Evaluation of Splenomegaly


The spleen is a secondary lymphoid organ that lies in intraperitoneally in the left hypochondrium, abuting the diaphragm. It spans from the 9th to 11th rib and weighs between 150-200g. Spleen is supplied by the splenic artery and drains into portal circulation via the splenic vein. It is a part of reticuloendothelial system, immune system and is a site of in utero haematopoiesis. The spleen is enlarged in a diverse set of disease of the above mentioned  systems and in portal hypertension.

Normal Functions of the Spleen

The normal functions of the spleen include

  1. Reticuloendothelial functions: The spleen as a component of the reticuloendothelial system is involved in clearing the blood of ageing or damaged erythrocytes, antibody coated cells and opsonised bacteria. It also removes particles from red cells. The spleen ensures that the red cell in circulation have adequate deformability for passage through microcirculation.
  2. Immune Functions: The spleen is a part of the immune system and plays a role in mounting the immune response . Splenectomy increases the risk of infections particularly with capsulated organisms (see Overwhelming Post-Splenectomy Infection (OPSI)).
  3. Haematopoiesis: Spleen is the site for haematopoiesis in utero. In extrauterine life spleen can become a site of haematopoiesis in disease.

Palpating the Spleen

  1. Palpation of the spleen should start from the right iliac fossa. If this is not done there is a risk of missing a massively enlarged spleen.
  2. Move towards the left costal margin in a direction perpendicular to the margin. Move with each breath. At every position ask the patient to take a deep breath. The tip of the spleen will hit your palpating finger.
  3. If the spleen does not hit your finger move your palpating finger to a position closer to coastal margin, ask the patient to take a deep breath and repeat the procedure described above till your finger hits the costal margin.
  4. If the spleen is felt measure the perpendicular distance between the tip and the left coastal margin. Also note the texture and presence of tenderness.
  5. If the spleen is not felt repeat the procedure with patients lying on right side.
  6. Large spleen can rupture with aggressive palpation. The spleen lies directly under the anterior abdominal wall. One does not need to be aggressive.

Causes of Splenomegaly

The spleen enlarges from the left coastal margin in the direction of the umbilicus. It needs to enlarge 2-3 times before it is palpable. Splenomegaly may be caused be increase in portal venous pressure, infiltrative conditions or when the spleen function needs to increase. Clinically it is useful to classify splenomegaly by size. Massive splenomegaly is enlargement of the spleen beyond the umbilicus. The causes of massive splenomegaly include

  1. Malignant: Chronic myeloid leukaemia, Idiopathic myelofibrois, hairy cell leukaemia, splenic marginal zone lymphoma, chronic lymphocytic leukaemia, prolymphocytic leukaemia
  2. Infections: Tropical splenomegaly, AIDS with Mycobacterium avium complex infections, Kala-azar (visceral leishmaniasis)
  3. Others: β-Thalassaemia major and intermedia, Extrahepatic portal venous obstructions,megaloblastic anaemia, diffuse splenic haemagiosis

The causes of splenomegaly include the above and the following

  1. Portal Hypertension: Cirrhosis, Budd-Chairy syndrome, splenic vein thosmbosis, congestive heart failure, hepatic schistosomiasis
  2. Increased splenic function:
    1. Increased functional demands: Haemolytic anaemia commonly hereditary spherocytosis, autoimmune haemolytic anaemia, β-thalassaemia, early sickle cell anaemia, sickle cell β-thalassaemia,
    2. Infections:
      1. Bacterial: Septicaemia, bacterial endocarditis, splenic abscess, brucellosis, tuberculosis, AIDS with Mycobacterium avium complex infections, secondary syphilis
      2. Viral: Viral hepatitis, infectious mononucleosis, cytomegalovirus,
      3. Parasitic: Malaria , Kala-azar (visceral leishmaniasis), Trypanosomiasis,
      4. Fungal: Histoplasmosis
    3. Immune Disorders:
      1. Autoimmune diseases: Rhumatoid arthritis (Felty’s syndrome), systemic lupus erythrmatosis
      2. Other immune disorders: Immune haemolytic anaemia, immune neutropenia, drug reaction, serum sickness, sarcoidosis
      3. Haemophgocytic lymphohistiocytosis
  3. Infiltrations
    1. Haematological Malignancy:
      1. Myeloid: Chronic myeloid leukaemia, myeloproliferative disease, idiopathic myelofibrosis, polycythaemia vera
      2. Lymphoid: Acute lymphoblastic leukaemia, hairy cell leukaemia, chronic lymphocytic leukaemia, prolymphocytic leukaemia, splenic marginal zone lymphoma, angioimmnoblastic T cell lymphoma
      3. Other: Histiocytosis X, eosinophilic granuloma
    2. Storage disorders:Gaucher disease, Niemann-Pick, Tangier disease, mucopolysachroidosis
    3. Other Infiltrations: Amyloid
  4. Others: Iron deficiency anaemia

