"What an Affliction": Mary Todd Lincoln's Fatal Pernicious Anemia.

To date, no single diagnosis has unified the psychiatric illness and the numerous poorly defined physical complaints that Mary Lincoln (née Todd, 1818-1882) suffered in adulthood. Here, I show that her physical ailments spanned 30 years and included sore mouth, pallor, paresthesias, the Lhermitte symptom, fever, headaches, fatigue, resting tachycardia, edema, episodic weight loss, progressive weakness, ataxia, and visual impairment. Long thought hypochondriacal, these findings, plus their time course and her psychopathology (irritability, delusions, hallucinations, with preserved clarity), are all consistent with vitamin B12 deficiency. Pernicious anemia most probably caused this deficiency: she lacked risk factors for other causes, and her consanguineous parents both derived from a region of Scotland having a high incidence of pernicious anemia. A diagnosis of chronic multisystem pernicious anemia would clarify the conduct of Mary Lincoln as First Lady and widow, and illuminate challenges faced by her husband, President Abraham Lincoln. Her case highlights many forgotten features of the natural history of untreated pernicious anemia and is unique in the medical literature in demonstrating such a course extending over a lifetime.

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.

A tissue-engineered stomach shows presence of proton pump and G-cells in a rat model, resulting in improved anemia following total gastrectomy.

Despite advances in surgical reconstruction, total gastrectomy still is accompanied by various complications, especially chronic ones, such as pernicious anemia, resulting in refractory malnutrition. As an alternative approach, we have proposed a tissue-engineered stomach as a replacement of the native stomach. This study aimed to assess the secretory functions of a tissue-engineered stomach in a rat model and the nutritional status of the recipients over an extended time period. Stomach epithelial organoid units were isolated from neonatal rats and seeded onto biodegradable polymers. These constructs were implanted into the omenta of adult recipient rats. After 3 weeks, cyst-like structures had formed, henceforth referred to as tissue-engineered stomachs. The recipient stomachs were resected and replaced by their tissue-engineered counterparts. At 24 weeks after implantation, the secretory function of the tissue-engineered stomach was evaluated using immunohistochemical staining. The hemoglobin levels and nutritional status of the recipients were compared with a control group that had undergone a simple Roux-en-Y reconstruction following total gastrectomy. Recipient rats tolerated the tissue-engineered stomachs well. X-ray examination using barium as contrast showed no bowel stenosis. Staining for proton pump alpha-subunit and gastrin demonstrated the existence of parietal cells and G-cells in the neogastric mucosa, respectively, suggesting secretory functions. The treatment group showed significantly higher hemoglobin levels than the control group, although no differences in the body weight change, total protein, or cholesterol levels were observed between the two groups. A tissue-engineered stomach has the potential to function as a food reservoir following total gastrectomy. It is conjectured that replacement with a tissue-engineered stomach might restore the proton pump parietal cells and G-cells, and thereby improve anemia after a total gastrectomy in a rat model.

Pernicious anemia associated with cryptogenic cirrhosis: Two case reports and a literature review.

RATIONALE: Pernicious anemia (PA) is an autoimmune gastritis that results from the destruction of gastric parietal cells and the associated lack of an intrinsic factor to bind ingested vitamin B12. While an association between PA and various liver diseases has been rarely reported, reports of associated diseases include primary biliary cholangitis, autoimmune hepatitis, and Interferon-treated hepatitis C. We present 2 cases of PA associated with cryptogenic cirrhosis (CC), which has not been previously reported in the literature. PATIENT CONCERNS: A 42-year-old man presented with fatigue, pallor, and sustained abdominal distension that had persisted for 15 days. An 87-year-old man was admitted to the hospital for an unsteady gait and loss of appetite that had persisted for 20 days. DIAGNOSES: Symptoms, laboratory tests, and imaging findings for both patients were indicative of PA and CC.Both had neurological and psychiatric symptoms during hospitalization that were ultimately linked to a vitamin B12 deficiency but not hepatic encephalopathy. INTERVENTIONS: Both patients received intramuscular injections of vitamin B12. OUTCOMES: Hemoglobin levels of the 2 patients increased gradually, and their neurological symptoms were alleviated. LESSONS: PA associated with a liver disease is rare, and the underlying mechanism can only now be clarified. We speculate that autoimmune dysfunction and chronic vitamin B12 deficiency caused by PA might be unique causes of liver cirrhosis. Additional investigations are needed to verify these findings.

