Oral Iron Therapy


Iron deficiency anaemia is treated by iron supplementation that may be administered orally or parenterally.  Oral iron absorption is inefficient, is interfered by food and is associated with high incidence of gastrointestinal adverse effects. About 17% of the world population is estimated to be suffering from iron deficiency. Iron deficiency is more common the poorer regions of the world. These regions have limited resources allocated for healthcare. Oral iron is inexpensive and convenient to administer making it the modality of choice for initiation of treatment of iron deficiency. The availability of safer parenteral iron preparations that can replete the iron deficit in one dose has reduced the threshold of switching a person intolerant to iron to parenteral iron.

Oral Iron Absorption

Dietary iron may be heme iron or non-heme iron. Heme iron is absorbed after oxidation to hematin. The absorption of heme iron is more efficient. Dietary non-heme iron is present in the ferric state. Ferric iron is insoluble and needs to be reduced to ferrous iron. Gastric acidity aids this conversion. Medicinal iron is most often administered in the ferrous state. Ferrous iron tends to oxidize to ferric iron at physiological pH. Gastric acid lowers the pH and retards oxidation. The absorption of non-heme iron is aided by ascorbate, animal proteins, human milk, keto sugars, organics, amino acids that form soluble chelates and retarded by phytates present in grains and vegetables, dietary fibre, polyphemols present in tea, coffee and wine, phosphates and phosphoproteins present in egg yolk, bovine milk, calcium and zinc. For a detailed discussion on iron absorption see intestinal iron absorption. Preparations containing iron in the ferric state have a 3-4 fold lower bioavailability than ferrous iron preparations. Ferric iron is insoluble in the alkaline medium of the duodenum and needs to be converted to ferrous iron (ScientificWorldJournal. 2012; 2012: 846824).

Oral Iron Preperations

Oral iron preparations may be heme or non-heme. Heme iron is available as heme iron polymer. Non-heme iron may be in the ferrous or ferric form. Carbonyl is pure iron prepared from the decomposition of iron pentacarbonyl. The preparations are listed in the table below.

 

Preparations Iron Content
Ferrous Sulfate, anhydrous 30%
Ferrous Fumarate 33%
Ferrous Sulfate 20%
Ferrous carbonate, anhydrous 48%
Ferrous Gluconate 12%
Ferric Ammonium Citrate 18%
Ferric bisglycinate 20%
Ferric pyrophosphate 12%
Carbonyl iron ~100%
Heme-iron peptide 100%
Polysaccharide iron complex 100%

Indications of Oral Iron Therapy

Oral iron is indicated for prevention and treatment of iron deficiency anaemia. The rate of iron delivery is insufficient to provide iron when erythropoiesis is stimulated by erythrocyte stimulating agents like erythropoietin and darbepoetin. Oral iron should not be used for such patients.

Trial of Oral Iron Therapy

Serum ferritin is an indicator of total body iron. It is also an acute phase reactant. Low ferritin indicates iron deficiency. The traditional cutoff is 12ng/mL. At this cutoff the sensitivity of ferritin for the diagnosis of iron deficiency anaemia is only 25%. The sensitivity can be increased to 92% with a positive predictive value of 83% if a cutoff of 30ng/mL is used. A trial of oral iron may be given if other causes of anaemia are excluded.

Contraindications to Oral Iron Therapy

  1. Primary hemachromatosis: Primary hemochromatosis is a is absolute contraindication
  2. Peptic ulcer, regional enteritis, or ulcerative colitis can be exacerbated by oral iron.
  3. β-Thalassaemia trait is a relative contraindication. Some patients may develop iron overload. Patients should be given iron only if iron deficiency is established by laboratory investigation.

