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SPLENOMEGALY By Dr Bashir Ahmed Dar Associate Professor Medicine Chinkipora Sopore Kashmir Email [email_address]

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Slight enlargement just palpable (less than 5 cm ) <ul><li>Infections –acute,subacute and chronic </li></ul><ul><li>SLE </li></ul><ul><li>Rheumatoid arthritis </li></ul><ul><li>Amyloidosis </li></ul>

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Moderate enlargement (to umbilicus) <ul><li>Lymphomas </li></ul><ul><li>Leukaemias </li></ul><ul><li>Congestive splenomegaly </li></ul><ul><li>Haemolytic anaemias </li></ul><ul><li>Polycythaemia Vera </li></ul><ul><li>ITP </li></ul><ul><li>Myelodysplastic disorders </li></ul>

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Marked enlargement (more than 8 cm or below umbilicus) <ul><li>Myelofibrosis </li></ul><ul><li>Hairy cell leukaemia </li></ul><ul><li>Tropical splenomegaly </li></ul><ul><li>Kala azar </li></ul><ul><li>Thalassaemia major </li></ul><ul><li>Gaucher’s disease </li></ul><ul><li>Felty’s syndrome </li></ul>

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Infective causes of splenomegaly <ul><li>Acute causes </li></ul><ul><li>Infectious mononucleosis </li></ul><ul><li>Typhoid </li></ul><ul><li>Brucellosis </li></ul><ul><li>Infective hepatitis </li></ul><ul><li>Toxoplasmosis </li></ul><ul><li>Typhus </li></ul><ul><li>Septicaemia </li></ul>

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Infective causes of splenomegaly <ul><li>Subacute and chronic causes </li></ul><ul><li>Bacterial endocarditis </li></ul><ul><li>Tuberculosis </li></ul><ul><li>Brucellosis </li></ul><ul><li>Syphilis </li></ul><ul><li>Histoplasmosis </li></ul><ul><li>Malaria </li></ul><ul><li>Kala azar </li></ul><ul><li>Hydatid </li></ul><ul><li>Trypanosomiasis </li></ul>

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Massive splenomegaly

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Rheumatoid arthritis (Felty’s syndrome) <ul><li>Comprises of </li></ul><ul><li>Arthritis,Splenomegaly,Leucopenia </li></ul>

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Features of Felty’s syndrome <ul><li>Arthritis,splenomegaly,leucopenia </li></ul><ul><li>Extra-Articular Manifestations </li></ul><ul><li>rheumatoid nodules (76%) </li></ul><ul><li>weight loss (68%) </li></ul><ul><li>Sjogren's Syndrome (56%) </li></ul><ul><li>lymphadenopathy (34%) </li></ul><ul><li>leg ulcers (25%) </li></ul><ul><li>pleuritis (19%) </li></ul><ul><li>skin pigmentation (17%) </li></ul><ul><li>neuropathy (peripheral) -17% </li></ul><ul><li>episcleritis (8%) </li></ul><ul><li>others: pericarditis </li></ul>

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Investigations Felty's syndrome <ul><li>high Rf titre in 98% </li></ul><ul><li>ANA in 67% </li></ul><ul><li>elevated ESR, immunoglobulins, circulating immune complexes </li></ul><ul><li>positive LE cell test in 33% </li></ul><ul><li>decreased complement levels </li></ul><ul><li>elevated transaminases and alkaline phosphatase in 25-50% </li></ul>

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Tropical Splenomegaly <ul><li>In tropical areas massive splenomegaly often seen </li></ul><ul><li>Areas like Uganda,Nigeria,new guinea and other parts of Africa </li></ul><ul><li>The evidence suggests a relationship between malaria and tropical splenomegaly </li></ul><ul><li>Rarely occurs in malarial free areas </li></ul>

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Tropical Splenomegaly <ul><li>Malarial parasite are not routinely seen in blood films of pts </li></ul><ul><li>The disorder usually presents in young adult life but may occur in children </li></ul><ul><li>The diagnosis is usually made by exclusion of other causes </li></ul><ul><li>There may also be 10 fold increase polyclonal igM concentration in serum of which small portion represents malarial antibodies liver may also show lymphocytic infiltration </li></ul>

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Kala azar (leishmaniasis) <ul><li>Visceral leishmaniasis </li></ul><ul><li>Cutaneous leishmaniasis </li></ul><ul><li>Mucocutaneous leishmaniasis (espundia) </li></ul><ul><li>Diffuse Cutaneous leishmaniasis </li></ul>

