What substances accumulate in acute intermittent porphyria?
Porphobilinogen, δ-ALA, and uroporphyrin (in the urine)
What treatment is available for patients with acute intermittent porphyria?
Glucose or heme, both of which inhibit ALA synthase to decrease buildup of heme precursors
A patient presents with blisters upon exposure to sunlight and you suspect a porphyria; what is the most likely cause?
Porphyria cutanea tarda, the most common porphyria
In porphyria cutanea tarda, there is a defect in the enzyme _____, resulting in an accumulation of _____.
Uroporphyrinogen decarboxylase; uroporphyrin, causing tea-colored urine
What enzyme is affected in patients with X-linked sideroblastic anemia?
δ-ALA synthase, which is responsible for the rate-limiting step of heme synthesis; conversion of glycine and succinyl-Co-A to aminolevulinic acid
What cofactor is necessary for the rate-limiting step in heme synthesis?
Vitamin B6, which is needed to convert glycine and succinyl-Co-A to aminolevulinic acid
Which step in heme synthesis requires iron?
The final step, where protoporphyrin is converted to heme by ferrochelatase
How does heme provide negative feedback for its own synthesis?
Heme inhibits ALA dehydratase, the second step in heme synthesis
What condition should be suspected in a patient who has bluish lines on his gums and thick white lines on long bone epiphyses on x-ray?
Lead poisoning; the blue lines around teeth are Burton;s lines, and the white lines near the epiphysis are lead lines
Name two hematologic manifestations of lead poisoning.
Basophilic stippling on erythrocytes and sideroblastic anemia
Name three neurologic manifestations of lead poisoning.
Encephalopathy, abdominal pain, and wrist and foot drop
What are the main treatments for lead poisoning in adults?
Chelation therapy; dimercaprol or EDTA are first-line treatments
What treatment is indicated in a child who has lead poisoning?
Succimer (remember: it sucks to be a kid who eats lead)
What coagulation test will indicate there is a problem with platelet function?
Bleeding time will be increased; there will be no change in prothrombin time or partial thromboplastin time
A patient has bleeding from the gums, epistaxis, petechiae, and purpura; what is the likely defect in coagulation?
These describe the microhemorrhages associated with a platelet disorder; there may or may not be a decreased number of platelets
Which platelet disorder has an increased bleeding time but normal platelet count?
Glanzmann;s thrombasthenia; all have an increased bleeding time, whereas Bernard-Soulier disease, immune thrombocytopenic purpura, and thrombotic thrombocytopenic purpura have decreased platelet counts
Bernard-Soulier disease causes a defect in the platelet;s interaction with what molecule?
Endothelial collagen; there is a decrease in the molecule glycoprotein Ib for platelet-to-collagen adhesion
Glanzmann;s thrombasthenia causes a defect in what platelet interaction?
Poor platelet-to-platelet aggregation in the platelet plug due to decreased glycoprotein IIb/IIIa
What is the antibody target in immune thrombocytopenic purpura?
Immune thrombocytopenic purpura is caused by antibodies to glycoprotein IIb/IIIa causing platelet destruction
What enzyme is deficient in patients with thrombotic thrombocytopenic purpura?
ADAMTS-13, a metalloproteinase that degrades von Willebrand;s multimers
What is the role that von Willebrand;s multimers play in the development of thrombotic thrombocytopenic purpura?
The large von Willebrand;s multimers cause increased platelet aggregation (bind glycoprotein Ib) and thrombosis
A patient develops renal failure, confusion, thrombocytopenia, fever, and schistocytes on peripheral smear; what is the diagnosis?
This is the classic pentad of thrombotic thrombocytopenic purpura
What coagulation factors are evaluated when you order a prothrombin time test?
Factors I, II, V, VII, and X; the extrinsic pathway
What coagulation factors are evaluated when you order a partial thromboplastin time test?
All coagulation factors except VII and XIII; the intrinsic pathway
Hemophilia A is caused by a deficiency of _____, whereas hemophilia B (Christmas disease) is caused by a deficiency of _____.
Factor VIII; factor IX
What are the prothrombin time and partial thromboplastin time results in a patient with hemophilia (A or B)?