Failure of Oral Iron Therapy

  1. Failure to take prescribed medication: Oral iron therapy causes gastrointestinal adverse effects in a large proportion patients that are severe enough in some to discontinue therapy. A detailed history must be taken to ascertain that the patient has taken the prescribed dose.
  2. Incorrect or incomplete diagnosis: Iron deficiency anaemia is hypochromic microcytic (see Evaluating Anaemia). Other diseases that result in hypochromic microcytic anaemia are thalassaemia and anaemia of chronic disease. Both are common and can both be confused with iron deficiency as well as co-exist with iron deficiency. Thalassemia trait affects about 1.5% of the world population. About 1.4% of the population is estimated to have anaemia due to infection, inflammation or chronic renal disease (https://dx.doi.org/10.1016%2FS0140-6736(15)60692-4). Incidental occurrence of iron deficiency with thalassaemia trait or anaemia of chronic disease will result in an incomplete response to iron supplementation. Some inflammatory conditions e.g. ulcerative colitis cause blood loss. Blood loss may be seen due to use of non-steroidal inflammatory agents in patients with autoimmune arthritis. Anaemia in these patients shows an incomplete response to iron supplementation because part of the anaemia results from chronic inflammation.
  3. Insufficient amount or inappropriately taken oral iron: The ideal dose is 200mg of elemental iron taken 2 hours before or 1 hour after food. Food interferes with iron absorption but also relieves gastrointestinal adverse effects. Gastrointestinal adverse effects are related to dose. Prescriptions of oral iron may have an insufficient dose or may be administered after food to reduce gastrointestinal adverse effects. This results in an inappropriate haemoglobin response.
  4. Iron demand exceeding intake: Iron demand may exceed supply if there is continued blood loss or in patients where erythropoiesis is stimulated with an erythropoiesis stimulating agent like erythropoietin or darbepoietin. In both these situations the rate of oral iron absorption limits iron availability. These patients need intravenous iron.
  5. Malabsorption of iron: Food interferes with oral iron absorption. Ferrous iron is rapidly oxidised to ferric iron at physiological pH. Gastric acid reduces ferric iron to ferrous iron. Proton pump inhibitors, H2 antagonists, antacids and gastrectomy reduce acidity and can interfere with iron absorption. Iron malabsorption may be seen as part of a malabsorption syndrome. Iron deficiency refractory to iron is rare. Iron refractory iron deficiency anaemia is a disorder resulting from mutations in the TMPRSS6. This mutations results in increase hepcidin production which is sensed by the body as an iron repeated state. Iron is not absorbed despite iron deficiency. The patients do not respond to oral iron and shows a partial response to parenteral iron.

 Interactions

  1. Interaction of iron with food: The absorption of non-heme iron is affected by food (See Intestinal Iron Absorption).
    1. Foods enhancing iron absorption: Ascorbate, animal proteins, human milk, keto sugars, organics, amino acids that form soluble chelates with iron enhance absorption of non-heme iron.
    2. Inhibiting iron absorption: `Inhibitors of absorption of non-heme iron include
      1. Phytates present in grains and vegetables
      2. Dietary fibre
      3. Polypohenols present in tea, coffee and wine,
      4. Phosphates and phosphoproteins present in egg yolk, bovine milk
      5. Calcium and zinc.
  2. Drug-Iron interactions
    1. Iron decreases the absorption of ACE inhibitors, bisphosphonates, levodopa, levothyroxine, penicillamine, quinolone and tetracyclines
    2. The absorption of iron is decreased by drugs that reduce gastric pH. These include H2 antagonists(Cimetidine, ranitidine, famotidine), proton pump inhibitors (omeprazole, pantoprqzole, esomeprazole, lansoprazole, rabeprazole, etc), antacids and cholesterol lowering agents (Cholestyramine and Colestipol).

Dose

  1. Children: 3–6 mg/kg daily in 3 divided doses.
  2. Adult: Usual therapeutic dosage: 50–100 mg 3 times daily but a dose of 200mg produces the maximal results. A smaller dosages (e.g. 60–120 mg daily) may be given if patients are intolerant of oral iron, but response in such patients takes a longer time.

Side Effects Of Oral Iron

  1. Gastrointestinal: The commonest adverse effects of iron are gastrointestinal symptoms, including heartburn, nausea, abdominal cramps, diarrhoea or constipation. These may be seen in up to a fifth of the patients. They can be reduced by decreasing the dose or taking iron after food. Taking iron with food can reduce the absorption by about 50%. Enteric coated preparation decrease the side effects by delaying the release of iron. Delaying release may bypass the duodenum that is the site of absorption of iron. The decrease in absorption is particularly marked in patients with aclorhydria as they can not dissolve the enteric coating. The stool of patients taking iron supplements may be discoloured black or green.
  2. Discolouration of teeth: Iron syrups may cause staining to teeth.
  3. Iron overload: Iron overload from oral iron therapy is rare. It has been described in patients with hemachromatosis and chronic haemolytic anaemias.
  4. Iron Poisoning: Iron poisoning usually occurs in children, particularly those younger than 5 years of age, because of accidental ingestion of medicinal iron. Children are likely to ingest these believing them to be candies.
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Granulocyte Colony Stimulating Factor (G-CSF)


