Porphyrias
Porphyrias are a rare group of hereditary illnesses caused by defects in 7 different enzymes in heme synthesis pathway and in which the heme, an important part of haemoglobin, does not develop properly (Porphyria, Medline Plus). Different forms of the illness have different symptoms. Some have the abdominal pain, an involvement of the autonomous nervous system. Others have photosensitivity symptoms characterized by persistent rashes on the skin which can be triggered by chemicals in the household. Urine becomes red in an acute attack. The precursors of heme are found in the skin and produce the photosensitivity. Acute attacks may be life threatening and produce electrolyte imbalance, low blood pressure and shock. The transmission is genetic, five are autosomal dominant and two are autosomal recessive (Porphyria, Medline Plus). Muscle weakness and tingling and numbness are also seen. The PROTO blood test, urinanalysis for the precursors, enzyme assay and renal function tests can help in the diagnosis of the illness, the status of the kidney and the enzyme which is deficient. Being hereditary the transmission cannot be prevented. However an acute attack may be prevented by avoiding exposure to the chemicals which could trigger the attack. The acute attack must be treated actively as it could be fatal. Intravenous hematin, pain medication, propranolol to control the heart rate, fluids to correct dehydration if any and electrolyte imbalance are the treatment given. Skin lesions may be given as soothening agents. Exposure to the sun is lessened.
The molecular mechanisms of dominant exposure in porphyrias were investigated in a recent study (Badminton, 2005, p. 284). Five of the porphyrias were found to have a low penetrance autosomal dominant nature where the clinical expression of the illness resulted from other factors (genetic and environmental) which increasing the demand for haem or caused an additional decrease in enzyme activity. The clinical implication has not been indicated yet. Another study was done in families to evaluate the role of oxidative cellular damage in these diseases by pro oxidant and anti oxidant factors (Rocchi, 2004, p. 251). No relationship was observed “between the increase of porphyrin metabolites and the presence of markers of oxidative damage or the decrease of circulating antioxidants” in patients with neoplastic disease (Rocchi, 2004, p. 251). If it were at all seen, it was found that iron supplementation had been given that patient.
Sepsis
Sepsis is derived from the word “sepsin” which in Greek means “to make putrid”.
(Singh, 2006, p. 349). It is a host response to an infectious process and is severe in that dysfunction of multiple organs occurs and has a high mortality rate of 10-40% (Kudo, 2009, p. 23). The systemic inflammatory response syndrome, the sepsis and the septic shock are together termed sepsis syndrome. The symptoms include fever with chills and severe shaking. The patient has tachycardia (increased heart rate) and tachypnoea (increased respiratory rate). There will be confusion, disorientation and agitation. Dizziness and oliguria (decreased urination) may also occur. There will be an accompanying rash of a reddish discoloration with dark red spots (Sepsis, DHHS). Joint pains may be present. The causative agents could be different microbes including bacteria, viruses, fungi; the commonest being the bacteria. Infections of lung like pneumonia, urinary tract infections, meningitis, appendicitis, postoperative infections and ICU infections could end up in sepsis due to an uncontrolled multiplication and spread of microbes through blood (Sepsis, DHHS). Pathophysiology involves a systemic inflammatory response to the pathogens which is self sustaining and progressive to organ dysfunctions. There will be accompanying tissue hypoperfusion, cellular hypoxia and metabolic dysfunction. The sepsis and sequelae cause the majority of patients to succumb to multiple organ dysfunction syndrome (MODS) and the multiple organ failure. The laboratory tests include a blood analysis to demonstrate leucocytosis (increased white cells). Blood culture may show growth of organisms in culture medium and they can be recognized from the pattern of growth. Sensitivity to different antibiotics also may be done along with the culture to decide on the antibiotic for the treatment Sputum, urine, abscess contents and spinal fluid may be examined for organisms. Prevention of sepsis can be done by appropriate treatment of illnesses based on the microbe involved, sanitary cleaning of hospital premises and perfect sterilization of operation theatres. Management involves treatment of the basic infection by the results of the culture and sensitivity, shock, hypoperfusion, metabolic dysfunction, electrolyte imbalance and through monitoring of the vital signs. A recent study investigates a new procedure of In-situ hybridization or ISH for checking the presence of bacteria in the blood of patients with suspected sepsis in place of the usual blood culture which takes a minimum of 24 hours for results. ISH is believed to show a more sensitive response to the pathogenic bacteria (Kudo, 2009, p. 23). Another study investigated whether a modified PIRO (predisposition, insult, response, and organ dysfunction) concept could be applied to predict mortality in patients with infection and sepsis (Moreno, 2008, p. 496).