 

History and Physical Examination

  1. Fever: Fever is a feature of splenomegaly due to infections, inflammations or malignancy, particularly haematological malignancy. Usually the fever is low grade. High grade fever suggests splenic abscess.
  2. Painful splenemegaly: The nature of pain associated with splenomegaly varies with the cause of splenomegaly.
    1. An enlargement spleen from any cause can cause a dragging pain in the left upper quadrant.
    2. Acute pain left upper quadrant pain is a feature of is a feature of splenic infarct and splenic abscess. Sickle Cell anaemia is associated with small fibrotic spleen because of repeated splenic infarcts. Early in disease the spleen enlarges. Patients may present with acute pain from splenic infarcts. Enlarged spleen from any cause is predisposed to infarction. Acute pain in the left upper quadrant is also a feature of acute splenic abscess.
    3. Splenic vein thrombosis can cause splenomegly and pain in left upper quadrant or epigastric region. It may also cause generalised abdominal pain.
    4. Pancreatitis presents with abdominal pain and can cause painful splenomegaly secondary to splenic vein thrombosis.
    5. Alcohol induced pain is an uncommon but unique feature of Hodgkin lymphoma. Spleen is a common site of involvement by Hodgkin lymphoma. Such patients may have alcohol induced pain in an enlarged spleen.
  3. Pallor: Pallor in a patient with splenomegaly suggests a diagnosis of haemolytic anaemia, haemolymphatic malignancy and infective endocarditis.
  4. Clubbing: Clubbing with splenomegaly is a feature of infective endocarditis and cirrhosis of the liver.
  5. Skin rash: Skin rash in a patient with splenomegaly is seen in systemic lupus erthomatosis, infective endocarditis, lymphoma (angioimmuniblastic T Cell lymphoma, mycosis fungiodes, skin involvement with lymphoma) and drug reaction.  Each of these conditions have a distinct type of rash.
  6. Skin Pigmentation: Hyperpigmantation suggests be seen in hemachromatosis or megaloblastic anaemia. The patients with megaloblastic anaemia may also have knuckle pigmentation.
  7. Jaundice: Jaundice with enlarged spleen is a feature of haemolytic anaemia. The jaundice is usually achloruric. Patients with haemolytic anaemia are predisposed to gallstones. Obstruction of the biliary system from a calculus dislodged from the gall bladder can cause obstructive jaundice with abdominal pain and signs of acute inflammation. Splenomegaly with jaundice is a feature of advanced cirrhosis. Patients with advanced cirrhosis almost always have ascites.
  8. Lymphadenopathy: The enlargement of lymph nodes and spleen is a feature of lymphoid malignancies or diseases that stimulate the lymphoid systems viz. infections and autoimmune diseases and lymphoid malignancy.
  9. Joint symptoms: Arthropathy with splenomegaly suggests the diagnosis of rheumatoid arthritis, systemic lypus erythrmatosis or haematochromatosis.
  10. Oral symptoms: infectious mononucleosis is charecterized by pharyngitis and generalised lymphadenopathy. Bleeding gums and/or gum hypertrophy suggests a diagnosis of leukaemia. Lymphoma can cause tomsillar enlargement. Amyloid is charectetized by macroglossia.
  11. Evidence of Portal Hypertension and Liver Cell Failure: Patients with portal hypertension often have history of haemetemesis. Examination may reveal periumbilical veins (capital medusae), anterior abdominal or flank veins. Patients with evidence liver cell failures with portal hypertension (e.g. jaundice, ascites, spider angiomas, asterxis etc. see Portal Hypertension) have cirrhosis. When the jugular venous pressure is high a diagnosis of congestive cardiac failure should be considered.