Neutropenia is a dose limiting toxicity of chemotherapy. It results in delay and dose reduction both of which adversely affect outcomes of treatment. Myeloid growth factors are biological agents that stimulate the production go granulocytes and offset the myelosupressive effect of chemotherapy. Two myeloid growth factors are available Granulocytic colony stimulating factor (G-CSF) and granulocytic monocytic colony simulating factor (GM-CSF). This article will discuss G-CSF as it is used more often than GM-CSF. Commertially available G-CSF is made by recombinant DNA technology and may be produced in E. coli (Filgrastim) or chinese hamster ovary cell lines (lenograstim). The half life of filgrastim can be increased by covalently linking it to polyethylene glycol (PEG) and converting it to pegfilgrastim.

Mechanism of Action of G-CSF

G-CSF is a 174 amino acid peptide the gene for which is on chromosome 17. It has a molecular weight of 18kDa. It is produced by monocytes, macrophages, fibroblasts, endothelial cells and keratinocytes in response to inflammatory cytokines and bacterial endotoxin.

G-CSF acts via the G-CSF receptor. G-CSF receptor is a transmembrane receptor that form a homodimer on binding G-CSF. Activation of G-CSF receptor results in activations of  JAK/STAT, SRC family of kinases, PI3/AKT and Ras/ERK 1/2. The details of the pathway are not completely understood.

G-CSF AAB.002

Activations of G-CSF has the following effects that lead to increased production of neutrophils

  1. Increased Proliferation of Neutrophilic precursors
  2. Shortened neutrophilic precursor bone marrow transit time
  3. Functions maturation of neutrophils – increased chemotaxis, phagocytosis and antibody dependent cytotoxicity

G-CSFs Available for Clinical Use

G-CSFs for clinical use is manufactured by recombinant DNA technology. Two molecules are available for clinical use. Filgrastim is produced using E. coli and lenograstim is obtained from Chinese hamster ovarian cells. Lenograstim is glycosylated (4% glycosylation).

Filgrastim on subcutaneous administration filgrastim has a half life of 2.5-5.8 hours. The drug is eliminated by uptake be G-CSF receptors on neutrophils and glomerular filtration. Pegylation, that involves attaching a 20kDa polyethylene glycol (PEG) molecule to the N terminal eliminates renal elimination prolonging the half life to 27-47 hours. The product, pegfilgrastim, is only eliminated by binding to neutrophil G-CSF receptors, patients with low neutrophil counts have a lower clearance. Prevention of glomerular filtration allows administration of pegfilgrastim only once in a chemotherapy cycle.

Indications for G-CSF

The discussion that follows applies to filgrastim and perfilgrastim as these drugs are used more commonly than lenograstim. The general principle apply to lenograstim but readers are advised to refer to information on lenograstim for details of use and adverse effects.

  1. Primary prevention of febrile neutropenia (FN) in patients with non-Myeloid malignancy on chemotherapy: Patients where on chemotherapy protocols that have a risk of febrile neutropenia equal to or greater than 20% should be administered G-CSF.
  2. Prevention of recurrence of febrile neutropenia: G-CFS may be used to prevent recurrence of febrile neutropenia in patients who have had an episode of infection in a previous chemotherapy cycle.
  3. Treatment of patients with febrile neutropenia: Initiating therapy with G-CSF after febrile neutropenia has set in has not been shown to decrease mortality of antibiotic use. It may however be used in patients who are at high risk of mortality.
  4. Mobilisation of stem cells for stem cell transplant
  5. Use in patients with myeloid malignancies: There is an apprehension that G-CSF may stimulate leukaemia cells and G-CSF is not used in induction. It may however be used after induction to reduct the duration of neutropenia.

Filgrastim is administered in a dose of 5μg/kg/day subcutaneously, by a short iv infusion or prolonged intravenous infection. therapy should be initiated at least 24 hours after the  chemotherapy. The adult dose of pegfilgrastim is 6mg. The paediatric dose depends on the weight of the child. Children less than 10 kg: 0.1 mg/kg, those between 10 to 20 kg be administered 1.5 mg, between 21 to 30 kg be administered 2.5 mg and between 31 to 44 kg administered 4 mg. Children weighing 45kg or more should be administered the adult dose of 6 mg. Pegfilgrastim should not be administered less than 14 days after a cycle of chemotherapy. It should be administered more than 24 hours after a cycle of chemotherapy.

