Can anemia cause pain

Angina Pectoris Caused by Pernicious Anemia

Pernicious anemia, expressed as megaloblastic anemia, exists in individuals who fail to produce a glycoprotein, Castle’s intrinsic factor (CIF). It is commonly thought that the parietal cells of the stomach do not secrete CIF due to autoantibodies, thus not allowing vitamin B1,2 (cobalamin) to bond with CIF and so to be absorbed by the distal ileum. The failure of CIF secretion is associated with achlorhydria and gastric mucosa atrophy.1x1Jandl, JH. in: Textbook of hematology. Little, Brown, Boston; 1987: 158–163
Google ScholarSee all References This acquired disease becomes symptomatic usually after the age of 50 and is most common in individuals of northern European descent, especially Scandinavians.2x2Pedersen, AB and Mosbech, J. Morbidity of pernicious anemia. Acta Med Scand. 1969; 185: 449–452
Crossref | Scopus (23) | Google ScholarSee all References It is diagnosed with the Schilling test.

Anemia of any cause may result in increased cardiac output, especially when the hemoglobin level drops to 7 g/dl or less.3x3Brannon, ES, Merrill, AJ, Warren, JV, and Stead, EA Jr. The cardiac output in patients with chronic anemia as measured by the technique of right atrial catheterization. J Clin Invest. 1945; 24: 332–336
Crossref | PubMed | Google ScholarSee all References Tachycardia may not be present in chronic anemia, and the increased cardiac output at rest usually reflects an increased cardiac stroke volume.4x4Bishop, JM, Donald, KW, and Wade, OL. Circulatory dynamics at rest and on exercise in the hyperkinetic states. Clin Sci. 1955; 14: 329–360
PubMed | Google ScholarSee all References,5x5Donald, KW, Bishop, JM, Cumming, G, and Wade, OL. The effect of exercise on the cardiac output and circulatory dynamics of normal subjects. Clin Sci. 1955; 14: 37–73
PubMed | Google ScholarSee all References The increased cardiac output is achieved at the cost of increased work of the left ventricle.6x6Graettinger, JS, Parsons, RL, and Campell, JA. A correlation of clinical and hemodynamic studies in patients with mild and severe anemia with and without congestive failure. Ann Intern Med. 1963; 58: 617–626
Crossref | PubMed | Scopus (50) | Google ScholarSee all References Right atrial, right ventricular, and pulmonary arterial pressures are usually normal unless cardiac decompensation develops.4x4Bishop, JM, Donald, KW, and Wade, OL. Circulatory dynamics at rest and on exercise in the hyperkinetic states. Clin Sci. 1955; 14: 329–360
PubMed | Google ScholarSee all References,7x7Shubin, H, Kaufman, R, Shapiro, M, and Levinson, DC. Cardiovascular findings in children with sickle cell anemia. Am J Cardiol. 1960; 6: 875–885
Abstract | Full Text PDF | Scopus (34) | Google ScholarSee all References Left ventricular end-diastolic pressure remains unchanged.8x8Varat, MA, Adolph, RH, and Fowler, NO. Cardiovascular effects of anemia. Am Heart J. 1972; 83: 415–426
Abstract | Full Text PDF | PubMed | Scopus (235) | Google ScholarSee all References

Increased cardiac output in pernicious anemia and in other severe chronic anemias is of importance in maintaining an adequate oxygen supply to the tissues, and is facilitated by alterations in left ventricular afterload and myocardial contractility. Although ventricular end-diastolic volume, which is the preload of the left side of the heart, seems to be unchanged, myocardial contractility appears to increase.6x6Graettinger, JS, Parsons, RL, and Campell, JA. A correlation of clinical and hemodynamic studies in patients with mild and severe anemia with and without congestive failure. Ann Intern Med. 1963; 58: 617–626
Crossref | PubMed | Scopus (50) | Google ScholarSee all References,9x9Sharpey-Schafer, EP. Cardiac output in severe anemia. Clin Sci. 1944; 5: 125–132
Google ScholarSee all References,10x10Escobar, E, Jones, NL, Rapaport, E, and Murray, JF. Ventricular performance in acute normovolemic anemia and effects of beta blockade. Am J Physiol. 1966; 211: 877–884
PubMed | Google ScholarSee all References Afterload and left ventricular wall stress, having as major determinants vascular resistance and blood viscosity, are reduced. Decrease in peripheral vascular resistance in severe pernicious anemia is of great importance in producing increased cardiac output.11x11Duke, M and Abelmann, WH. The hemodynamic response to chronic anemia. Circulation. 1969; 39: 503–515
Crossref | PubMed | Scopus (180) | Google ScholarSee all References Moreover, lowered blood viscosity associated with anemia complements the increased cardiac output. Effects of decreased viscosity with low hematocrit vaues can result in a fivefold increase in coronary perfusion.12x12Baer, WR, Vlahakes, JG, Uhlig, NP, and Hoffman, IEJ. Maximum myocardial oxygen transport during anemia and polycythemia in dogs. Am J Physiol. 1987; 252: H1086–95 (Heart Circ Physiol 21)
PubMed | Google ScholarSee all References

