Splenomegaly may be noted incidentally on physical examination or on imaging, or as a feature of a known or suspected entity such as hepatic, infectious, immunological, or traumatic disease.
The presence of constitutional symptoms should be elicited. A history of fevers, night sweats, or weight loss (B symptoms) suggests lymphoma, leukaemia, or infective endocarditis. However, some patients with lymphoma or leukaemia are asymptomatic. Clinical history in patients affected with non-Hodgkin's lymphoma (NHL) depends on the type of lymphoma and the stage at presentation. Although low-grade NHL is often minimally symptomatic or asymptomatic, high-grade NHL may present with B symptoms. Patients with polycythaemia vera evolving to a 'spent phase' may also exhibit B symptoms. In addition, fatigue and weight loss, accompanied by arthralgias, may be found in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus (SLE). Fever may be a late symptom in primary sclerosing cholangitis (caused by episodic bacterial cholangitis). Weight loss may occur in amyloidosis.
Patients may present with a history of abdominal pain, particularly left upper quadrant (LUQ) pain, in addition to other symptoms. Rarely, alcohol-induced pain is reported in the spleen area in Hodgkin's disease. Symptomatic chronic lymphocytic leukaemia (CLL) includes abdominal fullness and LUQ pain. In chronic myeloid leukaemia (CML), LUQ pain and/or early satiety indicates an extremely enlarged spleen. Patients with splenic vein thrombosis may report LUQ, epigastric, or generalised abdominal pain, including symptoms of acute pancreatitis. The onset of splenomegaly can be rapid and painful. Patients with splenic metastasis may report LUQ pain at presentation, in addition to the symptoms of the primary neoplasm (e.g., weight loss, cough, or change in bowel habits). Benign splenic tumours are often asymptomatic, and no unusual history of pain or abdominal swelling is reported. Right upper quadrant (RUQ) pain should arouse concern of chronic liver disease.
A history of pruritus should be noted, as generalised pruritus may be seen in Hodgkin's disease, and aquagenic (evoked by contact with water) pruritus can occur in polycythaemia vera. Furthermore, in the early phases of chronic liver disease (e.g., due to hepatic steatosis, primary biliary cirrhosis, primary sclerosing cholangitis), patients may present with pruritus in addition to fatigue, malaise, and RUQ discomfort. Later stages are characterised by jaundice and stigmata of cirrhosis.
Sex and age may provide important diagnostic clues when interpreted with other historical findings. Female sex and age between 45 and 60 years with a personal or family history of autoimmune disorders suggests primary biliary cholangitis (PBC). Male sex and age between 40 and 50 years with a history of inflammatory bowel disease (typically ulcerative colitis, but possibly Crohn's colitis) suggests primary sclerosing cholangitis (PSC).
Details of past medical history as well as a family history of chronic disease should be established. Family history of haemochromatosis along with a personal history of arthralgias and diabetes suggests haemochromatosis. Obesity along with a history of insulin resistance or diabetes, hyperlipidaemia and/or hypertension (metabolic syndrome), rapid weight loss, or total parenteral nutrition suggests hepatic steatosis. A personal or family history of thrombophilia, paroxysmal nocturnal haemoglobinuria (PNH), or myeloproliferative disorders can precede Budd-Chiari syndrome, whereas a history of PNH or antiphospholipid syndrome may suggest portal vein thrombosis. A history of pancreatitis may suggest splenic vein thrombosis. A personal or family history of haemoglobinopathy suggests thalassaemia or sickle cell disease. A personal or family history of lysosomal storage disease suggests Gaucher's or Niemann-Pick disease. Acute myeloid leukaemia (AML) patients may present with a history of haematological disease or genetic disorder such as chromosomal fragility and/or bone marrow failure disorders or chromosomal trisomies. Patients with acute lymphocytic leukaemia (ALL) often have a family history of the disease. People with Felty syndrome (rheumatoid arthritis, splenomegaly, and neutropenia) often have a personal (>10 years) and family history of rheumatoid arthritis. A family history of inherent red blood cell disorders is typical of these disorders, along with a lifelong history of jaundice.