Adverse Effects

  1. Bone Pain: Bone pain is the commonest side effect with about 20-30% of the patients suffering the side effect.
  2. Rare but serous side effects include splenic rupture, acute respiratory distress syndrome,  precipitation of sickle cell crisis and capillary leak syndrome

Drugs and Eosinophilia


Drugs, prescription and non-prescription,  and nutritional supplements are a common cause of eosinophilia across the world. In regions with a low prevalence of parasitic infestations drugs are the leading cause of eosinophilia.

Clinical Spectrum of Drug Induced Eosinophilia

The spectrum of drug induced eosinophilia extends from an asymptomatic eosinophilia discovered on a routine haemogram to a a serious disorder like drug induced drug reaction with eosinophilia and systemic syndromes (DRESS). Eosinophilia associated with specific organ complications includes

  1. Eosinophilic pulmonary infiltrates associated with the use of sulfadsalazine, nitrofurantoin and non-steroidal anti-inflammatory drugs (NSAID)
  2. Acute interstitial nephritis with eosinophilia  associated with the use of semisynthetic penicillins, cephalosporins, NSAID, sulphonamides, phenytoin, cimetidine and allopurinol
  3. Eosinophilia-myalgia syndrome (EMS) presents with increased eosinophil counts associated with  severe myalgia, neuropathy, skin rash and multi-system complications. The cause of EMS is not known but L-tryptophan has been implemented.
  4. Drug reaction with eosinophilia and systemic symptoms /Drug induced hypersensitivity syndrome (DRESS/DIHS): The syndrome is a form of delayed drug hypersensitivity the presents with fever lymphadenopathy and end organ damage. The spectrum of end-organ damage includes hepetitis, interstitial nephritis, pneumonitis and carditis. The drugs implicated in DRESS/DIHS include
    1. Anti-infective
      1. Antibiotics: Cephalosporins, doxycycline, fluoroquinolone, linezolid, metronidazole, nitrofurantoin, penicillins, tetracycline
      2. Sulfomaides: Sulfasalazine trimethoprim-sulfamethoxozole
      3. Sulfones: Dapsone
      4. Antiviral: Abacavir, Nevirapine
    2. Anti-epileptic: Carbamazepine, lamotrigine, phenobarbital, phenytoin, , valproate
    3. Anti-depressants: Amitriptyline, desimipramine, fluoxetine
    4. Anti-inflammatory: Diclofenac, ibuprofen, naproxen, piroxicam
    5. Antihypertensives: ACE inhibitors, β-blockers, hydrochlorthiazide
    6. Others:  Allopurinol, cyclosporine, ranitidine

Management

The incriminating drug should be withdrawn in symptomatic patients. Asymptomatic eosinophilia does not necessitate discontinuation of therapy. If equally effective therapy is available it is preferable to stop therapy. If this is not the case the drug may be continued with careful monitoring for symptoms.

Sickle β-Thalassaemia


Sickle cell anaemia and β-thalassaemia are two common haemoglobinopathies. Co-inheritance of the two is called sickle β-thalassaemia. Sickle β-thalassaemia seen in Africa, throughout the  Mediterranean, Arabian Peninsula and sporadically in india. It has heterogeneous clinical presentation. The severity depends on the severity of the thalassaemia allele and the extent to which the impaired haemoglobin synthesis is compensated by foetal haemoglobin synthesis.

Pathophysiology

With a very few exceptions (Blood 1989; 74: 1817-22) the sickle cell and the thalassaemia gene are arranged in trans i.e on different chromosomes (βsthal). One allele is inherited from the mother and one from the father. One parent carries the a β-thalassaemia trait the other parent has a sickle cell disease that may be sickle cell anaemia, sickle β-thalassaemia or a trait. Sickle β-thalassaemia in Africa and India/Arabia is mild whereas the patients from the Mediterranean region have severe disease. As mentioned above the differences in severity have to do with severity of the β-thalassaemia and the degree to which the impaired haemoglobin A synthesis is compensated by HbF. Weatherall suggested that patients with HbA <15% follow a course similar to severe HbA and those with HbA 20-30% follow a mild course.