The prothrombin time will be normal and the partial thromboplastin time will be elevated because hemophilia affects the intrinsic pathway
A patient presents to the emergency room with a large swollen joint tapped and found to be full of blood. He has a history of easy bruising. What condition should you consider in your diagnosis?
Spontaneous hemarthrosis, which is a macrohemorrhage seen in hemophilia (compared to petechiae or purpura in platelet disorders)
What are the prothrombin time and partial thromboplastin time changes in a patient with vitamin K deficiency?
Vitamin K deficiency causes both prothrombin time and partial thromboplastin time elevations
What are the platelet count, bleeding time, prothrombin time, and partial thromboplastin time in a patient with von Willebrand;s disease?
There is an elevated bleeding time due to a defect in platelet adhesion; in severe von Willebrand;s deficiency, there is also an increase in partial thromboplastin time due to decreased half-life of factor VIII
Why can you see an elevated partial thromboplastin time in a patient with von Willebrand;s disease?
von Willebrand;s factor carries and protects factor VIII; deficiencies in von Willebrand;s factor can cause intrinsic pathway coagulopathies related to factor VIII deficiency
What is the most common inherited bleeding disorder?
von Willebrand;s disease, an autosomal dominant disease that can have varying severity (typically mild)
What are the platelet count, bleeding time, prothrombin time, and partial thromboplastin time results of a patient in disseminated intravascular coagulation?
Widespread activation of all coagulation pathways results in global depletion: a low platelet count and an increased bleeding time, prothrombin time, and partial thromboplastin time
Name seven causes of disseminated intravascular coagulation.
Gram-negative Sepsis, Trauma, Obstetric complications, acute Pancreatitis, Malignancy, Nephrotic syndrome (loss of ATIII), or Transfusion (remember: STOP Making New Thrombi)
A patient presents with petechiae and gastrointestinal bleeding; initial labs show schistocytes, elevated fibrin split products, and decreased fibrinogen, factor V, and factor VIII. What condition should you be concerned about?
Disseminated intravascular coagulation
What is the pathogenesis of factor V Leiden?
There is a mutation in factor V, rendering it unable to be degraded by protein C, leading to a hypercoaguable state
How would a patient with antithrombin III deficiency react to administration of heparin?
The patient would not have the expected increase in partial thromboplastin time after heparin administration because heparin;s mechanism of action is dependent on AT III
Why does protein C or S deficiency lead to a hypercoaguable state?
There is an inability to inactivate factors V and VIII
What is the risk associated with administering warfarin in the setting of protein C or S deficiency?
Hemorrhagic skin necrosis
What is the difference in tumor location between leukemia and lymphoma?
In leukemia, tumor cells are typically found in the blood and bone marrow, whereas in lymphoma the tumor cells are lymphoid masses (large lymph nodes)
What malignancy is associated with Reed-Sternberg cells (cells with a distinctive bilobed nucleus that looks like owl;s eyes)?
Hodgkin;s lymphoma; these cells are necessary but not sufficient for the diagnosis
What pattern of lymph node involvement is seen in Hodgkin;s lymphoma? How does this differ from non-Hodgkin;s lymphoma?
Hodgkin;s lymphoma tends to be localized (especially mediastinal) and spread to contiguous nodes, whereas non-Hodgkin;s is more likely to be peripheral, with extranodal involvement and noncontiguous spread
A patient has night sweats, fevers, weight loss, and new palpable lymph nodes. Which type of lymphoma is more likely: Hodgkin;s or non-Hodgkin;s?
Hodgkin;s lymphoma; these are B symptoms, more common in Hodgkin;s
Which virus is implicated in Hodgkin;s lymphoma? Non-Hodgkin;s lymphoma?
Epstein-Barr virus is associated with 50% of cases of Hodgkin;s lymphoma; HIV and other immunosuppressed states are risk factors for non-Hodgkin;s lymphoma
What demographic group is most affected by Hodgkin;s lymphoma?
Hodgkin;s lymphoma is more common among men and is bimodal, seen in the young and elderly
What findings on biopsy portend a good prognosis in a patient with Hodgkin;s lymphoma?
A low number of Reed-Sternberg cells and an increased number of lymphocytes
Typically, non-Hodgkin;s lymphoma is a tumor derived from what type of cell?