In addition to a family history of chronic disorders, ancestry may be useful in determining the underlying aetiology. Gaucher's disease is the prototypical example of lysosomal storage disease-associated splenomegaly, a common genetic disease, particularly among those of Ashkenazi Jewish descent. Patients with Felty syndrome often have white ancestry. People affected with sickle cell anaemia often have black ancestry, and Mediterranean or Southeast Asian ancestry suggests thalassaemia.
A history of recent travel should be sought, particularly travel to a region of the world in which malaria is endemic. Residence in endemic areas (e.g., for hepatitis B infection) should also be excluded.
Medications, past and current, should be reviewed. Granulocyte colony-stimulating factor may be associated with splenic enlargement or, rarely, rupture. High-dose chemotherapy can lead to Budd-Chiari syndrome. Prior or current treatment with oral contraceptives raises the possibility of portal vein thrombosis. Patients with AML or ALL may have a history of chemotherapy or exposure to radiation or benzene.
Social history is valuable. Alcohol abuse suggests the possibility of chronic liver disease. History of intravenous drug abuse may suggest chronic hepatitis B or C infection or infective endocarditis. Exposure to environmental toxins or pollutants (including smoking) should also be ruled out, as malignancies may occur as a result.
Recent abdominal trauma and/or recent hospitalisation should be excluded. Splenomegaly due to splenic rupture or subcapsular haemorrhage, although rare, may occur following trauma to the abdomen or the use of iatrogenic foreign material (e.g., nasogastric tubes). In addition, intravenous line infections may be a source of infective endocarditis or splenic abscess (may also occur as a result of recent urinary, pulmonary, or soft tissue infection).
The presence of lymphadenopathy should be established. Several months of persistent adenopathy may be reported in Hodgkin's disease. Rarely, alcohol-induced pain occurs in pathologically enlarged nodes. Alternatively, patients may present with cervical and/or supraclavicular lymphadenopathy (young adults). Less commonly, patients present with shortness of breath, cough, chest pain, abdominal pain, or superior vena cava syndrome due to enlarged lymph nodes.
Other important factors to elicit on history taking include:
Presence of abnormal bleeding: bleeding from the nose and gums may occur in Waldenström's macroglobulinaemia or AML. Menorrhagia may occur in AML.
Respiratory symptoms: pharyngitis is typical of Epstein-Barr virus (EBV) infection (mononucleosis). Cough and dyspnoea occur in sarcoidosis. Amyloidosis may present with dyspnoea in addition to fatigue.
Skin and hair symptoms: alopecia may occur in SLE. Skin rashes or masses may occur in AML. Skin nodules may occur in NHL. Patients with SLE commonly present with a photosensitive rash.
Bowel function: steatorrhoea occurs in late PBC and PSC. Diarrhoea can occur in amyloidosis.
Musculoskeletal symptoms: bone pain may occur in AML, sickle cell disease (episodic), and Gaucher's disease. Patients with rheumatological arthritis may present with joint deformities; history of bilateral, symmetrical pain, and swelling of the small joints of the hands and feet (>6 weeks); and morning stiffness. Arthralgia (involving knees, ankles, elbows, and wrists) is a common symptom of sarcoidosis and SLE.
History of bruising, petechiae, or purpura: symptomatic CLL or CML may exhibit excessive bruising. Purpura (due to thrombocytopenia) may occur in NHL, and bruising or petechiae can occur in Hodgkin's lymphoma.
Neurological symptoms: features of high-grade NHL, Waldenström's macroglobulinaemia (headache, dizziness, and vertigo), or essential thrombocytosis (headache and erythromelalgia, painful burning in palms or soles).
History of recent dental work or blood transfusions: may suggest infective endocarditis or hepatitis C infection, respectively.
Presence of jaundice: patients with NHL may present with jaundice secondary to liver failure. Jaundice is a typical finding of late-stage chronic liver disease (e.g., due to hepatic steatosis, PBC, PSC). Lifelong jaundice is typical of inherent red blood cell disorders.
Presence of fatigue: although generally a non-specific symptom, symptomatic fatigue (indicating anaemia) following viral infections suggests hereditary spherocytosis.
