Tuesday, April 22, 2025

Immunotherapy Endocrine toxicity

 


Thyroid disorders

A. Thyrotoxicosis: ddx Grave's ( persistent eye symptoms indicates new onset Grave's), transient thyroiditis( progresses to hypothyroidism)

- if pt very symptomatic, hold IO

-hydrate, atenolol, metoprolol, NSAIDS for neck pain

-check EKG for Afib

-check anti TSH antibodies, anti TPO antibodies, NM thyroid uptake scan

- refer to endocrinology if considering carbimazole

B. Hypothyroidism: may develop de novo or after a phase of hyperthyroidism

-monitor TSH and FT4 every cycle for 6 months, then every other cycles. Monitor TFT for 1 yr after completion of IO. IV contrast can interfere with TFT. 

- G1: TSH elevated persistently > 4.5 times but less than 10 times. Asymptomatic. OK to monitor. Start levothyroxine if symptoms.

-G2: TSH > 10- start levothyroxine.  Start low dose in those with heart disease or elderly. 

-G3/4: severe symptoms, hospitalization. Hold IO. If central hypothyroidism is suspected i.e pituitary dysfunction ( pt will c/o severe fatigue, headache, visual sx, or loss of libido), always give stress dose steroids before starting levothyroxine. Before starting hormone supplementation, check AM cortisol, ACTH (am) , FT4, TSH

-Imaging:pituitary or sellar cut MRI. Specific to evaluate pituitary fossa if hypophysitis is suspected esp if visual sx. Also will rule out pituitary mets as a cause of hypophysitis rather than IO.

Primary Adrenal insufficiency 

  •  low ACTH and low am cortisol suggest pituitary dysfunction. High ACTH and low am cortisol suggests Primary adrenal insufficiency.
  • Always look at the CT to make sure no adrenal mets as the cause of adrenal insufficiency
  • Stress dose steroids, educate patients on importance of stress dose steroids when sicker


Hypopituitarism

Pituitary dysfunction may present as severe fatigue, headache, visual sx, or loss of libido. 

Before starting hormone supplementation, check AM cortisol, ACTH (am) , FT4, TSH. ACTH stim test may be falsely negative 

Always give stress dose steroids before starting levothyroxine if both cortisol and FT4 are low.

-Imaging:pituitary or sellar cut MRI. Specific to evaluate pituitary fossa if hypophysitis is suspected esp if visual sx. Also will rule out pituitary mets as a cause of hypophysitis rather than IO.

Treatment:

  • -saline supplementation
  • -stress dose steroids: over 2 months reduce daily dose to less than 7.5 mg 
  • -antibiotics as indicated
  • -thyroid supplementation after steroids are started
  • -estrogen or testosterone supplementation only if no hx of endocrine dependent ca such as breast cancer or prostate ca.

Diabetes mellitus

IO associated immune diabetes is similar to type 1 DM and should be managed as type 1 DM. At risk for DKA and needs insulin.

Acute onset of polyuria, polydipsia, weight loss, and lethargy are characteristic presenting features of diabetes that should be evaluated without delay. Urine ketones, acid base status, and electrolytes can be evaluated as screening for DKA and the need for inpatient evaluation. Antibodies, insulin, and C-peptide levels should also be sent to support diagnosis, although the initiation of therapy should not be delayed pending results.

G1: asymptomatic, blood glucose less than 160, no DKA: Continue IO.

G2: Moderate symptoms but no DKA.  Consult endocrinology.  Send urgently: Urine ketones, CMP to look for anion gap and acid base status, and electrolytes ( hyperkalemia in DKA and adrenal insufficiency) as screening for DKA and the need for inpatient evaluation. Antibodies, insulin, and C-peptide levels.

G3: glucose > 250 , G4: glucose > 500: moderate to severe symptoms, DKA or other abnormalities in electrolytes

Diabetes insipidus: rare, but has been reported.

Immunotherapy nephritis


 Presenting symptoms related to immune therapy–induced renal toxicities may include urinary frequency, dark cloudy urine; fluid retention (edema) of face, abdomen and extremities; sudden weight gain; abdominal or pelvic pain; nausea or vomiting; high blood pressure; and/or change in mental status, such as drowsiness.

