Massive Splenomegaly By Dr Bashir Ahmed Dar Chinkipora Sopore Kashmir Associate Professor Medicine

SPLENOMEGALY

By Dr Bashir Ahmed DarBy Dr Bashir Ahmed Dar

Associate Professor MedicineAssociate Professor Medicine

Chinkipora Sopore KashmirChinkipora Sopore Kashmir

Email [email protected] [email protected]

Slight enlargement just palpable (less

than 5 cm) Infections –acute,subacute and chronicInfections –acute,subacute and chronic SLESLE Rheumatoid arthritisRheumatoid arthritis AmyloidosisAmyloidosis

Moderate enlargement (to umbilicus) LymphomasLymphomas LeukaemiasLeukaemias Congestive splenomegalyCongestive splenomegaly Haemolytic anaemiasHaemolytic anaemias Polycythaemia VeraPolycythaemia Vera ITPITP Myelodysplastic disordersMyelodysplastic disorders

Marked enlargement (more than 8 cm or below umbilicus) MyelofibrosisMyelofibrosis Hairy cell leukaemiaHairy cell leukaemia Tropical splenomegalyTropical splenomegaly Kala azarKala azar Thalassaemia majorThalassaemia major Gaucher’s diseaseGaucher’s disease Felty’s syndromeFelty’s syndrome

Infective causes of splenomegaly

Acute causesAcute causes Infectious mononucleosisInfectious mononucleosis TyphoidTyphoid BrucellosisBrucellosis Infective hepatitisInfective hepatitis ToxoplasmosisToxoplasmosis TyphusTyphus SepticaemiaSepticaemia

Infective causes of splenomegaly Subacute and chronic causesSubacute and chronic causes Bacterial endocarditisBacterial endocarditis TuberculosisTuberculosis BrucellosisBrucellosis SyphilisSyphilis HistoplasmosisHistoplasmosis MalariaMalaria Kala azarKala azar HydatidHydatid TrypanosomiasisTrypanosomiasis

Massive splenomegaly

Rheumatoid arthritis (Felty’s syndrome)

Comprises of Comprises of Arthritis,Splenomegaly,LeucopeniaArthritis,Splenomegaly,Leucopenia

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

Investigations Felty's syndrome

high Rf titre in 98% high Rf titre in 98% ANA in 67% ANA in 67% elevated ESR, immunoglobulins, circulating elevated ESR, immunoglobulins, circulating

immune complexes immune complexes positive LE cell test in 33% positive LE cell test in 33% decreased complement levels decreased complement levels elevated transaminases and alkaline elevated transaminases and alkaline

phosphatase in 25-50% phosphatase in 25-50%

Tropical Splenomegaly

In tropical areas massive splenomegaly In tropical areas massive splenomegaly often seenoften seen

Areas like Uganda,Nigeria,new guinea and Areas like Uganda,Nigeria,new guinea and other parts of Africaother parts of Africa

The evidence suggests a relationship The evidence suggests a relationship between malaria and tropical splenomegalybetween malaria and tropical splenomegaly

Rarely occurs in malarial free areasRarely occurs in malarial free areas

Tropical Splenomegaly

Malarial parasite are not routinely seen in blood Malarial parasite are not routinely seen in blood films of ptsfilms of pts

The disorder usually presents in young adult life The disorder usually presents in young adult life but may occur in childrenbut may occur in children

The diagnosis is usually made by exclusion of The diagnosis is usually made by exclusion of other causesother causes

There may also be 10 fold increase polyclonal igM There may also be 10 fold increase polyclonal igM concentration in serum of which small portion concentration in serum of which small portion represents malarial antibodies liver may also show represents malarial antibodies liver may also show lymphocytic infiltrationlymphocytic infiltration

Kala azar (leishmaniasis)

Visceral leishmaniasis Visceral leishmaniasis Cutaneous leishmaniasis Cutaneous leishmaniasis Mucocutaneous leishmaniasis (espundia)Mucocutaneous leishmaniasis (espundia) Diffuse Cutaneous leishmaniasisDiffuse Cutaneous leishmaniasis

kala azar, black fever, sandfly disease, Dum-Dum fever and

espundia.

