• Diffuse Alveolar Hemorrhage is caused by disruption of the alveolar-capillary basement membrane
  • Diagnosed via progressively more hemorrhage after saline lavage on BAL (see image below!)
  • Chest Xray in DAH is non-specific, there can be new patchy/diffuse opacities
  • 33% DON’T have hemoptysis
  • Classically, DAH presents as acute onset cough, dyspnea, and hemoptysis
  • Causes
    • 1)  Vasculitis (MPA, GPA, Churg-Strauss)
    • 2) Pulmonary Renal Syndromes: Goodpastures, IgA Nephropathy
    • 3) Autoimmune: SLE, APLS
    • 4) Meds:  Amiodarone, cocaine, nitrofurantoin, anticoagulants
• Nephritic Syndromes: Rapidly progressive GN occurs among the nephritic syndromes (not nephrotic syndromes). The nephritic syndromes can be divided per the image below.
  • c-anca more associated with Wegener, mpa and churg strauss more associated with p-anca, but significant overlap
  • Wegeners a/w sinusitis and Churg-strauss associated with eosinophilia and asthma
  • Pauci-Immune GN is called that because there are no immune deposits seen on immunofluoroscopy
  • 

• Check out this excellent AAFP review of Hemolytic Anemia!
• Hemolytic anemias can be framed as Congenital and Acquired
  • Congenital: Sickle Cell, Thalassemia, G6PD, Spherocytosis
  • Acquired: PNH, MAHA, Infections, Immune.  Further categorization of Immune HA:
    • Autoimmune: Warm (ie SLE) or Cold (ie Mycoplasma)
    • Alloimmune (ABO incompatibility)
    • Drug-Induced: Many drugs but classically 3/4th general cephalosporins
• Hemolysis labs include Reticulocyte Count, Indirect bilirubin levels, Haptoglobin, LDH, hemoglobinurea, hemosiderinuria (elevated Hb on urine dipstick is an indicator of intravascular rather than extravascular hemolysis)
•  PNH median age of onset is 30, life expectancy prior to Eculuzimab (see below) was about 10-15 years after diagnosis although this new drug may prolong life expectancy but it’s too early to know
• Acute hemolytic events can occur after stress, infections, alcohol use
• PNH is associated with venous and/or arterial thrombosis (venous more common) likely due to the hypercoagulable state from free hemoglobin in the bloodstream. The thrombi form in unusual areas – cerebral veins and abdominal veins.
• Other clinical findings associated with PNH are cytopenias, smooth muscle dystonias (due to lack of NO, erectile dysfunction/dysphagia/abdominal pain)
• Nocturnal hemolysis is thought to be due to intestinal absorption of LPS, a complement activator, at night
• The pathophysiology of PNH is an acquired mutation causing lack of formation of phosphatidyllinositol (PGI) anchor on RBCS which present the CD59 and CD55 epitopes. Flow cytometry in PNH shows a lack of CD59 and CD55 cells. The lack of these markers causes the cells to be vulnerable to complement mediated lysis.
• Eculuzimab blocks complement C5 thereby blocking destruction of RBCs. Patients on this medication are at risk for infections due to encapsulated organisms (ie Strep Pneumo, Neisseria meningitidis, Haemophilus influenza etc). Note this drug is 10,000 bucks a pop (infusion every 2 weeks)!

• The natural history of Chronic Myeloid Leukemia is the chronic phase, accelerated phase, and the blast phase.
  • Chronic Phase: This is generally stable, chronic disease and patients can be asymptomatic. Often they are picked up on routine blood count showing leukocytosis. There is a 6% 5 year risk of progressing to blast phase when they are treated with Imatinib.
  • Accelerated Phase: This is when blasts are detected but they haven’t reached a high level of > 20%.
  • Blast Phase: This is conversion of CML to acute leukemia with > 20% blasts on peripheral smear or bone marrow. About 70% present with AML blast crisis and roughly 30% with ALL blast crisis. Treatment depends on whether flow cytometry/analysis shows AML or ALL.
• Imatinib (Gleevec) is a first generation tyrosine kinase inhibitor. It is used for patients with chronic CML to help prevent progression to blast phase. Side effects include pulmonary edema, peripheral edema, muscle cramps, QTC prolongation, arrhythmias, among others.
• Leukostasis which is defined as hyperleukocytosis (>50K WBC) with symptoms including CNS, respiratory, and cardiac. There are various thresholds for initiating leukapharesis depending on the type of leukemia, presence of symptoms, and level of WBC elevation. In general, AML is more likely than ALL to cause leukostasis. The acute leukemia’s are more likely to cause leukostasis than the chronic leukemias.
• Leukopharesis can have serious side effects so only used when absolutely necessary.
• Hydroxyurea blocks DNA synthesis and can be use in myeloproliferative disorders and CML. Of note also used in sickle cell disease as it increased Fetal Hemoglobin levels.
• Clinical Pearl: ALL is more likely than AML to present with tumor lysis syndrome.