  1. African sickle β-thalassaemia: African patients have a mild β-thalassaemia resulting in a relatively higher HbA level and a lower risk of sickling. These patients run a mild clinical course.
  2. Arab/Indian sickle β-thalassaemia: Patients from India and the Arabian peninsula have a sickle cell haplotype that is associated with a high HbF production. The HbF retards sickling. High levels of HbF attenuate symptoms. Patients carrying this haplotype have mild symptoms even when the inherit a severe β- chain defect. Another reason of a mild phenotype in India is the interaction with α thalassaemia.
  3. Mediterranean sickle β-thalassaemia: Mediterranean patients usually inherit a severe form of  β-thalassaemia. These patients have severe sickling because there is very little HbA or HbF to offset inhibit the crystallisation of HbS. Despite only one chromosome carrying HbS the phenotype of these patients resembles sickle cell anaemia.

Clinical Picture of Sickle-β Thalassaemia

The features of sickle-β thalassaemia resemble those of other sickling disease. It is a chronic haemolytic anaemia the course of which is interrupted by acute exacerbations known as crisis. The manifestations include haemolytic anaemia, painful and other crisis, leg ulcers, priapism and complications of pregnancy. The severity of symptoms is variable. One end of the spectrum are patients, usually of origin Mediterranean descent, whose presentation is indistinguishable from sickle cell anaemia. These patients have inherit severe forms of β (β0) chain defects. Those with sickle cell-β+ thalassaemia have milder symptoms. These patients are typically of African ancestory. Unlike patients with sickle cell anaemia patients with sickle-β thalassaemia may have splenomegaly that is more prominent patients with sickle cell-β+ thalassaemia. The spleen is usually moderately enlarged but massive splenomegaly that may be associated hypersplenism neccesisating splenectomy has been reported. The effect of co-inheritance of α-thalassaemia is small. A decrease in the frequency of acute chest syndrome and leg ulcers and a higher persistence of splenomegaly is seen. Co-inheritance of α thalassemia is one of the reasons that sickle-β thalassaemia runs a milder course in India (the other being the high HbF due to the Arab-Indian haplotype of HbS).

Diagnosis

The haematological findings vary with severity. More severe phenotypes shows greater anaemia, lower MCHC, higher reticulocytes, HbF and HbA2. A variable number of sickle cells may be found. Unlike sickle cell anaemia both forms of sickle cell-β thalassaemia have an elevated HbA2. The distribution of HbA2 is very similar to heterozygous β thalassaemia. The levels of HbF are variable. High levels are found in patients with the Arab-Indian and Senegal haplotype of HbS.

Sickle cell-β0 thalassaemia needs to be differentiated from sickle cell anaemia. The presentation of both may be identical. However an offspring of a sickle cell-β0 thalassaemia patients and a carrier of β-thalassamia trait has a 25% risk of suffering from β-thalassaemia major. The offspring of a patients with sickle cell anaemia and a carrier of β thalassaemia trait does not carry the risk of β thalassaemia major. Though sickle cell-β0 thalassaemia is characterised by an elevated HbA2 and splenomegaly this can not be relied upon to differentiate between the two conditions. Family and DNA studies are needed. If the studies show one parent to be heterozygous for HbS and the other a carrier of β thalassaemia trait no further studies are needed. If any of the parent has a phenotype of sickle cell anaemia DNA studies may be the only way to make the diagnosis.

Sickle Cell β thalassaemia in cis

Almost all patients with sickle-β thalassaemia have the disorder in trans i.e. the one β globin gene is thalassaemic and the other has a the sickle mutation. Patients with HbS and thalassaemia gene in cis have been described. These patients have a mild hemolysis, HbA2 levels were 6%–7%, HbF approximately 3% and HbS of 10%–11%.

Treatment

The symptoms of sickle-β thalassaemia are due to sickling need to be treated accordingly.

Superior Vana Caval Syndrome


Superior Vena Caval Syndrome (SVCS) results from a space occupying lesion (SOL) in the superior mediastinum. The presence of a SOL results in compression of structures passing through the mediastinum. The most prominent clinical manifestations result from compression of superior vena cava and for this reason it is also referred as superior vena caval syndrome. Superior mediastinal syndrome,  a term that captures the pathogenesis of the syndrome, is also used. SVCS was first described by William Hunter in 1757 in a patient with syphilitic aortic aneurysm. Today the most common cause is a malignancy.

Anatomy of the Superior Mediastinum

Superior mediastinum is bound

  1. Inferiority by an imaginary plane running from the sternal  angle to the fourth thoracic vertebra,
  2. Superiority by the thoracic inlet
  3. Anterior by manubrium of the sternum
  4. Posteriorly by the bodies of first four thoracic vertibrae.
  5. Laterally by the pleura.

