L-6 Anemia: Chronic Inflammation, Pernicious, Aplastic

• The presentation provides a clinical approach to anemia of chronic inflammation, pernicious anemia, and aplastic anemia.
• The content is by Gina Foster-Moumoutjis, MD, MS, Associate Professor of Family Medicine at Dr. Kiran C. Patel College of Osteopathic Medicine.

Objectives

• Identify distinguishing elements of the HPI, past medical/surgical history, and ROS to differentiate between anemia of chronic disease, pernicious anemia, and aplastic anemia.
• Describe the pathophysiology of anemia of chronic disease, pernicious anemia, and aplastic anemia.
• Identify and interpret appropriate lab tests used to diagnose anemia, including CBC, peripheral smear, iron studies, vitamins, methylmalonic acid, and homocysteine.
• Describe physical exam findings in anemia of chronic disease, pernicious anemia, and aplastic anemia.
• Describe the treatment approach for anemia of chronic disease, pernicious anemia, and aplastic anemia.

Fatigue and Dizziness

• Three patients reported fatigue and dizziness
• All three patients reported “I feel tired and weak, as if I have no energy. I find myself getting headaches more often, my legs feel crampy. Sometimes my ears ring and sometimes if I stand up too fast I see a few stars.”
• All three patients deny "I have not actually fainted. I do not feel like the room is spinning or that I am spinning. I do not feel imbalanced when walking"

Anemia

• Fatigue and dizziness can be signs of clinical anemia

Lab Results

• Ms. Little had low hemoglobin, and low MCV
• Mr. Middle had low WBC, low hemoglobin, and low platelets, and borderline high MCV
• Mr. Big had low hemoglobin and borderline low platelets, and a high MCV

Causes of Anemia

• Microcytic anemia (MCV < 80 fL) can be caused by iron deficiency, anemia of chronic inflammation (late), thalassemia, lead poisoning, and sideroblastic anemia.
• Normocytic anemia (MCV 80-100 fL) with low or normal reticulocyte count can be caused by anemia of chronic inflammation (early), anemia of chronic kidney disease, acute blood loss, and aplastic anemia.
• Normocytic anemias (MCV 80-100 fL) with high reticulocyte count can be caused by RBC membrane/enzyme defects, sickle cell anemia, microangiopathic disorders, acute infections, and macroangiopathic disorders.
• Macrocytic anemia (MCV > 100 fL) can be caused by B12 deficiency, folate deficiency, alcoholism, liver disease, celiac sprue (folate deficiency), and pernicious anemia (B12 deficiency).

HPI and ROS for Anemia

• Key questions to ask in the HPI and ROS include:
  • Does anyone in your family have anemia?
  • What is your diet like?
  • Do you drink alcohol?
  • Is there any chance you could be pregnant?
  • Do you take any prescription or over the counter medications, herbs or supplements?

Specific questions for Micro/normocytic anemias

• Do you have any chronic diseases?
• Do you have any recurrent joint pain?
• Do you have gastritis/acid reflux?
• Have you seen blood in your stool or do they look dark black colored?
• Do you live in an house with lead-based paints or appliances?

Specific questions for Macrocytic anemias

• Do you have any GI symptoms?
• Any Gl surgeries? If so, what part?
• Do you have any history of liver disease?
• Any mood changes?
• Any neurologic symptoms?

Anemia of Inflammation (AI)

• Anemia of Inflammation was previously called anemia of chronic disease (ACD).
• AI is hypoproliferative, endogenous erythropoietin is inadequate for the primary anemia.
• On peripheral smear, AI can be normocytic (early) or microcytic (late).
• Severity of anemia and microcytosis is determined by inflammatory markers.

Causes of Anemia of Chronic Inflammation

• Infectious causes include tuberculosis, HIV/AIDS, and chronic bacterial infections like endocarditis and osteomyelitis.
• Inflammatory causes include autoimmune disorders like rheumatoid arthritis and SLE, inflammatory bowel disease, heart failure, cancer, severe trauma, and diabetes mellitus.

Pathophysiology of Anemia of Inflammation

• Suppressed erythropoiesis is mediated by inflammatory cytokines.
• Tumor necrosis factor (TNF) and interferon ɣ (IFN-γ) from neoplasms and bacterial infections suppress erythropoietin (EPO) production and proliferation of erythroid progenitors.
• Mediators in vasculitis and rheumatoid arthritis include interleukin 1 (IL-1) and IFN-γ.

