Systemic Pathology PDF

0 #4 Introduction  The respiratory system: is responsible for gas exchange between the external and internal environments of the body.  Air enters through the airways into the lungs, where exchange occurs at the alveoli between the blood in the capillaries and the air inside the alveoli.  Oxygen...

0 #4 Introduction  The respiratory system: is responsible for gas exchange between the external and internal environments of the body.  Air enters through the airways into the lungs, where exchange occurs at the alveoli between the blood in the capillaries and the air inside the alveoli.  Oxygen is harvested, and carbon dioxide is expelled through this process.  Lung pathology may involve any or all of the followings:  The airways: which are the passages for air into and out of the lungs. (Inhalation and Exhalation)  The parenchyma and the interstitium: which are the lung tissues between the alveoli and the vasculature.  The pulmonary vascular system: responsible for oxygenating the blood in the lungs before it returns to the systemic circulation.  Some diseases can lead to heart failure. When heart damage is caused by a lung disease, it is called Cor pulmonale.  Cor pulmonale is defined as right-sided heart failure usually due to pulmonary disease because the right side of the heart is primarily responsible for pulmonary circulation.  Many lung diseases can be accompanied by Atelectasis.  (Picture 1) This is the normal histologic appearance of the lung which appear empty but actually contain air. (alveoli) 2 1  Between them, you'll find small capillary-sized blood vessels that facilitate gas exchange.  (Picture 2) This is the wall or partition between the air and the blood in the capillary consists of:  Endothelial cells lining the capillary wall.  Basement membrane.  Alveolar epithelium, and another basement membrane.  Alveolar space, where gas exchange occurs, is critical and any issues in this area can impede or affect the process of gas exchange, leading to hypoxia or reduced oxygenation. Atelectasis  Defined by loss of lung volume due to inadequate expansion of air space, leading to ventilationperfusion imbalance.  We have ventilation, which is the process of aerating the lungs, and perfusion, which is the blood supply to that area. If there are issues with either ventilation or perfusion, it is called ventilationperfusion imbalance. 1  In the case of atelectasis, there is a loss of lung volume, and a portion of the lung does not participate in ventilation. This leads to issues in gas exchange, causing hypoxia, which is a decrease in blood oxygenation.  Atelectasis can involve a small part of the lung, known as a segment, a whole lobe, or even an entire lung.  Atelectasis may be reversible if the underlying cause is removed. Therefore, we have reversible and irreversible atelectasis.  you can notice that we have open air spaces here in this area, and also in this area.  In atelectasis, the air spaces, or alveoli, collapse and are not inflated by air. This results in a characteristic appearance where the airways are compressed and collapsed together, devoid of air and not participating in the ventilation process.  We have two types of Atelectasis: 1.Resorption atelectasis (obstructive):  This type occurs due to airway obstruction.  The bronchi, which divide into the right and left bronchi, further divide into smaller branches that supply each lung. If one of these branches is blocked, air cannot enter that area, leading to the collapse of that part of the lung. This condition is known as resorption atelectasis.  The obstruction can occur due to various causes, primarily related to a foreign body (Something foreign, whether from outside or inside the lung, can obstruct the airways). For example, a mucus plug in conditions like asthma or chronic bronchitis.  In these diseases, there is excessive mucus production, and sometimes this mucus thickens, leading to airway obstruction.  Post-surgery, the healing process can result in fibrosis and obstruction of the airways.  Alternatively, Tumors, whether malignant or benign, can also cause airway obstruction.  In resorption atelectasis:  We usually observe a shift of the mediastinum to the affected side.  This means that on a chest x-ray, where the mediastinum normally lies centrally between both lungs, containing the heart, you'll see it shifted towards the same side as the atelectasis.  For instance, if there is resorption atelectasis in the right lung, the decreased space will cause the mediastinum to shift to the right, and vice versa.  