Chronic Lymphocytic Leukaemia (CLL) Prognostic Indicators

Chronic lymphocytic leukaemia (CLL) is a type of cancer that affects the blood and bone marrow. Patients with CLL often have genetic mutations, with trisomy 12 being a bad prognostic indicator. ZAP-70, a tyrosine kinase involved in cell signalling, is also measured in CLL patients, and high expression is associated with a poor prognosis. On the other hand, lactate dehydrogenase (LDH) is a marker of tumour burden, and a normal level suggests less tumour bulk, which is a good prognostic marker.

Many patients with CLL may not require treatment and may die with the disease rather than from it. It is often diagnosed in asymptomatic patients who undergo blood tests for other reasons. Treating the disease too early may actually lead to a worse outcome than monitoring the patient initially. Therefore, patients who do not need to start treatment immediately have a more favourable outlook.

B cells in secondary lymphoid tissue undergo somatic hypermutation when they recognise an antigen. This process fine-tunes antibody specificity, and cells that have undergone somatic hypermutation are more mature. If CLL arises from one of these cells, it is associated with a more favourable prognosis. these prognostic indicators can help healthcare professionals determine the best course of treatment for patients with CLL.

Iron deficiency anaemia is a prevalent condition worldwide, with preschool-age children being the most affected. The lack of iron in the body leads to a decrease in red blood cells and haemoglobin, resulting in anaemia. The primary causes of iron deficiency anaemia are excessive blood loss, inadequate dietary intake, poor intestinal absorption, and increased iron requirements. Menorrhagia is the most common cause of blood loss in pre-menopausal women, while gastrointestinal bleeding is the most common cause in men and postmenopausal women. Vegans and vegetarians are more likely to develop iron deficiency anaemia due to the lack of meat in their diet. Coeliac disease and other conditions affecting the small intestine can prevent sufficient iron absorption. Children and pregnant women have increased iron demands, and the latter may experience dilution due to an increase in plasma volume.

The symptoms of iron deficiency anaemia include fatigue, shortness of breath on exertion, palpitations, pallor, nail changes, hair loss, atrophic glossitis, post-cricoid webs, and angular stomatitis. To diagnose iron deficiency anaemia, a full blood count, serum ferritin, total iron-binding capacity, transferrin, and blood film tests are performed. Endoscopy may be necessary to rule out malignancy, especially in males and postmenopausal females with unexplained iron-deficiency anaemia.

The management of iron deficiency anaemia involves identifying and treating the underlying cause. Oral ferrous sulfate is commonly prescribed, and patients should continue taking iron supplements for three months after the iron deficiency has been corrected to replenish iron stores. Iron-rich foods such as dark-green leafy vegetables, meat, and iron-fortified bread can also help. It is crucial to exclude malignancy by taking an adequate history and appropriate investigations if warranted.

Hodgkin’s disease is characterized by the presence of Reed-Sternberg cells in histological examination.

Causes of Generalised Lymphadenopathy

Generalised lymphadenopathy refers to the enlargement of multiple lymph nodes throughout the body. There are various causes of this condition, including infectious, neoplastic, and autoimmune conditions. Infectious causes include infectious mononucleosis, HIV, eczema with secondary infection, rubella, toxoplasmosis, CMV, tuberculosis, and roseola infantum. Neoplastic causes include leukaemia and lymphoma. Autoimmune conditions such as SLE and rheumatoid arthritis, graft versus host disease, and sarcoidosis can also cause generalised lymphadenopathy. Additionally, certain drugs like phenytoin and to a lesser extent allopurinol and isoniazid can also lead to this condition. It is important to identify the underlying cause of generalised lymphadenopathy to determine the appropriate treatment.

Schistocytes on a blood film are indicative of intravascular haemolysis, which is the most likely cause in this clinical scenario. The presence of a mid-line sternotomy scar, metallic click to the first heart sound, and warfarin prescription suggests a metal heart valve, which can cause sheering of red blood cells and subsequent intravascular haemolysis. Vasculitis, thrombotic thrombocytopenic purpura (TTP), and B12 deficiency are less likely causes in this case.

