Evaluation of splenomegaly

May show hyponatremia and azotemia.

The underlying cause for the liver disease can be determined by biopsy (Mallory bodies).

Helpful in determining splenomegaly, especially in obese patients.

May be done in patients with evidence of portal hypertension or end-stage liver disease. In clinical practice, the most commonly used parameter to estimate portal pressure is hepatic venous pressure gradient (HVPG; normally <5 mmHg). The HVPG is the difference between the wedged and the free hepatic venous pressures. Measurements are usually obtained via a transjugular approach.

In the presence of cirrhosis and portal hypertension, a biopsy is unlikely to add value or change management.

These include sp100, gp210, and antibodies to the M2 antimitochondrial subtype.[65]Lindor KD, Bowlus CL, Boyer J, et al. Primary biliary cholangitis: 2018 practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018 Nov 6;69(1):394-419. https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.30145 http://www.ncbi.nlm.nih.gov/pubmed/30070375?tool=bestpractice.com

Rarely needed because presence of antimitochondrial antibodies is very specific.

Alkaline phosphatase elevated, although it can be normal in a small percentage of adult patients; mild-to-moderate elevation in serum alanine aminotransferase and/or gamma-glutamyl transferase concentration; normal or elevated bilirubin (conjugated).

Unsaturated iron binding capacity is the inverse of transferrin-iron saturation (TS) and is a one-step automated test. Comparable in diagnostic accuracy with TS.[50]Kowdley KV, Brown KE, Ahn J, et al. ACG clinical guideline: hereditary hemochromatosis. Am J Gastroenterol. 2019 Aug;114(8):1202-18. https://journals.lww.com/ajg/Fulltext/2019/08000/ACG_Clinical_Guideline__Hereditary_Hemochromatosis.11.aspx http://www.ncbi.nlm.nih.gov/pubmed/31335359?tool=bestpractice.com

Rules out ongoing inflammation.

Obviates the need for splenectomy.

Obviates the need for splenectomy. Provides diagnosis less often for lymphomas than for leukemias.

Although rarely necessary to establish diagnosis, splenectomy may be the only way to diagnose isolated splenic involvement.

May be helpful for establishing diagnosis when lymph node biopsy is not diagnostic and bone marrow is involved by lymphoma.

Metabolic derangements should raise suspicion for aggressive diffuse large B-cell or Burkitt lymphoma. These can be seen in T-cell lymphomas as well.

Helpful in circulating lymphomas, such as splenic marginal lymphomas, and cutaneous T-cell lymphoma (Sezary syndrome). Especially helpful when malignant cells are suspended as in pleural effusions.

Although rarely necessary to establish diagnosis, splenectomy may be the only way to diagnose isolated splenic involvement, as seen in primary splenic malignancies.

Confirms monoclonal IgM (kappa or lambda) secretion, required for diagnosis of Waldenström macroglobulinemia.

Monitors complete response to treatment and follows up remission in Waldenström macroglobulinemia.[12]Gertz MA. Waldenström macroglobulinemia: 2023 update on diagnosis, risk stratification, and management. Am J Hematol. 2023 Feb;98(2):348-58. https://pmc.ncbi.nlm.nih.gov/articles/PMC10249724 http://www.ncbi.nlm.nih.gov/pubmed/36588395?tool=bestpractice.com

≥10% clonal lymphoplasmacytic cells in bone marrow confirms diagnosis.[12]Gertz MA. Waldenström macroglobulinemia: 2023 update on diagnosis, risk stratification, and management. Am J Hematol. 2023 Feb;98(2):348-58. https://pmc.ncbi.nlm.nih.gov/articles/PMC10249724 http://www.ncbi.nlm.nih.gov/pubmed/36588395?tool=bestpractice.com

Elevated WBC count is usually accompanied by bone marrow failure, manifested as anemia, neutropenia, and/or thrombocytopenia.

Usually the presence of malignant blast cells on peripheral smear is diagnostic and establishes the need for treatment. [Figure caption and citation for the preceding image starts]: Peripheral blood film of a patient with acute myeloid leukemia showing myeloid blasts with an Auer rodFrom the collection Dr Priyanka Mehta; used with permission [Citation ends].

