Carcinoid syndrome: Mechanism of action

Carcinoid tumors are rare neuroendocrine tumors which originate most often in the bowel, less commonly in the lungs, and rarely in the reproductive tract.

Carcinoid syndrome will occur in a small percentage of patients  (~10%).

Symptoms include:

  • Facial flushing

  • Abdominal cramps and diarrhea

  • Bronchospasm

  • Palpitations
  • Shortness of breath

MECHANISM: Tumor-derived 5-HTP metabolites, such as serotonin, akinins, and prostaglandins entering systemic circulation cause these symptoms.

Carcinoid syndrome is usually seen in patients with lung primaries or liver metastases from bowel primary carcinoid tumour that escape the enterohepatic circulation and enter directly into the systemic blood supply.

Otherwise, if the mediators are released from a primary bowel carcinoid tumour, they are released into portal venous blood supply and are metabolized by the liver.

REFERENCES

  1. The MD Anderson Manual of Medical Oncology, 3e. Chapter 26: Neuroendocrine Tumors. Daniel M. Halperin; James C. Yao

What are Pseudo Pelger-Huet cells?

Psuedo Pelger-Huet cells have the morphological characterization of Neutrophils with hypolobation [hypo-segmented].

It can be a benign inherited defect (1/6000) of terminal Neutrophil differentiation due lamin B receptor gene mutations.

Or it can be seen in different pathological states like Myelodysplastic syndrome or CML, as well as with certain infections and drugs

REFERENCES

  1. Shetty VT, Mundle SD, Raza A. Pseudo pelger-huet anomaly in myelodysplastic syndrome: hyposegmented apoptotic neutrophil? Blood 2001;98:1273–75.
  2. Wang E, Boswell E, Siddiqi I, Lu CM, Sebastian S, Rehder C, et al. Pseudo-pelger-huet anomaly induced by medications: a clinicopathologic study in comparison with myelodysplastic syndrome-related pseudo-pelger-huet anomaly. Am J Clin Pathol 2011;135:291–303. 
  3. Ayan, Mohamed S. et al. “Case of Acquired or Pseudo-Pelger-Huët Anomaly.” Oxford Medical Case Reports 2015.4 (2015): 248–250. PMC. Web. 9 Oct. 2017.

What is Tumour Lysis Syndrome?

Tumour lysis syndrome (TLS) is an oncologic emergency that most often occurs following initiation of cytotoxic therapy, especially in patients with acute lymphoblastic leukemia (ALL). Lysis of tumour cells results in the release of large amounts of potassium, phosphate, and nucleic acids. Nucleic acids are catabolized into uric acid, which leads to hyperuricemia. Excess uric acid excretion can precipitate in the renal tubules and lead to acute kidney injury (AKI) through decreased renal blood blow and inflammation. Excess phosphate can also lead to AKI through calcium phosphate deposition in the renal tubules.

Img Cred: uspharmacist.com

 

Clinical Manifestations

  • Metabolic abnormalities (hyperkalemia, hyperphosphatemia, hpyocalcemia)
  • Nausea + Vomiting
  • Diarrhea
  • Anorexia
  • Lethargy
  • Hematuria
  • Heart failure
  • Cardiac dysrhythmias
  • Seizures
  • Muscle cramps
  • Syncope
  • Death

 

Treatment for TLS relies on risk stratification based on tumour-related factors and patient-related factors.

 

REFERENCES

  1. van den Berg H, Reintsema AM. Renal tubular damage in rasburicase: risks of alkalinisation. Ann Oncol 2004; 15:175.
  2. Hande KR, Garrow GC. Acute tumor lysis syndrome in patients with high-grade non-Hodgkin’s lymphoma. Am J Med 1993; 94:133.
  3. Coiffier B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 2008; 26:2767.