B lymphocytes, except for the few that have lymphoblastic T-cell origin
What is the CD profile of Reed-Sternberg cells?
CD30+ and CD15+
Lacunar cells are variants of Reed-Sternberg cells that are found in what variant of Hodgkin;s disease?
Nodular sclerosing (65% to 75% of all Hodgkin;s cases)
Histopathology in a 30-year-old female with Hodgkin;s lymphoma shows few Reed-Sternberg cells, many lymphocytes, and collagen banding with lacunar cells; what is the lymphoma type?
Nodular sclerosing, the most common type of Hodgkin;s lymphoma (65% to 75% of all Hodgkin;s cases), seen in young adults, in women more than men
Which two types of Hodgkin;s lymphoma have the most favorable prognosis?
Nodular sclerosing (65% to 75% of all Hodgkin;s cases) and lymphocyte predominant (6% of all Hodgkin;s cases)
Which type of Hodgkin;s lymphoma has an intermediate prognosis and is marked by numerous Reed-Sternberg cells and lymphocytes?
Mixed cellularity (25% of all Hodgkin;s cases)
Which type of Hodgkin;s lymphoma has a poor prognosis and is most often found in older men with disseminated disease?
Lymphocyte depleted (rare)
How does the ratio of Reed-Sternberg cells to lymphocytes correlate with prognosis of Hodgkin;s lymphoma?
The higher the lymphocyte to Reed-Sternberg cell ratio, the better the prognosis
Which variant of non-Hodgkin;s lymphoma is associated with t(14;18)/bcl-2 expression?
Follicular lymphoma (small cleaved cell); bcl-2 inhibits apoptosis in this B-cell lymphoma
What is the prognosis in a patient who has follicular lymphoma?
This has a slow, indolent course, but is difficult to cure so it becomes a chronic disease
Which variant of non-Hodgkin;s lymphoma is associated with t(8;14)/c-myc expression?
Burkitt;s lymphoma, a B-cell lymphoma
What is the gene product of the translocation associated with Burkitt;s lymphoma?
c-myc oncogene moves next to heavy-chain immunoglobulin gene promoter and is thus produced in large quantities
What infectious etiology is associated with Burkitt;s lymphoma?
What is the histological appearance of Burkitt;s lymphoma?
Sheets of lymphocytes interspersed with macrophages (starry-sky appearance)
What lesion is associated with the endemic form of Burkitt;s and where is this lymphoma endemic?
Jaw lesions, Africa; in the United States, pelvic or abdominal lesions are often the presenting complaint
Which form of non-Hodgkin;s lymphoma can be derived from either B or T cells?
Diffuse large-cell lymphoma (80% B-cell, 20% T-cell origin), the most common adult non-Hodgkin;s lymphoma
What translocation is associated with mantle cell lymphoma?
Lymphoma immunohistochemistry reveals a t(11:14) translocation and CD5 positivity; what is the prognosis?
This is mantle cell lymphoma, a type of non-Hodgkin;s lymphoma seen in older males that has poor prognosis
A Japanese patient presents to your office with multiple skin lesions and lab tests reveal HTLV-1 infection; what malignancy should you consider?
Adult T-cell lymphoma, an aggressive neoplasm seen in regions endemic for HTLV-1: Japan, West Africa, and the Caribbean
A patient presents with multiple cutaneous lesions, and a biopsy is consistent with mycosis fungoides; what is the prognosis?
Mycosis fungoides, or Szary syndrome, is a T-cell lymphoma seen in adults that has an indolent course
A 55-year-old male undergoes bone marrow biopsy, which reveals a proliferation of plasma cells that have a fried egg appearance; what is the diagnosis?
This is likely multiple myeloma, a plasma cell neoplasm that is the most common primary bone tumor in patients older than 40-50 years
Compared to Waldenstrom;s macroglobulinemia, multiple myeloma predominantly produces which immunoglobulin?
Myeloma produces immunoglobulin G (55%) or immunoglobulin A (25%), compared to immunoglobulin M produced in Waldenstrom;s macroglobulinemia
A patient presents with lower back pain, and in your work-up you note he has anemia, elevated creatinine, and elevated calcium; what diagnosis should you consider?