Palpation of an enlarged spleen is best accomplished by having the patient relax the abdominal wall. There should be mild flexion of the neck, the arms should be still at the sides (not over the head), and the knees should be flexed with the feet flat on the examining table. The examiner should stand at the patient's right and should start low in the mid abdomen and work upwards towards the left costal margin. Starting too high in the left upper abdomen might result in missing the edge of a massively enlarged spleen. Indeed, spleens can become so large as to occupy most of the abdomen. The higher edge can be very far to the right of the midline, and the lower edge may not be palpated because it is located in the pelvis.
Isolated splenomegaly (as opposed to hepatosplenomegaly) suggests chronic liver disease. The liver is usually shrunken in cirrhosis with secondary splenomegaly. Accompanying stigmata of chronic or end-stage liver disease of any aetiology include spider telangiectasias, ascites, palmar erythema, jaundice, or encephalopathy.
Hepatomegaly with an ill-defined soft edge may occur in CML; hepatomegaly is not a prominent feature of hairy cell leukaemia. However, in late stages of hairy cell leukaemia, pain and fever may be accompanied by parasplenic fluid or splenic rupture. Rarely, an acute abdomen is observed in AML.
Mild-to-severe splenomegaly and epigastric tenderness characterise portal vein thrombosis. LUQ tenderness and features of pancreatitis (tachycardia and hypotension in severe cases; discoloration around the umbilicus [positive Cullen sign] or flanks [positive Grey-Turner sign] in cases of haemorrhagic pancreatitis) suggest splenic vein thrombosis. Onset of splenomegaly can be rapid and painful. A classic triad of abdominal pain (especially RUQ), ascites, and hepatomegaly characterises Budd-Chiari syndrome.
Usually, splenic involvement by Hodgkin's disease is focal and multicentric, and it may or may not lead to palpable splenomegaly. However, if diagnosed late, the spleen can become quite enlarged. More unusual presentations of Hodgkin's disease are characterised by splenomegaly (splenectomy may be necessary for diagnosis) and are most often found in patients >60 years of age. Hepatosplenomegaly is a feature of high-grade NHL.
Features found on general examination can provide important diagnostic clues. Acute signs such as tachypnoea, tachycardia, and hypotension characterise sepsis with splenic abscesses or splenic rupture. Following abdominal examination, physical examination should focus on the following:
The presence of pallor indicates anaemia and is a common finding associated with many of the causes of splenomegaly (e.g., leukaemias). Purpura and petechiae suggest thrombocytopenia, as in sequestration syndromes. Periorbital purpura strongly suggests amyloidosis. Plethora is seen in polycythaemia vera. Skin infiltration and masses may be seen in AML or ALL; cutaneous ulcers (Sweet syndrome) or pyoderma gangrenosum are found in AML. Skin and mucosal bleeding are seen in Waldenström's macroglobulinaemia or essential thrombocytosis. Roth spots or Janeway lesions suggest endocarditis.
Jaundice is found in Budd-Chiari syndrome and haemolytic anaemias and may occur in NHL and late-stage chronic liver disease. Cutaneous infection may be evident on clinical examination and can occur in leukaemias. Erythema nodosum and lupus pernio may be seen in sarcoidosis. Xanthelasma is found early in PBC, whereas skin thinning and muscle mass loss occur late.
Lymphadenopathy should be assessed and may suggest reactive processes such as autoimmune disorders (rheumatoid arthritis, Felty syndrome, SLE, sarcoidosis) but is more typical of lymphomas and leukaemias (less prominently in hairy cell than in other types of leukaemia). Posterior cervical adenopathy is seen with EBV infection (mononucleosis). Generalised lymphadenopathy occurs with EBV infection in immunocompromised people.
Mucosal bleeding and retinopathy may be seen in Waldenström's macroglobulinaemia. Pharyngitis occurs with EBV infection. Macroglossia, jugular venous distension, or periorbital oedema suggest amyloidosis. Frontal bossing maxillary expansion is seen with thalassaemias.
New or changing murmurs suggest endocarditis.
Testicular masses may be found in AML.
Digital ischaemia or gangrene and/or thrombosis suggest essential thrombocytosis. Joint deformities are found in rheumatoid arthritis, SLE, and Felty syndrome. Lower extremity oedema may be seen in amyloidosis.
