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Pathology - -Septic Arthritis
I. Definition:
I. Definition:
- Infection within a joint. This is the core concept – remember this first.
- Any age: Septic arthritis can affect anyone.
- Increased Risk: Individuals with pre-existing joint conditions are significantly more vulnerable. Think of this as a weakened defense system making the joint more susceptible.
- Hematogenous Spread (Most Common): The infection travels through the bloodstream to the joint. This is the primary pathway.
- Penetrating Trauma (Less Common): Infection can be introduced directly into the joint via injury (e.g., a puncture wound).
- Staphylococcus aureus (S. aureus): This bacterium is the primary culprit in almost all cases. Memorize this.
- Phagocyte Limitation: The joint space has limited access for phagocytes (immune cells that engulf and destroy pathogens). This makes it difficult for the body to fight the infection naturally. This is a key factor in why the infection spreads so rapidly.
- Rapid Destruction: Septic arthritis progresses swiftly, causing irreversible joint damage if antibiotics aren't administered promptly. Early intervention is critical.
- Classic Signs of Inflammation: The affected joint is intensely painful, hot, red, and swollen. This is a hallmark of septic arthritis; remember these four key characteristics (pain, heat, redness, swelling).
- Microscopy: Joint fluid analysis reveals neutrophils (a type of white blood cell indicating infection) but no crystals (ruling out gout or pseudogout).
- Culture: Essential for identifying the specific bacteria (usually S. aureus) and determining its antibiotic susceptibility. Culturing both joint fluid and blood is crucial for accurate diagnosis and treatment.
- Irreversible Joint Damage: Without appropriate antibiotic treatment, permanent joint destruction is inevitable. This highlights the urgency of prompt diagnosis and treatment.
- S. aureus is the most common cause.
- Early antibiotic treatment is crucial to prevent irreversible joint damage.
- The four cardinal signs of inflammation (pain, heat, redness, swelling) are present.
- Joint fluid analysis is essential for diagnosis and guiding treatment.
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Pathology - Spondyloarthropathies
I. Definition & Epidemiology:
A. Ankylosing Spondylitis:
I. Definition & Epidemiology:
- Definition: Spondyloarthropathies are inflammatory joint diseases affecting the spine and peripheral joints, characterized by arthritis and enthesitis (inflammation at tendon/ligament-bone insertion sites).
- Epidemiology: These are common diseases (affecting ~1% of the population), predominantly affecting young adults (20-40 years old) with a slight male bias.
- HLA-B27 Association: A strong genetic association exists with the HLA-B27 allele. This is a crucial risk factor.
- Older Theories: Initially, researchers hypothesized that an unidentified "arthritogenic peptide" presented by HLA-B27 to CD8+ T cells triggered inflammation.
- Current Understanding: Recent focus is on HLA-B27 protein itself. The HLA-B27 heavy chain is prone to misfolding, forming abnormal homodimers. Studies (e.g., in transgenic rats) show that this misfolding leads to endoplasmic reticulum stress and IL-23 production via the T-helper 17 pathway, driving inflammation.
A. Ankylosing Spondylitis:
- Prevalence: Affects approximately 0.5% of the population, typically presenting in young adults (20-40 years).
- Presentation: Lower back pain due to sacroiliitis (inflammation of the sacroiliac joints) is the hallmark symptom.
- Extra-articular Manifestations: Inflammation can extend beyond the joints, affecting structures like the eyes (iritis), lungs (pulmonary fibrosis), and aorta (aortitis).
- Onset: Develops within one month of an infection elsewhere in the body.
- Infections: Commonly associated with genitourinary infections (e.g., Chlamydia) or gastrointestinal infections (e.g., Shigella, Salmonella, Campylobacter).
- Mechanism: Possibly due to bacterial antigens or DNA deposition in joints, although this isn't definitively proven.
- Presentation: Pain and stiffness in the lower back, knees, ankles, and feet; enthesitis is frequent.
- Prevalence: Occurs in approximately 5% of patients with psoriasis.
- Joint Involvement: Primarily affects distal interphalangeal joints (joints at the tips of the fingers and toes), potentially causing significant deformity.
- Cause: Currently unknown.
- Prevalence: Found in about 10% of individuals with inflammatory bowel disease.
- Joint Involvement: Typically affects sacroiliac and lower limb joints asymmetrically.
- Cause: Unknown.
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Pathology - Crystal Arthropathies
I. Definition & Pathogenesis
A. Gout
Microscopic examination of joint fluid is crucial for differentiating gout and pseudogout:
I. Definition & Pathogenesis
- Crystal Arthropathies: A family of joint diseases stemming from crystal deposition within the joints.