Pathological Red Cell Forms in Blood Films

Blood films are used to examine the morphology of red blood cells and identify any abnormalities. Pathological red cell forms are associated with various conditions and can provide important diagnostic information. Some of the common pathological red cell forms include target cells, tear-drop poikilocytes, spherocytes, basophilic stippling, Howell-Jolly bodies, Heinz bodies, schistocytes, pencil poikilocytes, burr cells (echinocytes), and acanthocytes.

Target cells are seen in conditions such as sickle-cell/thalassaemia, iron-deficiency anaemia, hyposplenism, and liver disease. Tear-drop poikilocytes are associated with myelofibrosis, while spherocytes are seen in hereditary spherocytosis and autoimmune hemolytic anaemia. Basophilic stippling is a characteristic feature of lead poisoning, thalassaemia, sideroblastic anaemia, and myelodysplasia. Howell-Jolly bodies are seen in hyposplenism, while Heinz bodies are associated with G6PD deficiency and alpha-thalassaemia. Schistocytes or ‘helmet cells’ are seen in conditions such as intravascular haemolysis, mechanical heart valve, and disseminated intravascular coagulation. Pencil poikilocytes are seen in iron deficiency anaemia, while burr cells (echinocytes) are associated with uraemia and pyruvate kinase deficiency. Acanthocytes are seen in abetalipoproteinemia.

In addition to these red cell forms, hypersegmented neutrophils are seen in megaloblastic anaemia. Identifying these pathological red cell forms in blood films can aid in the diagnosis and management of various conditions.

Hydroxyurea is a medication that is used to treat various diseases, including sickle cell disease and chronic myelogenous leukaemia. It works by inhibiting ribonucleotide reductase, which reduces the production of deoxyribonucleotides. This, in turn, inhibits cell synthesis by decreasing DNA synthesis. It is important to note that hydroxyurea does not work by causing the cross-linking of DNA, which is a mechanism used by other drugs such as Cisplatin. Methotrexate works through the inhibition of dihydrofolate reductase, while Irinotecan inhibits topoisomerase I, and Cytarabine is a pyrimidine antagonist. These drugs work through different mechanisms and are not related to hydroxyurea.

Cytotoxic agents are drugs that are used to kill cancer cells. There are several types of cytotoxic agents, each with their own mechanism of action and potential adverse effects. Alkylating agents, such as cyclophosphamide, work by causing cross-linking in DNA. However, they can also cause haemorrhagic cystitis, myelosuppression, and transitional cell carcinoma. Cytotoxic antibiotics, like bleomycin and anthracyclines, degrade preformed DNA and stabilize DNA-topoisomerase II complex, respectively. However, they can also cause lung fibrosis and cardiomyopathy. Antimetabolites, such as methotrexate and fluorouracil, inhibit dihydrofolate reductase and thymidylate synthesis, respectively. However, they can also cause myelosuppression, mucositis, and liver or lung fibrosis. Drugs that act on microtubules, like vincristine and docetaxel, inhibit the formation of microtubules and prevent microtubule depolymerisation & disassembly, respectively. However, they can also cause peripheral neuropathy, myelosuppression, and paralytic ileus. Topoisomerase inhibitors, like irinotecan, inhibit topoisomerase I, which prevents relaxation of supercoiled DNA. However, they can also cause myelosuppression. Other cytotoxic drugs, such as cisplatin and hydroxyurea, cause cross-linking in DNA and inhibit ribonucleotide reductase, respectively. However, they can also cause ototoxicity, peripheral neuropathy, hypomagnesaemia, and myelosuppression.

Haptoglobin plays a crucial role in binding free haemoglobin following haemolysis. This binding forms a complex that can be cleared and metabolized by macrophages through CD163 receptors. This process is essential in preventing local toxicity from haemoglobin degradation products, such as free radicals. Therefore, reduced haptoglobin levels upon testing can indicate intravascular haemolysis. It is important to note that haemopexin binds free haem, not haemoglobin itself, and haptoglobin does not bind complexed haemoglobin or free heme.