Abnormal neurological examination may be observed in essential thrombocytosis, NHL, or Waldenström's macroglobulinaemia.
Initial testing in the work-up of splenomegaly should include a comprehensive metabolic panel to assess liver function; full blood count with differential, review of the peripheral blood smear, and reticulocyte count (especially when the patient is anaemic); and blood cultures (when the patient is febrile).
Additional investigations should be based on clinical and/or initial laboratory findings.
The presence of indirect hyperbilirubinaemia on liver function tests suggests haemolysis and should be confirmed by haemoglobin electrophoresis (sickle cell disease, beta-thalassaemia), Coombs testing (positive: autoimmune haemolysis and cold agglutinin disease; negative: hereditary spherocytosis), red cell enzyme testing (as in glucose-6-phosphate dehydrogenase deficiency), or osmotic fragility testing (as in hereditary spherocytosis).
Lymphocytosis on peripheral smear accompanied by immature or abnormal lymphocytes should prompt flow cytometry for lymphoproliferative profile. This can help diagnose chronic lymphocytic leukaemia, hairy cell leukaemia, and several of the peripheralised lymphomas (such as splenic marginal zone lymphoma or Sezary cells in cutaneous T-cell lymphoma).
Erythropoietin levels may be performed when considering a diagnosis of polycythaemia vera; levels can be normal but are usually low.
Coagulation tests can be a marker of liver synthetic dysfunction and are therefore useful in suspected alcoholic or chronic liver disease, disseminated intravascular coagulation in AML, fulminant presentations of Budd-Chiari syndrome, and SLE.
Serum LDH is an indicator of acute or chronic injury to tissues and should be considered in cases of suspected NHL or AML.
Serum erythrocyte sedimentation rate may be of use in Waldenström's macroglobulinaemia, although this is a non-specific marker of inflammation.
Serum iron studies are necessary if haemochromatosis is suspected.
Protein and immunofixation electrophoresis (serum, urine, or both) should be performed when considering a diagnosis of sickle cell anaemia, thalassaemia, or amyloidosis.
Alpha-globin gene deletion analysis supports the diagnosis of alpha-thalassaemia (usually abnormal) and should be considered in suspected cases.
Bone marrow analysis is necessary in cases of suspected myeloproliferative neoplasms, lymphomas, immunological diseases (haemophagocytic lymphohistiocytosis [HLH], sarcoidosis, SLE, Felty syndrome, amyloidosis), and lysosomal storage diseases (Gaucher's disease). In lysosomal storage diseases, quantification of the suspected enzyme deficiency, such as glucocerebrosidase deficiency in Gaucher's disease, may obviate the need for bone marrow testing. Bone marrow biopsy, along with lymph node biopsy, may obviate the need for splenectomy in Hodgkin's lymphoma. It may even reveal a benign splenic tumour.
Specialised tests can be useful in several instances:
Antimitochondrial antibodies are usually associated with PBC but can also be seen in PSC.
High levels of IgG and IgM can also be indicative of PSC. High-resolution serum electrophoresis with immunofixation confirms monoclonal IgM (kappa or lambda) secretion, required for diagnosis of Waldenström's macroglobulinaemia.
The use of monoclonal antibodies for immunophenotyping and HLA typing may determine whether leukaemia is lymphoid or myeloid in origin (e.g., ALL).
Serology: approximately 30% of rheumatoid arthritis patients are rheumatoid factor (RF)-negative. Detection of anti-cyclic citrullinated peptide antibodies may be positive in these patients.
Serum ACE may be elevated in sarcoidosis.
Natural killer (NK) cell activity and a soluble CD25 (soluble interleukin-2 receptor) is used in the diagnosis of haemophagocytic lymphohistiocytosis (HLH). Diagnosis is based on either the presence of 5 out of 8 criteria (fever, splenomegaly, bicytopaenia, hypertriglyceridaemia and/or hypofibrinogenaemia, haemophagocytosis, low or absent NK-cell activity, hyperferritinaemia, and high levels of soluble interleukin-2 receptor), or a molecular diagnosis consistent with HLH.