It is space through which tubular structures pass from the neck to the thoracic organs. These include the following

  1. Arch of the aorta and its branches including Brachiocephalic artery, Left Common carotid artery, Left Subclavian artery – to the left upper limb.
  2. Superior Vena Cava and its tributaries Brachiocephalic veins, Left superior intercostal vein, Supreme intercostal vein, Azygos vein
  3. Lymph nodes draining the lung are found in the fatty tissues.
  4. Oesophagus

Pathogenesis of SVCS

Superior mediastinum has rigid walls, making the structures passing through it prone to compression by mass lesions. The commonest cause of compression is a malignancy arising from or involving structures of superior mediastinum. Lung cancer and lymphoma being the two commonest causes of SVCS. Some conditions like Mediastinal fibrosis may constrict rather than compress the mediastinum. Indwelling vascular lines has increased the risk of thrombosis of superior vena cava common. One needs to consider the possibility of thrombosis in patients who have indwelling venous access devices.  The table lists the causes of superior vena caval syndrome.

Malignant Non-Malignant
  1. Lung cancer
  2. Lymphoma
  3. Others: metastatic cancers, primary leiomyosarcomas of the mediastinal vessels, plasmocytomas
  1. Mediastinal fibrosis
  2. Vascular diseases, such as aortic aneurysm, vasculitis, and arteriovenous fistulas
  3. Infections, such as histoplasmosis, tuberculosis, syphilis, and actinomycosis
  4. Benign mediastinal tumors such as teratoma, cystic hygroma, thymoma, and dermoid cyst
  5. Cardiac causes, such as pericarditis and atrial myxoma
  6. Thrombosis related to the presence of central vein catheters

Manifestations

The common manifestations of superior vena cava syndrome include

  1. Dyspepsia
  2. Swelling of the face and upper extremities
  3. Cough, chest pain
  4. Dysphagia

Examination shows distended neck veins and chest wall oedema, plethora of face, and oedema of the arms.

Diagnosis

Radiology: Radiograph of chest usually shows a mediastinal mass. If not this is apparent of on a CT scan. The CT scan is also needed to define extent of disease and invasion of the great vessels, bronchus, and the spinal cord.

Biopsy and Cytology: The investigations to establish diagnosis include sputum cytology, examination of pleural fluid (if present) and histology. The tissue for histological examination may be obtained by bronchoscopy, thoracoscopy, mediastinoscopy guided lymph node biopsy, CT guided core needle biopsy of the mass. A bone marrow examination may be of value if the haemogram is abnormal. A careful examination of the supraclavicular region shows nodes in about 2/3rd of the patients with SVCS which can be biopsied.

Treatment

The aim of treatment of SVCS is to relive symptoms at the same time not compromise diagnosis or the possibility of cure. All patients should be given head elevation and oxygen. Diuretics can reduce oedema but this comes at the cost of dehydration. Tissue must be obtained for diagnosis. Unless there has been a substantial delay in diagnosis, initiation of treatment is not an emergency and tissue can be obtained. Vascular stents can be inserted in patients who are very symptomatic to relieve symptoms till diagnosis is made. 

The treatment of SVCS is disease specific. Chemotherapy with or without radiation is indicated in patients with lung cancer (small cell as well as non-small cell). The response rate in small-cell lung cancer exceeds 90% with 70% of the patients remaining disease free. Addition of radiation to chemotherapy reduces the risk of recurrence. About 60% of the patients with non-amall cell lung cancer respond to therapy. The disease recurs in about 20% of these. Patients with NSCLS presenting with SVCS have a poorer survival than those who do not. Lymphoma is treated with chemotherapy. 

Catheter-induced SVCS may be treated with thrombolytic agents early (< 5 days) in the course of the disease. Catheters of patients with prolonged symptoms should be removed and this should be done under cover of heparin.

Patients who have cancers that do not respond to chemotherapy or radiation can be palliated by placement of vascular and tracheal stents where possible.

Clinical Features of Megaloblastic Anaemia


Megaloblastic anaemia is a macrocytic anaemia resulting from the deficiency of vitamin B12 or folic acid characterised by the presence of megaloblasts in the bone marrow. It has haematological and neurological manifestations. The haematological manifestations are seen with folate as well as vitamin B12 deficiency. Folate deficiency in adults does not affect the nervous system.