Understanding Haemolytic Anaemias by Site

Haemolytic anaemias can be classified by the site of haemolysis, either intravascular or extravascular. In intravascular haemolysis, free haemoglobin is released and binds to haptoglobin. As haptoglobin becomes saturated, haemoglobin binds to albumin forming methaemalbumin, which can be detected by Schumm’s test. Free haemoglobin is then excreted in the urine as haemoglobinuria and haemosiderinuria. Causes of intravascular haemolysis include mismatched blood transfusion, red cell fragmentation due to heart valves, TTP, DIC, HUS, paroxysmal nocturnal haemoglobinuria, and cold autoimmune haemolytic anaemia.

On the other hand, extravascular haemolysis occurs when red blood cells are destroyed by macrophages in the spleen or liver. This type of haemolysis is commonly seen in haemoglobinopathies such as sickle cell anaemia and thalassaemia, hereditary spherocytosis, haemolytic disease of the newborn, and warm autoimmune haemolytic anaemia.

It is important to understand the site of haemolysis in order to properly diagnose and treat haemolytic anaemias. While both intravascular and extravascular haemolysis can lead to anaemia, the underlying causes and treatment approaches may differ.

Salmonella and Staphylococcus aureus as Causes of Osteomyelitis

Salmonella species are responsible for more than half of osteomyelitis cases in patients with sickle cell disease. The higher incidence of salmonella infections is due to various factors. The gut wall’s micro-infarcts allow the bacteria to enter the bloodstream, causing infection. Additionally, impaired splenic function leads to a weakened immune response against the pathogen.

On the other hand, Staphylococcus aureus is the most common organism that causes osteomyelitis in the general population. Although other organisms can also cause osteomyelitis, they are less frequently implicated.

Platelets in the UK are obtained through either pooling the platelet component from four units of whole donated blood, known as random donor platelets, or by plasmapheresis from a single donor. These platelets are suspended in 200-300 ml of plasma and can be stored for up to 4 days in the transfusion laboratory, where they are kept agitated at 22oC to maintain their function. One adult platelet pool can increase the normal platelet count (150 – 450 platelets x 109/litre) by 510 platelets x 109/litre. While ABO identical or compatible platelets are preferred for adults, rhesus compatibility is necessary for recipients who are children or women of childbearing age to prevent haemolytic disease of the newborn.

Blood Products and Cell Saver Devices

Blood products are essential in various medical procedures, especially in cases where patients require transfusions due to anaemia or bleeding. Packed red cells, platelet-rich plasma, platelet concentrate, fresh frozen plasma, and cryoprecipitate are some of the commonly used whole blood fractions. Fresh frozen plasma is usually administered to patients with clotting deficiencies, while cryoprecipitate is a rich source of Factor VIII and fibrinogen. Cross-matching is necessary for all blood products, and cell saver devices are used to collect and re-infuse a patient’s own blood lost during surgery.

Cell saver devices come in two types, those that wash the blood cells before re-infusion and those that do not. The former is more expensive and complicated to operate but reduces the risk of re-infusing contaminated blood. The latter avoids the use of donor blood and may be acceptable to Jehovah’s witnesses. However, it is contraindicated in malignant diseases due to the risk of facilitating disease dissemination.

In some surgical patients, the use of warfarin can pose specific problems and may require the use of specialised blood products. Warfarin reversal can be achieved through the administration of vitamin K, fresh frozen plasma, or human prothrombin complex. Fresh frozen plasma is used less commonly now as a first-line warfarin reversal, and human prothrombin complex is preferred due to its rapid action. However, it should be given with vitamin K as factor 6 has a short half-life.

Transfusion reactions can be classified as immunological or non-immunological. Immunological reactions are caused by anti-HLA or other antibodies in the donor blood, while non-immunological reactions are triggered by an inflammatory cascade with lipids found in blood products.

Symptoms of transfusion-related acute lung injury (TRALI) include dyspnea, cough, fever, and hypotension. Signs and investigations may reveal hypoxemia and pulmonary infiltrates visible on a chest x-ray.

Fluid overload, on the other hand, typically presents with dyspnea, orthopnea, and paroxysmal nocturnal dyspnea.

Severe allergic reactions are rare but may occur when the immune system attacks the donated blood, usually due to a mismatch in blood type. Symptoms may include urticaria, edema, dizziness, and headaches.