Coagulation profile derangements should raise suspicion of disseminated intravascular coagulation.

Should be ordered at baseline and monitored throughout treatment.

Complete hematologic response to therapy is measured by normalization of CBC parameters.

Almost all WBCs are myeloid maturing cells. Can be used for subsequent disease monitoring.

All patients require bone marrow biopsy carried out initially, and yearly after diagnosis.

Additional cytogenetic features will categorize patients in an accelerated phase that results in a poorer prognosis.

CBC and differential are used in initial evaluation and follow-up monitoring.

A positive finding requires additional bone marrow biopsy to confirm the diagnosis.

May be useful in patients presenting with bleeding or petechiae.

Confirms the diagnosis.

Monoclonal antibodies determine whether leukemia is lymphoid or myeloid in origin.

Often diagnosis follows incidental detection of an elevated WBC count.

Eventually, anemia and thrombocytopenia may result from either immunologic destruction or marrow overgrowth of the malignant cells.

Usually diagnostic.

Usually diagnostic. Immunophenotyping distinguishes between B-cell and T-cell CLL.

For morphology assessment and immunophenotyping (using immunohistochemistry or flow cytometry).

Flow cytometric immunophenotyping of bone marrow or peripheral blood specimens is diagnostic of hairy cell leukemia.

Reveals characteristic cell morphology. [Figure caption and citation for the preceding image starts]: Peripheral blood smear showing leukoerythroblastic reaction: teardrop red blood cells (black arrows), and myelocyte (red arrow) and promyelocyte (blue arrow)From the collection of Dr Ashkan Emadi and Dr Jerry L. Spivak; used with permission [Citation ends].

Patients with inflammatory or infectious conditions leading to reactive thrombocytosis may have neutrophilic leukocytosis.

Young people, particularly those <40 years, can tolerate elevated platelet counts better than older people, especially those >65 years.

Following splenectomy (a cause of secondary thrombocytosis), a peripheral blood smear may show nuclear fragments (Howell-Jolly bodies) in red blood cells, along with target cells and misshapen red blood cells.

May be difficult to discriminate between essential thrombocytosis and reactive thrombocytosis of inflammatory disorders.

Other tests such as colonoscopy or mammography may establish source of primary tumor.

Red blood cells become spherocytes, which are prone to destruction.

Direct antiglobulin tests reveal the presence of immunoglobulin on the surface of the red cells.

Cold-agglutinin disease is associated with complement on the surface of red cells.

Approximately 30% of RA patients are RF negative.

Positive in 70% to 80% of RA patients. Helpful in RF-negative patients because may be positive in these patients.

The neutropenia may be based on neutrophils being cleared by antibody coating the neutrophil surface and reticuloendothelial cells' Fc receptors interacting with the Fc segment of the immunoglobulins.

Some cases of neutropenia in Felty syndrome are mediated by excessive large granular lymphocytes (LGL) in the spleen or the systemic circulation.

Need to rule out other hematologic causes of neutropenia, including LGL syndrome.

Confirms the diagnosis.

May or may not be necessary if other laboratory tests confirm diagnosis.

Cytopenias can occur; may be exacerbated by marrow filled with noncaseating granulomas and decreased marrow output of leukocytes, red blood cells, and platelets.

If there is any cardiac involvement.

Characteristic noncaseating granulomas are found mostly in the lungs and nodes.

Characteristic noncaseating granulomas are found mostly in the lungs and nodes.

Giemsa-stained thick and thin blood smears can be used to identify malaria parasites.[37]World Health Organization. ​WHO Guidelines for malaria. Oct 2023 [internet publication]. https://www.who.int/publications/i/item/guidelines-for-malaria ​ Wright or Field stains may also be used.

Although not specific for EBV, a rapid qualitative slide agglutination test using horse or bovine red cells.

High sensitivity and specificity.

Conduction system disease can occur due to progression of infection. [Figure caption and citation for the preceding image starts]: ECG of a patient with infective endocarditis. Note the first-degree AV block, nonspecific intraventricular conduction delay, and nonspecific ST-T wave abnormalitiesFrom the collection of the Mayo Clinic Rochester, MN; used with permission [Citation ends].