Note:  Foreign bodies can be inhaled, especially by children.  For example, when they are eating certain foods and choke, the foreign body can be aspirated into the airways, leading to obstruction at a certain level, causing atelectasis. 2 2.Compression atelectasis:  From its name, compression atelectasis is simply caused by something compressing the lung, preventing it from expanding.  Normally, the lung expands during inhalation and collapses during exhalation to push air out. In compression atelectasis, something—like air or fluid in the pleural cavity—prevents the lung from fully expanding and participating in gas exchange.  So, when there is air or fluid inside the pleural cavity between the lung and the pleura, it prevents the lung from expanding.  Also, sometimes an elevated diaphragm can contribute to compression atelectasis.  This can occur if something is pushing the diaphragm downward from the abdomen or due to a congenital problem.  In compression atelectasis, the mediastinum will shift to the opposite side. For example, if there is compression atelectasis on the left, the mediastinum will shift to the right. This condition can usually be diagnosed by X-ray or physical examination.  This is the collapsed lung, and the space around it is the pleural space, which can be filled with air or fluid. When it's filled with fluid, it's called a pleural effusion, which can be serous, proteinaceous, or of various other types. This fluid occupies the pleural cavity, causing compression atelectasis. 3.Contraction atelectasis:  Which can be localized or generalized, depending on the cause.  Typically, the cause is post-inflammatory scarring:  When there is inflammation in the interstitial space (between the capillaries or pulmonary vasculature and the alveoli), fibrosis and scarring can occur.  Remember that: The lung is an elastic organ, meaning it can expand and collapse as needed for its function. During inhalation, it expands, and during exhalation, it collapses.  Now, when the elastic tissue of the lung is replaced by fibrous, inelastic tissue, the condition becomes irreversible.  Depending on the cause, if the foreign body is removed, or the fluid around the lung is aspirated, the elasticity may return. However, when the lung tissue is permanently changed to fibrotic tissue, the process is irreversible. 3 4. Microatelectasis:  Which is a minor type of atelectasis that typically occurs due to the loss of a substance called surfactant.  Surfactant:  is a crucial chemical in our bodies responsible for lung expansion after birth.  Surfactant is typically produced by Type 2 pneumocytes; a type of epithelium presents inside the alveoli.  Inside the uterus:  The baby's lungs are collapsed due to the absence of ventilation.  However, after delivery, the baby needs their lungs to expand for respiration, which is achieved by surfactant.  If surfactant is absent, this process will not occur, resulting in Neonatal respiratory distress syndrome.  Microatelectasis is typically generalized and commonly occurs in acute or neonatal respiratory distress syndrome.  Neonatal respiratory distress syndrome is usually caused by surfactant deficiency.  Acute respiratory distress syndrome is associated with various conditions and is usually not related to surfactant deficiency.  No mediastinal shift in Contraction or Microatelectasis.  In the picture:  We have only slit-like spaces, alveoli, with no air.  On the other side is the normal (non-atelectatic) lung. Morphology of Atelectasis:  Grossly:  You will see a shrunken, purple, subcrepidant lung. It could be nodular.  The lung will be smaller inside, and in case of contraction of atelectasis, it will be tough and inelastic.  Under the microscope:  You will see slit-like alveoli that are not expanded like normal.  The septae will appear congested due to dilated vasculature, and there will be fluid in the spaces.  In Microatelectasis, we will see Hyaline membranes.  These membranes are usually related to the pro-inflammatory process that occurs in acute respiratory distress syndrome, and they are composed of surfactant in cases of neonatal distress. 4 Outcome of atelectasis depends on:  The Cause: might be reversible or irreversible, regardless of the type of atelectasis.  For a foreign body, it can be removed.  If the patient has a tumor, surgery is needed.  In cases of compression atelectasis if it's due to air, a tube or surgery will help.  Size of involved area:  If the size is small, it can sometimes be subclinical, meaning the patient will not have any symptoms.  