Blood product transfusion complications can be categorized into immunological, infective, and other complications. Immunological complications include acute haemolytic reactions, non-haemolytic febrile reactions, and allergic/anaphylaxis reactions. Infective complications may arise due to transmission of vCJD, although measures have been taken to minimize this risk. Other complications include transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), hyperkalaemia, iron overload, and clotting.

Non-haemolytic febrile reactions are thought to be caused by antibodies reacting with white cell fragments in the blood product and cytokines that have leaked from the blood cell during storage. These reactions may occur in 1-2% of red cell transfusions and 10-30% of platelet transfusions. Minor allergic reactions may also occur due to foreign plasma proteins, while anaphylaxis may be caused by patients with IgA deficiency who have anti-IgA antibodies.

Acute haemolytic transfusion reaction is a serious complication that results from a mismatch of blood group (ABO) which causes massive intravascular haemolysis. Symptoms begin minutes after the transfusion is started and include a fever, abdominal and chest pain, agitation, and hypotension. Treatment should include immediate transfusion termination, generous fluid resuscitation with saline solution, and informing the lab. Complications include disseminated intravascular coagulation and renal failure.

TRALI is a rare but potentially fatal complication of blood transfusion that is characterized by the development of hypoxaemia/acute respiratory distress syndrome within 6 hours of transfusion. On the other hand, TACO is a relatively common reaction due to fluid overload resulting in pulmonary oedema. As well as features of pulmonary oedema, the patient may also be hypertensive, a key difference from patients with TRALI.

Angiosarcoma of the liver is a tumor that is not commonly found. However, it has been associated with exposure to vinyl chloride, as seen in this instance. While current factories have taken measures to reduce exposure to this substance, this was not always the case.

Occupational cancers are responsible for 5.3% of cancer deaths, with men being more affected than women. The most common types of cancer in men include mesothelioma, bladder cancer, non-melanoma skin cancer, lung cancer, and sino-nasal cancer. Occupations that have a high risk of developing tumors include those in the construction industry, coal tar and pitch workers, miners, metalworkers, asbestos workers, and those in the rubber industry. Shift work has also been linked to breast cancer in women.

The latency period between exposure to carcinogens and the development of cancer is typically 15 years for solid tumors and 20 years for leukemia. Many occupational cancers are rare, such as sino-nasal cancer, which is linked to wood dust exposure and is not strongly associated with smoking. Another rare occupational tumor is angiosarcoma of the liver, which is linked to working with vinyl chloride. In non-occupational contexts, these tumors are extremely rare.

The chemotherapy regime R-CHOP, which is likely being used to manage the patient’s non-Hodgkin’s lymphoma, includes cyclophosphamide, a drug that functions as an alkylating agent and promotes cross-linking of DNA. This can lead to haemorrhagic cystitis, which is likely the cause of the patient’s haematuria. Other drugs in the regime have different mechanisms of action, such as inhibition of microtubule formation with vincristine, inhibition of topoisomerase II and DNA/RNA synthesis with doxorubicin, and monoclonal antibody targeting of CD20 with rituximab. Pyrimidine analogues like 5-fluorouracil, which block thymidylate synthase and induce cell cycle arrest and apoptosis, are not commonly used in the management of non-Hodgkin’s lymphoma.

Cytotoxic agents are drugs that are used to kill cancer cells. There are several types of cytotoxic agents, each with their own mechanism of action and potential adverse effects. Alkylating agents, such as cyclophosphamide, work by causing cross-linking in DNA. However, they can also cause haemorrhagic cystitis, myelosuppression, and transitional cell carcinoma. Cytotoxic antibiotics, like bleomycin and anthracyclines, degrade preformed DNA and stabilize DNA-topoisomerase II complex, respectively. However, they can also cause lung fibrosis and cardiomyopathy. Antimetabolites, such as methotrexate and fluorouracil, inhibit dihydrofolate reductase and thymidylate synthesis, respectively. However, they can also cause myelosuppression, mucositis, and liver or lung fibrosis. Drugs that act on microtubules, like vincristine and docetaxel, inhibit the formation of microtubules and prevent microtubule depolymerisation & disassembly, respectively. However, they can also cause peripheral neuropathy, myelosuppression, and paralytic ileus. Topoisomerase inhibitors, like irinotecan, inhibit topoisomerase I, which prevents relaxation of supercoiled DNA. However, they can also cause myelosuppression. Other cytotoxic drugs, such as cisplatin and hydroxyurea, cause cross-linking in DNA and inhibit ribonucleotide reductase, respectively. However, they can also cause ototoxicity, peripheral neuropathy, hypomagnesaemia, and myelosuppression.

