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Questions and Answers
What is the inheritance pattern of Hereditary Hemochromatosis?
What is the inheritance pattern of Hereditary Hemochromatosis?
What gene is associated with Hereditary Hemochromatosis?
What gene is associated with Hereditary Hemochromatosis?
HFE
Which of the following mutations are associated with Hereditary Hemochromatosis?
Which of the following mutations are associated with Hereditary Hemochromatosis?
Is untreated Hereditary Hemochromatosis potentially fatal?
Is untreated Hereditary Hemochromatosis potentially fatal?
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What is the treatment of choice for Hereditary Hemochromatosis?
What is the treatment of choice for Hereditary Hemochromatosis?
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In patients with Hereditary Hemochromatosis, serum iron, serum ferritin, and serum transferrin levels are __________.
In patients with Hereditary Hemochromatosis, serum iron, serum ferritin, and serum transferrin levels are __________.
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What symptom is commonly associated with Hereditary Hemochromatosis?
What symptom is commonly associated with Hereditary Hemochromatosis?
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Which organ is commonly implicated in iron overload due to Hereditary Hemochromatosis?
Which organ is commonly implicated in iron overload due to Hereditary Hemochromatosis?
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How much dietary iron do patients with Hereditary Hemochromatosis absorb compared to normal individuals?
How much dietary iron do patients with Hereditary Hemochromatosis absorb compared to normal individuals?
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Secondary hemochromatosis can only be inherited and is not associated with acquired disorders.
Secondary hemochromatosis can only be inherited and is not associated with acquired disorders.
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Define anemia of chronic disease.
Define anemia of chronic disease.
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List some disorders associated with anemia of chronic disease.
List some disorders associated with anemia of chronic disease.
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Define sideroblastic anemia.
Define sideroblastic anemia.
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State the morphological findings for anemia of chronic disease.
State the morphological findings for anemia of chronic disease.
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Define porphyria.
Define porphyria.
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Describe iron overload and hereditary hemochromatosis.
Describe iron overload and hereditary hemochromatosis.
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List the characteristics of iron overload and hereditary hemochromatosis.
List the characteristics of iron overload and hereditary hemochromatosis.
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Anemia of chronic disease is the most prevalent anemia after iron deficiency anemia.
Anemia of chronic disease is the most prevalent anemia after iron deficiency anemia.
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Which of the following is associated with anemia of chronic disease? (Select all that apply)
Which of the following is associated with anemia of chronic disease? (Select all that apply)
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Which of the following is characteristic of sideroblastic anemia? (Select all that apply)
Which of the following is characteristic of sideroblastic anemia? (Select all that apply)
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What is the pathophysiology behind sideroblastic anemias?
What is the pathophysiology behind sideroblastic anemias?
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Lead poisoning impairs heme synthesis at several steps, affecting enzymes such as ________ and ________.
Lead poisoning impairs heme synthesis at several steps, affecting enzymes such as ________ and ________.
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What treatment is recommended for anemia of chronic disease?
What treatment is recommended for anemia of chronic disease?
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Study Notes
Anemia of Chronic Disease
- A common hematological disorder that often occurs as a consequence of other medical conditions.
- It is the second most prevalent anemia after Iron Deficiency Anemia.
- Often associated with chronic infections, autoimmune disease, chronic inflammation, and malignant neoplasms.
- It may appear 1-3 months after the onset of a chronic disease.
- Anemia is characterized by low serum iron levels, reduced TIBC, and decreased transferrin saturation.
- Serum ferritin levels are usually elevated due to iron being trapped in the RES cells of the bone marrow.
- This trapped iron can be visualized in bone marrow aspirates using Prussian Blue staining.
Anemia of Chronic Disease Pathophysiology
- The precise pathogenesis of ACD is unclear, but it's suggested that chronic disease states may obstruct the transfer of stored iron to developing red blood cells within the bone marrow.
- Possible causes of ACD include:
- Shortened red cell survival
- Impaired bone marrow red blood cell production
- A diminished release of iron from the RES.