Infectious causes of splenomegaly can be confirmed by detection of the causal micro-organism in blood or other specimen cultures (malaria, endocarditis, splenic abscesses secondary to sepsis). Alternatively, serum agglutination tests or detection of specific antigens or antibodies can be used for EBV or hepatitis B or C. For hepatitis, quantification by polymerase chain reaction provides further information about viral burden.
Radiographical tests are helpful in establishing splenomegaly, especially in obese patients. Ultrasound is a highly sensitive and specific non-invasive study for assessing spleen size. However, computed tomography (CT) scanning provides more detail and is the preferred modality when investigating the aetiology of splenomegaly. CT scans can determine the degree of splenic enlargement and liver size and heterogeneity or homogeneity. Therefore, abdominal CT scans add diagnostic value, particularly in splenomegaly associated with alcohol abuse, hepatic steatosis, myelofibrosis, and subcapsular haematoma. Upper abdominal CT scans may show multiple tumours in the spleen that have metastasised from other primary tumour sites, particularly colon and breast cancer. Unsuspected lymphadenopathy in the retroperitoneum or mesentery may be detected, as well as mediastinal adenopathy on CT of the chest. Furthermore, CT scans can detect a splenic abscess causing LUQ pain in endocarditis.
Liver-spleen scanning (a nuclear medicine test) is performed by injecting technetium99-labelled colloid, which is quickly phagocytosed by macrophages in the bone marrow, liver, and spleen. Liver-spleen scanning gives corroborative information about enlarged spleens and may be of value in patients with hepatic steatosis; if portal hypertension is present, a nuclear medicine study can detect colloid shift, in which the radionuclide used is preferentially shifted from the liver to the spleen (and marrow).
In select patients, especially those with portal vein or splenic vein thrombosis, further imaging studies such as Doppler ultrasonography may be necessary to determine whether veins draining the spleen are affected by clots (portal vein thrombosis, splenic vein thrombosis). Magnetic resonance imaging (MRI) is sometimes helpful, especially in cases of portal vein thrombosis with cavernous transformation. Usually, however, MRI confirms CT findings of the liver rather than the spleen, especially liver haemangiomas. An abnormal liver MRI pattern may also indicate iron overload in haemochromatosis. Bone imaging reveals distinctive changes, such as the 'Erlenmeyer flask' sign in the distal femurs (lysosomal storage diseases).
Positron emission tomography (PET) scans can help to determine the metabolic activity of cells in the spleen, though they do not necessarily distinguish between malignant and reactive changes in the spleen. PET scans can be of particular value in diagnosing and staging Hodgkin's lymphoma.
Upper gastrointestinal endoscopy can be useful to detect oesophageal varices in splenomegaly secondary to alcohol abuse or other chronic liver disease. ECG may detect cardiac involvement in sarcoidosis or endocarditis.
Further specialised tests may be required depending on the clinical findings and laboratory results. In cases of amyloidosis, abdominal fat pad aspiration may be positive for amyloid and can therefore support the diagnosis. JAK2 mutation analysis can be useful in suspected cases of polycythaemia vera (confirms diagnosis), Budd-Chiari syndrome (positive with underlying myeloproliferative disorder), and essential thrombocytosis (present in 60% of cases). Gene tests may be used to confirm the diagnosis of CML (BCR-ABL gene rearrangement positivity) and haemochromatosis (C282Y mutation homozygosity). Glucocerebrosidase activity should be determined in suspected Gaucher's disease. Sphingomyelinase assay can be used to assess Niemann-Pick disease.
Lymph node biopsy is necessary for diagnosis of lymphoma or sarcoidosis. Fine-needle aspiration biopsy of the spleen may be diagnostic and avoid the need for splenectomy in highly selected cases: for example, low-grade NHL exhibiting usually small lesions or diffuse splenic involvement, or Hodgkin's lymphoma. In some instances, however, splenectomy may be the only way to diagnose isolated splenic involvement (Hodgkin's lymphoma, primary splenic malignancies). Lung or skin biopsy can be valuable in sarcoidosis and should be considered. Liver biopsy can add value to the diagnosis of the underlying cause, and to the management of splenomegaly secondary to alcohol-induced liver disease, hepatic steatosis, PSC, or haemochromatosis.
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