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Case 30-2004 — A 37-Year-Old Woman with Paresthesias of the Arms and Legs
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     Presentation of Case

    A 37-year-old woman was seen in the clinic because of numbness in the arms and legs.

    Four months earlier, she had noticed tingling and numbness in the fingertips, without weakness, three weeks after having last ridden a bicycle. She consulted her primary care physician. The temperature was 37.2°C and the blood pressure 115/85 mm Hg. The height was 1.75 m and the weight 69.1 kg. The lungs were clear to auscultation, and the heart sounds were normal. No rash or lymphadenopathy was found. Examination of the breasts, abdomen, and arms and legs and a pelvic examination revealed no abnormalities. The range of motion of the neck and the hand-grip strength were normal; the sensation in the hands also seemed to be intact. No treatment was given, and the symptoms resolved after three weeks.

    Two and a half months later she noticed fresh blood on the toilet tissue after passing a stool. Rectal examination revealed a hemorrhoid. Shortly thereafter she had a brief illness, characterized by nausea, possible fever, and leg fatigue on exertion. During the next several weeks, she noticed the onset of numbness and tingling that extended from the fingertips to the upper arms; subsequently, numbness and tingling developed in the legs as well. She also noticed weakness in her legs, to the extent that she could no longer run a mile and was losing her balance. She recalled seeing apparent insect bites on her lower legs after riding a bicycle in tall grass in the spring, in the suburban areas west of Boston. She had not recently traveled outside the Boston area. A review of her diet revealed that she ate meat and dairy products as well as vegetables and grains. She was referred to a neurologist.

    Hypothyroidism had been discovered when the patient was 15 years old, and more recently depression had developed. A physical examination four months before the first episode of numbness and tingling had revealed no abnormalities. At that time, the levels of glucose, urea nitrogen, creatinine, calcium, total bilirubin, total protein, albumin, globulin, electrolytes, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase were normal. Tests for IgG antibodies to herpes simplex virus types 1 and 2 were positive; tests for IgM antibodies and antibodies to hepatitis A virus were negative. Other laboratory-test results obtained at the time of that examination are shown in Table 1 and Table 2. She took levothyroxine (200 μg) and sertraline (100 mg) daily. She was not married, and she worked in an office. She did not smoke or drink alcohol. She exercised regularly by running and riding a bicycle. Menarche had occurred when she was 14 years old, and she had regular menses. Her mother had had a coronary angioplasty, her father had lung and prostate cancer, a brother had asthma, and a paternal aunt had anemia of unknown nature.

    Table 1. Hematologic Laboratory Values.

    Table 2. Blood Chemical Values.

    At the time of the patient's first visit to the neurologist, four months after the initial onset of tingling and numbness, the blood pressure was 110/80 mm Hg, and the weight 68.8 kg. She appeared well. Her mental status was normal, as were her cranial-nerve and motor functions. There was a slight delay in the relaxation of the deep-tendon reflexes; the plantar responses were flexor. Vibratory sensation was reduced in the feet, as was proprioception; other sensory responses were intact. The result of Romberg's test was normal. Cortical sensation (including graphesthesia, stereognosis, and tactile extinction) was normal.

    Radiographs of the lumbar spine revealed no abnormalities. Cranial and cervical magnetic resonance imaging (MRI) and magnetic resonance angiographic studies, performed after the administration of gadolinium, disclosed no intracranial abnormalities. On T2-weighted images, there was apparent hyperintensity of the cervical spinal cord at the C2-to-C3 level, but at that level, the cord was incompletely evaluated. A subsequent, dedicated MRI study of the cervical spine revealed no abnormalities. Laboratory values obtained at the time of this visit are shown in Table 1 and Table 2.

    A diagnostic procedure was performed.

    Differential Diagnosis

    Dr. Peter W. Marks: This young woman, who had a history of hypothyroidism, had a gradual onset of paresthesias of the hands and arms, followed by paresthesias of the legs, and weakness that affected her ability to exercise. Although I am aware of the diagnosis in this case, it provides an opportunity to review the differential diagnosis of rather nonspecific initial symptoms.