Hepatitis C usually causes splenomegaly by inducing cirrhosis.

Hepatitis B usually causes splenomegaly by inducing cirrhosis.

Reveals characteristic red cell morphology. [Figure caption and citation for the preceding image starts]: Red cells in sickle cell diseaseFrom the collection of Dr Sophie Lanzkron; used with permission [Citation ends].

May see other bands in sickle variant, such as migration of hemoglobin S and C.

In hereditary spherocytosis, low platelets and WBC count are usually found.

Usually an element of focal abnormality is present. Diagnosis is important because of fear and anxiety regarding possibility of malignancy.

Usually the only way to confirm diagnosis, though a watch-and-wait approach may be advisable in some patients.

Useful to determine whether the veins draining the spleen are affected by clots.

Sometimes helpful, especially in cases of portal vein thrombosis with cavernous transformation.

Useful to determine whether the veins draining the spleen are affected by clots.

Use serum lipase testing in preference to serum amylase.[49]Tenner S, Vege SS, Sheth SG, et al. American College of Gastroenterology guidelines: management of acute pancreatitis. Am J Gastroenterol. 2024 Mar 1;119(3):419-37. https://journals.lww.com/ajg/fulltext/2024/03000/american_college_of_gastroenterology_guidelines_.14.aspx http://www.ncbi.nlm.nih.gov/pubmed/38857482?tool=bestpractice.com

Should also be performed at baseline before starting anticoagulant therapy.

Several criteria have been developed to identify patients with syndromes that may represent HLH, including HLH-2004, and the HScore.[31]Shakoory B, Geerlinks A, Wilejto M, et al. The 2022 EULAR/ACR points to consider at the early stages of diagnosis and management of suspected haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Ann Rheum Dis. 2023 Oct;82(10):1271-85. https://ard.bmj.com/content/early/2023/07/21/ard-2023-224123 http://www.ncbi.nlm.nih.gov/pubmed/37487610?tool=bestpractice.com [32]Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol. 2014 Sep;66(9):2613-20. https://acrjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/art.38690 http://www.ncbi.nlm.nih.gov/pubmed/24782338?tool=bestpractice.com [33]Henter JI, Horne A, Aricó M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007 Feb;48(2):124-31. http://www.ncbi.nlm.nih.gov/pubmed/16937360?tool=bestpractice.com ​​​ However, both lack sensitivity and specificity, therefore no single set of criteria is sufficient to diagnose a HLH across all populations.[31]Shakoory B, Geerlinks A, Wilejto M, et al. The 2022 EULAR/ACR points to consider at the early stages of diagnosis and management of suspected haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Ann Rheum Dis. 2023 Oct;82(10):1271-85. https://ard.bmj.com/content/early/2023/07/21/ard-2023-224123 http://www.ncbi.nlm.nih.gov/pubmed/37487610?tool=bestpractice.com ​​According to the HLH-2004 criteria, a diagnosis is based on either the presence of 5 out of 8 criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis, low or absent NK-cell activity, hyperferritinemia, and high levels of soluble interleukin-2 receptor), or a molecular diagnosis or family history consistent with HLH.[31]Shakoory B, Geerlinks A, Wilejto M, et al. The 2022 EULAR/ACR points to consider at the early stages of diagnosis and management of suspected haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Ann Rheum Dis. 2023 Oct;82(10):1271-85. https://ard.bmj.com/content/early/2023/07/21/ard-2023-224123 http://www.ncbi.nlm.nih.gov/pubmed/37487610?tool=bestpractice.com

A EULAR/ACR (European Alliance of Associations for Rheumatology/American College of Rheumatology) task force recommends that clinical and imaging abnormalities together should be used to recognize potentially life-threatening HLH.[31]Shakoory B, Geerlinks A, Wilejto M, et al. The 2022 EULAR/ACR points to consider at the early stages of diagnosis and management of suspected haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Ann Rheum Dis. 2023 Oct;82(10):1271-85. https://ard.bmj.com/content/early/2023/07/21/ard-2023-224123 http://www.ncbi.nlm.nih.gov/pubmed/37487610?tool=bestpractice.com