Teaching Pearls:

• Clinical manifestations include low energy, low libido, erectile dysfunction, hot flashes, etc
• Primary hypogonadism in males
  • Low total testosterone levels and elevated LH and FSH
• Secondary hypogonadism
  • Low total testosterone levels and normal to low LH and FSH levels
• In males, elevated prolactin levels lead to decreased production of LH and FSH
  • Decreased LH leads to decreased testosterone production from Leydig cells
  • Decreased FSH leads to decreased spermatogenesis from seminiferous tubules
• Elevated prolactin levels could result from medication use
  • Dopamine is secreted by the hypothalamus and leads to inhibition of prolactin secretion
  • Antipsychotic medications exert its effect by blocking dopamine receptors on lactotrophs, leading to increased prolactin secretion.
• Work-up:
  • Check TSH, total and free testosterone, FSH and LH, and prolactin level

• Teaching Points:
  • Clinical Manifestations
    • Neurologic
      • Can present with confusion, lethargy, coma, etc
      • Vision abnormalities can be seen
        • Patients can develop yellow vision
    • Cardiac
      • Most dangerous side effects
      • Classically produces an arrhythmia that could range from atrial tachycardia with AV delay, Bradycardia, junctional rhythm, alternating right and left AV nodal delay, ventricular arrhythmia
      • Alternating right and left BBB is one of the more specific arrhythmias for dig toxicity, although it’s not commonly seen.
    • Gastrointestinal
      • Patients often present with nausea/vomiting and abdominal pain
      • Most common side effects of digoxin toxicity
      • Rare complications include acute mesenteric ischemia
  • Elevation of digoxin level does not correlate with clinical manifestations
  • Digoxin toxicity commonly occurs in decompensated heart failure patients undergoing aggressive diuresis
    • Leads to hypokalemia and low magnesium levels, which potentiates digoxin toxicity.
  • Hyperkalemia is a poor prognostic indicator for acute digoxin toxicity
    • Studies have shown that for patients with K >5.5, mortality was significantly higher
    • Patients with K<5, mortality was much less.
  • Primary treatment of patients with acute digoxin toxicity and hyperkalemia is Digoxin-specific antibody fragment (Fab)
    • It is generally recommended that you do not aggressively treat the hyperkalemia with agents such as calcium gluconate, bicarb, insulin/glucose as Fab will cause potassium to be lowered.
    • Giving these agents could actually cause hypokalemia

Teaching Points:

• Clinical Manifestations of Normal Pressure Hydrocephalus
  • Gait Abnormalities
    • One of the first clinical signs of NPH
    • Occurs early on in the disease
    • Typically have “magnetic gait” in which their feet appeared stuck to the ground
    • Wide based gait with externally rotated feet
    • Most likely to respond to large volume lumbar taps
  • Cognitive impairment
    • Patients clinically appear more apathetic, similar to a depressed patient
  • Urinary incontinence
    • Also can occur early on in the disease progression
• Diagnosis
  • Clinical Manifestations as listed above
  • Imaging – MRI Findings
    • Presence of ventriculomegaly in the absence of sulcal enlargement.
    • Non-obstructing hydrocephalus
    • Presence of ventriculomegaly and increased sulcal size suggestive of generalized senile atrophy (hydrocephalus ex vacuo)
  • Lumbar Puncture with normal opening pressure
    • Other etiologies ruled out with CSF studies
  • Spinal Tap Test
    • Perform large volume spinal tap (30-50cc CSF drainage)
    • Have patient ambulate a certain distance, then turn around and ambulate back, before and after spinal tap test
    • Measure changes in mobility, steps, and timing of ambulation, along with MOCA/MMSE
    • If lumbar test shows significant improvement, patient is likely to respond to VP shunting.

Teaching Points:

• Clinical Manifestations
  • Patients present with worsening jaundice, abdominal distension, tender hepatomegaly with nausea and vomiting.
  • Many patients actually stop alcohol intake over the last several weeks due to their pro-inflammatory state of feeling malaise.
  • Amount of alcohol intake is the biggest risk factor to developing alcoholic hepatitis.
  • On average, patients present within their 4-5th decade in life. On average they drink about 100-120g EtOH daily for 10-20 years
    • Each standard EtOH drink – 14 grams
  • Patients may present with AST:ALT ratio >2, which is more specific for alcoholic liver disease.
    • AST can also be elevated in non-liver pathology, including cardiac, renal, rhabdo.
    • AST and ALT would should not be higher than 300-400 if this is solely due to alcohol-related liver disease.
• Diagnosis includes assessing patient’s clinical history, laboratory data, and exclusion of other causes of hepatitis
  • Exclude viral hepatitis and drug-induced
  • Patients can present with leukocytosis with neutrophilic predominance, fevers, and abdominal discomfort
    • Important to exclude infections such as spontaneous bacterial peritonitis.
  • Liver biopsy notable for neutrophilic inflammation of hepatocytes, whereas all other causes of viral hepatitis is due to mononuclear infiltration.
• Treatment
  • Most important intervention includes alcohol cessation.
  • Supportive care as patients can have multiple electrolyte abnormalities
  • Nutritional support with protein 1-1.5g/kg body weight
    • >90% of patients with AH have significant protein-calorie malnutrition
  • Medical Therapy for those with severe AH (DF>32) includes glucocorticoids (Prednisolone) but the evidence is rather weak.
  • Treatment – prednisolone 40mg daily for 4 weeks with a 2-3 week taper.
  • Associated with increased risk of infections and GI bleed.