    Paresthesias

    The term "paresthesia" is used to describe an abnormal burning or prickling sensation. It is often described by patients as numbness or tingling in a part of the body. Inadvertent compression of a nerve by pressure on an arm or leg may cause the transient paresthesia with which most of us are familiar. However, many diseases may be characterized by paresthesia as one of their initial features (Table 3).

    Table 3. Possible Causes of Paresthesias.

    Entrapment neuropathies, such as carpal tunnel syndrome, are relatively common. At the time of the patient's initial presentation, when she had paresthesias in the fingers after cycling, carpal tunnel syndrome may have been given serious consideration.1 However, the subsequent development of paresthesias in both the upper and lower limbs indicates the presence of a systemic disorder. Patients with central nervous system disorders may present with paresthesias, and in a young woman, multiple sclerosis is a concern. However, this patient's MRI examination revealed no abnormalities. No aspect of her history implicated agents such as alcohol, drugs, or other toxins. Many rheumatologic disorders can cause paresthesias, either through central nervous system effects, as in systemic lupus erythematosus, or through vasculitis that affects the peripheral nerves. Cancers may result in nerve compression, may invade or infiltrate the nerves, or may be associated with paraneoplastic phenomena. However, this patient does not have other signs or symptoms suggesting that she has a rheumatologic disease or cancer.

    Infectious causes of paresthesia include Lyme disease, which is endemic in several areas of the United States. The presumed insect bites on the patient's legs raise the possibility of a vector-borne disease. Metabolic disorders such as diabetes mellitus, hypothyroidism, porphyria, uremia, and vitamin B12 deficiency can cause paresthesias through damage to central or peripheral nervous system structures. The patient had a history of hypothyroidism, but her thyrotropin level was normal at the time of the most recent measurement, although previously it had been abnormally elevated. Vitamin B12 (cobalamin) deficiency may cause symmetric paresthesias and disorders of proprioception and vibratory sensation affecting the upper and lower limbs, even in the absence of overt anemia; this patient may have been at increased risk for this disorder, given her history of hypothyroidism. Though categorized as metabolic causes of paresthesias, both hypothyroidism and vitamin B12 deficiency may be caused by autoimmune processes. Thus, in broad terms, the most likely causes of paresthesia in this patient are infectious or metabolic.

    Macrocytic Anemia

    At the time the patient visited the neurologist because of her symptoms, a complete blood count revealed macrocytic anemia. Macrocytic anemias have a number of causes and may be categorized as megaloblastic or nonmegaloblastic (Table 4). Megaloblastic anemias, which result from defects in DNA synthesis and cell maturation, include anemias due to folate or vitamin B12 deficiency, chemotherapeutic agents, or myelodysplasia. Although the patient subsequently had an episode of rectal bleeding from a hemorrhoid, she did not appear to be losing blood rapidly, so a brisk reticulocyte response is unlikely to be the cause of the macrocytosis. Although myelodysplasia would be unusual in a 37-year-old woman, it may occur at this age. The patient was not taking any medication that could cause a macrocytic anemia, such as zidovudine or a folate antagonist such as methotrexate. She did not use alcohol and did not appear to have overt signs of liver disease. Although hypothyroidism may also cause macrocytic anemia, the increase in mean corpuscular volume in this condition is generally limited. Folate or vitamin B12 deficiency, on the other hand, may be associated with a substantial increase in the size of red cells. The mean corpuscular volume in this patient — 114 μm3 — would be consistent with such a deficiency.

    Table 4. Possible Causes of Macrocytic Anemia.

    In this case, the correct diagnosis is suggested by the intersection of causes of paresthesia and causes of marked macrocytosis: vitamin B12 (cobalamin) deficiency. Since this patient reported eating a diet containing some meat and dairy products, malabsorption of vitamin B12 seems more likely than poor intake. In the absence of a history of gastrointestinal surgery or achlorhydria, the most likely cause of this patient's inability to absorb vitamin B12 is pernicious anemia. This disorder would explain the patient's progressive paresthesias as well as her other neurologic findings. Although the prevalence of pernicious anemia increases with advancing age, it may occur in young persons, particularly if it is a manifestation of a heritable syndrome.