References:

Grade 1 : Creatinine level increase of >0.3 mg/dL; creatinine 1.5 to 2.0 times above baseline.
  • Management: Hold IO, rule out obstruction, UTI, fluid loss, recent IV contrast
  • Monitoring: resume routine monitoring if creatinine has returned to baseline.

Grade 2: Creatinine 2-3 times baseline

Management: 
  • Hold IO temporarily.
  • Consult nephrology.
  • Evaluate for other causes (recent IV contrast, medications, and fluid status). If other etiologies are ruled out, administer 0.5 to 1 mg/kg/day prednisone equivalents.
  • If worsening or no improvement after 1 week, increase to 1 to 2 mg/kg/day prednisone equivalents and permanently discontinue IO
  • If improved to ≤G1, taper steroids over at least 4 weeks.
  • If no recurrence of CRI discuss resumption of ICPi with patient after taking into account the risks and benefits. Resumption of IO can be considered once steroids have been successfully tapered to ≤10 mg/day or discontinued.
Monitoring
  • If improved to grade 1:
    • Taper corticosteroids over at least 4 weeks before resuming treatment with routine creatinine monitoring.
  • If elevations persist >7 days or worsen and no other cause found, treat as grade 3.

G3: Creatinine >3 times baseline or >4.0 mg/dL; hospitalization indicated.
G4: Life-threatening consequences; dialysis indicated; creatinine 6 times above baseline.

Management:
  • Permanently discontinue ICPi if ICPi is directly implicated in kidney toxicity.
  • Consult nephrology.
  • Evaluate for other causes (recent IV contrast, medications, fluid status, and UTI).
  • Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent).
  • If improved to grade 1:
    • Taper corticosteroids over at least 4 weeks.
  • If elevations persist >3 to 5 days or worsen, consider additional immunosuppression (eg, infliximab, azathioprine, cyclophosphamide [monthly], cyclosporine, and mycophenolate).

Routine kidney bx is discouraged. Most common Kidney bx finding is acute interstitial nephritis.

Saturday, April 19, 2025

Transfusion Medicine

 Shelf life of blood products

  • RBC- 42 days with AS1, 4 degrees C
  • Platelets- 5 days at room temp
  • FFP: Plasma: frozen within 8 hr of collection at minus 18 C for 1 yr, once thawed use within 5 days
  • PF24 is plasma frozen within 24 hr ( not 8 hr)
  • Cryoprecipitate: when FFP is thawed at 4 degrees and the supernatant is centrifuged, the precipitate is called cryoppt. Rich is fibrinogen, fibronectin, Factor 8, 13 and VWAg.


Plasma (FFP) versus cryoprecipitate
- plasma contains procoagulant and natural anticoagulant, so use for TTP, DIC, liver failure etc
- cryo was used to correct fibrinogen def, hemophilia and VWD although now specific factors are available
FFP dose 10-30 ml/kg bwt
Cryoppt dose: 10-20 donor units


Blood journal Feb 2025: How I treat fibrinogen disorders
Fibrinogen deficiency states: maintain fibrinogen trough 100 mg/dl and aim for > 150 mg/dl
DOAC can be used if pt develops thrombosis. Fibrinolysis is contraindicated.
In fibrinogen disorders, using cryoprecipitate rather than fibrinogen concentrate ( 50-75 mg/mg bwt) increases risk of thrombosis.

ASH review 2024- Hemolytic

 1. Thalassemia trait does not cause spherocytes on smear

2. High activity low titer antibodies can cause neg Coomb's. Other causes include Ig A type Ab.

3. Folate def presents with elevated homocysteine levels, whereas MMA is elevated in B12 def.

4. Copper deficiency questions-- hx of malabsorption or small bowel surgery/ gastric bypass surgery. Check ceruloplasmin levels

5. Lead poisoning in the vignette- hx of pica, microcytic anemia due to iron def seen in lead poisoning

6. Rasburicase can lead to hemolytic anemia esp due to G6PD --> drug induced hemolytic anemia

Primary CNS lymphoma

 Reference: Annals of Oncology  June 2024 ESMO guidelines Diagnosis  Recommendations • Contrast-enhanced cranial MRI is the recommended imag...