Hodgkin’s lymphoma is characterized by the presence of Reed-Sternberg cells.

Hodgkin’s lymphoma is a type of blood cancer that is often accompanied by painless swelling of the lymph nodes, as well as symptoms such as fever, weight loss, and night sweats. One of the defining features of this disease is the presence of Reed-Sternberg cells, which are large, abnormal lymphocytes that can have multiple nuclei. These cells are not typically seen in other types of blood cancer, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), or chronic lymphocytic leukemia (CLL). Instead, each of these diseases has its own characteristic features that can be identified through laboratory testing and other diagnostic methods.

Understanding Hodgkin’s Lymphoma: Symptoms and Risk Factors

Hodgkin’s lymphoma is a type of cancer that affects the lymphocytes and is characterized by the presence of Reed-Sternberg cells. It is most commonly seen in people in their third and seventh decades of life. There are certain risk factors that increase the likelihood of developing Hodgkin’s lymphoma, such as HIV and the Epstein-Barr virus.

The most common symptom of Hodgkin’s lymphoma is lymphadenopathy, which is the enlargement of lymph nodes. This is usually painless, non-tender, and asymmetrical, and is most commonly seen in the neck, followed by the axillary and inguinal regions. In some cases, alcohol-induced lymph node pain may be present, but this is seen in less than 10% of patients. Other symptoms of Hodgkin’s lymphoma include weight loss, pruritus, night sweats, and fever (Pel-Ebstein). A mediastinal mass may also be present, which can cause symptoms such as coughing. In some cases, Hodgkin’s lymphoma may be found incidentally on a chest x-ray.

When investigating Hodgkin’s lymphoma, normocytic anaemia may be present, which can be caused by factors such as hypersplenism, bone marrow replacement by HL, or Coombs-positive haemolytic anaemia. Eosinophilia may also be present, which is caused by the production of cytokines such as IL-5. LDH levels may also be raised.

In summary, Hodgkin’s lymphoma is a type of cancer that affects the lymphocytes and is characterized by the presence of Reed-Sternberg cells. It is most commonly seen in people in their third and seventh decades of life and is associated with risk factors such as HIV and the Epstein-Barr virus. Symptoms of Hodgkin’s lymphoma include lymphadenopathy, weight loss, pruritus, night sweats, and fever. When investigating Hodgkin’s lymphoma, normocytic anaemia, eosinophilia, and raised LDH levels may be present.

Filgrastim is a medication that stimulates the growth of granulocytes and is commonly used to treat neutropenia. In the case of a patient with a history of fever, low blood pressure, and tachycardia, it is likely that they have developed sepsis, which is a common complication in patients receiving chemotherapy. The main treatment for sepsis is fluid resuscitation and broad-spectrum antibiotics. While filgrastim is not a direct treatment for sepsis, it can be used to address leukopenia caused by chemotherapy, aplastic anemia, and congenital neutropenia.

Darbepoetin is a medication that mimics the effects of erythropoietin and is commonly used to treat anemia, particularly in patients with renal failure.

Eltrombopag is a medication that activates the TPO receptor and is often used to treat autoimmune thrombocytopenia.

IFN-γ is a medication used to treat chronic granulomatous disease.

Granulocyte-Colony Stimulating Factors for Neutropenia

Granulocyte-colony stimulating factors (G-CSFs) are synthetic versions of a natural protein that stimulates the production of white blood cells called neutrophils. These drugs are used to increase neutrophil counts in patients who are neutropenic, meaning they have abnormally low levels of neutrophils. Neutropenia can occur as a side effect of chemotherapy or radiation therapy, or due to other factors such as infections or autoimmune disorders.