 

MGUS vs. Multiple Myeloma vs. Waldenstrom’s

Monoclonal gammopathy of undetermined significance (MGUS)

  • Asymptomatic premalignant state
  • Common in elderly population (~10% in patients >75 years old)
  • Paraprotein <30g/L (<3g/dL)
  • Plasma cells <10% on bone marrow
  • No CRAB syndromes (see below)
  • No other B-cell proliferation disorder
  • No treatment needed, but must be monitored as 1-1.5% will progress to Multiple Myeloma per year

Multiple Myeloma

  • Neoplastic proliferation of a single plasma cell lineage aka M-protein (Usually of the IgG or IgA type)
  • Incidence is increased after age 50
  • Paraprotein >30g/L (>3g/dL) [serum and/or urine]
  • Plasma cells >10% on bone marrow
  • CRAB SYMPTOMS
  • HyperCalcemia: Due to bone destruction from lytic bone lesions
  • Renal Failure: Immunoglobulin precipitation in renal tubules leads to tubular casts of Bence Jones protein
  • Anemia: Normocytic normochromic. Also leukopenia, thrombocytopenia (look for rouleaux formation on peripheral smear—hyperglobulinemia causes the RBCs to stick together)
  • Bone pain: Due to osteolytic lesions and vertebral fractures 
  • Treated with bisphosphonates, steroids, chemotherapy (If below age 65 consider autologous hematopoietic stem-cell transplantation).

Waldenström’s macroglobulinemia

  • Malignant proliferation of plasmacytoid lymphocytes
  • IgM >50g/L (5 g/dL)
  • Bence Jones proteinuria in 10% of cases
  • Hyperviscosity syndrome (due to paraproteinemia of large sized IgM): visual changes due to retinopathy, headache, vertigo, mucosal bleeding, seizures and coma
  • Other Clinical features: constitutional symptoms, splenomegaly, anemia and lymphadenopathy
  • There is no definitive treatment (chemotherapy and plasmapheresis for hyperviscosity syndrome)

REFERENCES

  1. Lichtman  MA. Chapter 108. Essential monoclonal gammopathy. In: Lichtman  MA, Kipps  TJ, Seligsohn  U, Kaushansky  K, Prchal  JT, eds. Williams Hematology. 8th ed. New York, NY: McGraw-Hill; 2010
  2. Clinical Genomics: Practical Applications in Adult Patient Care. Chapter  37: Multiple Myeloma and Other Plasma Cell Disorders. Esteban Braggio; Rafael Fonsec.
  3. The MD Anderson Manual of Medical Oncology, 3e. Chapter Chapter 11: Multiple Myeloma and Other Plasma Cell Dyscrasias. Hans C. Lee; Krina Patel; Piyanuch Kongtim; Simrit Parmar; Pei Lin; Muzaffar H. Qazilbash; Sheeba Thomas; Elisabet E. Manasanch

pRBCs: Hypotonic solution vs. Ringer Lactate

Do not mix pRBC infusion with hypotonic solution (i.e D5W). Why?

  • The hypotonic solution has a lower osmolarity, will shift into the RBCs, causing swelling and then lysis.

Mixing of pRBC infusion with Ringer Lactate (RL) is not recommended by the AABB. Simultaneous use of 0.9% Normal Saline is the only recommended isotonic solution. Why?

  • This stems from a 1975 study that initially demonstrated formation of clots in vitro when whole blood was mixed with RL (ionized calcium catalyzing the coagulation cascade).
  • Another study has demonstrated this effect, however also showed no clotting depending on the ratio (1:1 vs. 1:2 or 1:5) used. Other studies [3], [4] support this. 

NOTE: A more recent study has found it to be safe. If you have any questions about transfusion practice at your hospital, consult your blood bank medical director.

REFERENCES

  1. S. E. Ryden, H. A. Oberman. Compatibility of Common Intravenous Solutions with CPD Blood. Transfusion. 1975 May-Jun;15(3):250-5.
  2. Cull DL, Lally KP, Murphy KD. Compatibility of packed erythrocytes and Ringer’s lactate solution. Surg Gynecol Obstet. 1991 Jul;173(1):9-12.
  3. Lorenzo M, et al. Can Ringer’s lactate be used safely with blood transfusions? Am J Surg. 1998 Apr;175(4):308-10.
  4. Albert K, et al. Ringer’s lactate is compatible with the rapid infusion of AS-3 preserved packed red blood cells. Can J Anaesth. 2009 May;56(5):352-6. doi: 10.1007/s12630-009-9070-5. Epub 2009 Apr 2
  5. Levac B, et al. Ringer’s lactate is compatible with saline-adenine-glucose-mannitol preserved packed red blood cells for rapid transfusion. Can J Anaesth. 2010 Dec;57(12):1071-7. doi: 10.1007/s12630-010-9396-z. Epub 2010 Oct 5.