- Pathogenic Mechanism: Crystals trigger an inflammatory response. Neutrophils attempt to phagocytose (engulf) the crystals, leading to degranulation and the release of damaging enzymes. This enzymatic action causes joint damage.
A. Gout
- Etiology: Deposition of urate crystals in joints. Primarily caused by hyperuricemia (high uric acid levels in the blood), often due to impaired renal (kidney) excretion of urate.
- Acute Gout: Presents as an acutely painful, swollen, and red joint. While any joint can be affected, the first metatarsophalangeal joint (base of the big toe) is highly characteristic.
- Chronic Tophaceous Gout: In individuals with persistently high urate levels, large urate deposits (tophi) can form in the skin and around joints.
- Etiology: Deposition of calcium pyrophosphate crystals in joints. Pyrophosphate is a byproduct of nucleotide triphosphate hydrolysis within cartilage chondrocytes.
- Pathogenesis: Shedding of these crystals into the joint space initiates an acute arthritis closely resembling gout.
- Clinical Presentation: Typically affects older women, commonly involving the knee and wrist joints.
Microscopic examination of joint fluid is crucial for differentiating gout and pseudogout:
- Joint Fluid: Contains neutrophils and crystals.
- Urate Crystals (Gout): Needle-shaped; exhibit negative birefringence under polarized light.
- Pyrophosphate Crystals (Pseudogout): Rhomboid or rod-shaped; exhibit positive birefringence under polarized light. The difference in birefringence is key for distinguishing between the two conditions.
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Pathology - Chronic myelogenous leukemia
A myeloproliferative neoplasm mostly affecting the granulocytic lineage, consistently related with the BCR-ABL1 fusion gene on the Philadelphia chromosome.
Epidemiology • Incidence ranges from 1 to 2 per 100,000 individuals annually. • The peak age of onset is between 50 and 70 years old.
Aetiology: Unknown. Genetics • Chronic myelogenous leukaemia (CML) is typically characterized by the t(9;22) translocation, which produces the Philadelphia chromosome. • This translocation fuses the BCR gene on chromosome 22 with the ABL1 gene on chromosome 9. • The resulting BCR-ABL1 protein exhibits increased tyrosine kinase activity, resulting in the persistent activation of signal transduction pathways and uncontrolled proliferation of myeloid cells.
Presentation • The majority of patients receive a diagnosis during the chronic phase of the disease, characterized by an elevated white cell count. • Hepatosplenomegaly frequently accompanies the diagnosis.
Peripheral blood • Leukocytosis resulting from elevated neutrophil counts at various maturation phases. • Basophilia and eosinophilia are prevalent. No dysplasia is observed.
Bone marrow • Bone marrow trephines exhibit hypercellularity attributed to elevated quantities of neutrophils and their precursors. • Megakaryocytes are generally diminutive and hypolobated. • Blasts constitute less than 5% of marrow cells throughout the chronic phase.
Prognosis • The outcome has significantly improved following the introduction of the tyrosine kinase inhibitor, imatinib, resulting in 5-year survival rates of 80–90%. • Disease progression is typically indicated by an elevation in circulating blasts to over 10% (accelerated phase) and culminates in acute leukemia when blasts constitute more than 20% of circulating cells.
A myeloproliferative neoplasm mostly affecting the granulocytic lineage, consistently related with the BCR-ABL1 fusion gene on the Philadelphia chromosome.
Epidemiology • Incidence ranges from 1 to 2 per 100,000 individuals annually. • The peak age of onset is between 50 and 70 years old.
Aetiology: Unknown. Genetics • Chronic myelogenous leukaemia (CML) is typically characterized by the t(9;22) translocation, which produces the Philadelphia chromosome. • This translocation fuses the BCR gene on chromosome 22 with the ABL1 gene on chromosome 9. • The resulting BCR-ABL1 protein exhibits increased tyrosine kinase activity, resulting in the persistent activation of signal transduction pathways and uncontrolled proliferation of myeloid cells.
Presentation • The majority of patients receive a diagnosis during the chronic phase of the disease, characterized by an elevated white cell count. • Hepatosplenomegaly frequently accompanies the diagnosis.
Peripheral blood • Leukocytosis resulting from elevated neutrophil counts at various maturation phases. • Basophilia and eosinophilia are prevalent. No dysplasia is observed.
Bone marrow • Bone marrow trephines exhibit hypercellularity attributed to elevated quantities of neutrophils and their precursors. • Megakaryocytes are generally diminutive and hypolobated. • Blasts constitute less than 5% of marrow cells throughout the chronic phase.