Recombinant human G-CSFs, such as filgrastim and perfilgrastim, are commonly used to treat neutropenia. These drugs work by stimulating the bone marrow to produce more neutrophils, which can help prevent infections and other complications associated with low white blood cell counts. G-CSFs are typically administered by injection, either subcutaneously or intravenously.

Overall, G-CSFs are an important tool in the management of neutropenia, particularly in patients undergoing chemotherapy or other treatments that can suppress the immune system. By boosting neutrophil production, these drugs can help reduce the risk of infections and improve outcomes for patients with compromised immune function.

The testes drain into the para-aortic lymph nodes, while the scrotum drains into the superficial inguinal lymph nodes and the glans penis drains into the deep inguinal lymph nodes. The anal canal above the pectinate line drains into the internal iliac lymph nodes, and the descending colon drains into the inferior mesenteric lymph nodes. For a comprehensive list of lymph nodes and their associated drainage sites, please refer to the attached notes.

Lymphatic drainage is the process by which lymphatic vessels carry lymph, a clear fluid containing white blood cells, away from tissues and organs and towards lymph nodes. The lymphatic vessels that drain the skin and follow venous drainage are called superficial lymphatic vessels, while those that drain internal organs and structures follow the arteries and are called deep lymphatic vessels. These vessels eventually lead to lymph nodes, which filter and remove harmful substances from the lymph before it is returned to the bloodstream.

The lymphatic system is divided into two main ducts: the right lymphatic duct and the thoracic duct. The right lymphatic duct drains the right side of the head and right arm, while the thoracic duct drains everything else. Both ducts eventually drain into the venous system.

Different areas of the body have specific primary lymph node drainage sites. For example, the superficial inguinal lymph nodes drain the anal canal below the pectinate line, perineum, skin of the thigh, penis, scrotum, and vagina. The deep inguinal lymph nodes drain the glans penis, while the para-aortic lymph nodes drain the testes, ovaries, kidney, and adrenal gland. The axillary lymph nodes drain the lateral breast and upper limb, while the internal iliac lymph nodes drain the anal canal above the pectinate line, lower part of the rectum, and pelvic structures including the cervix and inferior part of the uterus. The superior mesenteric lymph nodes drain the duodenum and jejunum, while the inferior mesenteric lymph nodes drain the descending colon, sigmoid colon, and upper part of the rectum. Finally, the coeliac lymph nodes drain the stomach.

Invasion is a characteristic of invasive disease and is not typically seen in cases of DCIS. However, angiogenesis may be present in cases of high grade DCIS.

Characteristics of Malignancy in Histopathology

Histopathology is the study of tissue architecture and cellular changes in disease. In malignancy, there are several distinct characteristics that differentiate it from normal tissue or benign tumors. These features include abnormal tissue architecture, coarse chromatin, invasion of the basement membrane, abnormal mitoses, angiogenesis, de-differentiation, areas of necrosis, and nuclear pleomorphism.

Abnormal tissue architecture refers to the disorganized and irregular arrangement of cells within the tissue. Coarse chromatin refers to the appearance of the genetic material within the nucleus, which appears clumped and irregular. Invasion of the basement membrane is a hallmark of invasive malignancy, as it indicates that the cancer cells have broken through the protective layer that separates the tissue from surrounding structures. Abnormal mitoses refer to the process of cell division, which is often disrupted in cancer cells. Angiogenesis is the process by which new blood vessels are formed, which is necessary for the growth and spread of cancer cells. De-differentiation refers to the loss of specialized functions and characteristics of cells, which is common in cancer cells. Areas of necrosis refer to the death of tissue due to lack of blood supply or other factors. Finally, nuclear pleomorphism refers to the variability in size and shape of the nuclei within cancer cells.

Overall, these characteristics are important for the diagnosis and treatment of malignancy, as they help to distinguish cancer cells from normal tissue and benign tumors. By identifying these features in histopathology samples, doctors can make more accurate diagnoses and develop more effective treatment plans for patients with cancer.

Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic form of intrinsic hemolytic anemia that can present with symptoms such as hematuria, anemia, and venous thrombosis. The classic triad of PNH includes hemolytic anemia, pancytopenia, and venous thrombosis. The gold standard test for PNH is flow cytometry for CD59 and CD55, which shows a deficiency of these proteins on red and white blood cells.

A deficiency of C3 is a complement deficiency disorder that increases the risk of recurrent bacterial infections. While a deficiency of CD59 or CD55 may be present in this patient, PNH patients typically have a deficiency of both proteins. Terminal complement deficiency, indicated by a deficiency of complements forming the membrane attack membrane, confers a high risk of infection with Neisseria organisms. Eculizumab, a humanized monoclonal antibody, is approved for the treatment of PNH and works by inhibiting the terminal complement cascade.

Understanding Paroxysmal Nocturnal Haemoglobinuria

Paroxysmal nocturnal haemoglobinuria (PNH) is a condition that causes the breakdown of haematological cells, mainly intravascular haemolysis. It is believed to be caused by a lack of glycoprotein glycosyl-phosphatidylinositol (GPI), which acts as an anchor that attaches surface proteins to the cell membrane. This leads to the improper binding of complement-regulating surface proteins, such as decay-accelerating factor (DAF), to the cell membrane. As a result, patients with PNH are more prone to venous thrombosis.

PNH can affect red blood cells, white blood cells, platelets, or stem cells, leading to pancytopenia. Patients may also experience haemoglobinuria, which is characterized by dark-coloured urine in the morning. Thrombosis, such as Budd-Chiari syndrome, is also a common feature of PNH. In some cases, patients may develop aplastic anaemia.

To diagnose PNH, flow cytometry of blood is used to detect low levels of CD59 and CD55. This has replaced Ham’s test as the gold standard investigation for PNH. Ham’s test involves acid-induced haemolysis, which normal red cells would not undergo.

Management of PNH involves blood product replacement, anticoagulation, and stem cell transplantation. Eculizumab, a monoclonal antibody directed against terminal protein C5, is currently being trialled and is showing promise in reducing intravascular haemolysis. Understanding PNH is crucial in managing this condition and improving patient outcomes.

The Relationship Between Chronic Diseases and Blood Cell Formation

Chronic liver disease, coeliac disease, and Crohn’s disease can all affect the formation of red blood cells in different ways. In chronic liver disease, cholesterol and lipids build up in the membrane of red blood cells, causing them to increase in size. However, DNA maturation is not impaired, so the nucleus is still ejected normally. Coeliac disease can lead to villous atrophy in the small intestine, which impairs the absorption of folic acid. Folate is necessary for DNA replication, and its deficiency can result in the formation of immature, large red cells with impaired DNA maturation. Crohn’s disease typically affects the terminal ileum, where vitamin B12 is absorbed. Vitamin B12 is important for the recycling of folate, which is essential for DNA synthesis. Without intrinsic factor, a co-factor in vitamin B12 absorption secreted by gastric parietal cells, vitamin B12 deficiency can occur. Chemotherapeutic agents that affect DNA synthesis can also lead to the formation of megaloblasts, as normal DNA maturation is impaired. Overall, these chronic diseases can have significant impacts on the formation of red blood cells and the body’s ability to produce healthy blood.

The leading cause of cancer deaths in the UK is lung cancer, while malignant melanoma does not rank in the top 10. Prostate cancer is the most prevalent cancer in men and the second most common cause of cancer-related deaths in men. Breast cancer is the second most common cause of cancer deaths in women.

Cancer in the UK: Common Types and Causes of Death

Cancer is a major health concern in the UK, with several types of cancer affecting a significant number of people. The most common types of cancer in the UK are breast, lung, colorectal, prostate, bladder, non-Hodgkin’s lymphoma, melanoma, stomach, oesophagus, and pancreas. However, when it comes to causes of death from cancer, lung cancer tops the list, followed by colorectal, breast, prostate, and pancreatic cancer. Other types of cancer that contribute to cancer-related deaths in the UK include oesophageal, stomach, bladder, non-Hodgkin’s lymphoma, and ovarian cancer. It is important to note that non-melanoma skin cancer is not included in these statistics. Despite the prevalence of cancer in the UK, there are various treatments and support available for those affected by the disease.