SYNONYMS

Protozoanin the family Trypanosomatidae

In the genus Leishmania

EstimatesAll over world exceptNot found in South-east Asia 350 million people at risk12 million people infected / yearThere are 59,000 deaths / year

Incubation – 1 week to monthsIncubation – 1 week to months Having (many reservoirs)Having (many reservoirs) No direct person to person transmissionNo direct person to person transmission Spontaneous healing can happen (cutaneous Spontaneous healing can happen (cutaneous

form) in months to yearsform) in months to years No vaccineNo vaccine

Some Facts

LEISHMANIASIS or KALA-AZAR

It is the result of the infection with one It is the result of the infection with one of the species of protozoa (leishmania). of the species of protozoa (leishmania). Conveyed by:Conveyed by:

Sandflies (Phlebotomus).Sandflies (Phlebotomus).

Visceral LeishmaniasisVisceral Leishmaniasis: L. donovani: L. donovani

MucocutaneousMucocutaneous : L. Braziliensis : L. Braziliensis

Have specific reservoirs

Leishmania Parasites

Rodents

Sloths

VectorsPhlebotomine Sand Flies

20 to 40 days

30 to 70 eggs

hatch 1 to 2 weeks

4 instars

diapauses in 4th instar

pupa

l dev

elop

men

t

5-10

day

sadults crepuscular

and nocturnal

Opossum

Armadillo

Visceral LeishmaniasisVisceral Leishmaniasis:: L. donovaniL. donovani MucocutaneousMucocutaneous L. BraziliensisL. Braziliensis

Cutaneous : L. tropica major L. tropica minor

New World : L. Braziliensis L. Mexicana

Oldworld

PATHOLOGY»» L. donovani parasitizes the L. donovani parasitizes the reticu. endoth. reticu. endoth. cellscells

»» Great proliferation of macrophageGreat proliferation of macrophage

»» Cells result:Cells result: Liver – spleen Liver – spleen enlarg.enlarg.

»» The red bone marrow extendThe red bone marrow extend..

»

Leishmania: an obligate intracellular protozoan parasite (2-6 µm in diameter)

parasitophorous

vacuoles of

macrophages

Promastigotes in Sand Fly gut and in Culture Media

(about 15-30 µm

by 2-3 µm),

Amastigote in macrophage

The The amostigotes of amostigotes of different different species are species are very similar on very similar on light light microscopy.microscopy.

CLINICAL PICTURE early stages is not easy for diagnose. early stages is not easy for diagnose.

There is no constant There is no constant physical signs.physical signs.

☺☺ Changes in the blood picture Changes in the blood picture particularly particularly Leucopenia.Leucopenia.☺☺ Outstanding physical sign is the Outstanding physical sign is the enlargement of the spleen 3 cm. a enlargement of the spleen 3 cm. a month.month.

●● LiverLiver : enlarged spleen + liver are : enlarged spleen + liver are neither tender nor painful. neither tender nor painful.

● ● SometimesSometimes: Jaundice = prognost. : Jaundice = prognost. Significance Significance

● ● Enlarged Enlarged : Lymph node, could be : Lymph node, could be but its not a feature of the but its not a feature of the disease. disease.

●● WastingWasting : Emaciated pat with a : Emaciated pat with a protuberant protuberant

Abdomen ( liver + spleen Abdomen ( liver + spleen enlarged) enlarged)

●●FeverFever : Without subjective symptoms : Without subjective symptoms of fever – no delirium. of fever – no delirium.

● ● SometimesSometimes: there is no fever: there is no fever

● ● SkinSkin: dry, rough. The natural : dry, rough. The natural pigmentation of the skin over pigmentation of the skin over the the bone and around the bone and around the mouth is mouth is deepened. (Kala deepened. (Kala azar??) azar??)

Clinical Forms of Leishmaniasis

• Cutaneous

• Mucocutaneous

• Diffuse Cutaneous

• Visceral

Cutaneous form

Wet lesion by L. major

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.

These are the commonest types of lesion caused by L. major.Prominent ‘rolled’ edge of the lesions is the best area to demonstrate the parasites

Lymphatic spread of L. major

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.The nodules usually resolve without complications when the primary lesin heals with or without specific therapy.

