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Hemolysis - Differential Diagnosis Framework 1) Environment - Fragmentation - MAHA: TTP, HUS, DIC, HELLP - Grafts, Valves, AS - HTN/Pre-eclampsia 2) External (RBC Membrane): - Autoimmune: Warm AIHA, Cold AIHA, Transfusion reactions, Drug-associated, PCH, Evans Syndrome - Non-immune: Membrane Defects, Drugs, Liver Disease, PNH 3) Internal (RBC) - Infections/toxins: Malaria, Babesiosis, Bartonella, Clostridium, Snakes, Spiders - Enzyme Defects: G6PD, Pyruvate kinase - Hemoglobin Defects: Sickle cell anemia, Thalassemias, Unstable Hgb - Electrolytes: Wilson's disease, Hypophostphatemia Laboratory Tests: - Haptoglobin ↓ - Lactate Dehydrogenase ↑ - Peripheral Blood Smear ↑ abnormal RBCs - Reticulocyte Count ↑ - Unconjugated Bilirubin ↑ - AST ↑ - Urinalysis ↑ Urobilinogen #Hemolysis #Differential #Diagnosis #hematology

Hodgkin's Lymphoma Overview Hodgkin's lymphoma (HL) is an uncommon hematological malignancy arising from mature B cells. It is characterized by the presence of Hodgkin's cells and Reed-Sternberg cells. Hodgkin Lymphoma Epidemiology: • Lymphoma is divided into Hodgkin's and Non-Hodgkin's • Hodgkin's lymphoma accounts for 10% of all lymphomas • Annual incidence of about three cases per 100,000 persons • It has a bimodal age distribution curve - most adolescent Hodgkin Lymphoma Risk Factors: • History of EBV infection • Family history • Young adults from higher socio-economic status • Immunosuppression • Autoimmune disorders Hodgkin Lymphoma - Clinical Presentation: • Lymphadenopathy - painless, firm cervical or supraclavicular node • Anterior mediastinal mass/adenopathy • Cough • Dyspnea • Fever • Night sweats • Weight loss • Anemia • Pruritis • Erythema nodosum • Immune hemolytic anemia • Pain in LN on alcohol ingestion • B symptoms in 1/3 of patients Classical Hodgkin Lymphoma (90-95% of cases) Classification: • The tumor cells in this group are derived from germinal center B cells, but typically fail to express many of the genes and gene products that define normal germinal center B cells. • Classical HL is further divided into the following subtypes: - Nodular sclerosis classical HL (NSHL) - (most common) - Mixed cellularity classical HL (MCHL) - Lymphocyte rich classical HL (LRHL) - Lymphocyte depleted classical HL (LDHL) - Nodular lymphocyte predominant HL - The tumor cells in this subtype retain the immunophenotypic features of germinal center B cells Hodgkin Lymphoma Workup: • Full Blood Count - Low Hb and platelets - WBC may be high or low • ESR (Inflammatory marker elevated) • Increased Serum Ferritin • Increased Serum Copper • Chest X-ray (Mediastinal mass) • CT scan - to check for other organ involvement • PET scan - activity • Excisional lymph node biopsy (diagnostic for HL and its variants) - LN biopsy shows Reed-Sternberg cells and inflammatory infiltrate • Immunohistochemical studies (to differentiate HL from other lymphomas, classical HL is characteristically CD30 positive and usually CD15 positive) • Staging laparotomies aren’t done anymore • Routine bone marrow biopsy - if blood abnormalities are present Hodgkin Lymphoma Staging: • Based on number of sites of disease and presence of extranodal involvement • Staging through Ann Arbor criteria • Involves physical exam, CT scans and can also involve PET scans Hodgkin Lymphoma Treatment • Early Stage (Favorable): - ABVD x 4-6 cycles without XR - ABVD x 2 cycles + XR • Early Stage (Unfavorable): - ABVD x 4 cycles + Localized XRT - ABVD x 6 cycles • Advanced Stage: - ABVD - Stanford V - Escalated BEACOPP #Hodgkins #lymphoma #diagnosis #classification #hematology #oncology #management