    Autoimmune Polyendocrine Syndrome

    Pernicious anemia is an autoimmune disorder.2 In this patient, in whom hypothyroidism and probable pernicious anemia had developed at an early age and who had a family history of anemia, we must consider one of the syndromes of polyglandular failure. At least three major constellations of findings have been identified; they are termed autoimmune polyendocrine syndrome types I, II, and III (Table 5).3 In type III disease, autoimmune thyroiditis is associated with another organ-specific autoimmune disease. Three subcategories of type III disease have been described, according to the disorder associated with the autoimmune thyroiditis. One of these, type IIIB, which consists of autoimmune thyroiditis and pernicious anemia, is consistent with this patient's characteristics on presentation.

    Table 5. Autoimmune Polyendocrine Syndromes.

    Pernicious Anemia

    Pathophysiological Features

    Dietary vitamin B12 binds to intrinsic factor, which is produced by cells in the gastric fundus and body, after it dissociates from protein carriers in the acidic environment of the stomach. It then travels through the gut to the terminal ileum, where it is absorbed through a receptor-mediated process.4 Deficiency can be caused by a variety of circumstances: dietary insufficiency (which is rare), food cobalamin deficiency (i.e., an inability to split cobalamin from food), achlorhydria (which may be caused by aging, drugs that inhibit gastric acid secretion, or surgery), loss of ileal receptors (which may be caused by resection of the terminal ileum or inflammatory bowel disease), biologic competition (from Diphyllobothrium latum or bacterial overgrowth syndromes), rare congenital syndromes (such as transcobalamin II deficiency), and lack of production of intrinsic factor in the stomach because of pernicious anemia, a process that reflects autoimmune destruction of the gastric parietal and zymogenic cells.

    Vitamin B12 is required for two key sets of reactions (Figure 1). In nucleic acid metabolism, it is involved in the folate cycle, and it serves as a methyl group acceptor in the conversion of methyltetrahydrofolate to tetrahydrofolate, which then goes on to participate in purine synthesis. In this process, homocysteine is converted to methionine. The other reaction is the conversion of propionyl–coenzyme A (CoA) to succinyl-CoA through the intermediate methylmalonyl-CoA. Although it has been hypothesized that vitamin B12 deficiency affects the central nervous system through this mechanism, findings in patients with enzymatic deficiencies in this pathway do not support this idea. Thus, the cause of the neurologic manifestations of vitamin B12 deficiency remains obscure.5

    Figure 1. Metabolic Reactions Involving Vitamin B12.

    Vitamin B12 is involved in both nucleic acid metabolism and lipid metabolism. Its function in nucleic acid metabolism is intimately intertwined with that of folate. Thus, folate supplementation can partially reverse the peripheral effects of vitamin B12 deficiency. CoA denotes coenzyme A.

    Whatever the mechanism, vitamin B12 deficiency can be associated with permanent neurologic damage, so appropriate diagnosis and management are critical. Folate supplementation can partially overcome the anemia and the effect of vitamin B12 deficiency on the peripheral nerves, but it does not affect the manifestations in the central nervous system.6

    Diagnostic Testing

    Diagnosing vitamin B12 deficiency is straightforward when the deficiency is profound and there is a hypoproliferative anemia characterized by marked macrocytosis, hypersegmentation of neutrophils, pancytopenia, and signs of ineffective erythropoiesis (such as elevated levels of lactate dehydrogenase and indirect bilirubin) on laboratory testing. Diagnosing a subtle deficiency, which appears to be increasingly common, is more challenging. In such cases, vitamin B12 levels are often in the range of 200 to 300 pg per milliliter (150 to 220 pmol per liter) — low, but often not below the lower limit of normal. Liver disease and myeloproliferative diseases can also lead to falsely low-normal or normal levels of vitamin B12 in patients with pernicious anemia.7 In such situations, measurement of homocysteine and methylmalonic acid levels may be useful for documenting true vitamin B12 deficiency and for distinguishing it from folate deficiency (Figure 2). In vitamin B12 deficiency, the levels of both homocysteine and methylmalonic acid are elevated, whereas in most cases of folate deficiency only the homocysteine level is increased. In the absence of renal insufficiency, which can also elevate the homocysteine level, a methylmalonic acid level above the normal range is highly suggestive of vitamin B12 deficiency. The combination of a significant elevation in both methylmalonic acid and homocysteine virtually confirms the diagnosis.