Prognosis • The outcome has significantly improved following the introduction of the tyrosine kinase inhibitor, imatinib, resulting in 5-year survival rates of 80–90%. • Disease progression is typically indicated by an elevation in circulating blasts to over 10% (accelerated phase) and culminates in acute leukemia when blasts constitute more than 20% of circulating cells.
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Pathology - Chronic lymphocytic leukemia
A malignant tumor consisting of tiny mature B-cells that typically coexpress CD5 and CD23.
Epidemiology The predominant leukemia, occurring at a rate of 5 per 100,000 individuals. • A condition prevalent among older persons, with a peak incidence occurring between the ages of 60 and 80 years. • Males are impacted twice as frequently as females.
Aetiology • Unidentified.
Pathogenesis The oncogenic B-cells progressively infiltrate the bone marrow and subsequently enter the peripheral circulation. • As the condition advances, lymph nodes become affected, followed by the liver and spleen. • In the terminal phases of the disease, the neoplastic cells dominate the bone marrow, resulting in bone marrow failure.
Presentation • Numerous people are diagnosed incidentally when a complete blood count indicates leukocytosis. The remainder exhibits lymphadenopathy or autoimmune manifestations, such autoimmune hemolytic anemia or autoimmune thrombocytopenia.
Peripheral blood film: Excess of mature lymphocytes. Smear cells are indicative of chronic lymphocytic leukaemia (CLL); they are neoplastic cells that get blurred during film preparation. Histopathology • Lymph nodes are substituted by small, slightly atypical B-cells exhibiting varied quantities of proliferation centers comprising bigger lymphoid cells. • Affected bone marrow contains aggregates of neoplastic lymphoid cells. Immunophenotype: Positive for PAX5, CD20, CD79a, CD5, and CD23. • Cyclin D1 is negative.
Prognosis • Typically exhibits an indolent course, with several patients surviving for several years post-diagnosis, frequently without intervention. • A minority of cases are compounded by the emergence of diffuse large B-cell lymphoma (Richter’s syndrome), which carries a bad prognosis.
A malignant tumor consisting of tiny mature B-cells that typically coexpress CD5 and CD23.
Epidemiology The predominant leukemia, occurring at a rate of 5 per 100,000 individuals. • A condition prevalent among older persons, with a peak incidence occurring between the ages of 60 and 80 years. • Males are impacted twice as frequently as females.
Aetiology • Unidentified.
Pathogenesis The oncogenic B-cells progressively infiltrate the bone marrow and subsequently enter the peripheral circulation. • As the condition advances, lymph nodes become affected, followed by the liver and spleen. • In the terminal phases of the disease, the neoplastic cells dominate the bone marrow, resulting in bone marrow failure.
Presentation • Numerous people are diagnosed incidentally when a complete blood count indicates leukocytosis. The remainder exhibits lymphadenopathy or autoimmune manifestations, such autoimmune hemolytic anemia or autoimmune thrombocytopenia.
Peripheral blood film: Excess of mature lymphocytes. Smear cells are indicative of chronic lymphocytic leukaemia (CLL); they are neoplastic cells that get blurred during film preparation. Histopathology • Lymph nodes are substituted by small, slightly atypical B-cells exhibiting varied quantities of proliferation centers comprising bigger lymphoid cells. • Affected bone marrow contains aggregates of neoplastic lymphoid cells. Immunophenotype: Positive for PAX5, CD20, CD79a, CD5, and CD23. • Cyclin D1 is negative.
Prognosis • Typically exhibits an indolent course, with several patients surviving for several years post-diagnosis, frequently without intervention. • A minority of cases are compounded by the emergence of diffuse large B-cell lymphoma (Richter’s syndrome), which carries a bad prognosis.
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Pathology - Essential thrombocythemia
Definition: A myeloproliferative neoplasm mostly affecting the megakaryocytic lineage.
Epidemiology: Estimated incidence ranges from 0.5 to 2.5 cases per 100,000 individuals annually. • The majority of occurrences occur in adults aged 50 to 60. • There is no gender preference.
Aetiology: Unknown. Genetics • No established molecular genetic or cytogenetic abnormalities have been identified.
Presentation • Approximately fifty percent of patients are diagnosed incidentally due to a significantly elevated platelet count identified in a complete blood count. • The remaining patients exhibit symptoms associated with vascular occlusion or hemorrhage, including transient ischemic attacks, digital ischemia and gangrene, as well as major arterial and venous thrombosis. • Splenomegaly occurs in only a minority of patients. Complete blood count • Persistently high platelet count (> 450 × 10^9/L). The leukocyte and erythrocyte counts are typically within normal limits. The bone marrow has normal cellularity, although displays an elevated presence of huge and enormous megakaryocytes characterized by ample cytoplasm and severely lobated 'stag-horn' nuclei. There is no significant proliferation of erythroid or granulocytic lineages.