Heparin-Induced Thrombocytopenia (HIT): Type 1 vs. Type 2

Type 1: Heparin directly causes platelets to aggregate (non-immune). Occurs within 48hrs after initiating heparin; mild, transient and no treatment needed.

Type 2: Heparin induces auto-immune mediated response (antibodies formed against heparin bound to platelet factor 4 (PF4). Characterized by the  4T score. (If the score is 0-3, HIT is unlikely, <5%)  

NOTE: HIT is generally not marked by bleeding; instead an increased risk of venous thromboembolism!

REFERENCES

  1. Warkentin, T. E. (2003), Heparin-induced thrombocytopenia: pathogenesis and management. British Journal of Haematology, 121: 535–555. doi:10.1046/j.1365-2141.2003.04334.x
  2. Warkentin TE, Heddle NM (March 2003). “Laboratory diagnosis of immune heparin-induced thrombocytopenia”. Curr Hematol Rep. 2 (2): 148–57.
  3. Greinacher, A., Michels, I., Schafer, M., Kiefel, V. & Mueller- Eckhardt, C. (1992) Heparin-associated thrombocytopenia in a patient treated with polysulphated chondroitin sulphate: evidence for immunological crossreactivity between heparin and polysulphated glycosaminoglycan. British Journal of Haematology, 81, 252–254.

Heinz bodies vs. Howell jolly bodies

Heinz bodies Howell jolly bodies
  • Inclusions within red blood cells composed of denatured hemoglobin
  • They are formed as a result of oxidative damage or mutations (i.e G6PD)
  • Macrophages in the spleen remove the denatured hemoglobin giving rise to the classic “bite cells” (see below)

bite-cells-heinzbodies

  • Nuclear (basophilic) inclusions within RBCs
  • Normally: During maturation, after leaving the bone marrow, erythroblasts’ nuclei are expelled within the spleen
  • HOWEVER, in patients without a spleen (asplenia) secondary to (i.e surgery, radiation or sickle cell disease) will retain these remnants (see below)

howell-jolly-bodies

 

 

 

REFERENCES

  1. Hutchison HE, Ferguson-Smith MA. THE SIGNIFICANCE OF HOWELL-JOLLY BODIES IN RED CELL PRECURSORS. Journal of Clinical Pathology. 1959;12(5):451-453.
  2. Mathew H, Dittus C, Malek A, Negroiu A. Howell-Jolly bodies on peripheral smear leading to the diagnosis of congenital hyposplenism in a patient with septic shock. Clinical Case Reports. 2015;3(8):714-717. doi:10.1002/ccr3.323.
  3.  
    Winterbourn CC, Carrell RW. Studies of Hemoglobin Denaturation and Heinz Body Formation in the Unstable Hemoglobins. Journal of Clinical Investigation. 1974;54(3):678-689.
    Webster, Stewart. Heinz Body Phenomenon in Erythrocytes. Blood 1949 4:479-497

Blood test (Iron Studies) results of Iron Deficiency Anemia

A common issue with multiple etiologies, the following test results will help to confirm your clinical suspicion:

  1. ↓ Ferritin (If low, virtually diagnostic, but cannot rule out if low/normal)
  2. ↓ MCV (typically <80fL)
  3. ↓ Hematocrit (Hct) and RBC countƒƒ
  4. ↓ Serum iron (*note this value can vary on a daily basis and with any iron supplementation)
  5. ↓ TSAT (Transferrin saturation)
  6. ↑ TIBC, Transferrin, RDWnormal-rbc-vs-iron-def-anemia
  7. Peripheral blood smear that shows microcytic, hypochromic RBCs [could also have anisocytosis and
    ƒ target cells]
  8. NOTE: There is commonly a mild thrombocytosis associated with Iron deficiency anemia