    Figure 2. Diagnostic Algorithm for Vitamin B12 Deficiency.

    Although the diagnosis of vitamin B12 deficiency may be straightforward when the levels are very low or well within the normal range, the levels may often be indeterminate. Serum homocysteine and methylmalonic acid levels can help to define true deficiency. To convert the values for vitamin B12 to picomoles per liter, multiply by 0.7378.

    Although the Schilling test, which involves the sequential administration of radiolabeled vitamin B12 and intrinsic factor, was once commonly used in the evaluation of vitamin B12 deficiency, it has fallen out of favor because of its complexity and the need to administer radioactive materials. A test for antibodies against parietal cells may be helpful in some cases, as may a test for antibodies against intrinsic factor, but the former is relatively nonspecific and the latter relatively insensitive (though very specific).

    In the patient under discussion, the initial diagnostic procedures should have included a review of the peripheral-blood smear as well as an evaluation of the vitamin B12 levels. The necessity of additional diagnostic procedures would then depend on the findings.

    Dr. Nancy Lee Harris (Pathology): Dr. Zarghamee-Gavami, you followed this patient during and after her initial evaluation. Would you summarize your thinking before the diagnostic testing?

    Dr. Manijeh Zarghamee-Gavami (Medicine): My first concern in this young woman with numbness of the arms and legs was multiple sclerosis, and I ordered the MRI study to evaluate this possibility. Vitamin B12 deficiency was my next consideration. Since her thyroid disease was well controlled, I did not think it was the cause of her problems.

    Clinical Diagnosis

    Pernicious anemia.

    Dr. Peter W. Marks's Diagnosis

    Pernicious anemia, possibly associated with the autoimmune polyendocrine syndrome, type IIIB.

    Pathological Discussion

    Dr. Lawrence R. Zukerberg: The peripheral-blood smear showed that approximately 10 percent of the mature neutrophils were hypersegmented, with six or more lobes (Figure 3). A few hypersegmented neutrophils may be seen in a variety of disorders, but when more than 5 percent of the neutrophils are hypersegmented, the probability of either vitamin B12 deficiency or folate deficiency is very high. Hypersegmented eosinophils with three lobes were also present. In addition, there were numerous oval macrocytes and small and fragmented erythrocytes. The high mean corpuscular volume, in conjunction with the findings on the peripheral blood smear, are evidence of megaloblastic anemia. Laboratory studies showed that the level of vitamin B12 was very low, at 68 pg per milliliter (50 pmol per liter) (normal, greater than 250 pg per milliliter ). The folate level was slightly above normal. Therefore, the diagnosis was megaloblastic anemia due to vitamin B12 deficiency.

    Figure 3. Peripheral-Blood Smear (Wright's Stain).

    One hypersegmented neutrophil (Panel A) and a three-lobed, hypersegmented eosinophil (Panel B) from different areas of the smear are shown. Many red cells are enlarged and have an oval shape (macro-ovalocytes).

    To evaluate the cause of the vitamin B12 deficiency, an upper gastrointestinal endoscopy was performed, and biopsy specimens were obtained from the duodenum, antrum, and fundus. The duodenum and antrum were normal, with no evidence of chronic gastritis. Low-power microscopical examination of the gastric body and fundus showed extensive atrophy and marked thinning of the mucosa (Figure 4A). Closer examination showed severe atrophy, with complete absence of fundic glands and of chief and parietal cells. The lamina propria contained a dense lymphocytic infiltrate, and the mucosa showed intestinal metaplasia with goblet cells (Figure 4B).

    Figure 4. Gastric Biopsy Specimen (Hematoxylin and Eosin).

    Low-power magnification of the gastric body (Panel A) shows atrophy with marked mucosal thinning. Higher-power magnification (Panel B and Panel C) shows that the lamina propria is filled with lymphocytes; there are no observable fundic glands or chief or parietal cells, and the surface shows focal intestinal metaplasia with goblet cells (arrows).

    The histologic features of severe chronic atrophic gastritis limited to the gastric body and fundus are those of autoimmune gastritis. A test for antibodies to intrinsic factor was positive. Therefore, the diagnosis was pernicious anemia due to autoimmune gastritis, with vitamin B12 deficiency.