Maximum myocardial oxygen transport shows an inverted U-shaped relationship with the hematocrit value.12x12Baer, WR, Vlahakes, JG, Uhlig, NP, and Hoffman, IEJ. Maximum myocardial oxygen transport during anemia and polycythemia in dogs. Am J Physiol. 1987; 252: H1086–95 (Heart Circ Physiol 21)
PubMed | Google ScholarSee all References At extremely low or extremely high concentrations of red blood cells, myocardial oxygen transport may decrease due to decreased oxygen carrying capacity on the one hand and increased blood viscosity on the other. Thus, the peak of the above curve occurs at or slightly above the normal hematocrit level.12x12Baer, WR, Vlahakes, JG, Uhlig, NP, and Hoffman, IEJ. Maximum myocardial oxygen transport during anemia and polycythemia in dogs. Am J Physiol. 1987; 252: H1086–95 (Heart Circ Physiol 21)
PubMed | Google ScholarSee all References Compensatory mechanisms to counteract the low hematocrit level include alterations in peripheral vascular resistance in order to redistribute cardiac output to selective vascular beds, so that during anemia; the increasing blood flow is proportionally greater in the coronary bed than in the renal, mesenteric, or femoral beds.13x13Fay, FC, Chen, ZYR, Schuessler, GB, and Chien, S. Effects of hematocrit variations on regional hemodynamics and oxygen transport in the dog. Am J Physiol. 1980; 238: H545–52 (Heart Circ Physiol 7)
Google ScholarSee all References This phenomenon is owed to vasoconstriction or vasodilation because of neurohumoral and/or local autoregulatory factors.13x13Fay, FC, Chen, ZYR, Schuessler, GB, and Chien, S. Effects of hematocrit variations on regional hemodynamics and oxygen transport in the dog. Am J Physiol. 1980; 238: H545–52 (Heart Circ Physiol 7)
Google ScholarSee all References Also, in chronic anemia the red blood cells develop increased levels of 2,3-diphosphoglycerate, which facilitates release of oxygen from hemoglobin;14x14Benesch, R and Benesch, RE. The effect of organic phosphates from the human erythrocyte on the allosteric properties of hemoglobin. Biochem Biophys Res Commun. 1967; 26: 162
Crossref | PubMed | Scopus (744) | Google ScholarSee all References however, this mechanism may be of secondary importance in severe anemia since the arteriovenous difference is decreased 3 volumes per 100 ml of blood, compared with 4 to 5 volumes per 100 ml of blood in normal subjects.11x11Duke, M and Abelmann, WH. The hemodynamic response to chronic anemia. Circulation. 1969; 39: 503–515
Crossref | PubMed | Scopus (180) | Google ScholarSee all References Another important mechanism of increased oxygen delivery to the heart in pernicious anemia may be increased utilization of coronary collateral vessels.15x15Scheel, KW and Williams, SE. Hypertrophy and coronary and collateral vascularity in dogs with severe chronic anemia. Am J Physiol. 1985; 249: H1031–37 (Heart Circ Physiol 18)
PubMed | Google ScholarSee all References Release of local vasodilators may help improve collateral blood flow after development of severe anemia.

If these adaptation mechanisms in severe anemia do not compensate adequately, angina pectoris may develop in these patients in spite of normal coronary arteries. Angina pectoris caused by severe anemia usually develops at very low hemoglobin levels, in the range of 3 to 4 g/dl. Coombs16x16Coombs, CF. A note on the cardiac symptoms of pernicious anemia, with particular reference to cardiac pain. BMJ. 1926; 2: 185
Crossref | PubMed | Scopus (4) | Google ScholarSee all References noted an association between severe pernicious anemia and anginalike pain, especially on exertion. The true incidence of angina pectoris associated with pernicious anemia could not be determined accurately, since many of the patients reported did not have adequate studies of the coronary circulation to rule out associated coronary artery disease. Clinically, the incidence appears to be in the range of 2 to 3 percent.17x17Willius, FA and Giffin, HZ. The anginal syndrome in pernicious anemia. Am J Med Sci. 1927; 174: 30–33
Crossref | Google ScholarSee all References Although severe anemia is not a common cause of angina, it should always be listed in the differential diagnosis of angina pectoris.

A Guide to Anemia Symptoms

There are many different types of anemia with many different causes. A handful of symptoms are shared by nearly all types of anemia, whether you have iron deficiency anemia or Fanconi anemia.

And each type of anemia shares a basic end effect: Your body does not have enough oxygen-bearing red blood cells for its needs.

How severe or frequent your symptoms are relates to how severe your anemia is. People who have mild anemia, from a mild iron deficiency, for instance, may not have any symptoms at all, while people with severe anemia can have much more noticeable and longer lasting symptoms.

Anemia symptoms include:

  • Fatigue. This is by far the most common anemia symptom. You may feel very tired or weak and unable to summon the energy for most daily activities.
  • Dizziness. Dizziness is most likely to occur when you stand up from a sitting or resting position.
  • Shortness of breath
  • Headaches
  • Cold skin, especially the hands and feet
  • Paleness. Your gums and the base of your nails may be especially pale.
  • Chest pain. Without enough oxygen-rich red blood cells, your heart has to work much harder to keep your body supplied with the nutrients it requires. You may feel pain and tightness in your chest when your heart muscle is not getting the oxygen it needs.
  • Arrhythmia. Also known as dysrhythmia or an abnormal heart rhythm, an uneven or altered rate or pattern of heartbeats can also result from your heart working harder to circulate blood.

If the condition is severe enough, these symptoms are found to some degree in every type of anemia.

Differentiating Anemia Symptoms

There are many different types of anemia, some with symptoms that set them apart:

  • Aplastic anemia. Nausea and skin rashes are known signs of this type of anemia, which occurs when the bone marrow stops making enough red blood cells.
  • Fanconi anemia. This is a rare inherited disorder that prevents your bone marrow from making all three needed types of blood cells and results in delayed development in a multitude of areas, from learning abilities to physical growth.
  • Folic acid deficiency anemia. Not having enough folic acid — one of the B vitamins, also known as folate — in your diet may lead to this type of anemia. Symptoms unique to this anemia include irritability, diarrhea, and a smooth tongue.
  • Hemolytic anemia. Jaundice, leg ulcers, and abdominal pain are hallmarks of this type of anemia, in which red blood cells are prematurely destroyed within the body. The excess hemoglobin released by this destructive process causes many of the symptoms.
  • Iron deficiency anemia. This type of anemia is due to a lack of iron in your diet or chronic blood loss. Iron deficiency anemia can be identified through symptoms that include unusual cravings (such as ice or dirt), brittle nails, a swollen or sore tongue, tiny cracks on the sides of your mouth, and frequent infections.
  • Pernicious anemia. This type of anemia is caused by a lack of vitamin B12. Not having enough vitamin B12, or being unable to absorb it, can lead to symptoms such as nerve damage, confusion, dementia, memory loss, depression, nausea, heartburn, weight loss, and a smooth, beefy red tongue.
  • Sickle cell anemia. Sudden pain throughout the body is a hallmark of this type of anemia, which occurs because the body makes red blood cells shaped like sickles (or a “C” shape) instead of smooth disc shapes. These abnormally shaped cells can clump together, blocking blood flow in many organs and causing painful sickle cell crises. Swelling in the hands and feet and damage to the spleen are also symptoms of this type of anemia.

Symptoms of anemia cover a wide range, depending on the cause of the anemia and the severity of the condition. However, there are a few symptoms, especially tiredness, that occur with all types of anemia. If you suspect you have anemia, talk to your doctor about your options.

