Pathology Final Study Guide PDF

Pathology Final Study Guide Overview of Dioxin and Ethylene Glycol 1.​ Dioxin (TCDD) a.​ Persistent environmental pollutants. TCDD is one the most toxic forms b.​ Sources: i.​ industrial processes (chemical manufacturing), herbicides (agent orange)...

Pathology Final Study Guide Overview of Dioxin and Ethylene Glycol 1.​ Dioxin (TCDD) a.​ Persistent environmental pollutants. TCDD is one the most toxic forms b.​ Sources: i.​ industrial processes (chemical manufacturing), herbicides (agent orange) and combustion c.​ Mechanism of Action: i.​ Binds to AhR to alter gene expression, oxidative stress and immune system dysregulation 2.​ Ethylene Glycol (EG) a.​ Colorless, odorless, sweet-tasting chemical used in antifreeze, coolants and solvents b.​ Sources: i.​ Accidental ingestion, industrial use, and contamination in certain products c.​ Mechanism of Action: i.​ Ethylene Glycol metabolized to glycolic acid and oxalic acid Toxicological Effects on organs ​ Dioxin 1.​ Liver a.​ Effects: induces oxidative stress, inflammation and apoptosis of hepatocytes b.​ Histopathology: Fatty change, and hepatocellular necrosis c.​ Mechanism: Activation of AhR pathway -> upregulation of CYP450s -> Increases ROS and lipid peroxidation 2.​ Lungs a.​ Effects: inhalation causes lung damage, inflammation and fibrosis. Lead to asthma or COPD. b.​ Histopathology: acute pulmonary edema, interstitial lung disease, and alveolar macrophage activation c.​ Mechanism: disrupts immune response in the lungs leading to chronic inflammation and damage lung tissue 3.​ Blood a.​ Effects: alter blood cell production, leading to hematological effects such as anemia, leukopenia and thrombocytopenia b.​ Mechanism: Activation of AhR -> immune suppression 4.​ Brain a.​ Effects: chronic exposure lead to cognitive deficits, neurodevelopmental effects and mood disorders b.​ Mechanism: disruption of dopamine, serotonin -> increases oxidative stress. Long term can impair the blood-brain barrier and induce neurodegeneration  5.​ Reproductive organs a.​ Effects: alter hormone levels and disrupting spermatogenesis and oogenesis b.​ Mechanism: interfere with estrogen and testosterone signaling, leading to altered reproductive organ development and function 6.​ GI a.​ Effects: Chronic exposure induces nausea, vomiting and abdominal pain b.​ Mechanism: disruption of gut motility, alteration in gut microbiota and induction of GI inflammation 7.​ Skin a.​ Effects:Cause Lesions such as Chlorance and pigmentation changes b.​ Mechanism: activation of AhR leads to inflammation and abnormal sebaceous gland function causing chloracne 8.​ Kidney a.​ Effects: causes nephrotoxicity leading to renal failure b.​ Histopathology: tubular necrosis, glomerular damage and interstitial fibrosis c.​ Mechanism: induce oxidative stress and inflammation. ​ Ethylene Glycol 1.​ Liver a.​ Effects: Poisoning leads to severe metabolic acidosis b.​ Histopathology: Fatty liver, centrilobular necrosis and hepatic failure c.​ Mechanism: metabolized glycolic acid is direct damage to hepatocytes and induces metabolic acidosis 2.​ Lungs a.​ Effects: lead to respiratory irritation, pulmonary edema and ARDS b.​ Histopathology: Edematous changes, alveolar damage, and inflammatory cell infiltration c.​ Mechanism: metabolites cause metabolic acidosis which affects the respiratory system by altering ventilation and leading to pulmonary edema 3.​ Blood a.