Cobalamin deficiency is slow and “pure”. Folate deficiency is rapid and “impure”. Deficiecy of vitamin B12 occurs because of loss of intrinsic factor resulting in an isolated defect of B12 absorption. No other nutrients are affected. The body stores of B12 can last months. This results in B12 deficiency being a slow and “pure” deficiency. Symptoms come on slowly, over months. Folate deficiency evolves relatively quickly and is most commonly because of alcoholism or malabsorption. It is associated with other deficiencies and is rapid and “not pure”.

 

Manifestationf o megaloblastic anaemia

Figure 1. Clinical Manifestations of Megaloblastic Anaemia

Haematological Manifestations

Haematological changes resulting from vitamin B12 deficiency and folate deficiency are indistinguishable. Megaloblastic anaemias are macrocytic anaemia but macrocytosis is not specific to megaloblastic anaemia. It is however exceptional for other diseases characterised by macrocytosis to have an mean capsular volume (MCV) > 110fl.  This value can considered the threshold above which an anaemia is unlikely to be anything other than megaloblastic anaemia.

The earliest change in a megaloblastic anaemia is macrocytosis. This precedes changes in erythrocyte indices. Changes in mean capsular haemoglobin (MCH) follow and then the MCV rises. Haemoglobin usually falls after the MCV increases to >97 fl. As the severity of anaemia increases the peripheral smear shows aniscytosis and poikilocytosis, nucleated cells, Howell-Jolly bodies and Cabot’s ring. Microcytes and erythrocyte fragments that represent dyserythropoiesis may be seen. Polychromasia is absent and this distinguishes megaloblastic anaemia from haemolytic anaemia.

The term megaloblatic anaemia is a misnomer. The disease is actually a panmyelosis.  Erythroid, myeloid and megakaryocytic series are affected. Thrombocytopenia and leucopenia (neutropenia and to a lesser extent lymphopenia) usually occur late in the course. It is uncommon for patients with mild anaemia to have platelets and neutrophils but occasionally changes in leucocytes and/or platelets may dominate.

Iron deficiency or β-thalassaemia trait result in microcytosis and hypochromia and may incidentally co-exist with megaloblastic anaemia. Co-existence of either of these diseases with megaloblastic anaemia may mask macrocytosis of megaloblastic anaemia. Presence of hypersegmented neutrophils in a patients with normocytic normochromic anaemia should raise the suspicion of a megaloblastic anaemia co-existing with Iron deficiency or β-thalassaemia trait.

Neurological Manifestations

Cobalamine deficiceny causes neurological dysfunction. Folate deficiency causes symptoms only in children. Children with inborn errors of folate metabolism may have myelopathy, brain dysfunction and seizures.

The neurological manifestations of B12 deficiency are a result of a combination of upper motor neuron manifestations from subacute combined degeneration of the spinal cord, sensory and lower motor neuron manifestations from peripheral neuropathy and neurophychiatratic manifestations. Subacute combined degeneration of the spinal cord (SACD) is a degerative disease of the spinal cord involving the posterior and lateral column (corticospinal and spinoceribellar tracts) that starts in the cervical and the thoracic region.

The earliest neurological manifestations are impaired sense of vibration and position and symmetric dysesthasia that involve the lower limb. This is frequently associated with sensory ataxia. With progression spastic paraparesis develops. The patients have brisk knee reflexes, reflecting an upper motor neuron involvement and depressed ankle reflex, reflecting a peripheral neuropathy. Bladder involvement is unusual. Some patients may have optic atrophy.

Neuropsychiatric manifestation include memory loss, depression, hypomania, paranoid psychosis with auditory and visual hallucinations.

Other manifestations

Skin and nails can show pigmentations. Mucosa of the villi undergoes megalobkastic change resulting in temporary malabsorption.

Response to therapy

Haematological Recovery

  • Day 1: Feeling better
  • Day2-3: Reticulocytosis appears
  • Day 7-10: Peak retuculocytosis
  • Day 15 onwards: Neutrophilic hypersegmentation disappears
  • Day 56 (8 weeks): Blood counts become fully .normal

Neurological Recovery

Neurologic improvement begins within the first week also and is typically complete in 6 weeks to 3 months. Its course is not as predictable as hematologic response and may not be complete.