If you’ve ever had that light-headed feeling after standing up too fast, you know how unpleasant and alarming it can be. You feel a little dizzy, your vision narrows, blurs or greys out and you may feel a little sick to your stomach. Some people experience it more frequently than others, but it can happen to anyone at any time.

Depending on what causes you to feel like you’re about to faint, it may not be a long-term problem or it could be a symptom of a medical condition that requires treatment. In either case, you should talk to your doctor as soon as possible if you feel faint or actually lose consciousness.
“The feeling that you’re about to faint is called presyncope,” said Lia F. Crispell, certified registered nurse practitioner at Careworks Convenient Healthcare in Wilkes-Barre. “It happens when the brain doesn’t get enough blood, oxygen or glucose to function properly, even momentarily.”
The common causes of presyncope
“People who experience presyncope usually dismiss it and move on with their day,” said Crispell. “This isn’t a good idea since some of the causes can be serious. It’s always best to get a diagnosis from a doctor.”

The potential causes of presyncope include:

  • Orthostatic hypotension: Also called postural hypotension, this is the head rush you sometimes feel when you stand up. It’s caused when blood pools in the blood vessels for too long and your heart doesn’t have enough blood to pump to your brain. It can happen to anyone, and more frequently if you’re taking certain medications and as you age.
  • Heart arrhythmia: Also known as an abnormal heart rate, this condition can cause your heart to beat too fast, too slow, or in a way that causes a sudden decrease in the blood supply to your brain. This can make you feel faint.
  • Medications: Medicines prescribed for pain, heart conditions and high blood pressure have the potential to affect your circulatory system in different ways that can lead to feeling faint. If this happens frequently, you should talk to your doctor about adjusting your dosage.
  • Dehydration: Not consuming enough fluids can cause nausea, weakness, dizziness, low blood pressure and fainting. Rehydrating will help to alleviate these symptoms quickly.
  • Anemia: Anemia is a condition that causes a lack of healthy red blood cells or hemoglobin in your blood, which carry oxygen to your organs – including your brain. The hallmark of anemia is tiredness, but it can also cause sufferers to feel faint and dizzy.
  • Autonomic neuropathy: This nerve disease disrupts electrical signals between the brain and the heart, blood vessels, and sweat glands. It can affect heart rate and blood pressure.
  • Stress and panic attacks: Anxiety can cause sufferers to breathe more rapidly and deeply, which can lead to lightheadedness and dizziness.

What you should do if you feel faint
“The most important thing to do if you feel faint is to get to a safe place,” said Crispell. “If you faint, you’ll eventually regain consciousness, but there is a chance you’ll be injured by falling or bumping your head.”
If you feel faint, lie down or sit down and place your head between your knees. If you’re with someone who complains about feeling faint, advise them to do the same.
After the fainting spell passes, it’s important to contact your doctor as soon as possible for a checkup. Only a trained medical professional will be able to pinpoint the exact cause of presyncope.
Lia F. Crispell sees patients at Careworks Convenient Healthcare in Wilkes-Barre. To make an urgent care reservation at one of 13 Geisinger Careworks locations across Northeastern and Central Pennsylvania, please visit https://www.careworkshealth.com/. Walk-ins are also welcome.

Management of Dizziness and Vertigo

Pharmacologic Management

Dizziness

In patients without apparent vertiginous symptoms, the distinction of the dizziness complaint remains broad and unclear. Oftentimes, dizziness is a multisensory disorder, affected by peripheral neuropathy, visual impairment, and musculoskeletal disease. Treatment of the underlying cause would relieve the dizziness. Anemia, iron deficiency, malignancy, vitamin deficiency, and chronic blood loss may result in insufficient blood flow to the brain and manifest as lightheadedness. Patients with thyroid dysfunction or hypoglycemia may also present with dizziness. Pregnancy or menstruation may cause lightheadedness due to acute changes in hormone levels.

Patients with orthostatic hypotension can be treated with midodrine and fludrocortisone to increase blood pressure; however, blood pressure monitoring is necessary to prevent any consequential complication. Midodrine should not be taken within 4 hours of bedtime or when lying down, as it could cause supine hypertension. Other common side effects include urinary frequency, urinary retention, and skin rash. Fludrocortisone is a mineralocorticoid that increases sodium and water retention. Thus, it is important to monitor potassium levels and for heart failure symptoms. Other common side effects include edema, hyperglycemia, increased risk of infection, and muscle weakness. Pseudoephedrine, paroxetine, and desmopressin are other options when midodrine and fludrocortisones are not effective.

Dizziness and vertigo can also present in patients with migraines. Migraines are a vascular disorder that manifest as periodic, unilateral headaches that are often preceded by neurologic symptoms called the aura. Acute migraine attacks can be treated with nonopioid analgesics, antiemetics, nonsteroidal anti-inflammatory drugs, and 5-HT antagonists. Preventative medications for migraines include amitryptyline, beta-blockers, calcium channel blockers, and acetazolamide.

Psychogenic dizziness can occur in patients with chronic anxiety. Panic attacks are described as sudden intense fear or discomfort and are often associated with dizziness, nausea, shortness of breath, chest tightness, paresthesias, and perspiration. Selective serotonin reuptake inhibitors are frequently used to treat chronic anxiety and panic disorders. Benzodiazepines can also be used for short-term treatment of anxiety.

Vertigo

Pharmacologic treatment of vertigo depends on the etiology of the condition. However, vestibular suppressants can be used to alleviate vertiginous symptoms. These drugs should only be taken for a short period of time (~1 week) and then be titrated off because of their potential to delay compensation. There are three main categories of vestibular suppressants: anticholinergics, antihistamines, and benzodiazepines. Anticholinergics decrease the rate of firing in the vestibular nuclei. Although not indicated for vertigo, glycopyrrolate is less sedating than the other drugs used to treat vertigo. Antihistamines, such as meclizine, have anticholinergic effects and are much more sedating than true anticholinergics. Benzodiazepines are effective for vertigo, but they may be habit-forming. For acute cases of severe vertigo, IM promethazine or IV droperidol can be used.