An acute transfusion reaction.

We present the case of a 67-year-old man who suffered an acute anaphylactic reaction during red cell transfusion due to the presence of anti-IgA antibodies. The incidence and clinical relevance of anti-IgA antibodies in IgA deficiency is reviewed, and the wider investigation and management of acute transfusion reactions is also discussed. This case highlights the need to consider the potential risks of blood component transfusion against the purported benefit.

Helicobacter pylori link to pernicious anaemia.

An immunological classification of chronic gastritis based on the detection of Helicobacter pylori (H. pylori) antibody, parietal cell antibody, intrinsic factor antibody, is reported. H. pylori chronic gastritis, slowly progresses to atrophic gastritis, in the majority of patients; in a few patients, with genetic susceptibility to form intrinsic factor antibody, it progresses to pernicious anaemia. In majority of patients of pernicious anaemia, H. pylori gradually disappears from the gastric mucosa, on development of intestinal metaplasia in them. Atrophic gastritis results from H. pylori or non H. pylori. H. pylori infection is diagnosed in the presence of H. pylori in the gastric mucosal biopsy and/or H. pylori antibody (IgG) in the serum. The presence of the genetic factor (intrinsic factor antibody) is essential for the diagnosis of pernicious aneamia. Pernicious anaemia patients without intrinsic factor antibody, should be correctly diagnosed as atrophic gastritis, in view of the absence of the genetic factor (intrinsic factor antibody) in them.

Pernicious anemia.

Pernicious anemia is severe anemia most often affecting older adults, caused by failure of the stomach to absorb vitamin B12 and characterized by abnormally large red blood cells, gastrointestinal disturbances, and lesions of the spinal cord. Pernicious anemia is caused by a lack of intrinsic factor and could be an autoimmune disorder. The identification of various autoantibodies helps in the confirmation of the diagnosis and hence towards the patient management. In such patients, oral supplements or intramuscular injections of vitamin B12 are indicated.

Pernicious Anemia: Fundamental and Practical Aspects in Diagnosis.

BACKGROUND: Pernicious Anemia (PA), the most common cause of cobalamin deficiency anemia worldwide, is an autoimmune disease of multifactorial etiologies involving complex environmental and immunological factors. Although it was first reported by Addison in 1849 with subsequent advances in understanding of pathogenesis and molecular biology, diagnosis of PA is still challenging for clinicians because of its complexity and diverse clinical presentations. CONCLUSION: Herein, we provide an overview of PA, mainly focusing on its scientific and practical aspects in diagnosis. We also discuss the limitations of currently available diagnostic tools for the evaluation of cobalamin deficiency and PA.

Pernicious anemia in Chinese: a study of 181 patients in a Hong Kong hospital.

To study the clinical and hematologic features of pernicious anemia in Chinese, we describe 181 Chinese with megaloblastic anemia and low serum cobalamin, in association with either classic Schilling test results (82 patients) or the presence of serum antibody to intrinsic factor (99 patients), encountered in a regional hospital in Hong Kong from May 1994 to May 2005. The median age was 75 years (range, 32-95 yr) and the male to female ratio was 1:1.5. The chief presenting feature was anemia, and fewer than 10% of patients presented predominantly with neurologic deficit. Gastric biopsies of 109 patients showed glandular atrophy in 73, endocrine cell hyperplasia in 5, polyps in 14, adenocarcinoma in 1, and chronic gastritis in the rest. Gastric adenocarcinoma occurred in 1.7% of patients after a median follow-up of 35 months (range, 0.5-132 mo). Diabetes mellitus occurred in 24% of patients and thyroid disease in 7%. No specific ABO blood group was associated with pernicious anemia. Serum antibody to intrinsic factor (73%) occurred more frequently than serum antibody to gastric parietal cell (65%) (p=0.353). The frequency of serum antibody to gastric parietal cell was higher in male (78%) than in female patients (53%) (p=0.018). Pernicious anemia is a major cause of megaloblastic anemia in Chinese.