Sickle cell anaemia
Sickle cell is an autosomal recessive disorder characterized by a high concentration of Haemoglobin S (HbS) which causes the distortion in the red blood cells leading to a vaso-occlusive accident, the most serious and painful complication in the illness (Mehdaoui, 2006, p.577). HbS is formed because mutation has replaced beta 6-glutamic acid with valine. This is a chronic condition with episodes of acute pains in the chest, back, abdomen, or extremities which constitute the crises lasting for days or weeks. Stroke occurs in 10% of children. Silent damage to the Central nervous system with cognitive impairment occurs. Acute lung injury is a frequent and fatal complication. Children have respiratory insufficiency. Several types of infections have been associated. Blood examined under the microscope shows the distorted shape of the red blood cells resembling a sickle or half moon. The Deoxygenated Hb results in a hydrophobic interaction with other red blood cells. Polymerisation of the Hb causes membrane damage and hydrolysis. Acute splenic sequestration crisis in sickle cell disease has been studied earlier as a major cause of morbidity and mortality in children with sickle cell disease but adults are not known to have this crisis even with splenomegaly. A recent study found that an adult with severe extensive blunt trauma developed the crisis within 2 days precipitated by a systemic inflammatory response (Koduri, 2006, p. 633). Another study investigates the “frequency of different sickle cell diseases and quantitative estimation of haemoglobin S and other haemoglobin variants using an automated high-performance liquid chromatography (HPLC) system” (Hashmi, 2008, p. 639). This study was the first to be done in Pakistan and has initiated a database for future sickle cell anaemia for future studies.
Thalassemia
Thalassemias are genetically inherited autosomal recessive blood disorders (Thalassemia, National Heart Lung and Blood Institute). The body makes lesser healthy red blood cells with lesser haemoglobin than usual. Thalassemias present with anaemia. Normal haemoglobin has 2 alpha and 2 beta chains. The defect is identified according to which chain is defective. Alpha thalassemia babies who have the most fatal of the types die before or shortly after birth. The beta type occurs when genes from both parents are altered. Symptoms are those of anemia which include fatigue, pallour, inability to work and other mild complaints. Blood tests ordered are complete blood count, blood chemistry tests, enzyme tests and blood tests to assess the heart’s risk for diagnosis. Prevention of the illness is not possible as it is a hereditary illness. However pre-natal screening is advised and coupled with abortion if positive. Usually no treatment is required. Occasionally treatment may have to be given for the condition. Thalassemia major requires symptomatic treatment. A recent study “characterizes the possible role of the osteoprotegerin (OPG) and receptor activator of the NF-κB ligand (RANKL) system in thalassemia-related bone loss” (Angelopoulose, 2007, p. 60.). The results suggest that the circulating OPG/s-RANKL system could be playing a role in bone metabolism in beta thalassemia patients. Another study conducted in South India showed the presence of a rare mutation in the beta globin gene in beta thalassemia (Bashyam, 2004, p. 408).
Thrombosis
Thrombosis is the clotting of blood in a blood vessel, vein or artery, mechanically hindering blood flow (Thrombosis, NHS). Thrombosis can occur as cerebral venous thrombosis, deep vein thrombosis or arterial thrombosis. Arterial thrombosis affects blow flow to the heart and causes a heart attack or produces a stroke. Thrombosis is a main cause for death. It is a silent condition with no symptoms and affects the elderly mainly but could affect young people too. Being aware of the risks is the best way to prevent the illness. Vein thrombosis is characterized by a redness, ache and swelling locally, on the leg if it is deep vein thrombosis. An itchy rash may be present. A delay in treatment produces fatal pulmonary embolism. The risk factors are age, hypertension, high cholesterol levels, immobility, thrombophilia, cancers, obesity, pregnancy, smoking and hormone replacement therapy. D-dimer blood test, Doppler study and venogram for deep vein thrombosis, pulmonary scan and other investigations depending on the system involved help the diagnosis. The illness is treated according to the system involved: heart, brain or deep vein thrombosis. Imaging may have to be done. A recent study has shown the similarities of features of cerebral venous thrombosis to acute unilateral vestibular syndrome.