Multiple myeloma (think CRAB: hyperCalcemia, Renal insufficiency, Anemia, and Bone/Back pain)
What findings on radiograph should elevate your suspicion for multiple myeloma?
Round punched-out lytic bone lesions
What is the etiology of renal failure in multiple myeloma?
Immunoglobulin light chains excreted in the urine (Bence Jones proteins) are toxic to renal tubules; the elevated proteins also cause primary (AL) amyloidosis
What are two minimally invasive tests that can be used to further corroborate the diagnosis in a patient you suspect has multiple myeloma?
Bence Jones proteins (immunoglobulin light chain) in the urine, and monoclonal immunoglobulin spike on protein electrophoresis; bone marrow is required for definitive diagnosis
A patient has a monoclonal spike on protein electrophoresis; what symptoms and imaging would suggest this is due to Waldenstrom;s macroglobulinemia rather than multiple myeloma?
Waldenstrom;s macroglobulinemia is more likely to have symptoms of hyperviscosity due to immunoglobulin M pentamers and does not have bone lesions, unlike myeloma
Name a characteristic finding of multiple myeloma that can be seen on peripheral blood smear.
Rouleaux formation, in which red blood cells appear to be stacked like poker chips
A 65-year-old man has a monoclonal immunoglobulin spike on serum protein electrophoresis. He is asymptomatic. What is the likely diagnosis?
Monoclonal gammopathy of undetermined significance; the condition may or may not progress to multiple myeloma
A patient with multiple myeloma presents with a fever; what dangerous complication of his disease is he at risk for?
Infection. Multiple myeloma is an immunosuppressed state: the immunoglobulins produced are nonfunctional and neoplastic plasma cells crowd out functional leukocytes
Patients with acute lymphoblastic leukemia are most likely to be in what age range?
Patients with acute lymphoblastic leukemia (ALL) are typically younger than than 15 years of age
A patient has an unregulated proliferation of clonal leukocytes in the bone marrow; what is the effect on circulating red blood cells, white blood cells, and platelets?
The patient has leukemia, which crowds the bone marrow causing decreased red blood cells (anemia), decreased mature white blood cells (and variable numbers of circulating white blood cells), and decreased platelets (bleeding risk)
Patients with chronic myelogenous leukemia are most likely to be in what age range?
Patients with chronic myelogenous leukemia are typically between the ages of 30 and 60 years
Patients with chronic lymphocytic leukemia are most likely to be in what age range?
Patients with chronic lymphocytic leukemia are typically over the age of 60 years
A child presents with a mediastinal mass, and immunohistochemistry reveals a population of cells that are positive for terminal deoxynucleotidyl transferase (TdT) and common acute lymphoblastic leukemia antigen (CALLA); what is the diagnosis?
Acute lymphocytic leukemia/lymphoma; TdT is a marker of prelymphocytes
Bone marrow biopsy of a child with a mediastinal mass and immature white blood cell forms in the peripheral blood reveals an extreme elevation in lymphoblasts; what cell characteristic would portend a better prognosis?
Translocation (12;21) conveys a better prognosis; although acute lymphoblastic leukemia (ALL) is generally responsive to chemotherapy
In which tissues, outside of the blood and lymphatic system, might neoplastic leukocytes be found in a patient with acute lymphoblastic leukemia (ALL)?
ALL often metastasizes to the central nervous system and testes
The peripheral smear of an adult patient has multiple granulated blast forms and you note small, stick-like crystals in the cytoplasm; what is the diagnosis?
This patient has myeloblasts (granulated blasts), and Auer rods (bundles of sticks) consistent with acute myelogenous leukemia
What is the treatment for the M3 type of acute myelogenous leukemia?
All-trans retinoic acid, which causes the myeloblasts to differentiate into mature forms
What diagnosis is confirmed by the presence of the Philadelphia chromosome (t[9;22], bcr-abl)?
Chronic myelogenous leukemia
A patient with massive splenomegaly has a leukocyte count of 100,000 with a differential including elevated neutrophils, metamyelocytes, basophils, and occasional immature myeloid cells; what is the likely diagnosis?
Chronic myelogenous leukemia; all myeloid cell lines are increased in this condition
In the course of chronic myelogenous leukemia, what event causes the beginning of the terminal phase of the illness?