Two newborns with nutritional vitamin B12 deficiency: challenges in newborn screening for vitamin B12 deficiency.

Vitamin B12 deficiency causes decreased Methionine Synthase and L-Methylmalonyl-CoA Mutase activity and results in accumulation of Homocysteine, Methylmalonic acid and Propionylcarnitine. Propionylcarnitine is included in tandem mass spectrometry-based newborn screening programs for detection of certain inborn errors of metabolism. We report two asymptomatic newborns with Vitamin B12 deficiency due to maternal deficiencies. One was detected incidentally at 3 weeks of age; the second on supplemental newborn screening based on elevated Propionylcarnitine at 2 days of age. This illustrates the potential for false negative results for Vitamin B12 deficiency screening by acylcarnitine profiling in newborn screening. Homocysteine and Methylmalonic acid may be better markers of Vitamin B12 deficiency. In conclusion, we suggest measuring Methylmalonic acid, Propionylcarnitine and Homocysteine levels in blood spots in expanded newborn screening in order to detect asymptomatic newborns with Vitamin B12 deficiency. Further studies are needed to establish the sensitivity of these three markers in screening for Vitamin B12 deficiency.

False-normal vitamin B12 results in a patient with pernicious anaemia.

Pernicious anaemia is a common autoimmune disorder with a prevalence of approximately 4% amongst Europeans. If untreated, it can result in permanent neurological disability or death. Central to the diagnosis is establishing the presence of vitamin B12 deficiency. Concern has been raised recently regarding false-normal results obtained with competitive-binding vitamin B12 assays performed on automated biochemistry platforms in patients with pernicious anaemia due to the presence of interfering anti-intrinsic factor antibodies in the patient sample. We report a case in which diagnosis of pernicious anaemia was delayed due to false-normal vitamin B12 results. Questioning the results in light of high pre-test probability, and knowledge of the role of functional markers of vitamin B12 deficiency enabled the correct diagnosis to be made so that effective treatment could be initiated. It is crucial that those who frequently request vitamin B12 are aware of the potential problems with the available assays and how these problems can be addressed. We suggest that all patients with normal vitamin B12 levels where there is a high clinical suspicion for deficiency such as a macrocytic anaemia, neurological symptoms or megaloblastic bone marrow should have a functional assay of vitamin B12 (plasma homocysteine or methylmalonic acid) checked to further investigate for vitamin B12 deficiency.

Visual evoked responses in pernicious anemia.

We describe three newly diagnosed and untreated cases of pernicious anemia (PA) with clinical features suggestive of subacute combined degeneration. Visual evoked responses (VERs) were evaluted in all three patients. In each instance, delayed responses were obtained, suggesting that involvement of the visual pathways may be an early and perhaps not uncommon manifestation in PA, even in the absence of clinical stigmata of visual impairment. The need for excluding PA in cases of myelopathy with impaired VERs is stressed.

Effect of a single oral dose of enprostil on gastric secretion and gastrin release. Studies in healthy volunteers and patients with pernicious anemia.

In healthy human volunteers, a single oral dose of enprostil (35 micrograms) inhibited basal gastric acid output by a mean of 71 percent, pentagastrin-stimulated output by 46 percent, sham-meal-stimulated output by 48 percent, and histamine-stimulated output by 16 percent. In each case, there was a reduction in both the volume and acidity of the gastric juice. Pepsin output was unchanged. Although enprostil increased the gastric pH, it did not induce basal or post-prandial hypergastrinemia. In patients with hypergastrinemia secondary to achlorhydria, enprostil lowered the basal gastrin level and reduced or abolished the post-prandial gastrin rise in a dose-related fashion. Enprostil reduces basal and stimulated gastric acid secretion and inhibits gastrin release.

Pernicious anemia and giant cell myocarditis. New association.