Role of Hepcidin in Anemia of Inflammation

• Hepcidin is an acute phase reactant released from the liver in cases of rheumatoid arthritis, tuberculosis and bacterial infections.
• Hepcidin is a negative regulator of iron availability
• Hepcidin binds to ferroportin in the intestinal mucosa, preventing iron transport from food sources and interfering with iron release from macrophages and preventing recycling of iron from senescent red blood cells.

Diagnosis of Microcytic Anemia

• Peripheral blood smear shows borderline microcytic/hypochromic cells
• Serum iron concentration may be normal, TIBC is low
• % transferrin saturation may be low normal, and ferritin is normal.

Treatment of Anemia of Chronic Inflammation

• Focus on treating the underlying condition.
• Rheumatoid Arthritis/SLE can be treated with disease-modifying agents (DMARDs).
• Infections must be treated with antibiotics.
• Cancer requires cancer treatment.
• EPO can be used for severe, symptomatic anemia not responding to initial treatments.

Aplastic Anemia

• Aplastic anemia is hypoproliferative
• Bone marrow failure is secondary to damage to hematopoietic stem cell components
• Aplastic anemia is a pancytopenia
• Peripheral blood smear shows normocytic or macrocytic anemia, thrombocytopenia, and granulocytopenia.
• Severe aplastic anemia is characterized by low PMNs, low reticulocyte count, and low platelets.
• Prognosis of severe aplastic anemia is rapid deterioration and death.
• T-cell mediated injury to hematopoietic stem cells in the bone marrow.

Causes of Aplastic Anemia

• Infection: Seronegative hepatitis, Mononucleosis (EBV, CMV), HIV, Parvovirus B19
• Drugs: Chemotherapy, Nsaids, psychotropics, Sulfonamides
• Pregnancy
• Radiation: Nuclear plant accidents/Hospitals
• Chemicals: benzene
• Paroxysmal Nocturnal Hematuria
• Constitutional disorders: Fanconi anemia, Dyskeratosis congenita, telomeropathies

Clinical Presentation of Aplastic Anemia

• Thrombocytopenia can lead to easy bruising, bleeding gums, nose bleeds, petechiae, and heavy menstrual flow.
• Anemia can lead to fatigue, headache, and pounding sensations.
• Granulocytopenia (less common): Infections

Diagnosis of Aplastic Anemia

• Bone marrow biopsy is conducted
• Aplastic anemia would show as a fatty hypocellular bone marrow

Treatment of Aplastic Anemia

• Remove the offending agent, if possible.
• Bone marrow transplant from a fully biocompatible sibling may lead to a 90% recovery
• Immunosuppression is used if no bone marrow donor is available, use anti-thymocyte globulin + cyclosporine.

Etiologies of Vitamin B12 Deficiency

• Nutritional deficiency
• Malabsorption syndromes: Food-bound B₁₂ malabsorption, Prolonged use of proton pump inhibitors, Prolonged use of histamine H₂ receptor blockers, Lack of intrinsic factor or parietal cells, Pernicious anemia, Atrophic gastritis, Postgastrectomy
• Other gastrointestinal causes: Ileal malabsorption, Enteritis (Crohn's disease), Ileal resection, Bacterial overgrowth, Tapeworm infestation
• Defective transport: Transcobalamin II deficiency

Pernicious Anemia: Pathophysiology

• Autoimmune production of anti-intrinsic factor antibodies and anti-parietal cell antibodies leads to decreased formation of intrinsic factor to B12 complex.
• This coupled with atrophy of the gastric fundus and body leads to decreased absorption of B12 in the ileum.

Pernicious Anemia details

• It is a megaloblastic anemia with impaired metabolism of amino acids, reduced cell division efficiency, and nuclear cytoplasmic desynchrony.
• Impaired DNA synthesis affects rapidly dividing bone marrow cells, delaying nucleus maturation compared to the cytoplasm.
• Bone marrow is hypercellular
• Peripheral smear shows hypersegmented neutrophils, oval macrocytes, anisocytosis, poikilocytosis, and may or may not show low platelets or WBCs.

DNA Synthesis Details

• B12 (cobalamin) and folic acid (CH3-THF1) are involved in purine synthesis
• Purines = adenine, guanine

Lab Tests for B12 and Folate Deficiency

• In B12 deficiency, serum MMA and homocysteine levels are high.
• In folate deficiency, homocysteine is high, but serum MMA is normal.
• Homocysteine is involved in the metabolism of both B12 & Folate, it it be elevated in b12 deficiency and in folate deficiency
• Methylmalonic acid (MMA) involved in metabolism of MMA. Thus, MMA will be elevated in B12 deficiency and not in folate deficiency.