Examples of genetic mutations associated with primary HLH include PRF1, RAB27A, STX11, STXBP2, UNC13D, LYST, AP3B1, SH2D1A, XIAP, NLRC4, CDC42, the Epstein-Barr virus susceptibility diseases and XLP.[27]Canna SW, Marsh RA. Pediatric hemophagocytic lymphohistiocytosis. Blood. 2020 Apr 16;135(16):1332-43. https://ashpublications.org/blood/article/135/16/1332/452577/Pediatric-hemophagocytic-lymphohistiocytosis http://www.ncbi.nlm.nih.gov/pubmed/32107531?tool=bestpractice.com [28]Allen CE, McClain KL. Pathophysiology and epidemiology of hemophagocytic lymphohistiocytosis. Hematology Am Soc Hematol Educ Program. 2015;2015:177-82. https://ashpublications.org/hematology/article/2015/1/177/20676/Pathophysiology-and-epidemiology-of-hemophagocytic http://www.ncbi.nlm.nih.gov/pubmed/26637718?tool=bestpractice.com

Hemoglobin <90 g/L [<9 g/dL] (infants <4 weeks: hemoglobin <100 g/L {<10 g/dL}), platelets <100 x 10⁹/L [<100 x 10³/microliter], neutrophils <1 x 10⁹/L [<1 x 10³/microliter][33]Henter JI, Horne A, Aricó M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007 Feb;48(2):124-31. http://www.ncbi.nlm.nih.gov/pubmed/16937360?tool=bestpractice.com

≥500 ng/mL (≥1123 pmol/L)[33]Henter JI, Horne A, Aricó M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007 Feb;48(2):124-31. http://www.ncbi.nlm.nih.gov/pubmed/16937360?tool=bestpractice.com

≤150 mg/dL (≤4.41 micromoles/L)[33]Henter JI, Horne A, Aricó M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007 Feb;48(2):124-31. http://www.ncbi.nlm.nih.gov/pubmed/16937360?tool=bestpractice.com

≥265 mg/dL (≥3 mmol/L)[33]Henter JI, Horne A, Aricó M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007 Feb;48(2):124-31. http://www.ncbi.nlm.nih.gov/pubmed/16937360?tool=bestpractice.com

Vessel walls particularly prone to involvement. [Figure caption and citation for the preceding image starts]: Congo red stain blood vessel in a bone marrow biopsy demonstrating green birefringence pathognomonic of amyloidosisFrom the collection of Dr Morie A. Gertz; used with permission [Citation ends].

Usually elevated if glomerulus involved.

A bone marrow biopsy is usually not necessary. When done, "onion skin" changes can be observed in macrophages (so-called Gaucher cells). [Figure caption and citation for the preceding image starts]: Bone marrow aspirate showing a typical Gaucher cellFrom the collection of Dr Atul B. Mehta; used with permission [Citation ends].

Bone imaging provides distinctive changes, such as the Erlenmeyer flask sign in the distal femurs. Bone density is compromised.

Identification of virus/viral RNA/viral antigen together with detection of an antibody response is preferable to either approach alone.[67]World Health Organization, Special Programme for Research and Training in Tropical Diseases (TDR). Dengue: guidelines for diagnosis, treatment, prevention and control. New edition. Oct 2009 [internet publication]. https://www.who.int/publications/i/item/9789241547871

Identification of virus/viral RNA/viral antigen together with detection of an antibody response is preferable to either approach alone.[67]World Health Organization, Special Programme for Research and Training in Tropical Diseases (TDR). Dengue: guidelines for diagnosis, treatment, prevention and control. New edition. Oct 2009 [internet publication]. https://www.who.int/publications/i/item/9789241547871

Splenic changes associated with abdominal pain and decreased gallbladder emptying.[68]Ferreira BDC, Correia D. Ultrasound assessment of hepatobiliary and splenic changes in patients with dengue and warning signs during the acute and recovery phases. J Ultrasound Med. 2019 Aug;38(8):2015-24. http://www.ncbi.nlm.nih.gov/pubmed/30549307?tool=bestpractice.com

Frequent monitoring, potentially with periodic radiographic tests, may be important to demonstrate stability. Emergency splenectomy or repair of the splenic capsule may be necessary in case of rupture.