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kala azar, black fever, sandfly disease, Dum-Dum fever and espundia. SYNONYMS

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Protozoan in the family Trypanosomatidae In the genus Leishmania

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Estimates All over world except Not found in South-east Asia 350 million people at risk 12 million people infected / year There are 59,000 deaths / year

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<ul><li>Incubation – 1 week to months </li></ul><ul><li>Having (many reservoirs) </li></ul><ul><li>No direct person to person transmission </li></ul><ul><li>Spontaneous healing can happen (cutaneous form) in months to years </li></ul><ul><li>No vaccine </li></ul>Some Facts

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LEISHMANIASIS or KALA-AZAR It is the result of the infection with one of the species of protozoa (leishmania). Conveyed by: Sandflies (Phlebotomus). Visceral Leishmaniasis : L. donovani Mucocutaneous : L. Braziliensis

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Have specific reservoirs Leishmania Parasites

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Rodents Sloths

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Vectors Phlebotomine Sand Flies

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30 to 70 eggs hatch 1 to 2 weeks 4 instars diapauses in 4 th instar pupal development 5-10 days adults crepuscular and nocturnal 20 to 40 days

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Opossum Armadillo

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<ul><li>Visceral Leishmaniasis : </li></ul><ul><li>L. donovani </li></ul><ul><li>Mucocutaneous </li></ul><ul><li>L. Braziliensis </li></ul>

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Cutaneous : L. tropica major L. tropica minor New World : L. Braziliensis L. Mexicana Old world

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PATHOLOGY <ul><li>» L. donovani parasitizes the reticu. endoth. cells </li></ul><ul><li>» Great proliferation of macrophage </li></ul><ul><li>» Cells result: Liver – spleen enlarg. </li></ul><ul><li> » The red bone marrow extend . </li></ul>»

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Leishmania : an obligate intracellular protozoan parasite ( 2-6 µm in diameter) parasitophorous vacuoles of macrophages

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Promastigotes in Sand Fly gut and in Culture Media (about 15-30 µm by 2-3 µm),

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<ul><li>The amostigotes of different species are very similar on light microscopy. </li></ul>Amastigote in macrophage

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CLINICAL PICTURE <ul><li> early stages is not easy for diagnose. There is no constant physical signs. </li></ul><ul><li>☺ Changes in the blood picture particularly Leucopenia. </li></ul><ul><li>☺ Outstanding physical sign is the enlargement of the spleen 3 cm. a month. </li></ul>

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<ul><li>● Liver : enlarged spleen + liver are neither tender nor painful. </li></ul><ul><li>● Sometimes : Jaundice = prognost. Significance </li></ul><ul><li>● Enlarged : Lymph node, could be but its not a feature of the disease. </li></ul><ul><li>● Wasting : Emaciated pat with a protuberant </li></ul>

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<ul><li> </li></ul><ul><li> Abdomen ( liver + spleen enlarged) </li></ul><ul><li>● Fever : Without subjective symptoms of fever – no delirium. </li></ul><ul><li>● Sometimes : there is no fever </li></ul><ul><li>● Skin : dry, rough. The natural pigmentation of the skin over the bone and around the mouth is deepened. (Kala azar??) </li></ul>

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Clinical Forms of Leishmaniasis <ul><li>Cutaneous </li></ul><ul><li>Mucocutaneous </li></ul><ul><li>Diffuse Cutaneous </li></ul><ul><li>Visceral </li></ul>

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Cutaneous form

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Wet lesion by L. major <ul><li>L. major occurs most commonly in rural areas, causing moist, ulcerative lesions which may be extensive and sometimes involve the epithelium of lips and nose. </li></ul><ul><li>These are the commonest types of lesion caused by L. major . </li></ul><ul><li>Prominent ‘rolled’ edge of the lesions is the best area to demonstrate the parasites </li></ul>

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Lymphatic spread of L. major <ul><li>The ink marks indicate a line of subcutaneous nodules along the lymphatic, passing proximally from the lesion on the lower part of this man’s arm. </li></ul><ul><li>The nodules usually resolve without complications when the primary lesin heals with or without specific therapy. </li></ul>

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Clinical Forms of Leishmaniasis