However, if the size is large, the consequences can be fatal, especially in acute conditions.  Duration to start treatment: If the patient develops atelectasis and hypoxia and is treated urgently, the consequences will be much less severe than if the patient were left untreated for a prolonged period of hypoxia.  Note: The Hypoxia can have toxic effects on various organs. Acute Lung Injury Acute(Adult) Respiratory Distress Syndrome:(ARDS)  It is a clinical syndrome caused by many conditions.  Clinical manifestations include:  Sudden and acute onset of severe dyspnea, which means shortness of breath or difficulty breathing.  Hypoxemia and Hypercapnia, which indicate decreased oxygen concentration and increased carbon dioxide levels in the blood.  Diffuse bilateral pulmonary infiltrates are seen on radiology.  All of these criteria are usually required in the absence of left-sided heart failure. If left-sided heart failure is present, these changes are not related to ARDS.  Additionally, all cases of ARDS result in acute respiratory failure.  Therefore, the manifestations of hypoxemia, hypercapnia, severe dyspnea, and infiltrates on the chest X-ray should occur in the absence of left-sided heart failure.  The underlying conditions that could lead to ARDS are variable, and many of them result in endothelial or epithelial injury within the alveoli. This injury is the triggering event for ARDS.  ARDS is considered a severe form of acute lung injury, and the histologic pattern of damage seen in ARDS is called diffuse alveolar damage.  This injury can result from various causes, including systemic diseases, certain tumors, and exposure to certain chemicals.  The process of epithelial and endothelial injury triggers an inflammatory response, leading to the release of pro-inflammatory mediators such as cytokines and interleukins. 5  These mediators magnify the damage, leading to significant destruction of lung tissue and the formation of hyaline membranes.  This cascade of events can result in life-threatening conditions due to the impairment of gas exchange. According the picture:  In normal alveolar environment: We have type 1 cells, type 2 cells, and macrophages.  In acute lung injury:  You will have damage to the epithelium and necrosis of type 1 cells.  This leads to the production of cellular debris due to the necrosis affecting these cells.  The cellular debris triggers an inflammatory response, leading to the release of chemokines, which recruit acute inflammatory cells from the blood into the alveoli.  These cells release more inflammatory mediators, and macrophages begin laying down damaging mediators like leukotrienes, platelet-activating factor, and proteases.  This process increases the damage, resulting in acute lung injury. Aetiology:  We have causes that directly affect the lung or causes that indirectly affect the lung.  The direct causes include:  Pneumonia and aspiration of gastric contents, Toxic inhalation which are common because they trigger an inflammatory response and cause damage to the alveolar epithelium.  Uncommon causes include pulmonary contusion(trauma), fat embolism, near-drowning, inhalational injury, and reperfusion injury after lung transplantation.  The Indirect causes include:  Sepsis and severe trauma (Multiple bone fractures, Head trauma, Severe Burns) with shock. In these cases, there is severe hypotension and a significant amount of inflammatory mediators that can result in the recruitment of inflammatory cells or this inflammatory process into the lung, causing ARDS. (most common)  Other causes include acute pancreatitis, cardiopulmonary bypass, drug overdose, transfusion of blood products, and uremia (uncommon causes).  Sepsis and pneumonia account for 40 to 50 percent of cases of acute respiratory distress syndrome. 6  The Risk factors:  Multiple predisposing medical conditions, especially in cases of severe critical illness, can enhance the possibility of developing ARDS.  Older age.  Chronic alcohol abuse.  Metabolic acidosis.  And many others can cause or can be risk factors for ARDS. Pathogenesis:  As we mentioned, injurious agents can enter through the airways, causing direct lung injury, or through hematogenous spread, such as infectious organisms or toxic materials, all of which can cause injury.  And the pattern is called diffuse alveolar damage(DAD), which affects the vascular endothelium and the alveolar epithelium:  Endothelial injury causes increased permeability, resulting in significant and severe edema.  