Hyperthyroidism Overview Clinical Manifestation of Hyperthyroidism: • Fatigue • Weight loss • Heat intolerance • Depression, nervousness • Irritability, anxiety or agitation • Menstrual irregularities • Weakness or tremors • Palpitations • Exertional dyspnea • Hyperdefecation • Anterior neck pain • Insomnia Primary Hyperthyroidism: • Toxic multinodular goiter (Hot nodule) • Toxic uninodular goiter • Toxic diffuse goiter (Graves' disease) • Thyrotoxicosis associated with thyroiditis Secondary Hyperthyroidism: • Factitious thyrotoxicosis • T3 Toxicosis • Iodine loads • Metastatic Follicular CA • Malignancies with circulating thyroid stimulators • TSH-producing pituitary tumors • Struma Ovarii with hyperthyroidism Diagnosis: • ↓ Low TSH • ↑ Total T3 • ↑ Free T4 • Thyroid stimulating immunoglobulin (TSI) or Thyrotropin (TSH) receptor antibodies (TRAb) if Graves' disease is suspected • Thyroid scintigraphy with radioactive iodine uptake • Thyroid US: Vascularity, Nodules, Size Thyroid Storm: • Life threatening: - Tachycardia. Cardiac arrhythmia - Fever (Hyperpyrexia) - Perspiration - Diarrhea - Anxiety, agitation, psychosis - CHF - Hypotension • Labs: - ↓ TSH, ↑ FT4 and/or ↑ T3 - Mild hypercalcemia, Hyperglycemia - ↑ AST/ALT • Treatment: - Beta blocker - Thionamide - Iodine solution - Iodinated radiocontrast agent - Glucocorticoids: Reduce T4 -> T3 - Bile acid sequestrants Hyperthyroidism Physical Examination: • Moist palms • Thickening of skin: pretibial • Bulging eyes (lid retraction or proptosis), unblinking stare • Tremor • Eye irritation, peri orbital edema, diplopia, change in visual acuity • Hyperreflexia • Tachycardia • Tachypnea • Goiter (+/- bruit) • Thyroid thrill • Ophthalmoplegia • Atrial fibrillation/flutter • Abdominal tenderness Treatment: • Beta blockers • Thioamides (Methimazole and PTU) • Radioactive iodine therapy • Thyroidectomy #hyperthyroidism #causes #diagnosis #differential #endocrinology #signs #symptoms #thyroid

Hyperkalemia - Differential Diagnosis Framework PseudoHyperkalemia: • Lab error • Traumatic venipuncture • Hemolysis, thrombocytosis, leukocytosis • Clenching of fist during phlebotomy High Suspicion for Hyperkalemia: • CKD • Poorly controlled DM • Chemotherapy • Burns • Trauma/Crush injury • Blood transfusion • HTN and edema • Jaundice/Hemolytic reactions Common Drugs Causing Hyperkalemia: • Digoxin • K sparing diuretics • NSAIDs • ACE Inhibitors • Recent IV potassium • Beta blockers • Antibiotics: amoxicillin • Heparins • Tacrolimus • TMP-SMZ • Penicillin G Intracellular Shift: • K release due to cell lysis: - Hemolysis - Transfusion reaction - Tumor lysis syndrome - Rhabdomyolysis, burns, trauma - Ischemic colonic necrosis • K release with intact cell membrane - Beta adrenergic receptor blockers - Succinylcholine - Hyperosmolar states (Uncontrolled diabetes, glucose infusions) - Metabolic acidosis - Hyperkalemia Periodic paralysis - Insulin deficiency or resistance Impaired Renal Excretion: • Addison’s disease/Hypoaldosteronism • Acquired hyporeninemic hypoaldosteronism • Mineralocorticoid deficiency • Renal insufficiency/Failure • SLE • Type IV RTA • Renal hypoperfusion Increased K Intake: 1. Medications 2. K supplement 3. Blood transfusion 4. TPN 5. Food - Avoid in CRF: • Dried fruits, Seaweed, Nuts, molasses, Avocados, Lima beans • Vegetables: spinach, potatoes, tomatoes, broccoli, carrots • Fruits: kiwis, mangoes, oranges, bananas, cantaloupe Updated Version Here: https://www.grepmed.com/images/12834 #hyperkalemia #differential #diagnosis #causes #potassium #high #nephrology

