were included in a battery of further investigations. B(12) replacement was followed by prompt improvement. This case provides an argument for wider screening for B(12) deficiency in certain individuals with psychiatric disorders.

[Allergic reaction after intravenous application of vitamin B12]. / Allergische Reaktion nach i.v. Gabe von Vitamin B12.

Allergic reactions of parenteral vitamin B12 (cobalamin) for therapy of pernicious anaemia are very rare, but repeatedly described in the literature. In case of allergic reactions oral instead of intravenous substitution of vitamin B12 is tolerated. Very high dosages of vitamin B12 (1,000-2,000 microg per day) are necessary due to the underlying vitamin B12 malabsorption.

Pernicious anemia: new insights from a gastroenterological point of view.

Pernicious anemia (PA) is a macrocytic anemia that is caused by vitamin B(12) deficiency, as a result of intrinsic factor deficiency. PA is associated with atrophic body gastritis (ABG), whose diagnosis is based on histological confirmation of gastric body atrophy. Serological markers that suggest oxyntic mucosa damage are increased fasting gastrin and decreased pepsinogen I. Without performing Schilling's test, intrinsic factor deficiency may not be proven, and intrinsic factor and parietal cell antibodies are useful surrogate markers of PA, with 73% sensitivity and 100% specificity. PA is mainly considered a disease of the elderly, but younger patients represent about 15% of patients. PA patients may seek medical advice due to symptoms related to anemia, such as weakness and asthenia. Less commonly, the disease is suspected to be caused by dyspepsia. PA is frequently associated with autoimmune thyroid disease (40%) and other autoimmune disorders, such as diabetes mellitus (10%), as part of the autoimmune polyendocrine syndrome. PA is the end-stage of ABG. Long-standing Helicobacter pylori infection probably plays a role in many patients with PA, in whom the active infectious process has been gradually replaced by an autoimmune disease that terminates in a burned-out infection and the irreversible destruction of the gastric body mucosa. Human leucocyte antigen-DR genotypes suggest a role for genetic susceptibility in PA. PA patients should be managed by cobalamin replacement treatment and monitoring for onset of iron deficiency. Moreover, they should be advised about possible gastrointestinal long-term consequences, such as gastric cancer and carcinoids.

Severe pernicious anaemia in an 8-year-old African girl.

An 8-year-old girl presented with severe muscular weakness, peripheral neuropathy, ataxia, fever and macrocytic anaemia. Clinically, vitamin B(12) (cobalamin) deficiency was considered. Despite the lack of pre-treatment laboratory confirmation of the diagnosis, a therapeutic trial of hydroxocobalamin injections was begun. After several days, a partial clinical response was seen. Within 5 months all symptoms had resolved. After treatment was initiated, laboratory analysis of pre-treatment blood samples confirmed the presence of vitamin B(12) deficiency. Auto-antibodies to intrinsic factor and parietal cells, pathognomonic for pernicious anaemia, were confirmed. Vitamin B(12) deficiency owing to dietary deficiency is not uncommon in children in developing countries. Although nutritional deficiency might have played a role in our patient, this case illustrates that the neurological manifestations of pernicious anaemia can present at a young age in African populations.

[New proposals for old vitamins]. / Nouvelles indications pour de vieilles vitamines.

Complementary to their specific metabolic actions, several vitamins are given for new previously unsuspected properties. In addition to its role in calcium absorption, vitamin D has been proven to possess beneficial effects for some autoimmune diseases, several cancers and cardiovascular illnesses. It also increases muscle strength and prevents falls particularly in elderly people. Low dose oral vitamin K supplementation is a new indication for people with unstable coumarinic anticoagulant treatment. Oral vitamin 812 administration is an alternative to the classical parenteral intramuscular administration in pernicious anemia. However, the possible antioxidant beneficial effects of vitamin A and E are largely disputed taking into account an increased mortality associated to their consumption.