Antiemetics may also be used to help with nausea associated with vertigo. Metoclopramide is a dopamine antagonist that also enhances gastrointestinal (GI) tract motility and accelerates gastric emptying. It has been associated with lightheadedness, drowsiness, headache, GI upset, diarrhea, and muscle weakness. Ondansetron is a serotonin antagonist used to prevent chemotherapy-induced emesis, but it has been used for other types of nausea as well. Side effects include headache, fatigue, malaise, constipation, and dizziness. Prochlorperazine and promethazine are both phenothiazines that affect several neurotransmitters (e.g., histamine, dopamine, norepinephrine, acetylcholine) and produce an antiemetic response. Side effects include dizziness, blurred vision, constipation, dry mouth, and photosensitivity. Prochlorperazine can also cause changes in gait, muscular tremors, and weight gain. The severity of the patient’s nausea and the drug’s sideeffect profile will help determine which drug is more appropriate for the patient.

Table 3 summarizes drugs that can be used to treat symptoms of dizziness, vertigo, and associated nausea.

How to Recognize and Treat an Anemia Rash

Aplastic anemia

Aplastic anemia is one of the most common causes of anemia rashes. Aplastic anemia is a rare condition, but it can be serious. It can develop or be inherited. It’s most often seen in teenagers and older adults. According to the National Heart, Lung, and Blood Institute, it’s two to three times more common in Asian countries than anywhere else in the world.

Aplastic anemia occurs when the body’s bone marrow doesn’t make enough new blood cells. The rashes resemble patches of pinpoint red or purple spots, known as petechiae. These red spots may be raised or flat on the skin. They can appear anywhere on the body but are more common on the neck, arms, and legs.

The petechial red spots do not typically cause any symptoms like pain or itching. You should notice that they stay red, even if you press on the skin.

In aplastic anemia, not only is there a shortage of red blood cells, there is also a lower than normal level of platelets, another type of blood cell. Low platelet count tends to result in bruising or bleeding more easily. This leads to bruises that look like rashes.

Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura is a rare blood disorder that causes tiny blood clots to form throughout your body. This can cause the tiny red or purple spots known as petechiae, as well as unexplained purplish bruising that can look like a rash. The bruising is known as purpura.

Paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria is a very rare genetic disorder in which a genetic mutation causes your body to produce abnormal red blood cells that break down too quickly. This can cause blood clots and unexplained bruising.

Hemolytic uremic syndrome

Hemolytic uremic syndrome is a condition in which an immune reaction causes the destruction of red blood cells. The immune reaction can be triggered by bacterial infections, some medications, and even pregnancy. It can cause small, unexplained bruising and swelling, particularly of your face, hands, or feet.

Iron deficiency anemia is one of the most common types of anemia. People with iron deficiency of any kind may develop pruritus, which is the medical term for itchy skin. As you itch, you may scratch your skin, which can cause redness and bumps that look like rashes.

In some cases, treatment for iron deficiency anemia may also cause rashes. Ferrous sulfate is a type of iron supplement that your doctor may prescribe to you if you have iron deficiency anemia. Some people may develop an allergy to the ferrous sulfate therapy. This can cause you to develop an itchy rash and hives. The hives or rash can appear anywhere on the body and may also come with some skin swelling under the red areas.

You should seek medical attention immediately if you think you have hives or an allergic rash due to ferrous sulfate, especially if you experience any swelling of the lips, tongue, or throat.

57-Year-Old Woman With Anemia and Rash

A 57-year-old woman had an 8-day history of watery diarrhea, six times a day, without evidence of blood or mucus. This symptom began shortly after she ate in a restaurant with four other persons, in whom diarrhea also developed. Her appetite was good, and she denied having weight loss. Before the current illness, she averaged two bowel movements per day and had never noticed bloody or black stools. Although her diarrhea had diminished during the past few days, she had noticed some fatigue and dyspnea on minimal effort.

Her past medical history included microcytic anemia documented for 30 years, since her first pregnancy. She had been on iron therapy since but had required periodic hospitalizations for treatment of anemia by blood transfusions. The patient had undergone hysterectomy at age 45 years for uterine fibroids. She gave no history of foreign travel, special diet, smoking, or alcohol use. She was of Norwegian descent and had no family history of chronic anemia. Chronic edema of the lower extremities had been present for 20 years, but the patient had no history of varicose veins, venous insufficiency, or deep vein thrombosis. Chronic pruritus with small skin ulcers suspected to be caused by psychogenic itching had been present for 10 years.

Physical examination revealed a thin, very pale patient who was afebrile and had normal vital signs. Her weight was 47 kg. She wore a wig to hide mild diffuse alopecia, which she had for 20 years. A patchy papulovesicular rash with several shallow ulcers, 1 to 3 mm, were noted on the scalp, back, buttocks, and extensor surfaces of all extremities (Fig. 1Fig. 1). No lesions were noted on the hands, feet, intertriginous areas, or groin. The mucous membranes were normal. No lymphadenopathy or neck masses were noted. Cardiovascular and respiratory examinations revealed normal findings. Her protuberant abdomen was soft without masses, ascites, or organomegaly. Findings on pelvic and rectal examinations were normal. A guaiac test was negative. Soft pitting edema (+3) of both lower extremities was present up to knee level. Initial laboratory findings included a hemoglobin level of 6.4 g/dL., mean corpuscular volume (MCV) of 54.0 fL, leukocyte count of 8.2 × 109/L, and platelet count of 952 × 109/L. The reticulocyte count was 2.6%.

Fig. 1

Shallow ulcers (l to 3 mm)and vesicles on right elbow.

  • 1.

    Which one of the following conditions is the most likely cause of anemia in this patient?

    • a.

      α-Thalassemia

    • b.

      Iron deficiency

    • c.

      Chronic disease-related anemia

    • d.

      Hereditary sideroblastic anemia

    • e.

      Aplastic anemia

α-Thalassemia is unlikely in our patient because it is a lethal disease and most patients die before the age of 20 years. β-Thalassemia could be suspected because the MCV is extremely low, a common finding in this hereditary defect of globin chain production. The most common cause of microcytic anemia, however, is iron deficiency. Although classically the MCV is mildly decreased, the thrombocytosis and previous use of iron therapy make this the most likely diagnosis in our patient. The patient had no evidence or past history of chronic disease, such as chronic inflammation, connective tissue disease, uremia, endocrine failure, or liver disease. The severity of chronic disease-associated anemia usually correlates with the severity of the primary disease and would be unlikely to reach such levels without previous detection of the primary disease. The patient had no family history of hereditary sideroblastic anemia, a rare X-linked disorder of heme synthesis that affects male patients and produces iron-laden ringed sideroblasts with secondary reticulosis. Aplastic anemia, a bone marrow disorder that is frequently associated with leukopenia and thrombocytopenia, causes anemia that is normocytic or macrocytic but not microcytic, as in this patient.