​ Effects: results in metabolic acidosis, hemolysis, and renal failure. Causes anemia and thrombocytopenia b.​ Mechanism: hemolysis due to glycolic acid and oxalic acid causing oxidative damage to red blood cells 4.​ Brain a.​ Effects: acute poisoning affect the CNS causing confusion, seizures and comas b.​ Histopathology: Cerebral edema and necrosis of neurons c.​ Mechanism: glycolic acid and oxalic acid cause CNS depression by disrupting cellular metabolism and causing acidosis 5.​ Reproductive Organs a.​ Effects: not direct toxicity but can cause systemic acidosis b.​ Mechanism: indirect effects on fertility through systemic organ damage  6.​ GI a.​ Effects: acute poisoning lead to nausea, vomiting and abdominal pain due to metabolic acidosis and GI irritation b.​ Mechanism: metabolites cause direct mucosal injury, leads to GI distress and inflammation 7.​ Skin a.​ Effects: exposure can lead to skin irritation and redness due to corrosive properties b.​ Mechanism: is mildly corrosive and cause chemical burns if it comes into direct contact with skin 8.​ Kidney a.​ Effects: leads to AKI and renal failure b.​ Histopathology: renal tubular necrosis, oxalate crystal and renal edema c.​ Mechanism: oxalic acid forms insoluble calcium oxalate crystals that deposit in renal tubules causing mechanical obstruction and tubular damage Mechanisms of Toxicity ​ Dioxin ○​ Primarily exerts toxicity through the activation of the AhR, leading to altered gene expression, oxidative stress, immune suppression and hormonal disruption ​ Ethylene Glycol ○​ Metabolized by the liver into glycolic acid and oxalic acid, both of which are toxic to tissues and organs. The metabolic by products lead to metabolic acidosis, oxidative stress and organ dysfunction Rank of organ Effect (1 most toxic - 8 least toxic) ​ Dioxin 1.​ Liver a.​ Mech: Fatty changes & hepatocellular necrosis b.​ Effects: Inflammation & hepatocyte damage 2.​ Skin a.​ Mech: Increase AhR -> inflammation -> abnormal sebaceous gland b.​ Effects: Lesions (chloracne) & pigmentation changes 3.​ Lungs a.​ Mech: disrupts immune response -> chronic inflammation b.​ Effects: lung damage, inflammation & fibrosis 4.​ Blood a.​ Mech: Increase AhR -> decrease immunity -> affects hematopoiesis b.​ Effects: alters blood production (anemia, leukopenia, & thrombocytopenia) 5.​ Kidney a.​ Mech: Induces oxidative stress b.​ Effects: tubular necrosis, glomerular damage, & Interstitial fibrosis  6.​ Brain a.​ Mech: Disrupts dopamine & serotonin -> increases ROS -> decreases BBB b.​ Effects: cognitive deficits, neurodevelopment, and mood disorders 7.​ GI a.​ Mech: Disrupts gut motility, alters microbiota, and indices GI inflammation b.​ Effects: nausea, vomiting, and abdominal pain 8.​ Repro organ a.​ Mech: Decrease of estrogen & testosterone -> decreases spermatogenesis & oogenesis b.​ Effects: Alters hormone levels & infertility ​ Ethylene Glycol 1.​ Kidney a.​ Mech: Metabolize oxalic acid -> calcium oxalate crystal -> obstruct renal tubules -> tubular damage b.​ Effects: renal tubular necrosis leads to AKI & renal failure 2.​ Brain a.​ Mech: Glycolic acid & oxalic acid -> decrease CNS -> acidosis b.​ Effects: Decrease CNS -> seizures, confusion & coma 3.​ Liver a.​ Mech: Glycolic acid -> direct damage to hepatocytes b.​ Effects: Acidosis -> liver failure 4.​ Blood a.​ Mech: oxidative damage -> hemolysis -> decrease blood production b.​ Effects: anemia 5.​ Lungs a.