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Simple ‘dry’ lesion by L. tropica <ul><li>dry, usually self-healing lesions, </li></ul><ul><li>Generally single </li></ul><ul><li>Urban area in North Africa and the Middle East to the former USSR, Afghanistan, western states of India </li></ul><ul><li>The lesions frequently contain very large numbers of parasites. </li></ul>

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Leishmaniasis recidivans <ul><li>Infection with L. tropica may become very chronic, with a hyperallergic reaction leading to lupus-like lesions such as seen in this child. </li></ul><ul><li>Amastigotes may be very difficult to find in the lesions. </li></ul>

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Mucocutaneous lesion by L. aethiopica <ul><li>In addition to simple cutaneous lesions due to infection with L. aethiopica , other forms are seen in the Ethiopian highlands where rock hyraxes are the reservoirs. It has not yet been ascertained whether the mucocutaneous condition seen here is due to this or another species of Leishmania . </li></ul>

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<ul><li>Forest workers collecting gum from wild chicle trees commonly sleep near the forest floor and are bitten on exposed parts of the head by vectors. </li></ul><ul><li>Ulcers leading to erosion of the auricular cartilage. </li></ul>Chiclero’s ulcer by L. mexicana

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Lymphatic spread of L. mexicana <ul><li>As noted for L. major , lymphatic spread may also occur with New World species. </li></ul><ul><li>This patient was infected with L. guyanensis the agent of ‘Pian bois’. In such infections the lymphatic nodules may ulcerate. </li></ul>

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<ul><li>The lesions of mucocutaneous leishmaniasis due to infection with L. braziliensis may first become evident as ulcers involving the mucocutaneous junctions of the mouth and nose </li></ul><ul><li>This condition frequently follows a primary cutaneous lesion which may have healed with or without specific therapy some years earlier. </li></ul>Early lesion of Espundia

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Pharyngeal involvement <ul><li>Ulceration often extends to the pharynx and soft palate, and the first symptoms may be related to tissue destruction in this area. </li></ul><ul><li>This man had the scar of a large ulcer which had apparently healed on his leg some 30 years before. </li></ul>

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PKDL Post Kalazar Dermal Leishmaniasis

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Visceral form

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Clinical picture of kala-azar in Kenya <ul><li>Increasing enlargement of the spleen and liver is a characteristic feature while, in dark-complexioned subjects, deepening skin pigmentation is seen-hence the synonym kala-azar, the ‘black sickness’. </li></ul><ul><li>A generalized lymphadenopathy is common in African kala-azar; the parasite in this area is considered to be in the L. donovani complex. </li></ul>

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Diagnosis <ul><li>Demonstration of Parasite from aspirate - lymph node ; inguinal LN, sensitivity 60% - bone marrow ; iliac crest, sensitivity 70% - spleen; sensitivity 95~99% - liver </li></ul><ul><li>PB smear (HIV infected patient) </li></ul><ul><li>Serology - a void the necessity for the more invasive procedure - direct agglutination test </li></ul><ul><li>PCR </li></ul>

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Iliac crest aspiration of bone marrow <ul><li>The most direct means of diagnosis of kala-azar is the detection of amastigotes in bone-marrow, spleen or blood; the organisms are recognized in dried smears of material stained with a Romanowsky stain by their characteristic morphology. </li></ul>

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L. infantum in macrophage from bone marrow <ul><li>While typically found in macrophages as shown here, isolated extracellular amastigotes from disrupted host cells are commonly seen in such preparations. </li></ul>

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Amastigotes in macrophage from skin <ul><li>The diagnosis is confirmed by demonstraing amastigotes in smear made from the cutaneous lesions. </li></ul>

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Punch biopsy <ul><li>A piece of tissue may be removed under local anesthetic with a disposable skin punch for histology, culture and the direct demonstration of amastigotes. </li></ul>

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Parasitised macrophage in skin section <ul><li>Many parasitised macrophages can be seen in this section from an acute lesion caused by L. major. </li></ul>

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DIAGNOSIS <ul><li>Needle aspiration </li></ul><ul><li>Bone – sternum – liver, spleen </li></ul><ul><li>Histology – culture </li></ul><ul><li>L. donovani body </li></ul><ul><li>2. a. Leucopenia : Neutropenia – relative mononucleosis. </li></ul><ul><li>b. Progressive fall with the red cell count </li></ul>

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<ul><li>Formalin gel (aldehyde ) </li></ul><ul><li>2 drops formalin + 2 ml serum </li></ul><ul><li>After 20 min, white ring </li></ul><ul><li>Complement fixation and fluorescent </li></ul><ul><li>False positive trypanosomal infection </li></ul><ul><li>The complement fixation – early positive – negative after cure. Sometimes + or – lung. Other diseases. </li></ul>