Disorders Associated With Anemia of Chronic Disease
-
Infections:
- Tuberculosis
- Chronic osteomyelitis
- Fungal infections
- Burns
-
Neoplasms:
- Carcinomas / Cancers
- Malignant Lymphomas
- Multiple Myeloma
-
Autoimmune Disorders:
- Systemic lupus erythematosus (SLE)
- Rheumatoid arthritis
- Sarcoidosis
Clincal Features of Anemia of Chronic Disease
- Anemia may be present for several months after the development of a chronic disorder.
- ACD may present as mild to moderate anemia.
- In some cases, the anemia presents as a normocytic normochromic and in some other cases, the anemia presents as a microcytic hypochromic.
- The signs and symptoms of the disease are associated with the underlying cause.
Laboratory Findings for Anemia of Chronic Disease
- ACD is defined by a combination of clinical, morphological, and laboratory findings.
-
Peripheral blood findings:
- Microcytic hypochromic or normocytic normochromic.
- The red cell distribution width (RDW) may be moderately increased.
-
Iron Studies:
- Decreased serum iron, decreased total iron-binding capacity (TIBC), and decreased transferrin saturation.
- Increased serum ferritin
-
Bone marrow findings:
- An adequate number of erythroid precursors.
- The M:E ratio may be increased because of decreased erythropoiesis.
- Sideroblasts are decreased, but macrophages appear to have an increased amount of storage iron.
- Hemosiderin is the long-term storage of iron and may appear as very coarse aggregates of iron and is expected to be absent in IDA.
Anemia of Chronic Disease Treatment
- Primary treatment is to address the underlying disease.
- Blood transfusions may be used for a rapid and effective intervention in cases of severe or life-threatening anemia.
Sideroblastic Anemia
- A group of disorders characterized by a hypochromic anemia, ineffective erythropoiesis, increased serum and tissue iron, and the presence of ringed sideroblasts in the bone marrow.
- The sideroblastic anemias are a diverse group and can be inherited or acquired.
- Inherited forms include:
- Sex-linked congenital sideroblastic anemia.
- Autosomal recessive sideroblastic anemia.
- Acquired forms can be:
- Primary (idiopathic) or secondary (see table 6-4).
- Secondary sideroblastic anemias are often caused by toxins or drugs, such as chloramphenicol.
Sideroblastic Anemia Pathophysiology
- The sideroblastic anemias involve abnormalities in the enzymes that regulate heme synthesis.
- Ringed sideroblasts are a distinctive marker of this group of anemias.
- Deficiencies in specific enzymes are identified, including:
- Deficiencies in delta 5-aminolevulinic acid synthetase (ALA), a key enzyme that initiates the heme synthetic pathway.
- Heme synthesis is disrupted, leading to iron accumulating within the erythroid precursor. This iron cannot be incorporated into the heme molecule because the protoporphyrin ring cannot be formed.
- The accumulated iron is deposited within the mitochondria of erythroid precursor cells.
- Ringed sideroblasts are described as cells containing iron accumulated in the mitochondria surrounding the nucleus.
- These siderotic granules are visible with Prussian Blue staining.
Sideroblastic Anemia Clinical Presentation
- Typically, the clinical presentation of sideroblastic anemia varies depending on whether it is acquired or inherited.
Sideroblastic Anemia Laboratory Findings
-
Peripheral blood findings:
- The anemia is moderate to severe.
- Red blood cells demonstrate dimorphism, showing a mixture of microcytes and normocytes.
- MCV, MCH, and MCHC values are usually normal.
- RDW is elevated, reflecting the dual population of red blood cells.
- Additional red cell abnormalities may include anisocytosis (variation in cell size), poikilocytosis (variation in cell shape), target cells, Pappenheimer bodies, and basophilic stippling.
- The WBC and platelet counts are largely normal.
Sideroblastic Anemia Bone Marrow Findings
- A defining characteristic of all sideroblastic anemias is the presence of ringed sideroblasts in bone marrow aspirates.
- Ineffective erythropoiesis, erythroid hyperplasia, and increased stainable bone marrow iron are common findings in sideroblastic anemia.