Epithelial damage causes decreased surfactant production and what is called Microatelectasis.  The injury is caused by imbalance of pro-inflammatory and anti-inflammatory mediators:  We have an inflammatory process that is augmented by multiple factors, leading to a cascade of inflammation and resulting in damage to the lung tissue.  For example, the activation of (Nuclear factor KB), which is pro-inflammatory, causes activated macrophages to release more pro-inflammatory mediators such as interleukin-8, interleukin-1, and tumor necrosis factor.  Some of these mediators act as chemotactic factors, leading to the activation of neutrophils in the microcirculation and their recruitment into the alveoli or lungs.  This process causes a severe release of oxidants, proteases, and other mediators, resulting in tissue damage. This leads to an imbalance between pro-inflammatory and antiinflammatory mediators.  Later on:  After the acute phase, some patients who survive can progress to a late fibrogenic phase.  This phase is characterized by macrophage-derived fibrogenic factors, including (TGF, PDGF, IL-1, TNF) which stimulates fibroblasts and leads to fibrogenesis.  These changes can be counteracted by endogenous antiproteins, antioxidants, and antiinflammatory cytokines. Additionally, in the process of ARDS, there is activation of the coagulation(clotting) cascade, leading to the formation of fibrinogenesis. 7 Phases of ARDS Acute Phase:  Accumulation of protein-rich fluid in the interstitium and alveoli, mostly in dependent areas, leading to diminished gas exchange and atelectasis.  Significant concentration of cytokines in the lung, resulting in neutrophil infiltration.  Presence of plasma protein in air spaces with cellular debris and dysfunctional surfactant, leading to the formation of hyaline membranes.  Vascular injury leading to microthrombi and fibrocellular proliferation, ultimately leading to pulmonary hypertension. Organizing Phase:  If the patient survives the acute phase, they will enter the organizing phase.  Patients may recover rapidly or still experience dyspnea and hypoxemia during this phase.  Histologically:  There will be the organization of alveolar exudates, with macrophages coming to phagocytose all the exudates and necrotic debris.  There will be a lymphocyte-predominant infiltrate in this phase, and proliferation of type 2 pneumocytes to replace the damaged type 1 pneumocytes. Fibrosis Phase:  This phase may or may not occur, depending on the individual's healing process.  Most patients recover lung function within three to four weeks after the acute phase, but some may progress to a fibrotic phase.  Treatment may require long-term mechanical ventilation and/or supplementary oxygen.  Histologically, in this phase:  Extensive fibrosis is observed.  Disrupted architecture leads to an emphysema-like appearance, with areas filled with air and areas that are compressed.  Intimal proliferation of the microcirculation occurs, leading to vascular occlusion and pulmonary hypertension.  The end result is known as Honeycomb lung:  This is a honeycomb lung. It has a fixed dilated bronchus, and it looks like a small emphysema.  This is a fibrotic lung that could not expand or recoil. 8  Clinical features: Manifested as Acute Respiratory Distress Syndrome  Acute severe dyspnea, rapid hypoxemia & cyanosis.  That usually develops within 72 hours of insult in 85% of patients.  Bilateral severe pulmonary edema in the absence of left ventricular failure.  Radiological evidence of bilateral pulmonary infiltrates.  Multisystem failure, secondary infection & DIC. Asthma  Asthma is defined as a chronic inflammatory disorder of the airways that causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough, particularly at night or early in the morning. Why?  This is due to parasympathetic activation, which causes bronchoconstriction, and lower steroid concentrations at those times of the day.  Mainly, it is because of the parasympathetic stimulation; at night, the bronchi are already constricted. (‫)السبب األهم‬  It is characterized by increased responsiveness of the tracheobronchial tree, leading to the abovementioned symptoms.  Asthma is not simply bronchoconstriction but involves chronic inflammation, which has more consequences.  Asthma is usually related to hypersensitivity reactions.  Patients with asthma have hyperresponsive airways or increased airway responsiveness. Triggers such as cold air, pollen, and others can cause hypersensitivity reactions resulting in an asthma attack.  