Clinical Forms of

Leishmaniasis

Simple ‘dry’ lesion by L. tropica

dry, usually self-healing lesions, Generally singleUrban area in North Africa and the Middle East to the former USSR, Afghanistan, western states of IndiaThe lesions frequently contain very large numbers of parasites.

Leishmaniasis recidivans

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

Mucocutaneous lesion by L. aethiopica

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.

Chiclero’s ulcer by L. mexicana

Forest workers Forest workers collecting gum from collecting gum from wild chicle trees wild chicle trees commonly sleep commonly sleep near the forest floor near the forest floor and are bitten on and are bitten on exposed parts of the exposed parts of the head by vectors.head by vectors.

Ulcers leading to Ulcers leading to erosion of the erosion of the auricular cartilage.auricular cartilage.

Lymphatic spread of

L. mexicana

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

Early lesion of Espundia

The lesions of The lesions of mucocutaneous mucocutaneous leishmaniasisleishmaniasis due to infection due to infection with with L. braziliensisL. braziliensis may first may first become evident as ulcers become evident as ulcers involving the mucocutaneous involving the mucocutaneous junctions of the mouth and junctions of the mouth and nosenose

This condition frequently This condition frequently follows a primary cutaneous follows a primary cutaneous lesion which may have healed lesion which may have healed with or without specific with or without specific therapy some years earlier.therapy some years earlier.

Pharyngeal involvement

Ulceration often extends to the pharynx and soft palate, and the first symptoms may be related to tissue destruction in this area.

This man had the scar of a large ulcer which had apparently healed on his leg some 30 years before.

PKDLPost Kalazar Dermal Leishmaniasis

Visceral form

Clinical picture of kala-azar in Kenya

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’.

A generalized lymphadenopathy is common in African kala-azar; the parasite in this area is considered to be in the L. donovani complex.

Diagnosis

Demonstration of Parasite from aspirateDemonstration of Parasite from aspirate- lymph node- lymph node ; inguinal LN, sensitivity 60% ; inguinal LN, sensitivity 60%- bone marrow- bone marrow ; iliac crest, sensitivity 70% ; iliac crest, sensitivity 70%- spleen; sensitivity 95~99%- spleen; sensitivity 95~99%- liver- liver

PB smear (HIV infected patient)PB smear (HIV infected patient) SerologySerology

- a- avoid the necessity for the more invasive procedurevoid the necessity for the more invasive procedure- direct agglutination test- direct agglutination test

PCRPCR

Iliac crest aspiration of bone marrow

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.

L. infantum in macrophage from bone marrow

While typically found in macrophages as shown here, While typically found in macrophages as shown here, isolated extracellular amastigotes from disrupted host isolated extracellular amastigotes from disrupted host cells are commonly seen in such preparations.cells are commonly seen in such preparations.

Amastigotes in macrophage from skin

The diagnosis is confirmed by demonstraing amastigotes in smear made from the cutaneous lesions.

Punch biopsy

A piece of tissue may be removed under local anesthetic with a disposable skin punch for histology, culture and the direct demonstration of amastigotes.

Parasitised macrophage in skin section

Many parasitised macrophages can be seen in this section from an acute lesion caused by L. major.

DIAGNOSIS1.1. Needle aspirationNeedle aspiration

Bone – sternum – liver, spleenBone – sternum – liver, spleenHistology – cultureHistology – cultureL. donovani bodyL. donovani body

2.2. a.a. LeucopeniaLeucopenia:: Neutropenia – Neutropenia – relative mononucleosis.relative mononucleosis.

b.b. Progressive fall with the red cell Progressive fall with the red cell countcount

3.3. Formalin gel (aldehydeFormalin gel (aldehyde))

2 drops formalin + 2 ml serum2 drops formalin + 2 ml serum

After 20 min, white ringAfter 20 min, white ring

4.4. Complement fixation and fluorescentComplement fixation and fluorescentFalse positive trypanosomal infectionFalse positive trypanosomal infection

5.5. The complement fixationThe complement fixation – early positive – – early positive – negative after cure. Sometimes + or – lung. Other negative after cure. Sometimes + or – lung. Other diseases.diseases.