Causes of Lactate Elevation, Lactic Acidosis - Differential Diagnosis The most common causes of hyperlactatemia are usually: - hypoxemia - tissue hypoperfusion - toxic-induced impairment of cellular metabolism, - regional ischemia or the mechanism is unknown - Many other causes are listed as Type A and B categories Lactate levels depend on: - ongoing production - removal from the blood by excretion (e.g., urine, sweat) - its metabolism (e.g., uptake by cells as a direct source of energy, conversion to glucose by the liver) Why do we emphasize this parameter? The use of lactate as a clinical prognostic tool was suggested in 1964 by Broder and Weil - they observed that a lactate excess of > 4 mmol/L was associated with poor outcomes in patients with undifferentiated shock. ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3975915/ ) Therefore, time and time again we might see an urgency to bolus these values as we somehow equate that an elevated lactate means the patient is in impending shock. What we should be teaching is that elevated lactate is encountered in a multitude of clinical presentations and disease states one of which is the critically ill patient with shock/hypoxemia/Sepsis etc. Persistent hyperlactatemia is particularly difficult to interpret. Causes of elevated lactate apart from tissue hypoperfusion have been recognized and should be considered in the appropriate clinical context. One of these is the contribution of liver or renal injury in the production and clearance of Lactate. Both of these organs can ↑ lactate With ↑ Lactate, our response should be to determine the underlying cause. - hypoperfusion/ hypoxemia -> focus on improving perfusion - shock->treatments include fluid administration, vasopressors, or inotropes. - regional ischemia, surgery may be needed to restore circulation If drugs, seizures, malignancy, or thiamine deficiency are the cause: stop, reverse and treat the offending agent. Multiple conditions can contribute to lactic acidosis, therefore carefully: - evaluate the patient’s complete medical history - conduct a thorough physical assessment - assess other laboratory or diagnostic tests before beginning treatment. Join the resistance simply to bolus! Causes of Lactate Elevation Type A Lactic Acidosis: Hypoxic/Failure of Circulatory System • Increased Oxygen Demand: - Heavy exercise - Seizures - Severe asthma - accessory muscle use • Decreased Oxygen Availability: - Reduced tissue perfusion - Cardiac arrest - Shock - Hypovolemia - LV failure - Low cardiac output - Acute pulmonary edema - Mesenteric ischemia (90% sensitivity/98% specific) - Compartment syndrome - Sepsis - Bacterial peritonitis - Acute pancreatitis - Gangrene/Fournier’s • Reduced Arterial Oxygen Content: - Hypoxemia (PaO2 < 30mmHg) - Severe anemia - Carbon monoxide - Methemoglobinemia Type B Lactic Acidosis: Nonhypoxic • Type B1: - Diabetes mellitus/DKA - Liver failure - Neoplasia/Warburg effect - Thiamine deficiency - Renal failure - Hypoglycemia - Alcohol • Type B2: Drugs and Toxins: - Metformin - Salicylates - Ethylene glycol - HIV/HAART medications - Beta agonists - Cocaine - Cyanide - Propofol • Type B3: Hereditary Defects: - Mitochondrial myopathies - Defects in gluconeogenesis Liver Injury: • Reduced clearance of lactate and can act as source of lactate production Renal Failure: • Diminished lactate clearance #Lactate #Lactic #Acidosis #Elevation #Differential #Diagnosis #causes #typea #typeb #classification