Further laboratory evaluations demonstrated a ferritin level of 3 μg/L (normal, 20 to 120) and a hemoglobin A 2of 1.5% (normal, 1.5 to 3.0%); thus, iron deficiency was confirmed, and β-thalassemia was excluded. Serum sodium, potassium, bilirubin, and creatinine levels were normal. Aspartate transaminase (AST) was 45 U/L (normal, 12 to 31). The international normalized ratio was 1.1. Urinalysis showed normal findings and no evidence of proteinuria. Electrocardiographic and chest and abdominal roentgenographic findings were normal. The patient was admitted to the hospital for blood transfusion, to eliminate a possible active bleeding source, and for evaluation of the severe anemia and bilateral lower extremity edema. We suspected hypoalbuminemia as the cause of her edema. Laboratory evaluations revealed a serum albumin level of 2.1 g/dL (normal, 3.5 to 5.0).

  • 2.

    Which one of the following is the most likely cause of hypoalbuminemia in this patient?

    • a.

      Hepatic cirrhosis

    • b.

      Crohn’s disease

    • c.

      Malnutrition

    • d.

      Food poisoning

    • e.

      Malabsorption

The patient had no history of hepatitis, jaundice, or alcohol abuse and no clinical manifestations of chronic liver disease or portal hypertension. Inherited metabolic causes of liver disease might also have extrahepatic manifestations such as skin pigmentation or neurologic symptoms not present in this patient. Although the AST was increased, the patient had a normal international normalized ratio and bilirubin level. In patients with Crohn’s disease, hypoalbuminemia may develop because of reduced dietary intake related to systemic or gastrointestinal symptoms or because of protein exudation into the gut. In addition, fibrotic strictures may form in such patients, and secondary bacterial overgrowth can lead to intestinal malabsorption. Such features often cause bloody diarrhea and symptoms of intestinal obstruction. These symptoms were never present in our patient. Malnutrition may contribute to iron deficiency but was considered an unlikely independent cause of the severe hypoalbuminemia in our patient. Although food poisoning may have caused this patient’s transient diarrhea before her admission, food poisoning does not cause protein loss. Intestinal malabsorption may cause severe loss of protein, fat, minerals, and vitamins and can explain this patient’s low weight, edema, alopecia, and iron deficiency anemia.

Because of the suspicion of malabsorption, we had further tests performed, which disclosed the following deficiencies: cholesterol 130 mg/dL, carotene 15 μg/dL (normal, 48 to 200), folate 2.5 μg/L, magnesium 1.59 mg/dL, and iron 5 μg/dL. On the basis of the clinical features and the laboratory results, our clinical diagnosis was malabsorption syndrome.

  • 3.

    Which one of the following is the most likely cause of the clinical syndrome suspected in this patient?

    • a.

      Whipple’s disease

    • b.

      Giardia lamblia infection

    • c.

      Celiac sprue

    • d.

      Chronic pancreatitis

    • e.

      Intestinal lymphoma

Whipple’s disease and G. lamblia are acute small bowel infections with the usual initial manifestations of severe diarrhea, abdominal pain, bloating, nausea, and vomiting. Occasionally, they may infect patients for several months and cause less prominent symptoms and weight loss, but these conditions are unlikely to persist for many years. Whipple’s disease is also associated with extraintestinal manifestations such as arthritis, fever, lymphadenopathy, and central nervous system involvement. Our patient had none of these features. Celiac sprue (nontropical sprue) usually manifests with diarrhea, although the wide spectrum of findings in this disease may include normal bowel habits. This chronic disorder causes intestinal villous atrophy and resultant malabsorption of protein, carbohydrates, fat, vitamins, and minerals; therefore, it is the most likely cause of this patient’s multiple nutritional deficiencies. Chronic pancreatitis may cause malabsorption of fat and fat-soluble vitamins but would not explain the albumin, mineral, and folate deficiencies. Lymphoma could cause all the findings in our patient if it involved the small intestine, but the chronicity of the condition reduced the likelihood of this possibility.

The patient underwent upper intestinal endoscopy, and small intestinal biopsy specimens showed villous shortening in conjunction with areas of subtotal villous atrophy, crypt elongation, and lymphocytic infiltrate in the lamina propria and epithelium consistent with celiac sprue.

  • 4.

    Which one of the following dermatologic diagnoses is most likely to be responsible for the skin lesions (Fig. 1Fig. 1) in this patient?

    • a.

      Dermatitis herpetiformis

    • b.

      Erythema multiforme

    • c.

      Herpes simplex

    • d.

      Herpes zoster

    • e.

      Bullous pemphigoid

The rash (Fig. 1Fig. 1) is most consistent with dermatitis herpetifonnis, a chronic intensely pruritic rash commonly noted on the extensor aspects of extremities and present in less than 10% of patients with celiac sprue.1x1Katz, SI. Dermatitis herpetiformis. in: TB Fitzpalrick, AZ Eisen, K Wolff, IM Frccdbcrg, KF Austen (Eds.) Dermatology in General Medicine. Vol 1. 4th ed. McGraw-Hill, New York; 1993: 636–641
Google ScholarSee all References Papulovesicular lesions develop, ulcerate, and then heal as similar other new lesions develop at other sites. Erythema multiforme is usually an acute drug reaction that may manifest with similar lesions, but as the name implies, multiple types of skin lesions (for example, target lesions) are usually present and may involve the palms and soles. Herpes simplex can manifest in any skin area, but it is an intermittent vesicular rash and seldom involves a widespread area of skin. Herpes zoster is an acute painful vesicular rash that is dermatomal in distribution, and although recurrences are common, chronic ulcerations usually do not occur. Bullous pemphigoid, an autoimmune skin eruption, may be chronic and have a distribution that is similar to that for dermatitis herpetiformis, but the blisters are usually larger occasionally several centimeters in diameter.

Our patient underwent skin biopsies of early lesions as well as normal skin. Analysis showed dermal collections of neutrophils and upper dermal perivascular lymphocytic infiltrates in the involved lesions. The findings were nondiagnostic, but immunofluorescent staining of both normal and lesional skin biopsy specimens revealed granular IgA papillary deposits in the dermis, which are pathognomonic of dermatitis herpetiformis.