Simply, asthma is a reversible recurrent bronchospasm. Reversible means it can go away either as a chronic disease on its own or with drugs. And recurrent means it can happen multiple times. Manifests as:  Episodic attacks, particularly at night or after exercises.  Widespread narrowing of the airways.  Complete recovery between attacks early in disease.  Occurs predominantly in early life.  Male-to-female ratio of 2:1 in childhood, 1:1 in adults. Clinical Features:  9  Recurrent attacks of severe dyspnea with expiratory wheeze. Lasts from minutes – several hrs.  Relieved spontaneously or by drugs.   Acute nonresponsive attack → Status Asthmaticus. Rarely hypercapnia, acidosis, & severe hypoxia. This clinical picture is caused by:  Repeated immediate hypersensitivity and late-phase reactions in the lung.  Those reactions will give rise to the triad of:  Intermittent and reversible airway obstruction.  Chronic bronchial inflammation with eosinophils.  Bronchial smooth muscle cell hypertrophy and hyperactivity. Types of asthma Type I: Allergic Asthma  The most common, or the most important one.  The majority of the cases, and usually develops early in life.  Atopy is the largest risk factor for the development of asthma:  In patients with atopy, abnormal hypersensitivity reactions occur to triggers that are not harmful to their bodies.  These reactions do not cause the same changes in other populations.  The body recognizes certain materials as harmful and triggers an inflammatory response against them, leading to similar hypersensitivity reactions.  Asthma is associated with a personal or family history of allergic diseases such as allergic rhinitis, eczema, and urticaria.  Patients with allergic asthma often have elevated serum IgE levels. Type II: Non-atopic asthma  Typically develops later in life and is not accompanied by allergies.  Patients with this type of asthma usually have normal IgE levels. (Negative test)  It is often associated with viral or pollutant exposure, which can result in chest pain. Pathogenesis in Atopic Asthma  There is a type 1 hypersensitivity reaction that involves abnormalities in T helper cells, particularly TH2 cells.  Instead of producing cytokines that induce a normal or minimal inflammatory response, these cells release cytokines such as interleukin-4, interleukin-5, and interleukin-10, which activate eosinophils and lead to mucus overproduction.  This type of asthma often has a genetic basis (Genetic predisposition) and involves mast cells and eosinophil activation in response to allergens. 10 Allergens(causes of the allergic process) Tree Grass House dust mite Fungi Pets Occupational Triggers(induce the acute attack) Exercise Fumes/ Smoke Cold air Aspirin Occupational Viral URTIs & Emotional stress Two Phases of asthma Early or Acute phase - (30- 60 minutes):  The allergen will activate the TH-2 cells.  Interleukins stimulate IgE production, and eosinophils activate mast cells.  When the allergen is attached to the IgE on the surface of the mast cell, this will cause degranulation of the mast cell.  And the release of inflammatory mediators and chemotactic factors, such as histamine, leukotrienes, thromboxane, and others, as well as the release of cytokines.  This will cause loosening of epithelial junctions, allowing antigens to enter the subepithelial tissue. This results in stimulation of vagal receptors and bronchoconstriction.  And there will also be the direct effects of the chemical mediators and the recruitment of more eosinophils and mast cells. Protracted late phase: 4-8 hrs. later  The antigen in the submucosa will cause recruitment of more mast cells and eosinophils and also neutrophils.  The mast cells will release chemotactic factors for eosinophils and neutrophils (IL 4 &5, PAF, TNF).  Result : Epithelial damage more mediators Amplification of the inflammation. Pathology:  Edema, congestion, inflammatory cells, ↑↑ eosinophils.  Mucus gland hypertrophy & hyperplasia, with goblet cell metaplasia (chronic change).  Necrosis of surface epithelium.  ↑basement membrane collagen deposition.  Smooth muscle hypertrophy & hyperplasia.  Lumen of bronchi & bronchioles contain: 11  Thick mucus plugs, Charcot Leyden crystals from eosinophil protein and Curshmann’s spirals from epithelial necrosis.  Pathologically, asthma results in remodeling of bronchial tissues and a change in the structure of the respiratory passages. Prognosis:  Mortality rate is small.  May achieve spontaneous permanent remission specially in children.  May remain in a state of exacerbations & remissions. Best wishes Adeem 12