6.6. Fluorescent antibodyFluorescent antibody

7.7. IV + V:IV + V: In trypanosomal infection In trypanosomal infection

8.8. Skin test (Montenegro)Skin test (Montenegro)Delayed hypersensitivity reactionDelayed hypersensitivity reaction

0.2 ml. suspension0.2 ml. suspension

TREATMENT1.1. Antimonial Antimonial – –

i.i. Urea, stibamine, pentavalen + antmonyiaUrea, stibamine, pentavalen + antmonyia I.V. daily or every 2 daysI.V. daily or every 2 days 6 – 10 dose6 – 10 dose First 100 mg then 200 then 250First 100 mg then 200 then 250 Total dose 2 – 5 g. adultTotal dose 2 – 5 g. adult

Side EffectSide Effect:: Nausea, vomiting, joint pain, Nausea, vomiting, joint pain, Abdominal pain, diarrhea Abdominal pain, diarrhea

ContraindicationContraindication:: Liver and kidney Liver and kidney failurefailure

ii.ii. Sodium stibogluconate (Pentostam Sodium stibogluconate (Pentostam)) I.M. – 600 mg total daily for 6-10 daysI.M. – 600 mg total daily for 6-10 days Repeated after 14 days; if neededRepeated after 14 days; if needed Side effectSide effect::Anaphylactic shockAnaphylactic shock

2.2. Diamidiem – Diamidiem – Pentamidine isothionatePentamidine isothionate Dose 3 -4 mg / kg / BW total 300 mgDose 3 -4 mg / kg / BW total 300 mg

Side effectSide effect:: HypoglycemiaHypoglycemia

Treatment

Sodium stibogluconateSodium stibogluconate Pentavalent antimony (SbPentavalent antimony (Sb+5+5))

demonstration of amastigotes(L. donovani bodies) demonstration of amastigotes(L. donovani bodies)

intracellular form is usually 2-4 micron consists of intracellular form is usually 2-4 micron consists of nucleus and is rod like with a homogeneous mass nucleus and is rod like with a homogeneous mass of cytoplasm,while the extracelluar or culture of cytoplasm,while the extracelluar or culture form is14-20 microns in length 1.5 to 3.5 breadthform is14-20 microns in length 1.5 to 3.5 breadth

L. donovani bodyL. donovani body

Myelofibrosis or myelosclerosis

Fibrosis and collagen formation in marrowFibrosis and collagen formation in marrow Primary –developing in polycythemia veraPrimary –developing in polycythemia vera Secondary – in TB,secondary Secondary – in TB,secondary

carcinoma,hodgkins disease,leukaemia,and carcinoma,hodgkins disease,leukaemia,and variety of other conditions.variety of other conditions.

Myeloid metaplasia ,spleenomegaly Myeloid metaplasia ,spleenomegaly hepatomaegaly etc etchepatomaegaly etc etc

GAUCHER’S DISEASE

History

Discovered by Philippe Gaucher, a medical Discovered by Philippe Gaucher, a medical student in Paris, in 1882.student in Paris, in 1882.

He was studying a woman with an enlarged He was studying a woman with an enlarged spleenspleen

DefinitionDefinition Gaucher's (go-SHAYZ) disease occurs Gaucher's (go-SHAYZ) disease occurs

when certain harmful fatty substances when certain harmful fatty substances build to excessive levels in your liver, build to excessive levels in your liver, spleen, lungs, bone marrow and, less spleen, lungs, bone marrow and, less commonly, your brain. This accumulation commonly, your brain. This accumulation of fatty material in tissues interferes with of fatty material in tissues interferes with the normal functioning of organs, and the normal functioning of organs, and may cause organ enlargement and bone may cause organ enlargement and bone pain.pain.

Gaucher's disease results from an Gaucher's disease results from an enzyme deficiency, and sometimes the enzyme deficiency, and sometimes the term "glucocerebrosidase deficiency" is term "glucocerebrosidase deficiency" is used to describe this condition.used to describe this condition.

Gaucher's disease is most common in Gaucher's disease is most common in Eastern and Central European Eastern and Central European (Ashkenazi) Jews. It can occur at any (Ashkenazi) Jews. It can occur at any age in life, and affects males and age in life, and affects males and females approximately equally.females approximately equally.