The following treatment was initiated: a gluten-free diet, dapsone (150 mg daily), supplemental multivitamins, iron sulfate, and folic acid. After 6 weeks of therapy, the patient underwent reassessment, and clinical examination showed considerable improvement of her diffuse alopecia and complete resolution of rash and edema of the lower extremities. Laboratory investigations revealed a hemoglobin of 13.8 g/dL and normal ferritin, AST, and albumin. These clinical observations confirmed the diagnosis of celiac sprue.

  • 5.

    Which one of the following is least likely to help in the long-term management of this patient’s illness?

    • a.

      Regular periodic physical examination, including blood tests, to exclude persistence ofmalabsorption syndrome

    • b.

      Attempt to taper dosage of dapsone after 6 to 12 months of gluten-free diet

    • c.

      Periodic assessment of liver and renal function

    • d.

      Repeated small intestinal biopsies if weight loss or signs of malabsorption recur

    • e.

      Maintenance therapy with low-dose prednisone

Regular physical examinations may indicate whether the patient is compliant with the restrictive gluten-free diet. The skin lesions recur in most patients not taking dapsone within 12 weeks of a gluten challenge.2x2Fry, L, McMinn, RM, Cowan, JD, and Hoffbrand, AV. Glutcn-free diel and reintroduction of gluten in dermatitis herpetiformis. Arch Dermalol. 1969; 100: 129–135
Crossref | Scopus (63) | Google ScholarSee all References The examination may show weight loss or edema, which may imply malabsorption. If the patient is compliant with dietary restrictions, tapering of the dapsone dosage is reasonable; almost 50% of patients may be able to discontinue use of the drug altogether without resurgence of the pruritic rash. In most patients, this goal can be achieved after 6 to 12 months of a gluten-free diet.3x3Galvez, L and Falchuk, ZM. Dermatitis herpetiformis: gastrointestinal association. Clin Dermalol. 1991 Jul-Sep; 9: 325–333
Abstract | Full Text PDF | Scopus (7) | Google ScholarSee all References Dapsone, like other sulfones, is potentially toxic and may cause a drug-induced hepatitis, nephrotic syndrome, and renal papillary necrosis as well as bone marrow suppression, methemoglobinemia, hemolytic anemia, rash, and peripheral neuropathy. With daily doses of less than 300 mg, toxic reactions are uncommon, but regular assessment of liver and renal function is recommended while the patient is taking this medication.4x4Adverse reactions to dapsone. Lancet. 1981; 2: 184–185
Google ScholarSee all References Patients with celiac sprue have a 11 to 13% risk for a malignant lesion, 45% of which are lymphomas (most commonly, non-Hodgkin’s intestinal lymphoma). This risk is decreased and may be abolished by prolonged strict compliance with a gluten-free diet.5x5Holmes, GK, Prior, P, Lane, MR, Pope, D, and Allan, RN. Malignancy in cocliac disease—effect of a gluten free diet. Gut. 1989; 30: 333–338
Crossref | PubMed | Scopus (881) | Google ScholarSee all References Hence, one should not always dismiss recurrence of malabsorption as noncompliance with dietary restrictions, and repeated intestinal biopsies should be considered. If symptoms of malabsorption persist despite adequate therapy, reperformance of endoscopy and biopsy of the small intestine may help exclude the presence of gastrointestinal tumors and may occasionally detect intestinal lymphomas. Corticosteroids are used only in high doses in refractory sprue that is unresponsive to a gluten-free diet or in severely ill patients. They have no role in the long-term management of celiac sprue.6x6Trier, JS, Falchuk, ZM, Carey, MC, and Schreiber, DS. Celiac sprue and refractory sprue. Gastroenterology. 1978; 75: 307–316
Google ScholarSee all References

Further follow-up of this patient will include periodic clinical examinations and weight measurements in conjunction with laboratory tests that would reveal any recurrence of malabsorption or dapsone side effects. The dose of dapsone will be tapered gradually unless the rash recurs.

Discussion

Celiac sprue has a wide variety of clinical manifestations that may include an asymptomatic state. Typically, gastrointestinal symptoms may become evident in infants after a gluten challenge. Such symptoms, however, decrease or disappear during adolescence, only to recur in the third or fourth decade of life. The most common gastrointestinal symptoms are diarrhea, flatulence, and weight loss. Extraintestinal manifestations are commonly associated with malabsorption. These findings include anemia, fatigue, paresthesias, infertility, amenorrhea, male impotence, and osteopenic bone disease attributable to hypocalcemia and vitamin D deficiency. Secondary hyperparathyroidism may also occur.

Clinical signs include short stature, a protuberant abdomen, proximal muscle wasting and muscle weakness, edema, clubbing, ecchymoses, cheilosis, glossitis, and follicular hyperkeratosis as a result of vitamin A deficiency. If malabsorption is suspected, a stool fat measurement can confirm the diagnosis. The recent acute diarrhea in our patient would have interfered with the precision of this test. Malabsorption due to abnormal mucosa of the proximal small intestine might be detected by using the d-xylose tolerance test.7x7Trier, JS. Celiac sprue. in: MH Sleisenger, JS Fordtran, BF Scharschmidt, M Feldman (Eds.) Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. Vol 2. 5th ed. Saunders, Philadelphia; 1993: 1078–1096
Google ScholarSee all References

Celiac sprue is associated with autoimmune diseases such as chronic hepatitis, primary biliary cirrhosis, ulcerative colitis, and pernicious anemia. The high prevalence (10%) of this disease in first-order relatives stimulated considerable research about the possible cause of this disease. Multiple hypotheses have been proposed, encompassing genetic factors, enzymatic or glycoprotein deficiencies, and possible environmental factors causing an autoimmune mechanism. The most intriguing hypothesis includes the involvement of type 12 adenovirus that sensitizes the genetically predisposed hosts (HLA-DQw2) to antigenic determinants in gluten that resemble those of the viral protein. The patient then develops antibodies against certain proteins such as gliadin, which are thought to be the toxic fractions of gluten.8x8Kagnoff, MF, Patcrson, YJ, Kumar, PJ, Kasarda, DD, Carbone, FR, Unsworth, DJ et al. Evidence for the role of a human intestinal adenovirus in the pathogencsis of coeliac disease. Gut. 1987; 28: 995–1001
Crossref | PubMed | Scopus (133) | Google ScholarSee all References Exposure to gluten frequently occurs because it is a common constituent of our regular diet, especially in wheat, barley, rye, and oats.