​ Mech: Glycol acid -> metabolic acidosis -> pulmonary edema b.​ Effects: Irritation, edema & ARDs 6.​ GI a.​ Mech: Increases metabolites -> increase mucosal injury -> GI stress & Inflammation b.​ Effects: nausea, vomiting & abdominal pain 7.​ Skin a.​ Mech: Chemical burn with direct contact b.​ Effects: skin irritation & redness 8.​ Repro organs a.​ Mech: causes systemic acidosis b.​ Effects: Infertility Dioxin: Chemical used in Vietnam war as a herbicide to destroy foliage and crops (AKA TCDD or Agent Orange) Dioxin Ingestion -​ The immune system -​ Disrupts immune cell homeostasis by driving cell proliferation in the bone marrow of damaged white blood cells -​ Causes multiple myeloma: The production of damaged white blood cells, causing plasma cells to grow uncontrollably, leading to an excess of antibodies (M proteins) -​ Clinical signs: bone pain, nausea, constipation, mental fogginess, infections, tried, weakness, weight loss -​ XRAY: Shows formation of osteolytic lesions -​ MOA: activates osteoclasts and suppresses osteoblasts, leading to bone loss -​ Anemia: myeloma crowds the bone marrow leading to reduced and abnormal production of RBCs -​ Symptoms: Fatigue, shortness of breath, malaise -​ Kidney Impacts -​ Direct: When myeloma proteins/antibodies are filtered, causes damage to the tubules -​ Indirect: Myelome causes bone degradation releasing calcium into the bloodstream, excess Ca leads to even further damage of the kidneys by reducing kidneys filtering abilities and building up in the kidney tissues and forming calcium salts (~kidney stones) -​ Lung Impacts: disrupts body’s immune response, leading to chronic inflammation and damage of lung tissues (could lead to fibrosis of the lungs) -​ Clinical Signs: ASthma or COPD -​ First pass effect: TCDD is metabolized in the liver by p450 enzymes (Zone 3) -​ Associated with steatosis (fatty droplet buildup from lipid peroxidation) Dioxin Absorption -​ MOA: activates the AhR receptor in skin cells -​ Leads to the production of mall pale yellow acne-like lesions, cysts, and hyperpigmentation that lasts weeks-years (Chloracne) Dioxin as an EDC -​ Known MOA: Interacts with the AhR receptors -​ Female reproductive system -​ Interferes with the estrogen synthesis pathway -​ Consequences: Ovarian function, irregular menstrual cycles, delayed puberty, early menopause, reduced fertility, increases risk of reproductive cancers  -​ Male Reproductive system -​ Affects spermatogenesis THROUGH generations -​ Most common side effect: Decreased sperm count and prostate diseases -​ Others: Reduced sperm motility, abnormal morphology, and lowered testosterone levels Practice problems Case 1: Hepatic and Renal (9 points) A 40-year-old male presents to the emergency room with jaundice, fatigue, and nausea. He reports being exposed to a large amount of contaminated water during an industrial cleanup 3 weeks ago. Laboratory tests show elevated liver enzymes, and his kidney function is slightly impaired. 1. What is the most likely toxicant involved in this case? (2 points) ​ Answer: Dioxin (due to industrial exposure and hepatic/renal effects) 2. What organs are most affected by dioxin exposure in this case? (2 points) ​ Answer: Liver and Kidneys 3. Describe the mechanisms by which dioxin affects these organs. (4 points) ​ Liver: Dioxin activates the aryl hydrocarbon receptor (AhR), leading to oxidative stress, inflammation, and hepatocyte apoptosis. This causes fatty change and hepatocellular necrosis. ​ Kidneys: Dioxin induces oxidative stress and inflammation, leading to nephrotoxicity and tubular necrosis, contributing to renal failure. 