The association of pernicious anemia, an autoimmune disease, with other immunologic disorders such as dermatitis herpetiformis, Hashimoto's thyroiditis, hypothyroidism, hyperthyroidism, vitiligo, adrenal insufficiency, adult-onset immunoglobulin deficiency, hypoparathyroidism, and possibly diabetes mellitus has been reported. The association of pernicious anemia with giant cell myocarditis, a rare fatal illness believed by some to represent an autoimmune abnormality occurring with other autoimmune diseases such as thymoma, systemic lupus erythematosus, dermatomyositis, thyrotoxicosis, Wegener's granulomatosis, and Sjogren's syndrome, is reported for the first time. A common underlying autoimmune abnormality is suggested.

Intestinal absorptive and digestive function in pernicious anemia.

We examined the digestive and absorptive function of the small intestinal mucosa in three patients with pernicious anemia to determine the functional correlates of the morphologic changes previously described. Digestive brush border enzymes (disaccharidases and leucyl-naphthylamidase) in jejunal biopsy specimens from the patients followed a normal distribution compared with those in the control group. With the exception of one patient with mild steatorrhea, the rest of the absorption test results were within the normal range. Jejunal perfusion studies, however, with glucose, sodium and water showed intestinal secretion of sodium and water, i.e., net movement of sodium and water from plasma to lumen, in the presence of normal glucose absorption. Follow-up studies in two patients after treatment with vitamin B12 did not reveal any significant improvement in the absorption rates from the pretreatment period. This abnormality of sodium and water transport in pernicious anemia represents another intestinal defect of a systemic disease which is not corrected by vitamin B12 replacement therapy.

Twenty-four-hour intragastric acidity and plasma gastrin concentration in healthy subjects and patients with duodenal or gastric ulcer, or pernicious anaemia.

Twenty-four-hour intragastric acidity and plasma gastrin concentration were measured in healthy subjects (n = 16), and patients with duodenal (n = 12) or gastric (n = 10) ulceration, or pernicious anaemia (n = 8). Median integrated 24-hour intragastric acidity was highest in duodenal ulcer patients and lowest in pernicious anaemia patients (1148 and 0 mmol.hour litre-1, respectively). Median integrated 24-hour plasma gastrin was highest in pernicious anaemia and lowest in the healthy subjects (9886 and 238 pmol.hour litre-1, respectively). Pernicious anaemia patients have unremitting hypergastrinaemia throughout the 24 hours. The results of this study not only provide a reference range of acidity and plasma gastrin in health and disease, but also will act as a baseline for future studies using antisecretory drugs.

The effect of H2-blockade on plasma gastrin concentration in patients with an achlorhydric stomach.

The mechanisms of hypergastrinaemia during H2-receptor antagonist therapy remain unclear. In addition, the effect of food stimulation in conditions of hypergastrinaemia is poorly understood. These effects may be important when considering long-term therapy with potent acid inhibitory agents. To investigate this we studied the effect of H2-receptor antagonist therapy on basal and meal-stimulated plasma gastrin concentrations in 9 patients with pentagastrin fast gastric achlorhydria associated with pernicious anaemia. The subjects received in double-blind randomized fashion 28-day courses of 300 mg ranitidine q.d.s. and placebo, with one-month wash-out between. The fasting and peptone meal-stimulated gastrin concentrations were studied on the final day of each course of treatment. The median fasting gastrin concentrations (ng/L) were similar following placebo (1100, range 25-2100), and 300 mg ranitidine q.d.s. (1075, range 15-2600) and both markedly elevated when compared with our laboratory's normal range of 0-100. Despite the elevated basal levels the pernicious anaemia patients still showed a further increase in response to the peptone meal. Their median peak percentage rise over basal in response to the meal was similar following placebo (96%, range 0-375) and 300 mg ranitidine q.d.s. (100%, range 25-425) (both P less than 0.02 c.f. basal). This study shows that: (a) in hypergastrinaemia in pernicious anaemia subjects, meal stimulation leads to a marked and prolonged increase in plasma gastrin concentrations; (b) H2-receptor antagonists have no effect on plasma gastrin in the neutral stomach and this is consistent with their gastrin effect being entirely secondary to acid inhibition.