(Kim, 2008, p. 41). A suggestion has been made for including cerebral venous thrombosis in the differential diagnosis of acute unilateral vestibular syndrome. Another study focuses on the arterial thrombosis that occurs in a cancer patient who has had a therapy of cytotoxic drugs. Though it is rare, the possibility is to be considered (Hida, 2007, p. 275).
Von Willebrand Disease
It is an inherited bleeding disorder affecting the blood’s ability to clot (Von Willebrand, NHLBI.). Deficiency of the Von Wllebrand factor (a protein), causes a defect in the clumping together of platelet and the absence of Factor VIII which prevents hemophilia. There are three types depending on the extent of deficiency. Type 3 is the worst with no Von Willebrand factor and very little Factor VIII. The bleeding tendency is not life threatening if diagnosed early and treated. Bruises from bumps, hard-to-stop nosebleeds, prolonged bleeding from gums after dental procedures, heavy menstrual bleeding, bleeding into stools and urine, heavy bleeding after a cut or surgery are some of the presenting symptoms. The diagnostic tests are the Von Willebrand factor antigen, Von Willebrand factor ristocetin (ris-toe-SEE-tin) cofactor activity, Factor VIII clotting activity, Von Willebrand factor multimers and Platelet function test. Medicine treatment is aimed at increasing the release of the two factors involved (using Desmopressin) or replacing the Von Willebrand factor through an infusion or preventing the breakdown of clots using antifibrinolytic agents. Oral contraceptives control menstrual bleeding by releasing the two factors. Hormone containing IUD or aminocaproic acid could also be used for ladies. A recent study has confirmed the necessity for a prophylactic replacement therapy prior to surgery to prevent venous thromboembolism (Franchini, 2008). Another study investigated the beneficial effect of rituximab in a case of essential cryoglobulinaemia and acquired Von Willebrand’s disease (Pasa, 2009, p. 220). The study showed that rituximab may have an effective treatment option in the mentioned illness.
Aplastic anaemia
Aplastic anaemia is a syndrome affecting bone marrow with features of peripheral pancytopenia, marrow hyperplasia, mild macrocytosis, stress erythropoiesis and increase in foetal haemoglobin (Aplastic Anaemia, Medscape). Patients have low counts for all the cells of blood: red, white and platelets. It could be an autoimmune disease where the white blood cells attack the bone marrow or result from the ingestion of certain drugs like chloramphenicol, carbamazepine and quinine or along with viral hepatitis. Symptoms include anaemia, leucopenia, thrombocytopenia and reticulocytopenia. Lab tests include a complete blood count (CBC), renal function and electrolytes, liver enzymes, thyroid function tests, vitamin B12 and folic acid levels.
Frequent blood counts during treatment could expose any changes which are leading to the illness. Therapy includes anti-thymocyte globulin (ATG) or anti-lymphocyte globulin (ALG) and several months of treatment with cyclosporin to modulate the immune system. More severe cases may require bone marrow transplant. The illness is fatal in 6 months if undiagnosed. Timely intervention allows patients to live from 5 to 10 years or more. A recent study highlights a case of a lady with glioblastoma mulitforme who had treatment with Temozolomide following surgery and then developed aplastic anaemia (Jalali, 2007, p. 105). Aplastic anaemia had been unexpected in this patient. Acquired aplastic anaemia occurs due to non funtioning of bone marrow. Immunosuppressive therapy (IST) was given to children with the acquired disease in a study on children (Chandra, 2008, p. 229). They found that only half the children were cured. 10% saw a complete response. 45% were able to live without transfusions and no longer required treatment.