- Iron stains typically reveal more than 15% ringed sideroblasts.
Sideroblastic Anemia Iron Studies
-
Iron studies demonstrate:
- Elevated serum iron.
- Increased ferritin.
- Normal to decreased TIBC.
- Increased percent saturation levels.
- Serum soluble transferrin receptor levels are typically normal or decreased.
Sideroblastic Anemia Treatment
- It's crucial to determine whether the anemia is hereditary or acquired.
- In the case of secondary sideroblastic anemia caused by medications, swift improvement may be seen upon stopping the offending drug.
Lead Poisoning and Sideroblastic Anemia
- Lead poisoning impairs heme synthesis at various points in the pathway.
- The heme enzymes affected are 5-aminolevulinic acid dehydrase and ferrocheletase.
- Basophilic stippling of red blood cells is a frequent feature of lead poisoning.
Porphyrias
- Rare diseases with diverse subtypes.
- Caused by disturbances in heme biosynthesis.
- Disorder due to a disruption in the normal pathway of heme biosynthesis resulting in buildup of toxic metabolites/byproducts.
- For example, mutations in the enzymes responsible for metabolizing aminolevulinic acid (ALA) and porphobilinogen (PBG) into heme lead to accumulation of these intermediate metabolites, causing a variety of physiological symptoms/effects.
Porphyrias Spectrum of Clinical Symptoms
- A spectrum of clinical symptoms exists, ranging from neurovisceral (abdominal pain with neurological symptoms) to cutaneous (skin manifestations - lesions, skin blistering, lesions, pain).
- Acute attacks may be neurological (fatigue, mental confusion, seizures) or gastrointestinal (abdominal pain/nausea/vomiting, constipation).
Acute Intermittent Porphyria (AIP)
- An inherited disorder where there are elevations in ALA and PBG, which cause acute attacks that can last for hours, days, or weeks.
- AIP can be life-threatening.
- This kind of Porphyria has an autosomal dominant inheritance pattern.
Porphyrias Diagnosis
- Acute attacks are marked by elevated ALA or PBG in the urine (red wine color).
- Serum and stool can be tested for ALA and PBG.
- Genetic testing can help confirm the diagnosis.
- Elevated liver enzymes may also be found.
- Diagnosis is usually made during an attack.
Porphyrias Management
- Management focuses on avoiding precipitating factors/eliminating triggers (for example, alcohol, steroids, estrogen).
- Treatment of acute symptoms includes pain medication and anti-nausea medications.
Iron Overload and Hemochromatosis
- Iron overload refers to the excessive accumulation of iron in the reticuloendothelial cells of various tissues.
- It describes a clinical disorder where tissue damage results from excess iron.
- In this disorder of iron storage, an inappropriate increase in intestinal iron absorption leads to excess iron in the tissues.
- Iron overload can be primary (inherited) or secondary to chronic anemias and their treatment.
- The excess iron is stored in organs like the liver, heart, and pancreas, causing damage to these organs.
Hereditary Hemochromatosis (HH)
- A common genetic disorder, particularly among individuals with European ancestry.
- Almost always a diagnosis of exclusion (ruled out after other possibilities are considered).
- An autosomal recessive disorder linked to chromosome 6.
- Can be inherited in two ways:
- Homozygous (* / *)
- Heterozygous ( * / N)
- Homozygotes are more susceptible to iron overload.
Hereditary Hemochromatosis Pathophysiology
- Iron absorption and storage become imbalanced due to inheritance of an abnormal gene called HFE.
- HFE regulates the amount of iron absorbed from the diet.
- Two mutations, C282Y and H63D, are linked to HH.
- Iron is constantly loaded into storage sites.
- This leads to multi-organ damage.
Hereditary Hemochromatosis Symptoms
- Chronic fatigue and weakness
- Cirrhosis of the liver
- Hyperpigmentation
- Diabetes
- Impotence
- Sterility
- Cardiac arrhythmias
- Tender swollen joints
- Hair loss
- Abdominal symptoms
Hereditary Hemochromatosis Laboratory Diagnosis
- Screening for iron status:
- Serum iron, serum ferritin, and transferrin saturation are elevated.