Transformation to either acute myelogenous leukemia or acute lymphoblastic leukemia (ALL), termed a blast crisis; until this phase, chronic myelogenous leukemia typically follows a more indolent course
What lab test can help distinguish between chronic myelogenous leukemia and a leukemoid reaction in a patient with an elevated white blood cell count?
Leukocyte alkaline phosphatase; it will be low in chronic myelogenous leukemia and elevated in a leukemoid reaction (exuberant leukocyte response to infection)
An elderly male presents with fatigue and you note anemia with a positive Coombs test and smudge cells on the peripheral smear; what is the likely diagnosis?
Chronic lymphocytic leukemia (indistinguishable from small lymphocytic lymphoma)
What is the treatment of choice of chronic myelogenous leukemia?
Imatinib, a compound that inhibits the bcr-abl tyrosine kinase
An elderly patient presents with a mature B-cell tumor that has cells on the peripheral smear with filamentous, hairlike projections; what lab study should you obtain to confirm the diagnosis?
Tartrate-resistant acid phosphatase test; the factors suggest hairy cell leukemia, which will stain tartrate-resistant acid phosphatase positive
What are two laboratory tests that would indicate a patient more likely has a leukemoid reaction than leukemia?
Increased white blood cell count with a left shift (approximately 80% bands) and increased levels of leukocyte alkaline phosphatase
What is a complication of treatment of acute promyelocytic leukemia (M3)?
Treatment of acute myelogenous leukemia M3 with all-trans retinoic acidretinoic acid can lead to release of Auer rods, which can lead to disseminated intravascular coagulation
What are Auer rods?
Peroxidase-positive cytoplasmic inclusions found in granulocytes and myeloblasts in patients with acute promyelocytic leukemia
Name the abnormal protein and the chromosomal translocation that are associated with chronic myelogenous leukemia.
bcr-abl; t(9;22), the Philadelphia chromosome (remember: Philadelphia CreaML cheese)
Name the abnormal protein and the chromosomal translocation that are associated with Burkitt;s lymphoma.
Name the abnormal protein and the chromosomal translocation that are associated with follicular lymphomas.
Name the chromosomal translocation associated with promyelocytic leukemia (M3).
Name the chromosomal translocation that is associated with Ewing;s sarcoma.
Name the chromosomal translocation that is associated with mantle cell lymphoma.
From what lineage do the cells that cause histiocytosis X originate?
Histiocytosis X is a proliferation of dendritic cells (Langerhans cells) that are from the monocyte lineage
Immunohistochemistry reveals cells that express S-100 and CD1a surface proteins, and you note tennis racket-shaped objects in cells on electron microscopy; what is the diagnosis?
Histiocytosis X; the tennis racket inclusions are Birbeck granules
Histiocytosis X can commonly present in three disease patterns known by what names?
Letterer-Siwe disease (hepatosplenomegaly and seborrhea), Hand-Schüller-Christian disease (exophthalmos, lytic skull lesions, and diabetes insipidus), or eosinophilic granulomas
What are the relative levels of red blood cells, white blood cells, and platelets in polycythemia vera?
Increase in all three lines
What are the relative levels of red blood cells, white blood cells, and platelets in essential thrombocytosis?
Increase in platelets, no change in red blood cell and white blood cell levels
What are the relative levels of red blood cells, white blood cells, and platelets in myelofibrosis?
Decreased in red blood cells with variable levels of white blood cells and platelets
What are the relative levels of red blood cells, white blood cells, and platelets in chronic myelogenous leukemia?
Decrease in red blood cells, increase in white blood cells and platelets
What myeloproliferative disorders are associated with the JAK2 mutation (involved in hematopoietic signaling)?
Polycythemia vera, essential thrombocytosis, myelofibrosis
What is the basic pathophysiology of polycythemia vera?
An abnormal stem cell clone acquires a JAK2 mutation, which allows it to proliferate independent of growth factors
What is the expected erythropoietin level in a patient with polycythemia vera?
Low; because of the JAK2 mutation, erythrogenic precursor cells divide independently of erythropoietin, and increased red blood cells provide negative feedback to the kidneys