Primary Biliary Cirrhosis (PBC) - Summary PBC Epidemiology: • Female:Male 9:1 • Common European descent • Age: 30-65 years PBC Pathophysiology: • T lymphocyte mediated attack on small intralobular bile ducts • Loss of intralobular bile ducts causes cholestasis → Cirrhosis/Liver failure PBC Signs and Symptoms: • 50-60% are asymptomatic • Pruritus • Fatigue PBC Physical Examination: • Skin hyperpigmentation • Jaundice (later manifestation) • Xanthomas • Hepatosplenomegaly • Spider nevi • Temporal/Proximal limb muscle wasting PBC Labs: • Alkaline phosphatase • Gamma-glutamyltransferase (GGT) • 5-Nucleotidase • ALT & AST normal or slightly elevated • Bilirubin - Normal early on but elevated as disease progresses • +AMA - 95% of patients • +ANA - up to 70% • IgM • Hypercholesterolemia (85%) • Ceruloplasmin • Antithyroid antibodies PBC Diagnosis: • No extrahepatic biliary obstruction • ALP > 1.5 x ULN • AMA titer 1:40 or higher • Liver biopsy - Histo shows nonsuppurative destructive cholangitis and destruction of interlobular bile ducts Differential Diagnosis: • Viral hepatitis, TPN, Intrahepatic cholestasis of pregnancy, Cardiac diseases, Endocrinopathy, Lymphoma and solid organ malignancies, Hepatic amyloidosis, Bacterial, fungal, viral infections, Sarcoidosis, Drug-induced cholestasis, Primary sclerosis group cholangitis, IgG4 related disease, Bile duct obstruction - gallstone or malignancy #Primary #Biliary #Cirrhosis #PBC #cholangitis #diagnosis #workup #hepatology

Cauda Equina Syndrome Overview Cauda Equina Syndrome: • Prevalence: 1:33,000-100,000 ppl/yr • Incidence: 1.5-3.4 million ppl/yr • Urgent condition due to severe compression of nerve roots of lumbar spine • MCC- acute lumbar disc herniation • Involves lumbar spine L1-L5 Symptoms - Cauda equina syndrome (CES) is usually characterized by these so-called ‘red flag’ symptoms: • Severe low back pain (LBP) • Sciatica: often bilateral but sometimes absent, especially at L5/S1 with an inferior sequestration • Saddle and/or genital sensory disturbance • Bladder, bowel and sexual dysfunction SPINE Mnemonic: • S - Saddle anesthesia • P - Pain • I - Incontinence • N - Numbness • E - Emergency Causes of Cauda Equina Syndrome: • large lower lumbar disc herniation, prolapse or sequestration • epidural hematoma • infections • primary and metastatic neoplasms • trauma • post surgical • prolapse after manipulation • after chemonucleolysis • after spinal anaesthesia • ankylosing spondylitis • gunshot wounds • constipation Differential Diagnosis: • Spinal cord infarct • HIV related myelopathy • Transverse myelitis • Multiple sclerosis • Syringomyelia • Spinal AVM • Multilevel lumbar stenosis • Vascular intermittent Claudia toon • Spinal infection/abscess • Ankylosing spondylitis • Tethered cord • Guillain-Barre syndrome • Neurosarcoidosis • Multiple sclerosis • Diastematomyelia Physical Exam: • Inspection - lower extremity muscle atrophy • Palpation - lower back pain/tenderness is not a distinguishing feature - palpation of the bladder for urinary retention • Neurovascular Examination - bilateral or unilateral lower extremity weakness and sensory disturbances - decreased or absent lower extremity reflexes - reduced or absent sensation to pinprick in the perianal region (S2-S4 dermatomes), perineum, and posterior thigh - decreased rectal tone or voluntary contracture • Provocative Tests - diminished or absent bulbocavernosus reflex - diminished or absent anal wink test - reflex contraction of the external anal sphincter upon pinprick stimulation of skin around the anus Laboratory studies: • CBC, ESR, CRP • Urodynamic studies (PVR) Imaging studies: • MRI- Sagittal, axial T1 and T2 Treatment: • Surgical decompression #CaudaEquina #Cauda #Equina #syndrome #differential #diagnosis #causes #neurology