 

 

The M-Band


Monoclonal Gammopathy-02

Figure 1. Each plasma cell produces a different type of antibody. Normal γ globin band is depicted in the left column. The plasma cell numbers are normal and each produces an antibody with a different amino acid structure and electrophoretic mobility. Patients with monoclonal gammopathy have expansion (increase number) of a plasma cell clone (red in the diagram) resulting in the production of a disproportionate large amount of immunoglobulin from one type of plasma cell. This results in the M Band (see below). Patients with polyclonal gammopathy have an expansion (increased number) of plasma cells. This is usually occurs in response to infection/inflammation that result in production of a diversity of antibodies. The diversity is reflected in increase in the γ but as no one clone dominates the sharp M band is not seen.

What is an M-Band?

Immunoglobulins are antigen binding molecules secreted by plasma cells. Immunoglobulins bind antigens and play a role acquired immunity. Plasma cells develop from antigen exposed B-lymphocytes. The process of maturation of lymphocytes involves inducing mutations in region of the immunoglobulin gene that encodes for antigen binding regions, the hypervariable regions. This makes the DNA and consequently the amino acid sequence of the immunoglobulin secereted by a plasma cell unique. This is true even when two plasma cells make antibody against the same antigen or antigenic epitope (see figure 1).

Monoclonal Gammopathy-01

Figure 2. The serum protein separate into many bands on electrophoresis. The albumin is a dark band closest to the anode. This is followed by the α1, α2, β and γ bands. The immunoglobulin are mainly found in the γ globulin band but some may be found in the β globin band. The electrophoretic mobility of a molecule depends on the charge it carries which in turn depends on the amino acid sequence. Amino acid sequence determines the antigen specificity and differs between antibodies resulting in a slight variation in electrophoretic mobility of immunoglobulins and resulting in the γ region being a broad band.


The amino acid sequence determines the charge on the immunoglobulin. The electrophoretic mobility is determined by the charge. Majority of the immunoglobulins move to the γ-globulin fraction of serum proteins, some move with β-globulin. The γ-globulin band is a wide electrophoretic band reflecting the diversity in electrophoretic mobility of immunoglobulins arising from the diversity in amino acid sequences (figure 2).

Monoclonal Gammopathy-03

Figure 3. Patinets of monoclonal gammopathies have an expansion of one clone of plasma cells. This reflects in production of a disproportionally large amount of immunoglobulin with identical electrophoretic mobility resulting in a dense band with in γ globin region


Patients of monoclonal gammopathies have clonal expansion of plasma cells. The cells of a clone have identical DNA and produce identical immunoglobulin molecules. When the clone grows to level that it forms a significant proportion of the plasma cell pool the immunoglobulin it produces forms a significant proportion of the total serum immunoglobulins. The identical electrophoretic mobility of molecules produced by the clone results in a disproportionately large number of immunoglobulin concentrating to a point on electrophoresis forming a band.  This is known as the M band.  Lymphoma cells, notably those of lymphoplasmacytic lymphoma, can secrete immunoglobulin and are associated with an M band for similar reasons.

Diseases associated with an M-Band

The M-Band is a serum marker for plasma cell dycrasias and Waldenström macroglobulinemia. IgM and non-IgM (mainly IgG and IgA) monoclonal bands have differing clinical implications. The former is more commonly associated with lymphoproliferative disease and the latter with plasma cell dycrasias. The presence of an M band only indicates a clonal expansion of immunoglobulin producing cells. It does not indicate malignancy. The diagnosis of malignancy is made by features that suggest end organ damage. The absence of end organ damage indicates a premalignant disease including monoclonal gammopathy of uncertain significance (MGUS), soldering multiple myeloma or smoldering Waldenström macroglobulinemia.  The evidence of end-organ damage includes

  1. non-IgM Monoclonal Gammoathies: CRAB (elevated calcium, renal involvement, anaemia and osteolytic (bone) lesions) creatinine,
  2. IgM Monoclonal Gammapathies: Anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder if diagnosis is Waldenström macroglobulinemia or CRAB (elevated calcium, renal involvement, anaemia and osteolytic (bone) lesions) creatinine if the diagnosis of IgM myeloma

False positive M-Band

The presence of M band indicates presence of a clonal expansion of plasma cells. When end organ damage co-exists with M band a diagnosis of a malignancy (multiple myeloma or Waldenström macroglobulinemia) is made. In the absence of end organ damage the diagnosis of a premalignant disease is made. Proliferation a of plasma cells are seen in infections/inflammation. These are polyclonal and result in s polyclonal gammopath. They do not result in the presence of an M-band.