Prognosis: A rather indolent disease with a median survival of 10 to 15 years. • A minimal percentage of patients advance to bone marrow fibrosis or acute myeloid leukemia.
Definition: A myeloproliferative neoplasm mostly affecting the megakaryocytic lineage.
Epidemiology: Estimated incidence ranges from 0.5 to 2.5 cases per 100,000 individuals annually. • The majority of occurrences occur in adults aged 50 to 60. • There is no gender preference.
Aetiology: Unknown. Genetics • No established molecular genetic or cytogenetic abnormalities have been identified.
Presentation • Approximately fifty percent of patients are diagnosed incidentally due to a significantly elevated platelet count identified in a complete blood count. • The remaining patients exhibit symptoms associated with vascular occlusion or hemorrhage, including transient ischemic attacks, digital ischemia and gangrene, as well as major arterial and venous thrombosis. • Splenomegaly occurs in only a minority of patients. Complete blood count • Persistently high platelet count (> 450 × 10^9/L). The leukocyte and erythrocyte counts are typically within normal limits. The bone marrow has normal cellularity, although displays an elevated presence of huge and enormous megakaryocytes characterized by ample cytoplasm and severely lobated 'stag-horn' nuclei. There is no significant proliferation of erythroid or granulocytic lineages.
Prognosis: A rather indolent disease with a median survival of 10 to 15 years. • A minimal percentage of patients advance to bone marrow fibrosis or acute myeloid leukemia.
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Pathology - Polycythemia vera
A myeloproliferative neoplasm primarily affecting the erythroid lineage, typically linked to a somatic gain-of-function mutation in the JAK2 gene. Epidemiology: Incidence ranges from 1 to 2.5 cases per 100,000 individuals annually. The median age upon diagnosis is 60 years. • There is a minor masculine predominance.
Aetiology: Unknown. Genetics: Over 95% of cases exhibit the JAK2 V617F mutation, resulting in uncontrolled proliferation of all myeloid cells, particularly affecting the erythroid lineage. The advancement of the disease correlates with the development of chromosomal abnormalities.
Presentation • May be incidentally detected with a full blood count or manifest with symptoms associated with hyperviscosity (headache, dizziness, visual disturbances, venous or arterial thrombosis). • The majority of individuals exhibit plethoric conditions and hepatosplenomegaly. Complete blood count: elevated hemoglobin, increased red cell count, heightened hematocrit (HCT), and augmented packed cell volume (PCV). • Frequently, I monitor white blood cell count and platelet levels. The bone marrow exhibits hypercellularity resulting from an elevation in all myeloid lineages, termed 'panmyelosis.' Erythroid progenitors and megakaryocytes are the most prominent cell types. Megakaryocytes exhibit loose clustering and frequently demonstrate considerable variation in size and morphology.
Prognosis: Median survival exceeds 10 years with treatment. The majority of patients succumb to thrombosis or hemorrhage. Approximately 20% succumb to the progression of myelodysplasia or acute myeloid leukemia (AML).
A myeloproliferative neoplasm primarily affecting the erythroid lineage, typically linked to a somatic gain-of-function mutation in the JAK2 gene. Epidemiology: Incidence ranges from 1 to 2.5 cases per 100,000 individuals annually. The median age upon diagnosis is 60 years. • There is a minor masculine predominance.
Aetiology: Unknown. Genetics: Over 95% of cases exhibit the JAK2 V617F mutation, resulting in uncontrolled proliferation of all myeloid cells, particularly affecting the erythroid lineage. The advancement of the disease correlates with the development of chromosomal abnormalities.
Presentation • May be incidentally detected with a full blood count or manifest with symptoms associated with hyperviscosity (headache, dizziness, visual disturbances, venous or arterial thrombosis). • The majority of individuals exhibit plethoric conditions and hepatosplenomegaly. Complete blood count: elevated hemoglobin, increased red cell count, heightened hematocrit (HCT), and augmented packed cell volume (PCV). • Frequently, I monitor white blood cell count and platelet levels. The bone marrow exhibits hypercellularity resulting from an elevation in all myeloid lineages, termed 'panmyelosis.' Erythroid progenitors and megakaryocytes are the most prominent cell types. Megakaryocytes exhibit loose clustering and frequently demonstrate considerable variation in size and morphology.
Prognosis: Median survival exceeds 10 years with treatment. The majority of patients succumb to thrombosis or hemorrhage. Approximately 20% succumb to the progression of myelodysplasia or acute myeloid leukemia (AML).