4. What is the potential long-term effect of chronic exposure to dioxin on these organs? (2 points) ​ Answer: Chronic exposure can result in liver cirrhosis and chronic kidney disease, with potential progression to hepatic fibrosis and end-stage renal disease. Case 2: Dermal and Systemic (7 points) A 50-year-old male construction worker has been experiencing chronic skin lesions, including rashes, discoloration, and scaly patches, after working with pesticides and herbicides in his occupation for several months. He also complains of systemic fatigue, weight loss, and low-grade fever. 1. What chemical is most likely causing these symptoms? (2 points)  ​ Answer: Dioxin (commonly found in industrial herbicides and pesticides) 2. What layer of the skin and cell types are most affected by dioxin exposure? (4 points) ​ Answer: ○​ Affected skin layer: Epidermis ○​ Affected cells: Keratinocytes, Langerhans cells, and Basal cells​ Dioxin activates the aryl hydrocarbon receptor (AhR), leading to inflammation, abnormal sebaceous gland function, and skin lesions such as chloracne. 3. What secondary systemic effect can dioxin exposure have on this individual? (1 point) ​ Answer: Chronic exposure to dioxin can lead to immune system suppression and endocrine disruption, causing hormonal imbalances and increasing the risk of cancer. Case 3: Metabolic and Renal (9 points) A 30-year-old woman presents to the hospital with severe abdominal pain, vomiting, confusion, and difficulty breathing after ingesting antifreeze from a household container. Lab results show elevated blood lactate, low bicarbonate, and a markedly elevated anion gap. Urinalysis shows the presence of oxalate crystals. 1. What toxicant is most likely responsible for her symptoms? (2 points) ​ Answer: Ethylene glycol (commonly found in antifreeze) 2. What risk factors contribute to the severity of ethylene glycol toxicity? (2 points) ​ Answer: ○​ Ingestion of a large amount (or repeated ingestion) of ethylene glycol ○​ Delayed treatment (as ethylene glycol is metabolized into toxic metabolites like glycolic acid and oxalic acid) 3. Describe the mechanisms by which ethylene glycol causes the symptoms and organ damage. (4 points) ​ Metabolism of Ethylene Glycol: Ethylene glycol is metabolized by alcohol dehydrogenase into glycolic acid, which leads to metabolic acidosis and lactic acid buildup. Glycolic acid and oxalic acid are also toxic to the kidneys, leading to renal tubular necrosis and formation of calcium oxalate crystals in the kidneys, which causes mechanical obstruction and acute renal failure. ​ Oxalate crystals can precipitate in tissues, including the kidneys, liver, and brain, leading to further organ damage. 4. What pathological findings would you expect to see on kidney histopathology in a patient with severe ethylene glycol poisoning? (1 point) ​ Answer: Renal tubular necrosis with the presence of calcium oxalate crystals in renal tubules. Case 4: Neurotoxicity and Respiratory (9 points) A 45-year-old factory worker presents with dizziness, confusion, and difficulty breathing. He has a history of prolonged exposure to hazardous chemicals used in the manufacturing of various industrial products. His blood gas shows acidosis, and his chest X-ray reveals pulmonary edema. He also presents with muscle weakness and altered reflexes. 