Teaching Points:

• Calcium oxalate crystals
  • Seen in patients with ethylene glycol toxicity, leading to renal failure
  • Urine microscopy notable for envelope-shaped or dumb bell shaped crystals
• Uric Acid crystals
  • Seen in high uric acid excretion states (tumor lysis syndrome)
  • Urine microscopy notable for rhomboid shaped crystals
• Struvite crystals
  • Seen in urine infections with bacteria that produce basic pH
  • Examples include ureaplasma urealyticum infections
  • Formation of magnesium ammonium phosphate crystals
  • Urine microscopy notable for coffin-shaped crystals
• Cystine crystals
  • Seen in patients with cysteinuria
  • Urine microscopy notable for hexagon-shaped crystals

Teaching Points:

• Wound Botulism is due to a bacterial toxin that disturbs the transmission of acetylcholine to bind to nicotinic/muscarinic receptors.
• Majority of patients get botulism primary from foodborne illnesses, only a small percentage get botulism from wounds.
• Wound botulism can also be commonly seen in patients who use black tar heroin (skin poppers). Injection of material into subcutaneous and/or muscle tissue provides the ideal environment for anaerobic bacteria – Clostridium botulinum.
• Clostridium botulinim can produce 8 different strains of toxin – A – H
• Clinical Manifestations
  • Patients present initially with bulbar symptoms and occasionally ocular abnormalities (diplopia, disconjugate eye movement, pupillary defects)
  • Also present as a symmetric descending paralysis complicated respiratory drive
  • Check history for evidence of skin popping
  • Wound botulism is more likely to cause fever and leukocytosis compared to other forms of botulism.
  • Patients with foodborne botulism typically present first with GI symptoms prior to onset of neurologic abnormalities
• Diagnosis
  • Important to suspect this in a patient with evolving neurologic deficits
  • Important to obtain wound culture for those who perform skin popping.
  • Diagnosis made by injecting mice and observing clinical manifestation. Then you reinject a second mouse with patient’s serum and antitoxin. If second mouse lives, that’s the diagnosis.
• Treatment
  • Supportive care including close airway monitoring (intubation if needed)
  • Botulinum heptavalent antitoxin
  • Monitor clinical status – typically a prolonged course of recovery as new axons grow from neurons to develop new neuromuscular junctions for function.
• Differential Diagnosis
  • Myasthenia Gravis
    • fluctuating weakness worse with repetition/activity
    • Initially involves the bulbar muscles, ptosis
    • Classically associated with thymomas (~80%)
  • Lambert Eaton Syndrome
    • No bulbar involvement. Proximal muscle involvement, ptosis.
    • Improves with repetition
    • Classically associated with small cell lung CA
  • Guillan Barre Syndrome
    • ascending paralysis, sensation intact although patients complain of vague symptoms.
    • Preceding viral URI or GI symptoms
    • Presence of autonomic symptoms such as hyper/hypotension, fluctuating temperatures, urinary incontinence/retention, brady/tachycardia, etc
  • Tick paralysis
    • Very similar presentation to GBS except no autonomic symptoms
    • Often times a tick can be found on the patient’s skin.

Teaching Points

• Symptoms of hypercalcemia include constipation, delayed reflexes, lethargy, confusion
• Etiologies for hypercalcemia (top 2) include:
  • Primary hyperparathyroidism
  • Malignancy
• Hypercalcemia secondary to malignancy can arise by different mechanisms:
  • PTHrP
    • Many of your solid tumors
    • Non-Hodgkin’s lymphoma
  • Bone Disease
    • Breast cancer
    • Multiple myeloma
  • Increased production of active Vitamin D
    • Hodgkin’s lymphoma
• Management of hypercalcemia of malignancy includes the following:
  • IV fluids for immediate effect
    • Many patients with high calcium levels are dehydrated.
    • This is due to hypercalcemia causing nephrogenic DI picture.
  • Calcitonin
    • Works within hours
    • Prone to tachyphylaxis
  • Bisphosphonates
    • Takes up to 48 hours before effect is seen
    • Pamidronate or Zolendronate
    • Caution in use for renal failure
  • Lasix
    • Only used in the setting of symptomatic hypervolemia.
• Diagnosis of Multiple Myeloma includes the following:
  • M-spike
  • Bone marrow biopsy with >10% plasma cells
  • Clinical manifestations based on the CRAB criteria:
    • HyperCalcemia – 25%
    • Renal dysfunction – 50%
    • Anemia – 75%
    • Bone involvement – 50%