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<ul><li>6. Fluorescent antibody </li></ul><ul><li>IV + V: In trypanosomal infection </li></ul><ul><li>Skin test (Montenegro) </li></ul><ul><li>Delayed hypersensitivity reaction </li></ul><ul><li>0.2 ml. suspension </li></ul>

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TREATMENT <ul><li>Antimonial – </li></ul><ul><li>i. Urea, stibamine, pentavalen + antmonyia </li></ul><ul><li> I.V. daily or every 2 days </li></ul><ul><li>6 – 10 dose </li></ul><ul><li>First 100 mg then 200 then 250 </li></ul><ul><li>Total dose 2 – 5 g. adult </li></ul><ul><li>Side Effect : Nausea, vomiting, joint pain, Abdominal pain, diarrhea </li></ul>

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<ul><li>Contraindication : Liver and kidney failure </li></ul><ul><li>ii. Sodium stibogluconate (Pentostam ) </li></ul><ul><li> I.M. – 600 mg total daily for 6-10 days </li></ul><ul><li> Repeated after 14 days; if needed </li></ul><ul><li>Side effect : Anaphylactic shock </li></ul><ul><li>Diamidiem – </li></ul><ul><li>Pentamidine isothionate </li></ul><ul><li>Dose 3 -4 mg / kg / BW total 300 mg </li></ul><ul><ul><li>Side effect : Hypoglycemia </li></ul></ul>

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Treatment <ul><li>Sodium stibogluconate </li></ul><ul><li>Pentavalent antimony (Sb +5 ) </li></ul>

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<ul><li>demonstration of amastigotes(L. donovani bodies) </li></ul><ul><li>intracellular form is usually 2-4 micron consists of nucleus and is rod like with a homogeneous mass of cytoplasm,while the extracelluar or culture form is14-20 microns in length 1.5 to 3.5 breadth </li></ul><ul><li>L. donovani body </li></ul>

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Myelofibrosis or myelosclerosis <ul><li>Fibrosis and collagen formation in marrow </li></ul><ul><li>Primary –developing in polycythemia vera </li></ul><ul><li>Secondary – in TB,secondary carcinoma,hodgkins disease,leukaemia,and variety of other conditions. </li></ul><ul><li>Myeloid metaplasia ,spleenomegaly hepatomaegaly etc etc </li></ul>

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GAUCHER’S DISEASE

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History <ul><li>Discovered by Philippe Gaucher, a medical student in Paris, in 1882. </li></ul><ul><li>He was studying a woman with an enlarged spleen </li></ul>

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<ul><li>Definition </li></ul><ul><li>Gaucher's (go-SHAYZ) disease occurs when certain harmful fatty substances build to excessive levels in your liver, spleen, lungs, bone marrow and, less commonly, your brain. This accumulation of fatty material in tissues interferes with the normal functioning of organs, and may cause organ enlargement and bone pain. </li></ul>

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<ul><li>Gaucher's disease results from an enzyme deficiency, and sometimes the term &quot;glucocerebrosidase deficiency&quot; is used to describe this condition. </li></ul><ul><li>Gaucher's disease is most common in Eastern and Central European (Ashkenazi) Jews. It can occur at any age in life, and affects males and females approximately equally. </li></ul>

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What Is It? <ul><li>Gaucher’s Disease - rare inherited metabolic disease or disorder ; due deficiency or lack of an enzyme called Glucocereborsidase </li></ul><ul><li>Results in an accumulation of glucocerebroside within cells in various body tissues ( spleen, liver, bone marrow, and skeleton) </li></ul><ul><li>Severity of the disease can vary and thus disease divided into following types </li></ul>

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TYPE 1 <ul><li>Most common and can begin at any age </li></ul><ul><li>1 in 10,000 </li></ul><ul><li>Patients are bruised very easily </li></ul><ul><li>Fatigued due to anemia </li></ul><ul><li>Lung and kidney injuries </li></ul><ul><li>Weakening of the skeleton </li></ul>

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TYPE 1 (continued) <ul><li>Victims have a shortened life-span </li></ul><ul><li>Usually die from clots and pneumonia </li></ul>

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TYPE 2 <ul><li>Rarest of all the types </li></ul><ul><li>Appears during the first few months of life in a baby </li></ul><ul><li>Great brain damage – mental retardation </li></ul>