Peripheral Edema - Differential Diagnosis Framework for Lower Extremity Edema Edema occurs when any of the following conditions exist: (1) Increased capillary hydrostatic pressure (2) Increased plasma volume (3) Decreased plasma oncotic pressure (hypoalbuminemia) (4) Increased capillary permeability (5) Lymphatic obstruction Unilateral Lower Extremity Edema: • DVT • CHF • Cellulitis • Venous insufficiency • Varicose veins • May-Thurner Syndrome • Complex regional pain syndrome type 1 (reflex sympathetic dystrophy) • Compartment syndrome • Lymphedema (Non-pitting) • Neoplasm Bilateral Lower Extremity Edema: • CHF • Cirrhosis • Nephrotic Syndrome • SVC syndrome • DVT: Bilateral • Protein-losing enteropathy • Venous insufficiency • Medications • Preeclampsia • Lipema • Capillary leak syndrome • Lymphedema (Non-pitting) • Pre-tibial Myxedema; (Non-pitting) • Allergic reaction, urticaria, and angioedema Note: • Left leg often swells first, stays slightly more swollen and the edema resolves after the right leg with diuresis • This is due to the compression of the left iliac vein which crosses under the right common iliac artery anteriorly causing compression/stasis. by Dr. Ravi Singh @rav7ks and Dr. Zaven Sargsyan @sargsyanz #Peripheral #Edema #differential #diagnosis #unilateral #Bilateral #Lower #Extremity #PhysicalExam #Pathophysiology

Leg Pain - Differential Diagnosis Framework Bone/Joint Causes of Leg Pain: • Fracture • Arthritis • Gout/pseudogout • Trauma • Osteomyelitis • Patellofemoral pain syndrome • Arthritis • Popliteus tendinitis • Malignancy: Osteosarcoma, Ewing sarcoma • Legg-Calve-Perthes disease • Slipped capital femoral epiphysis • Bursitis • IBD • Psoriasis • Hepatitis • Hematoma Venous Causes of Leg Pain: • DVT • Varicose veins • Superficial thrombophlebitis Skin Causes of Leg Pain: • Infection: Cellulitis, Abscess, Necrotizing fasciitis • Inflammation: Wounds/ulcers, Edema Arterial Causes of Leg Pain: • PAD • Limb ischemia • Aortic/Iliac artery aneurysms Nerve Causes of Leg Pain: • Neuropathy (DM, Vit B12, B6, Cu deficiency etc) • Spinal stenosis/nerve compression • Sciatica • Tarsal tunnel syndrome, peroneal neuropathy • Sural nerve entrapment • Infections causing nerve damage: - Epidural abscess - Herpes zoster - HIV - Lyme disease Muscle Causes of Leg Pain: • Rhabdomyolysis • Compartment syndrome • Myositis/pyomyositis • Cramps (electrolyte imbalance) • Tendinitis • Repetitive strain injury • Iliotibial band syndrome • Shin splints • Hamstring strain • Piriformis syndrome Leg Pain Red Flags: • Trauma • Crush injury • DVT (Risks: Recent surgery, Smoking, Contraceptive pill, Immobilization) • Acute limb ischemia/cyanosis - Cool extremity - Prolonged capillary refill - Poor pulses - Hair loss- feet and legs - Brittle nails - Skin ulcers - Shiny skin • Inflammation/cellulitis/abscess • Compartment syndrome - History of blunt trauma, crush - Rigorous exercise - Excessive training 1) Pain 2) Pallor-bruising 3) Paralysis 4) Paresthesia 5) Pulselessness 6) Poikilothermia • Septic arthritis - Rapid onset - Intense joint pain/swelling - Fever/chills - Inability to move the joint #Leg #pain #differential #diagnosis #lower #extremity #msk #physicalexam

Causes of Arterial and Venous Thrombosis - Differential Diagnosis Framework STRUCTURAL: - PFO: paradoxical emboli - Popliteal artery aneurysm: Causes arterial clot, venous compression and DVT MALIGNANCY: - TMA: TTP - Arterial thrombosis - Migratory superficial thrombophlebitis - Idiopathic deep venous thrombosis and other sites of venous thrombosis - NBTE (marantic endocarditis) - Disseminated intravascular coagulation (DIC) INFLAMMATORY DISEASE: - Behcet disease - Buerger's disease - Hyperhomocysteinemia - Lipoprotein a ↑ - IBD - APLS:PLT ↓ HEMATOLOGIC DISEASE: - Myeloproliferative neoplasms - PNH - HIT - MAHA: TTP, HUS, DIC #Arterial #Venous #Thrombosis #Differential #Diagnosis #clots #hematology