*Bone marrow iron stores is the gold standard for the diagnosis of Iron deficiency anemia (rarely done)

rbc-iron-def-anemia

REFERENCES

  1. Camaschella C. Iron-deficiency anemia. N Engl J Med. 2015 May;372(19):1832-43.
  2. Lynch EC. Peripheral Blood Smear. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 155.
  3. Short MW, Domagalski JE. Iron deficiency anemia: evaluation and management. Am Fam Physician. 2013 Jan 15;87(2):98-104.

Cryoglobulins vs. Cold Agglutinins

Cold Agglutinins => Autoimmune hemolytic anemia (AIHA) occurring around 28-31°C -> Typically IgM auto antibodies directed against red blood cells, causing clumping (agglutination) of RBCs (i.e Mycoplasma pneumoniae, CMV, EBV, infectious mononucleosis, varicella zoster virus, HIV, lymphoma, CLL, Waldenström’s)

Cryoglobulins =>  Insoluble immunoglobulins (also IgM/IgG) that precipitate out of serum in cold temperatures and re-dissolve upon rewarming (i.e Hepatitis C, Multiple Myeloma, lymphoma, CLL, sarcoidosis, SLE, RA) 

TYPE 1 CRYOGLOBULINS
Monoclonal IgM. Think Myeloma/ Lymphoma. Hypervisocity, Raynauds. Digital ischemia
TYPE 2 CRYOGLOBULINS
Monoclonal IgM, Poly IgG. Think Infections/ Hepatitis C. Fatigue, Mylagia, Purpura 
TYPE 3 CRYOGLOBULINS
Poly IgM, Poly IgG. Think autoimmune (i.e Sjogrens).  
TESTS
ANA, ENA, RF (elevated in 2/3) and C3 and C4 (typically low) 

REFERENCES

  1. CHAPTER 126: Rheumatology in the ICU. Scott Vogelgesang; Vijay Raveendran Pottathil; John A. Robinson. Principles of Critical Care, 4e
  2. Chapter 41. Hematologic Emergencies. MK Strecker-McGraw, MD; Wilson Mark Andrew, MD. CURRENT Diagnosis & Treatment Emergency Medicine, 7e

Sickle Cell Anemia Occlusion: Mechanism

  • Normally, RBCs remain soluble and flexible in the blood when passing through the circulation at varying degrees of oxygen saturationSickle-Cell-Anemia-Occlusion-1Mechanism
  • In Sickle cell anemia: substitution of VALINE for GLUTAMIC ACID in position 6 of the Beta-chain => This substitution results in an alteration of the quaternary structure of the hemoglobin molecule
  • When de-oxygenated, the mutated RBCs will form long polymers & cross linking; thus becoming rigid and insoluble
  • MECHANISM: The loss of the hydrophilic AA for a hydrophobic AA will allow it to interact with hydrophobic AA helices on another B chain and form aggregates
  • These sickled cells form polymers with themselves; they lose flexibility and a collection of rigid sickle cells will cause occlusion in the micro circulation
  • Upon returning to oxygenated tissue, the cells will be able to return to their discoid cell shapes
  • Repeated sickling will cause ion channel dysfunction (loss of Ca2+/K+), cellular dehydration (will be permanently sickled and destroyed in the spleen)

REFERENCES

  1. Deepa Manwani and Paul S. Frenette. Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies. ASH Education Book December 6, 2013 vol. 2013 no. 1 362-369
  2. Chapter 49: Disorders of Hemoglobin Structure: Sickle Cell Anemia and Related Abnormalities. Kavita Natrajan; Abdullah Kutlar. Williams Hematology, 9e
  3. Odièvre M-H, Verger E, Silva-Pinto AC, Elion J. Pathophysiological insights in sickle cell disease. The Indian Journal of Medical Research. 2011;134(4):532-537.