    The pathophysiology of autoimmune gastritis is centered on the hydrogen–potassium ATPase gastric proton pump.2 This pump is present only in the parietal cells of the gastric body. The initial event appears to be a CD4+ T-cell reaction against the proton pump. The T cells cause parietal-cell injury and result in exposure of both intrinsic factor and the hydrogen–potassium ATPase to antigen-presenting cells, activation of the immune response with secretion of interferon and cytokines, and formation of antibodies against intrinsic factor and the gastric proton pump.

    Although the immune response is directed only against the components of the parietal cell, over time there is destruction of both the chief and parietal cells. There is loss of gastric glands and infiltration of the lamina propria by lymphocytes and plasma cells, as in the case under discussion. Intestinal metaplasia of the surface mucosa eventually develops, leading to an increased risk of dysplasia and carcinoma. In addition, the lack of acid leads to increased gastrin production and endocrine-cell hyperplasia and, in some patients, the development of multiple carcinoid tumors.

    There are additional considerations. First, it has been reported that in some patients both the gastritis and anemia can be reversed by treatment with corticosteroids or azathioprine.8,9 In some patients treated with immunosuppression, the chronic gastritis disappeared, the gastric mucosa returned to normal, and acid output increased. Thus, immunosuppression may be one way to decrease the risk of dysplasia and carcinoma in these patients, although data showing a reduction in the risk of cancer with such therapy are lacking. Helicobacter pylori gastritis may lead to multifocal gastric atrophy, which in some patients leads to hypoacidity and the development of pernicious anemia. In a study of 138 patients with vitamin B12 deficiency, H. pylori was detected in 56 percent of the patients, and eradication of H. pylori improved the anemia and vitamin B12 levels in 40 percent of this subgroup.10 Thus, H. pylori appears to be a causative agent in some cases of vitamin B12 deficiency in adults; overall, this may be a more common cause than autoimmune gastritis. In this case, there was no evidence of H. pylori infection, and the absence of the antral inflammation that is typical of this infection is further evidence against this diagnosis.

    Discussion of Management

    Dr. Marks: A hundred years ago, pernicious anemia was a major cause of illness and death. Thanks to the efforts of pioneers in the field of hematology, a treatment for this disorder was developed before its pathophysiology was understood.11 George Minot, William Murphy, and George Whipple demonstrated that a daily diet that included about 100 to 200 g of beef liver (which we now know contains about 100 to 200 μg of vitamin B12) could rapidly reverse the anemia. In an elegant series of experiments in which red meat was incubated with gastric juice for various lengths of time and then was administered to patients, William Castle demonstrated that gastric juice appeared to contain an "intrinsic factor" that was required for absorption of the "extrinsic factor" (vitamin B12). Vitamin B12 was isolated almost simultaneously by two independent groups in 1948, and the nature of its structure was determined by x-ray crystallography.

    Today, the treatment of pernicious anemia involves either parenteral or oral administration of vitamin B12. Although monthly intramuscular injection of 100 to 1000 μg of vitamin B12 has long been a standard treatment for vitamin B12 deficiency, properly administered oral replacement is equally effective.12 In patients with mild vitamin B12 deficiency, oral administration of 1 to 2 mg of vitamin B12 daily can be effective, even as initial therapy. In practice, it is prudent when treating patients with severe deficiency to give parenteral vitamin B12 initially. After initial restoration of normal vitamin B12 levels, a transition to oral therapy is not unreasonable, although periodic monitoring of the vitamin B12 levels in such patients may be desirable. Those who doubt that vitamin B12 can be absorbed by mass action in the absence of intrinsic factor need only look to the work of Minot and colleagues: by administering large quantities of liver, they accomplished the same goal.

    A lingering question with respect to pernicious anemia is whether surveillance for gastric adenocarcinoma, carcinoids, and colonic polyps is warranted. Although some studies have shown that patients with pernicious anemia have a severalfold increase in the rate of gastric and colorectal cancers, others have not. At this time, there are no formal recommendations in the literature for screening patients with pernicious anemia for gastrointestinal cancers, although periodic screening of younger persons may be reasonable.