Ion and iron deficiency
Ion deficiency occurs when there is an overload of metals. Haemachromatosis and thalassemia are caused by overloads of iron. In primary hypoparathyroidism, ionized calcium concentration falls low. Magnesium ions stabilize cell membranes. A deficiency causes the stability to be lost. This action was similar to that of Novobiocin. A suggestion.has been made that Novobiocin acts by causing a magnesium ion deficiency Iron deficiency anaemia occurs when the total body content of iron is reduced and is severe enough to reduce erythropoiesis and cause anaemia. The normal body concentration of iron is 60 parts per million. It is regulated by the cells in the proximal small intestine. Iron is essential for metabolic processes including oxygen transport, DNA synthesis, and electron transport. Deficiency can be caused by reduced absorbable dietary iron or excessive loss of body iron. Blood estimation of Haemoglobin confirms diagnosis. Symptoms could include fatigue, pallour, general weakness, proneness to infections, koilonychia, dysphagia and oesophageal webbing and poor performance in academics. Prevention is possible by a balanced nutrition inclusive of vegetables. If the Haemoglobin is not adequate, other measures like iron tablets or infusions or transfusions may be necessary depending n the extent of anaemia (Milman, N., 2006). A recent study evaluated iron prophylaxis in pregnancy from the individual aspects according to the serum ferritin levels and to find out which dose of iron prevented the deficiency and which prevented the anaemia in pregnancy. It was found that 40 mg ferrous iron/day to women having ferritin ≤70 μg/l prevents the deficiency and the anaemia and that women with ferritin >70 μg/l have no need for iron supplement. Another study found that the G2777S transferrin mutation does not affect iron absorption in women (Sarria, 2007, p. 57).
Pernicious anaemia
It is a hereditary disease of autosomal recessive type also known as macrocytic anaemia and exhibits a megaloblastic picture in the blood smear. Pernicious anemia is a decrease in red blood cells that occurs when the body cannot properly absorb vitamin B12 from the gastrointestinal tract. Vitamin B12 is necessary for the proper development of red blood cells (Pernicious anaemia, Medline Plus). Lack of an intrinsic factor poduced by the stomach that binds to Vitamin B12 causes a defective absorption of the Vitamin B12. Other causes are a defect in the stomach lining, autoimmunity against the parietal cells of the stomach and autoimmunity against the intrinsic factor itself. The congenital form appears in children and the adult form in adults below 30. Risk factors include family history, Addison’s disease, chronic thyroiditis, Grave’s disease, hypoparathyroidism and hypopituitarism. Symptoms are bleeding gums, diarrhoea, fatigue, impaired sense of smell, loss of appetite, pallour and memory changes. Diagnosis is made from the typical megaloblasts in the peripheral blood smear. Blood count, serum transholocobalamin, reticulocyte count, Schilling test etc. can be done (Pernicious anaemia, Medline Plus). The deficiency is permanent and Vitamin B12 can be prescribed as life-long monthly injections. Early diagnosis and timely intervention with a well balanced diet helps to keep away the anaemia. A recent study investigated the “molecular defect underlying MGA1 (megaloblastic anaemia 1) in nine Tunisian patients belonging to six unrelated consanguineous families” (Bouchlaka, 2007, p. 262). These families had either the cubilin (CUBN) or amnionless (AMN) genes. One family did not have either. The existence of a third locus was evident.
Another study of a lady with gastric carcinoid and gave a history of neurofibromatosis was found to have no pernicious anaemia as expected (Stewart, 2007, p. 147). Neurofibromatous patients presenting with upper gastrointestinal haemorrhage without pernicious anaemia must still be thought of having gastric carcinoid which must be duly ruled out.
Myelodysplastic syndrome
Myelodysplatic syndromes are common haematological diseases in the elderly which are clonal haemopoietic disorders with peripheral blood cytopenia (due to increased apoptosis) and the absence of genetic disorders. In children, dysplastic features are seen in benign disorders (Rajnoldi, 2005, p.429). It is considered to be a pre malignant condition due to a clonal mutation. The diagnosis is made from the presence of dysplasia in the bone marrow and blood cells. 5 morphological types have been identified : refractory anaemia, refractory anaemia with ring sideroblasts, Refractory anaemia with excess of blasts (RAEB), RAEB in transformation (RAEB-T) and chronic myelomonocytic leukemia. Juvenile myelomonocytic leukemia has also been identified. It can be primary or secondary to aggressive treatment of cancers, irradiation, or in persons heavily pre-treated with bone marrow transplants. Balanced translocations leading to fusion oncogenes and other aberrations have been suggested. Treatment is by transfusion of cells that are missing and treatment of infections. Lenalidomide is good for treating low-risk myelodysplastic syndromes. Supportive and symptomatic care is given. The study by Rajnoldi
achieved a concordance for measuring dysplasia.(2005, p. 432). These include the cytological criteria of megaloblastoid changes in erythropoiesis and hypogranulation in granulopoiesis. Another study investigated the effectiveness of antithymocyte globulin cyclosporin A in low risk myelodysplastic syndromes and showed consistent findings which proved the possibility of using Cyclosporin A for them (Ishikawa, 2007, p. 150).
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