1. What chemical is likely responsible for these symptoms? (2 points) ​ Answer: Ethylene glycol (due to its neurotoxic and respiratory effects) 2. What organs are most affected by ethylene glycol toxicity in this case? (2 points) ​ Answer: Central nervous system (CNS) and Lungs 3. Describe the mechanisms by which ethylene glycol causes neurotoxicity and respiratory failure. (4 points) ​ Neurotoxicity: Ethylene glycol metabolites, especially glycolic acid and oxalic acid, disrupt cellular metabolism in the CNS, leading to cerebral edema and neurological dysfunction such as confusion, seizures, and coma. ​ Respiratory effects: The metabolites also cause metabolic acidosis, leading to respiratory compensation via rapid, deep breathing (Kussmaul respirations), and can cause pulmonary edema due to the acid-base disturbance. 4. What clinical findings on a blood smear would help confirm ethylene glycol toxicity? (1 point) ​ Answer: Hemolysis, seen as schistocytes (fragmented red blood cells) and reticulocytes (immature red blood cells), indicating hemolytic anemia caused by oxidative damage to red blood cells. Practice Problem 1 A 25-year-old woman presents to the ER with confusion, deep rapid breathing (Kussmaul respirations), and fruity-smelling breath. Her medical history includes type 1 diabetes mellitus. Blood Gas:  ​ pH: 7.29 (7.35-7.45) ​ pCO2: 22 mmHg (35-45) ​ HCO3-: 12 mEq/L (22-26) Blood Chemistry: ​ Na+: 140 mEq/L ​ K+: 5.5 mEq/L (3.5-5.0) ​ Cl-: 110 mEq/L (98-106) 1.​ Acidosis or Alkalosis? ○​ Acidosis (pH < 7.35) 2.​ What diagnosis does the anion gap indicate? ○​ Anion gap calculation: Anion Gap=(Na+)−(Cl−+HCO3−)\text{Anion Gap} = (\text{Na}^+) - (\text{Cl}^- + \text{HCO}_3^-)Anion Gap=(Na+)−(Cl−+HCO3−​) Anion Gap=140−(110+12)=140−122=18 mEq/L(normal: 8-12 mEq/L)\text{Anion Gap} = 140 - (110 + 12) = 140 - 122 = 18 \, \text{mEq/L} \quad (\text{normal: 8-12 mEq/L})Anion Gap=140−(110+12)=140−122=18mEq/L(normal: 8-12 mEq/L) ​ Elevated anion gap indicates metabolic acidosis, commonly due to diabetic ketoacidosis (DKA). 3.​ Calculate the excess anion gap and provide a diagnosis. ○​ Excess anion gap: The normal anion gap is 12, and the current gap is 18. The excess gap is: Excess Anion Gap=18−12=6\text{Excess Anion Gap} = 18 - 12 = 6Excess Anion Gap=18−12=6 ​ Diagnosis: Diabetic ketoacidosis (DKA). 4.​ What is the final diagnosis for this condition considering all parts? ○​ Final diagnosis: Diabetic ketoacidosis (DKA) due to the elevated anion gap, low pH, low bicarbonate, and associated clinical findings (fruity breath, Kussmaul respirations). Practice Problem 2 A 50-year-old man with a history of chronic kidney disease presents with shortness of breath, confusion, and nausea. Blood Gas: ​ pH: 7.24 (7.35-7.45) ​ pCO2: 30 mmHg (35-45) ​ HCO3-: 12 mEq/L (22-26) Blood Chemistry: ​ Na+: 135 mEq/L  ​ K+: 6.2 mEq/L (3.5-5.0) ​ Cl-: 106 mEq/L (98-106) 1.​ Acidosis or Alkalosis? ○​ Acidosis (pH < 7.35) 2.​ What diagnosis does the anion gap indicate? ○​ Anion gap calculation: Anion Gap=135−(106+12)=135−118=17 mEq/L\text{Anion Gap} = 135 - (106 + 12) = 135 - 118 = 17 \, \text{mEq/L}Anion Gap=135−(106+12)=135−118=17mEq/L ​ Elevated anion gap suggests metabolic acidosis. Chronic kidney disease (CKD) is a common cause of metabolic acidosis. 3.​ Calculate the excess anion gap and provide a diagnosis. ○​ Excess anion gap: Excess Anion Gap=17−12=5\text{Excess Anion Gap} = 17 - 12 = 5Excess Anion Gap=17−12=5 ​ Diagnosis: Chronic kidney disease with metabolic acidosis due to impaired renal function. 