    This patient could well have an autoimmune polyendocrine syndrome, probably type IIIB. Autoimmune polyendocrine syndrome type IIIB is associated with risks of other disorders, including hypogonadism, myasthenia gravis, rheumatoid arthritis, and sarcoidosis. The patient currently has no evidence of these disorders, but her increased risk for them should be kept in mind as she is followed.

    Dr. Deborah J. Wexler (Medicine): What is the prognosis for the recovery of neurologic function?

    Dr. Marks: Unfortunately, about 50 percent of patients are left with at least a mild neurologic deficit after the vitamin B12 deficiency is corrected. Such residual deficits are more common in patients with long-standing or severe neurologic symptoms before therapy than in those with symptoms of recent onset or those with mild symptoms.

    Dr. Lloyd Axelrod (Endocrinology): Could you comment on the risk of hypokalemia in patients with pernicious anemia who are treated with vitamin B12? When is potassium replacement indicated?

    Dr. Marks: Parenteral vitamin B12 replacement can result in a dramatic proliferation of bone marrow cells, which take up potassium, and patients can become hypokalemic very quickly. In a person whose vitamin B12 deficiency is severe, I would monitor potassium levels and provide replacement therapy as necessary. Sudden death may occur in patients after treatment for vitamin B12 deficiency is initiated; in addition to hypokalemia, volume overload may lead to death. When one sees a patient with severe vitamin B12 deficiency and a hematocrit of 12 to 15 percent, one may be tempted to transfuse immediately to raise the hematocrit to a normal level. However, most of these patients have arrived at a low hematocrit over the course of years and tolerate it well; a transfusion volume sufficient to raise the hematocrit to a normal level can cause volume overload and cardiac complications.

    Dr. Zarghamee-Gavami: In the case under discussion, we gave the patient 1 mg of parenteral vitamin B12 daily for one week, followed by weekly injections for two months and monthly injections thereafter. The response was dramatic. Within 7 to 10 days, she was completely free of symptoms and had no neurologic deficits. I last saw her six months after the diagnosis was made, and she had completely recovered. She subsequently moved away from Massachusetts.

    Anatomical Diagnosis

    Pernicious anemia with autoimmune gastritis and vitamin B12 deficiency.

    Dr. Marks reports that he is now a senior clinical research physician at Novartis.

    Source Information

    From the Department of Medicine, Division of Hematology, Brigham and Women's Hospital (P.W.M.); the Departments of Medicine (P.W.M.) and Pathology (L.R.Z.), Harvard Medical School; and the Department of Pathology, Massachusetts General Hospital (L.R.Z.) — all in Boston.

    References

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    Muir A, Maclaren NK. Autoimmune diseases of the adrenal glands, parathyroid glands, gonads, and hypothalamic-pituitary axis. Endocrinol Metab Clin North Am 1991;20:619-644.

    Pruthi RK, Tefferi A. Pernicious anemia revisited. Mayo Clin Proc 1994;69:144-150.

    Carmel R, Melnyk S, James SJ. Cobalamin deficiency with and without neurologic abnormalities: differences in homocysteine and methionine metabolism. Blood 2003;101:3302-3308.

    Carmel R. Prevalence of undiagnosed pernicious anemia in the elderly. Arch Intern Med 1996;156:1097-1100.

    Snow CF. Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician. Arch Intern Med 1999;159:1289-1298.

    Wall AJ, Whittingham S, Mackay IR, Ungar B. Prednisolone and gastric atrophy. Clin Exp Immunol 1968;3:359-366.

    Jorge AD, Sanchez D. The effect of azathioprine on gastric mucosal histology and acid secretion in chronic gastritis. Gut 1973;14:104-106.

    Kaptan K, Beyan C, Ural AU, et al. Helicobacter pylori -- is it a novel causative agent in vitamin B12 deficiency? Arch Intern Med 2000;160:1349-1353.

    Chanarin I. A history of pernicious anemia. Br J Haematol 2000;111:407-415.

    Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood 1998;92:1191-1198.

    Related Letters:

    Case 30-2004: A Woman with Paresthesias

    Davies S. V., Marks P. W.(Peter W. Marks, M.D., Ph.)