- TIBC and transferrin levels fall within the normal range.
- Liver biopsy
Hereditary Hemochromatosis Treatment
- Untreated HH can be fatal.
- Advanced iron overload can lead to liver cancer.
- Therapeutic phlebotomy, or "blood-letting," is the primary treatment.
- The goal of therapeutic phlebotomy is to reduce serum ferritin levels.
Iron Overload Summary
- Iron overload refers to the excessive accumulation of iron in the reticuloendothelial cells of various tissues.
- It describes a clinical disorder where tissue damage results from excess iron.
- In this disorder of iron storage, an inappropriate increase in intestinal iron absorption leads to excess iron in the tissues.
- Iron overload can be primary (inherited) or secondary to chronic anemias and their treatment.
- The excess iron is stored in organs like the liver, heart, and pancreas, causing damage to these organs.
Classifications of Hemochromatosis
-
Hereditary:
- Classical hemochromatosis type 1
- Juvenile type 2
- Transferrin receptor type 3
- African overload type 4
-
Secondary:
- Hereditary Disorders
- Thalassemia
- Sickle cell anemia
- Sideroblastic anemia
- Enzyme-deficiency anemia
- Hereditary spherocytosis
- Acquired Disorders
- Anemia not due to blood loss in which multiple transfusions are required
- Dyserythropoietic anemia
Hereditary Hemochromatosis (HH)
- HH is a genetic disorder that causes iron overload in the body.
- It is characterized by an abnormal gene that leads to increased iron absorption from the digestive tract.
- HH progresses through four stages:
- Stage 1: No symptoms, iron overload is not present.
- Stage 2: 2 - 5g iron overload without symptoms.
- Stage 3: Iron overload with early symptoms such as lethargy and arthralgia.
- Stage 4: Iron overload with organ damage and cirrhosis.
- The liver organ commonly implicated in HH, with hepatomegaly present in 95% of cases.
Clinical Features
- Symptoms of HH usually develop in middle age.
- The most common symptom is joint pain.
- Other symptoms include:
- Fatigue
- Bronze discoloration of the skin
- As the disease progresses:
- Hepatomegaly develops which can lead to cirrhosis and liver fibrosis.
- Iron deposits in the heart tissue can cause cardiomyopathy.
- Other complications are:
- Diabetes mellitus
- Hypoparathyroidism
Laboratory Findings
- Despite abnormal iron metabolism, erythropoiesis is normal and hematologic abnormalities are usually not seen.
- Increased liver function enzyme tests are common, such as aspartate aminotransaminases (AST).
IRON STUDIES
- In patients with HH:
- Serum iron, serum ferritin, and serum transferrin levels are increased.
- The Total Iron Binding Capacity (TIBC) is usually within normal limits.
- Increased percent transferrin saturation is a key indicator of the disease.
- Laboratory criteria for diagnosing HH:
- Transferrin saturation of greater than 50% for females.
- Transferrin saturation of greater than 60% for males.
- Diagnosis can be confirmed by direct analysis of the HFE gene.
Treatment
- The goal of treatment for iron storage disease is to remove excess iron from the body.
- Patients with symptoms of HH require therapeutic phlebotomy.
- The goal of therapeutic phlebotomy is to have:
- Serum ferritin levels less than 50 μg/L.
- Transferrin saturation below 30%.
- Once these goals are achieved, phlebotomy frequency is reduced to 2-4 times per year depending on the patient.
- If therapeutic phlebotomy is not appropriate, desferrioxamine, a chelating agent, is used to reduce iron stores.
Secondary Hemochromatosis
- Secondary hemochromatosis can be acquired or secondary to other inherited hemolytic anemias.
- Common characteristics of secondary hemochromatosis are:
- Anemia
- Ineffective erythropoiesis
- Iron overload
- Secondary hemochromatosis patients are transfused repeatedly, leading to increased iron storage because there is no mechanism for iron excretion.
- Iron overload from transfusion therapy may be treated with chelation therapy.
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