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TYPE 2 (continued) <ul><li>Loss of muscle control </li></ul><ul><li>Enlargement of liver and spleen </li></ul><ul><li>Nervous system fails to function well </li></ul><ul><li>Patients usually die by age 2 </li></ul>

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TYPE 3 <ul><li>Begins in childhood </li></ul><ul><li>Liver and spleen enlargement </li></ul><ul><li>Causes bone marrow and damages the central nervous system </li></ul><ul><li>Mental retardation is quite common </li></ul><ul><li>Usually die around the ages 15-30 </li></ul>

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Symptoms <ul><li>Bone pain </li></ul><ul><li>Victim bruises easily and there are many fractures in their bones </li></ul><ul><li>Difficulty walking </li></ul><ul><li>Blood clotting </li></ul>

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Symptoms (continued) <ul><li>Muscle weakness </li></ul><ul><li>Poor coordination </li></ul><ul><li>Seizures </li></ul>

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How Do You Get It? <ul><li>Acquired if both parents of the disease are carriers </li></ul><ul><li>A victim receives an abnormal form of the genes- a Gaucher Gene from both parents </li></ul><ul><li>Carrier - person with one normal gene and one Gaucher Gene ( a carrier will not show signs of the disease) </li></ul>

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If 2 Carriers Have Children <ul><li>There is a one in four chance of a child inheriting the disease </li></ul>

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Who Has It? <ul><li>10,000 to 20,000 Americans </li></ul><ul><li>High rate found in the Ahkenazi Jewish population-1 out of 500-1000 births </li></ul><ul><li>Types 2 & 3 are found in 1 out of 50,000-100,000 births </li></ul><ul><li>Type 3-mainly found in people of northern Swedish Ancestry </li></ul>

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Prevention <ul><li>No real prevention </li></ul><ul><li>Genetic Counseling is recommended for parents with a family history of the disease </li></ul>

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Treatments <ul><li>No CURE </li></ul><ul><li>Enzyme replacement therapy-injections of the enzyme </li></ul><ul><li>Result: decrease liver and spleen size </li></ul><ul><li> reduce skeletal abnormalities </li></ul><ul><li> restores normal growth & development </li></ul><ul><li> restores well being of the patient </li></ul>

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Hairy cell leukaemia <ul><li>Hairy cell leukaemia is an uncommon disorder of middle and late adult life. </li></ul><ul><li>Characterized by the presence in bone marrow,spleen,and peripheral blood of abnormal mononuclear cells with hairy cytoplasmic projections and best detected by phase contrast microscopy. </li></ul>

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<ul><li>Males affected more than females </li></ul><ul><li>Marked by splenomegaly , however lymphadenopathy is unusual </li></ul><ul><li>Splenectomy is usually regarded as treatment of choice </li></ul><ul><li>Long term use of injections of alpha interferon cause regression of hairy cells </li></ul>

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<ul><li>Hairy cell leukemia is actually a mature B cell neoplasm. It is usually classified as a sub-type of chronic lymphoid leukemia for convenience. It is uncommon, representing about 2% of all leukemias, or less than a total of 2000 new cases diagnosed each year in the North America and Western Europe combined. </li></ul>

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<ul><li>Originally known as histiocytic leukemia, malignant reticulosis, or lymphoid myelofibrosis in publications dating back to the 1920s, this disease was formally named leukemic reticuloendotheliosis </li></ul>

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<ul><li>Symptoms </li></ul><ul><li>In hairy cell leukemia, the broken &quot;hairy cells&quot; build up in the bone marrow, which means that the bone marrow has difficulty producing enough normal cells: white blood cells to fight infections, red blood cells to carry oxygen, and platelets to stop bleeding. Consequently, patients usually present with infection, anemia-related fatigue, and/or easy bleeding. </li></ul>

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Hematologic Disorders Causing Massive Splenomegaly <ul><li>Polycythemia Vera </li></ul><ul><li>Multiple Myeloma </li></ul><ul><li>POEMS Syndrome </li></ul><ul><li>Waldenström's Macroglobulinemia </li></ul><ul><li>chronic lymphocytic leukemia </li></ul><ul><li>non-Hodgkin lymphoma </li></ul><ul><li>chronic myelocytic leukemia </li></ul><ul><li>malaria (hyper-reactive malarial splenomegaly) </li></ul>