4.​ What is the final diagnosis for this condition considering all parts? ○​ Final diagnosis: Chronic kidney disease with metabolic acidosis. Practice Problem 3 A 16-year-old boy presents with dizziness, lethargy, and a recent history of binge drinking. Blood Gas: ​ pH: 7.48 (7.35-7.45) ​ pCO2: 45 mmHg (35-45) ​ HCO3-: 30 mEq/L (22-26) Blood Chemistry: ​ Na+: 145 mEq/L ​ K+: 3.5 mEq/L (3.5-5.0) ​ Cl-: 98 mEq/L (98-106) 1.​ Acidosis or Alkalosis? ○​ Alkalosis (pH > 7.45) 2.​ What diagnosis does the anion gap indicate? ○​ Anion gap calculation: Anion Gap=145−(98+30)=145−128=17 mEq/L\text{Anion Gap} = 145 - (98 + 30) = 145 - 128 = 17 \, \text{mEq/L}Anion Gap=145−(98+30)=145−128=17mEq/L ​ Normal anion gap is within the reference range (8-12), indicating that the alkalosis is likely not associated with an anion gap. 3.​ Calculate the excess anion gap and provide a diagnosis.  ○​ Excess anion gap: There is no excess anion gap, and the likely cause of the alkalosis is respiratory alkalosis due to hyperventilation from anxiety or alcohol intoxication. 4.​ What is the final diagnosis for this condition considering all parts? ○​ Final diagnosis: Respiratory alkalosis due to alcohol intoxication or hyperventilation. Practice Problem 4 A 65-year-old man with a history of myocardial infarction two weeks ago presents with chest pain, confusion, and shortness of breath. Blood Gas: ​ pH: 7.30 (7.35-7.45) ​ pCO2: 50 mmHg (35-45) ​ HCO3-: 18 mEq/L (22-26) Blood Chemistry: ​ Na+: 135 mEq/L ​ K+: 4.0 mEq/L (3.5-5.0) ​ Cl-: 104 mEq/L (98-106) 1.​ Acidosis or Alkalosis? ○​ Acidosis (pH < 7.35) 2.​ What diagnosis does the anion gap indicate? ○​ Anion gap calculation: Anion Gap=135−(104+18)=135−122=13 mEq/L\text{Anion Gap} = 135 - (104 + 18) = 135 - 122 = 13 \, \text{mEq/L}Anion Gap=135−(104+18)=135−122=13mEq/L ​ Normal anion gap, indicating respiratory acidosis. 3.​ Calculate the excess anion gap and provide a diagnosis. ○​ Excess anion gap: No excess anion gap. The diagnosis is respiratory acidosis due to hypoventilation, which may be related to myocardial infarction complications like heart failure. 4.​ What is the final diagnosis for this condition considering all parts? ○​ Final diagnosis: Respiratory acidosis likely due to heart failure after myocardial infarction. Practice Problem 5 A 3-year-old child is brought to the clinic with a history of fever, lethargy, and irritability after ingesting a cleaning product containing methanol. Blood Gas: ​ pH: 7.15 (7.35-7.45) ​ pCO2: 30 mmHg (35-45) ​ HCO3-: 10 mEq/L (22-26) Blood Chemistry: ​ Na+: 130 mEq/L ​ K+: 5.1 mEq/L (3.5-5.0) ​ Cl-: 105 mEq/L (98-106) 1.​ Acidosis or Alkalosis? ○​ Acidosis (pH < 7.35) 2.​ What diagnosis does the anion gap indicate? ○​ Anion gap calculation: Anion Gap=130−(105+10)=130−115=15 mEq/L\text{Anion Gap} = 130 - (105 + 10) = 130 - 115 = 15 \, \text{mEq/L}Anion Gap=130−(105+10)=130−115=15mEq/L ​ Elevated anion gap indicates metabolic acidosis. 3.​ Calculate the excess anion gap and provide a diagnosis. ○​ Excess anion gap: Excess Anion Gap=15−12=3\text{Excess Anion Gap} = 15 - 12 = 3Excess Anion Gap=15−12=3 ​ Diagnosis: Methanol poisoning, which can cause metabolic acidosis with an elevated anion gap. 4.​ What is the final diagnosis for this condition considering all parts? ○​ Final diagnosis: Methanol poisoning with metabolic acidosis.