To treat solid tumours, immune checkpoint inhibitors are becoming a popular substitute for cytotoxic chemotherapy. These inhibitors function by reactivating and boosting the body’s T-cell population. While radiotherapy harms cancer cell DNA, chemotherapy directly impacts the growth and multiplication of cancer cells.

Understanding Immune Checkpoint Inhibitors

Immune checkpoint inhibitors are a type of immunotherapy that is becoming increasingly popular in the treatment of certain types of cancer. Unlike traditional therapies such as chemotherapy, these targeted treatments work by harnessing the body’s natural anti-cancer immune response. They boost the immune system’s ability to attack and destroy cancer cells, rather than directly affecting their growth and proliferation.

T-cells are an essential part of our immune system that helps destroy cancer cells. However, some cancer cells produce high levels of proteins that turn T-cells off. Checkpoint inhibitors block this process and reactivate and increase the body’s T-cell population, enhancing the immune system’s ability to recognize and fight cancer cells.

There are different types of immune checkpoint inhibitors, including Ipilimumab, Nivolumab, Pembrolizumab, Atezolizumab, Avelumab, and Durvalumab. These drugs block specific proteins found on T-cells and cancer cells, such as CTLA-4, PD-1, and PD-L1. They are administered by injection or intravenous infusion and can be given as a single-agent treatment or combined with chemotherapy or each other.

However, the mechanism of action of these drugs can result in side effects termed ‘Immune-related adverse events’ that are inflammatory and autoimmune in nature. This is because all immune cells are boosted by these drugs, not just the ones that target cancer. The overactive T-cells can produce side effects such as dry, itchy skin and rashes, nausea and vomiting, decreased appetite, diarrhea, tiredness and fatigue, shortness of breath, and a dry cough. Management of such side effects reflects the inflammatory nature, often involving corticosteroids. It is important to monitor liver, kidney, and thyroid function as these drugs can affect these organs.

In conclusion, the early success of immune checkpoint inhibitors in solid tumors has generated tremendous interest in further developing and exploring these strategies across the oncology disease spectrum. Ongoing testing in clinical trials creates new hope for patients affected by other types of disease.

The cervix primarily drains into the internal iliac lymph nodes. The deep inguinal lymph nodes do not drain the cervix, but they do drain the clitoris and glans penis. The external iliac lymph nodes are not significantly involved in the lymphatic drainage of the cervix, but they do play a role in the drainage of the bladder fundus, prostate, and adductor region of the thigh. The para-aortic nodes drain the ovaries, but not the cervix. The superficial inguinal lymph nodes are not involved in the drainage of the cervix, but they are important in the drainage of the anal canal (below the pectinate line), scrotum, and perineum.

Lymphatic drainage is the process by which lymphatic vessels carry lymph, a clear fluid containing white blood cells, away from tissues and organs and towards lymph nodes. The lymphatic vessels that drain the skin and follow venous drainage are called superficial lymphatic vessels, while those that drain internal organs and structures follow the arteries and are called deep lymphatic vessels. These vessels eventually lead to lymph nodes, which filter and remove harmful substances from the lymph before it is returned to the bloodstream.

The lymphatic system is divided into two main ducts: the right lymphatic duct and the thoracic duct. The right lymphatic duct drains the right side of the head and right arm, while the thoracic duct drains everything else. Both ducts eventually drain into the venous system.

Different areas of the body have specific primary lymph node drainage sites. For example, the superficial inguinal lymph nodes drain the anal canal below the pectinate line, perineum, skin of the thigh, penis, scrotum, and vagina. The deep inguinal lymph nodes drain the glans penis, while the para-aortic lymph nodes drain the testes, ovaries, kidney, and adrenal gland. The axillary lymph nodes drain the lateral breast and upper limb, while the internal iliac lymph nodes drain the anal canal above the pectinate line, lower part of the rectum, and pelvic structures including the cervix and inferior part of the uterus. The superior mesenteric lymph nodes drain the duodenum and jejunum, while the inferior mesenteric lymph nodes drain the descending colon, sigmoid colon, and upper part of the rectum. Finally, the coeliac lymph nodes drain the stomach.