Laboratory Evaluation

Haemogram; The haemogram is the most important laboratory test in evaluating a patient with splenomegaly. The significance of findings on haemogram is described in the table below.

Haemogram Finding Conditions
Pancytopenia Hypersplenism, Lymphoma (splenic marginal zone lymphoma), Hairy cell leukaemia, Myelofibrosis, systemic lupus erythrmotosis
Neutrophilic Leucocytosis Acute infections, inflammation
Leucocytosis with premature white cells Chronic myeloid leumaemia, Myeloproliferative disease, Myeloproliferative/Myelodysplastic overlap, Acute lymphoblastic leukaemia
Leucoerythroblastic anaemia Idiopathic myelofibrosis, Bone marrow infiltration
Polycythaemia Polycythaemia vera
Atypical Lymphocytes Infectious mononucleosis
Thrombocytosis Myeloproliferative disease (Chronic myeloid leukaemia, idiopathic myelofibrosis, polycythaemia vera), chronic infections like tuberculosis
Parasites Malaria, bartonelosizs, babesiosis

Other investigations are dictated by the clinical presentations. Commonly performed investigations include biochemistry, microbiology, echocardiography, endoscopy and biopsy of any lymph node or any other mass. Other investigation may be performed as indicated

Imaging

Imaging is an important aspect of evaluation of the spleen but is beyond the scope of this article. Several good reviews exist e.g Singapore Med J 56(3):133-144.

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Overwhelming Post-Splenectomy Infection (OPSI)


Splenectomy is a treatment for haematological disorders, palliation of hypersplenism, symptom relief in patients with symptomatic splenomegaly, splenic trauma and as a diagnostic procedure when tha pathology can not be ascertained by any other intervention. Sickle cell anaemia results in “autosplenectomy” and loss of splenic function. One of the risk of loss of splenic function is overwhelming post-splenectomy sepsis, a condition that proceeds from a mild flu-like illness to fulminating sepsis in a short time and when fully established has a mortality of 50-80%.

Pathogenesis

Microbiology

Pneumococcus is the commonest organism responsible for about 50-90% of the infections.  H. influenza, Meningococcus, Streptococcus, Staphylococcus and E. Coli are the other organisms responsible for OPSI.

Role of spleen in Immunity

The spleen is involved in production of IgM producing memory cells to polysaccharide antigens. These responses are T cell independent. The spleen also produces the following molecules

  1.  Properdin which is an activator of C3 by the alternate pathway
  2. Tuftsin a tetrapeptide that stimulates phagocytosis
  3. C3a is a chemotactic factor
  4. Factor B is a component of the alternate complement pathway

Splenectomized individuals have a defect in cell mediated immunity because of depletion of CD45RA+

Clinical Presentation
The risk of OPSI appears to vary with the underlying pathology. Conditions that impair immunity are associated with a higher risk of OPSI. The risk is about 1-2% in splenectomies because of trauma or idiopathic thrombocytopaenic purport, 6% in Hodgkin Lymphoma and increases to as high 11% in patients with thalassaemia.

The risk diminishes with age at splenectomy. Infants have a risk of 15%, children 10.4% older children 4.4% and adults about 0.9%. Splenectomized patients are at a higher risk of death from infection. Though the adults with splenectomy as predisposed to infection as those without splenectomy the risk of mortality in those with splenectomy is 58 times higher than those without.

About half the infections occur within 2 years and about three-fourth within 5 years of splenectomy. However OPSI may be seen decades after splenectomy.

OPSI presents as a mild illness upper respiratory infection that rapidly progresses to a fulminant illness. The patients develop septic shock, multi system organ failure and disseminated intravascular coagulation within hours. Early suspicion and initiation of antibiotics is the key to success.

Investigations

The focus of management of patients with OPSI is early initiation of antibiotics. When recognised early the mortality of OPSI can be reduced to 10%. There is no test that can predict the risk of OPSI. Haematological and biochemical test as appropriate for patients with sepsis should be performed. Blood culture should be performed to identify the organism. Antibiotics therapy should be initiated immediately and not await the results of blood culture.

Management

Patient Education: The key to successful treatment of  OPSI is the timely initiation of antibiotics. The importance of seeking medical consultation as soon as symptoms occur should be emphasised to the patient. The patient must carry a card or a bracelet identifying him/her as a person who has undergone splenectomy.