Antigliadin and antireticulin antibody titers are now used as part of the laboratory assessment of patients with possible celiac sprue, with IgA antigliadin antibodies being more specific (84%) but less sensitive (73%) than IgG antibodies (corresponding values, 52% and 94%). Recently, IgA antibodies against smooth muscle endomysium were found to be highly specific (98%) and sensitive (100%) for this disease and the titer of which correlates with the severity of mucosal damage. Moreover, all three of these antibodies decrease or disappear with treatment and can be used in the follow-up management of patients with celiac sprue.9x9Calabuig, M, Torregosa, R, Polo, P, Tuset, L, Tomas, C, Alvarez, V et al. Serological markers and celiac disease: a new diagnoslic approach?. J Pediatr Gaslrocntcrol Nutr. 1990; 10: 435–442
Crossref | Scopus (38) | Google ScholarSee all References Biopsy findings suggestive of celiac sprue in the absence of these antibodies should increase the suspicion of an alternative diagnosis.

Intestinal biopsy samples may be consistent with celiac sprue but are not pathognomonic. The differential diagnosis would include tropical sprue, lymphoma, eosinophilic gastroenteritis, Crohn’s disease, Zollinger-Ellison syndrome with pronounced gastric hypersecretion, bacterial overgrowth, refractory sprue, and, in infants, viral gastroenteritis and intolerance of cow’s milk. Therefore, for a definite diagnosis of celiac sprue, one should note the appearance of flat small intestinal mucosa, the histologic features of villous atrophy, and a prompt, unequivocal response to a gluten-free diet,7x7Trier, JS. Celiac sprue. in: MH Sleisenger, JS Fordtran, BF Scharschmidt, M Feldman (Eds.) Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. Vol 2. 5th ed. Saunders, Philadelphia; 1993: 1078–1096
Google ScholarSee all References A gluten rechallenge in equivocal cases that improve during a gluten-free dietary trial is seldom necessary. The finding of two of three circulating antibodies at the time of diagnosis and their disappearance with ingestion of a gluten-free diet add considerable weight to the diagnosis10x10Revised criteria for diagnosis of cocliac disease: report of Working Group of European Society of Paediatric Gastroenterology and Nutrition. Arch Dis Child. 1990; 65: 909–911
Crossref | Scopus (1629) | Google ScholarSee all References and would eliminate the need to rechallenge the patient with a gluten load.

Refractory sprue is an uncommon complication that may occur at any time and can lead to progressive malabsorption and death. Use of corticosteroids, azathioprine, or cyclosporine has yielded limited benefit.6x6Trier, JS, Falchuk, ZM, Carey, MC, and Schreiber, DS. Celiac sprue and refractory sprue. Gastroenterology. 1978; 75: 307–316
Google ScholarSee all References

Dermatitis herpetitormis is infrequently associated with celiac sprue, occurring in less than 10% of patients, but more than 85% of patients with this unusual rash have some evidence of gastrointestinal changes suggestive of celiac sprue. Patients with dermatitis herpetiformis also have the same HLA markers and antigliadin antibodies that are found in patients with celiac sprue.11x11Sachs, JA, Aawad, J, McCloskcy, D, Navarrete, C, Festenstein, H, Elliot, E et al. Different HLA associated gene combinations contribute to susceptibility for coeliac disease and dermatitis herpetiformis. Gut. 1986; 27: 515–520
Crossref | Scopus (62) | Google ScholarSee all References The diagnosis is confirmed by immunofluorescent staining of skin biopsy specimens showing granular IgA deposits in the upper dermis. Linear IgA deposits are now considered a separate entity (called “linear IgA disease“) that has minimal association with celiac sprue; they are indicative of other autoimmune processes such as scarring pemphigus or bullous pemphigoid.12x12Jonion, RF, Triftshauscr, CT, and Schroeter, AL. Direct immunofluorescent studies of pemphigus and bullous pemphigoid. Arch Dermatol. 1971; 103: 486–491
Crossref | Scopus (117) | Google ScholarSee all References Interestingly, dermatitis herpetiformis also responds to a gluten-free diet. If dapsone or sulfapyridine is administered, however, the response is usually dramatic-absence of development of new lesions or pruritus within 48 hours after implementation of therapy. Therefore, this unusual rash may be of help to the physician in the assessment of patients with malabsorption or, as in the current case, anemia.

Anemia and skin problems
Fast facts
Anemia rash most often appears as pinpoint red spots or unexplained bruising on your skin.
Anemia rash is most often caused by aplastic anemia, a rare disorder.

If you’re experiencing a rash or skin changes, you should make an appointment to see your doctor or dermatologist.
There are many different types of anemias with different causes. They all have the same effect on the body: an abnormally low amount of red blood cells. Red blood cells are responsible for carrying oxygen through the body.

Some types of anemia can cause rashes, which are abnormalities on the skin. Sometimes, the rash that presents with anemia may be due to the anemia condition itself. Other times, the rash may be due to complications from the treatment of the anemia.

What causes anemia rash and what does it look like?What causes anemia rash and what does it look like?Aplastic anemiaAplastic anemia is one of the most common causes of anemia rashes. Aplastic anemia is a rare condition, but it can be serious. It can develop or be inherited. It’s most often seen in teenagers and older adults. According to the National Heart, Lung, and Blood Institute, it’s two to three times more common in Asian countries than anywhere else in the world.

Aplastic anemia occurs when the body’s bone marrow doesn’t make enough new blood cells. The rashes resemble patches of pinpoint red or purple spots, known as petechiae. These red spots may be raised or flat on the skin. They can appear anywhere on the body but are more common on the neck, arms, and legs.
The petechial red spots do not typically cause any symptoms like pain or itching. You should notice that they stay red, even if you press on the skin.

In aplastic anemia, not only is there a shortage of red blood cells, there is also a lower than normal level of platelets, another type of blood cell. Low platelet count tends to result in bruising or bleeding more easily. This leads to bruises that look like rashes.