Diagnosing Pernicious Anemia

• Diagnosed by confirming a B12 deficiency with previous testing.
• Note serum B12 will be low or normal.
• Note MMA is high, Homocysteine will be high.
• Anti-Intrinsic Factor antibodies are considered diagnostic
• Anti-parietal cell antibody (may also be seen in other conditions), It is said because of low specificity this test is NOT often used in the diagnosis.

Other clinical presentations of B12 deficiency

• Glossitis is a condition
• Neuropsychiatric symptoms: Gait disturbance, Symmetric paresthesia or numbness, Degeneration of the dorsal and lateral white matter of the spinal cord, slowly progressive weakness, sensory ataxia, and paresthesias, and ultimately spasticity, paraplegia, and incontinence
• Less common: Depression, Insomnia, Cognitive slowing, Dementia, Psychosis, Forgetfulness
• Increased risk of gastric cancer

Treatment of Pernicious Anemia

• Parenteral B12 administration (intramuscular or deep subcutaneous tissue)

Anemia Workup: Initial Labs

• For Microcytic anemia;
  • Ferritin, Serum Iron, Total iron binding capacity (TIBC), % Saturation.
• For Normocytic anemia;
  • Reticulocyte Count, Peripheral Smear.
• For Macrocytic anemia
  • Serum B12, Serum Folate, Methlymalonic acid (MMA), Homocysteine, Liver function tests

Patient Cases

• Three patient cases are presented to illustrate the diagnostic process.

Mr. Big Case

• A 57-year-old male with a PMHx significant for alcoholism, presents with lightheadedness and headaches.
• The patient noted some imbalance when walking and some discomfort on the tongue for years, but it’s never been evaluated
• The patient eats a balanced diet and doesn’t have other medical problems
• ROS: Depressed mood, heartburn, occasional palpitations, numbing in hands and feet
• Blood in stool is negative, and they have no blood in stool
• Physical exam: BP 152/76, HR 92 regular, T 98.9 F, RR 16, O2sat 97%, no apparent distress, obese. Cardio: RRR, no murmurs, normal PMI, no JVD, occasional ectopic beat. Pulm: clear. GI: no hepatosplenomegaly. Integ: conjunctival pallor. HEENT: smooth red tongue. Neuro: decreased proprioception, decreased vibratory sensation in toes, hyporeflexia bilaterally.
• Mr Big’s labs: Serum B12 borderline low, Serum Folate normal, Methylmalonic Acid (MMA) high, Homocysteine high, Liver function tests normal.
• Mr. Big diagnosis will therefore be B12 Deficiency Anemia

Ms. Little Case

• A 63yo F has a PMH significant for rheumatoid arthritis (RA).
• The patient presents with dizziness, described as lightheadedness, fatigue, and headaches.
• Also denies vertigo and near syncope.
• Experiencing fatigue SX progressively worsening over the past year and now struggles walking up 2 flights of stairs.
• Also experiencing shortness of breath
• The patient has not seen a doctor in 2 years due to a lack of insurance and therefore hasn’t been taking the medications
• ROS: + joint pain, + joint swelling and warmth. Negative for wheezing, chest pain, palpitations, and neuro changes
• Blood Results: - Normal Ferritin levels, Borderline Low Serum Iron, Low Total Iron Binding (TIBC), Borderline Low % Saturation. Normal: Reticulocyte count + A borderline microcytic / normochromic peripheral smear.
• Patient diagnosis is Anemia of Inflammation

Mr. Middle Case

• A 25-year-old male presents with fatigue, muscle aches and dizziness. Started to feel weak about 1–2 weeks ago and seems to be more pronounced. Notes some bleeding when brushing his teeth.
• The patient Has no reported chronic medical illnesses, and he denies any etoh use.
• The patient however was travelling in South America 2 months ago and was hospitalized with hepatitis, though they could not find an infectious cause.
• The hepatitis SX resolved under antibiotics. The patient is not currently taking other prescription medications but is using ibuprofen for the muscle cramps
• ROS:+ headaches, + bloody nose last week, + easy bruising, Neg: abdominal pain, nausea, vomiting. O:
• bp 120/76, hr 89 regular, T 98.6 F, RR 16, 02sat 98% Gen: no apparent distress, well groomed
• Cardio: RRR, no m/t/g, normal PMI, no jvd Pulm: no wheezes, rales, rhonchi, normal chest diameter
• Physical examination: GI: no hepatosplenomegaly, integ: + nailbed, mucosal, conjunctival pallor, no jaundice, + petechia on lower extremities,+ scattered echymosis on arms and legs
• Blood Results:. Very Borderline macrocytic/thrombocytopenic / granulocytopenic level. & a Very LOw Reticulocyte count & a normal peripheral smear.
• Mr Middle has Aplastic Anemia.