Initial Antibiotics: The antibiotics chosen for initial treatment of OPSI are directed against pneumococcus, H. Influenzae and meningococcus. Penicillin for many years was the drug of choice but with the emergence of penicillin resistant pneumococcus it is no longer an appropriate first line antibiotic in OPSI. The patient should be instructed to take oral antibiotics at the first sign of infection making it very clear that this is not a substitute for seeking immediate medical consultation. This strategy ensures that some effective antibiotic is administered at the earliest but these antibiotics are insufficient to treat OPSI. The oral antibiotics recommended include a combination of amoxicillin and clavlunate, cefuroxime aexetil or a fluoroquinolone with a gram positive cover like moxifloxacin. If a patient of suspected OPSI is seen in the clinic an intramuscular dose ceftriaxone 100mg/kg (maximum 2g) should be administered before immediately transporting the patient to the nearest intensive care facility for further treatment.

The initial choice of antibiotics for OPSI is as follows

  1. Patient not Hypersensitive to β-lactams: Vancomycin 10–15mg/kg  i.v. every 12 hours (maximum 1g, dose to be adjusted according to creatinine clearance) with Ceftriaxone 2g i.v. daily (50mg/kg i.v. every 12 hours for children)
  2. Patients Hypersensitive to β-lactams: Vancomycin 10–15mg/kg  i.v. every 12 hours (maximum 1g, dose to be adjusted according to creatinine clearance) with Levofloxacin 750mg i.v. q 24h

The local treatment recommendations need to be followed in case of a significant prevalence of penicillin resistant pneumococci. The therapy should be modified according to microbiological results and antibiotic sensitivity.

Prevention of OPSI

Prevention of OPSI rests on patient education, vaccination and use of prophylactic antibiotics.

Patient Education

The patients must be made aware of the symptoms of OPSI. The importance of seeking prompt professional opinion in case of fever. They should carry a card/bracelet identifying them as patients having undergone splenectomy. They should keep a supply of antibiotics listed above to be taken immediately in case of fever.

Vaccination

(See British Committee for Standards in Haematology guidelines for prevention and treatment of infection  in patients with an absent or dysfunctional spleen)

Patients should be vaccinated against pneumococcus, meningococcus and H. influenzae. The three vaccines may be administered together but at different locations.

  1. Pneumococcal Vaccination: Two pneumococcal vaccines are available. The 23 valent polysaccharide vaccine  (PPV) and the 13 valent protein conjugated vaccine (PCV).  PPV is ineffective in children younger than two years. The vaccination should be administered at least two weeks, ideally six weeks before the splenectomy. In case it is not possible, vaccinations should be delayed to two weeks after splenectomy. The vaccination schedule in the link mentioned above may be followed.
  2. H. Influenzae: H. Influenzae vaccine is a conjugate between capsular polysaccharide of H. influenzae type b and either non-toxic variant of diphtheria toxin or tetanus toxoid. Hib is a part of primary vaccination. If splenectomy is performed before primary immunisation is completed the primary vaccination should be continued as per schedule. If splenectomy is performed after completion of primary immunisation an additional dose of Hib vaccination should be given
  3. Meningococcus: Meningococcal vaccines may be polysaccharide or conjugated. Conjugated vaccines may be monovalent only against serogroup C or quadravalent against serogroups A, C, W and Y. Patients should be vaccinated at least 2 weeks (6 weeks) before splenectomy.

Prophylactic Antibiotics

Despite there being no evidence to prove their efficacy, most agree with the use of prophylactic antibiotics in patients with splenectomy. The main concern is infection by resistant stains. While the British Committee for standards in Haematology has taken the position that antibiotic prophylaxis should be administered lifelong (Br J Haematol 2011;155:308-17), the American and the French advocate use of prophylactic antibiotics in adults for 1-2 years after splenectomy when the risk of infection is the highest (Mayo Clin Proc. 2011; 86: 686–701). Children with splenectomy should be administered antibiotics directed against Pneumococcus till the age of 5 years. If the child remains free of infection one may consider discontinuation of antibiotics.  Penicillin V (125mg twice a day till the age of 3 and 250mg twice a day thereafter) is the drug of choice in areas where penicillin resistant pneumococcus are not prevalent. Other antibiotics including macrolides, co-trimoxazole and a fluoroquinolone with a gram positive cover like moxifloxacin may be used where penicillin resistant pneumococcus is prevalent.