Thrombotic thrombocytopenic purpuraThrombotic thrombocytopenic purpura is a rare blood disorder that causes tiny blood clots to form throughout your body. This can cause the tiny red or purple spots known as petechiae, as well as unexplained purplish bruising that can look like a rash. The bruising is known as purpura.
Paroxysmal nocturnal hemoglobinuriaParoxysmal nocturnal hemoglobinuria is a very rare genetic disorder in which a genetic mutation causes your body to produce abnormal red blood cells that break down too quickly. This can cause blood clots and unexplained bruising.

Hemolytic uremic syndromeHemolytic uremic syndrome is a condition in which an immune reaction causes the destruction of red blood cells. The immune reaction can be triggered by bacterial infections, some medications, and even pregnancy. It can cause small, unexplained bruising and swelling, particularly of your face, hands, or feet.
Other causesIron deficiency anemia is one of the most common types of anemia. People with iron deficiency of any kind may develop pruritus, which is the medical term for itchy skin. As you itch, you may scratch your skin, which can cause redness and bumps that look like rashes.

In some cases, treatment for iron deficiency anemia may also cause rashes. Ferrous sulfate is a type of iron supplement that your doctor may prescribe to you if you have iron deficiency anemia. Some people may develop an allergy to the ferrous sulfate therapy. This can cause you to develop an itchy rash and hives. The hives or rash can appear anywhere on the body and may also come with some skin swelling under the red areas.

You should seek medical attention immediately if you think you have hives or an allergic rash due to ferrous sulfate, especially if you experience any swelling of the lips, tongue, or throat.

DIAGNOSIS
Diagnosing anemia rashYour doctor may suspect anemia as the cause of your rash if it meets the physical description and is accompanied with other common anemia symptoms. These include:

pale skinfatigueshortness of breathYour doctor may check you for aplastic anemia if you display symptoms like:
rapid or irregular heartbeatunexplained, easy bruisingprolonged bleeding from cuts, especially minor onesdizziness and headachesnosebleedsbleeding gumsfrequent infections, especially those that take longer to clear up than normalIf you’re experiencing a rash or skin changes, you should make an appointment to see your doctor or dermatologist, especially if:

the rash is severe and comes on suddenly with no explanationthe rash covers your whole bodythe rash lasts more than two weeks and hasn’t improved with home treatmentyou also experience other symptoms like tiredness, fever, weight loss, or changes in bowel movementsIf you believe that the rash is a reaction to new iron supplements that you’ve started taking, seek immediate medical attention. You could be having an allergic reaction or may be taking too high of a dose.

source: Healthline

Anemia

What is anemia?

Anemia is a condition defined by deficiency of hemoglobin in the blood. Hemoglobin is a protein molecule contained in red blood cells and is responsible for carrying oxygen. The normal level of hemoglobin in the blood is approximately 12-14 grams per deciliter in men and 11-13 gm/dl in women, although normal value ranges may vary slightly among different laboratories.

An illustration depicting red blood cells.

Anemia can occur rapidly when there is a sudden loss of blood. Often, the source of this blood loss can be from the esophagus, stomach, or small intestines. This is often seen as vomiting blood or rectal bleeding. Patients usually feel dizzy because their blood pressure drops, especially when standing up.

Anemia occurs more chronically when the body does not produce enough hemoglobin or red blood cells to maintain its normal level.

What causes anemia?

By far, the most common cause of anemia is shortage of iron. Iron is essential to make new red blood cells. In women, this is usually due to menstrual loss of blood.

Other possible causes of anemia could include:

  • a slow loss of blood in the GI tract that cannot be seen in a person’s stool
  • deficiencies of vitamin B12 for which a special substance in the stomach is needed in order for the vitamin to be absorbed from food
  • major stomach surgery that may cause an inability to absorb proper nutrients, such as B-vitamins
  • folic acid deficiency (also referred to as folate deficiency), which is when a person’s body does not get enough folic acid

There are other less common causes of anemia. It can be seen in patients with a chronic disease (such as severe arthritis, inflammation, etc.), in which the red blood-forming tissues (blood marrow) become sluggish. There are specific diseases of the bone marrow in which all of the main blood cells are not made efficiently or adequately.

Symptoms

Mild chronic anemia does not usually cause significant symptoms. More severe anemia, however, will result in:

  • an unhealthy, pale appearance of the skin (pallor)
  • a lack of energy
  • shortness of breath

Other symptoms, based on the cause of the anemia, may also be present. Patients with bone marrow problems may have inadequate white blood cells and platelets, whereas patients with hemolysis may develop yellow jaundice of the skin and eyes.

Diagnosis

Tests for anemia are simple and logical. Blood levels of hemoglobin are measured and the red blood cells are observed under a microscope to assess the likely cause of the condition.

Red blood cells have characteristic appearances according to the specific deficiency. It is possible to recognize very “young” red blood cells, called reticulocytes. More than the usual number of these in the blood indicates a rapid turnover of red blood cells in response to hemolysis or blood loss.

Assessment of the other blood constituents (white cells and platelets) will demonstrate whether the problem is solely due to hemoglobin development, or a more diffuse bone marrow disease. The lack of iron can be recognized easily on a blood smear, and the levels can be measured. Blood levels of iron, folate, and B12 are measured when appropriate. When discovered, further investigations can determine the precise cause of any deficiency.

The finding of iron deficiency anemia, particularly in women who are not menstruating and men, should prompt the investigation for chronic bleeding into the bowel. This bleeding may not be obvious to the patient, but can be detected by tests on the stool.

These then lead logically to examination of the lining of the intestine to seek a source for the bleeding. These are most commonly found in the stomach and colon using standard endoscopic techniques such as:

  • upper endoscopy
  • colonoscopy

These investigations are particularly important in older patients since this bleeding is an important early sign of possible gastrointestinal cancer.

Capsule Endoscopy

In some people, a source of bleeding can not be found in the esophagus, stomach or colon. These people may need further evaluation of their small intestines for bleeding. This can now be accomplished vis the swallowing of a small capsule with a camera in it that can take pictures from within the small intestines and transmit them to a recorder that the patient wears on a belt. These pictures can then be reviewed by a physician for areas of bleeding that can not be reached by standard endoscopes.

Treatment

Some treatment options include:

  • iron supplements, usually given by mouth, for iron deficiency anemia
  • iron infusions, given by injection, for more severe cases of iron deficiency anemia
  • vitamin B12 infusions
  • stricter diet and nutrition management for cases of folic acid deficiency

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