What Is It?

Gaucher’s DiseaseGaucher’s Disease- rare inherited metabolic - rare inherited metabolic disease or disorder ; due deficiency or lack of an disease or disorder ; due deficiency or lack of an enzyme called enzyme called GlucocereborsidaseGlucocereborsidase

Results in an accumulation of Results in an accumulation of glucocerebrosideglucocerebroside within cells in various body tissues ( spleen, liver, within cells in various body tissues ( spleen, liver, bone marrow, and skeleton)bone marrow, and skeleton)

Severity of the disease can vary and thus disease Severity of the disease can vary and thus disease divided into following typesdivided into following types

TYPE 1

Most common and can begin at any ageMost common and can begin at any age

1 in 10,000 1 in 10,000 Patients are bruised very easily Patients are bruised very easily Fatigued due to anemiaFatigued due to anemia Lung and kidney injuriesLung and kidney injuries Weakening of the skeletonWeakening of the skeleton

TYPE 1 (continued)

Victims have a shortened life-spanVictims have a shortened life-span

Usually die from clots and pneumoniaUsually die from clots and pneumonia

TYPE 2

Rarest of all the typesRarest of all the types

Appears during the first few months of life Appears during the first few months of life in a babyin a baby

Great brain damage – mental retardationGreat brain damage – mental retardation

TYPE 2 (continued)

Loss of muscle controlLoss of muscle control

Enlargement of liver and spleenEnlargement of liver and spleen

Nervous system fails to function wellNervous system fails to function well

Patients usually die by age 2Patients usually die by age 2

TYPE 3

Begins in childhoodBegins in childhood Liver and spleen enlargement Liver and spleen enlargement Causes bone marrow and damages the Causes bone marrow and damages the

central nervous systemcentral nervous system Mental retardation is quite commonMental retardation is quite common Usually die around the ages 15-30 Usually die around the ages 15-30

Symptoms

Bone painBone pain

Victim bruises easily and there are many Victim bruises easily and there are many fractures in their bonesfractures in their bones

Difficulty walkingDifficulty walking Blood clottingBlood clotting

Symptoms (continued)

Muscle weaknessMuscle weakness

Poor coordinationPoor coordination

SeizuresSeizures

How Do You Get It?

Acquired if both parents of the disease are Acquired if both parents of the disease are carrierscarriers

A victim receives an abnormal form of the A victim receives an abnormal form of the genes- a genes- a Gaucher GeneGaucher Gene from both parents from both parents

CarrierCarrier- person with one normal gene and - person with one normal gene and one Gaucher Gene ( a carrier will not show one Gaucher Gene ( a carrier will not show signs of the disease)signs of the disease)

If 2 Carriers Have Children

There is a one in four chance of a There is a one in four chance of a child inheriting the diseasechild inheriting the disease

Who Has It?

10,000 to 20,000 Americans10,000 to 20,000 Americans High rate found in the Ahkenazi Jewish High rate found in the Ahkenazi Jewish

population-1 out of 500-1000 birthspopulation-1 out of 500-1000 births Types 2 & 3 are found in 1 out of 50,000-Types 2 & 3 are found in 1 out of 50,000-

100,000 births100,000 births Type 3-mainly found in people of northern Type 3-mainly found in people of northern

Swedish AncestrySwedish Ancestry

Prevention

No real preventionNo real prevention

Genetic Counseling is recommended for Genetic Counseling is recommended for parents with a family history of the diseaseparents with a family history of the disease

Treatments

No No CURECURE Enzyme replacement therapy-injections of Enzyme replacement therapy-injections of

the enzyme the enzyme Result: decrease liver and spleen sizeResult: decrease liver and spleen size reduce skeletal abnormalitiesreduce skeletal abnormalities

restores normal growth & restores normal growth & developmentdevelopment

restores well being of the patientrestores well being of the patient

Hairy cell leukaemia

Hairy cell leukaemia is an uncommon Hairy cell leukaemia is an uncommon disorder of middle and late adult life.disorder of middle and late adult life.

Characterized by the presence in bone Characterized by the presence in bone marrow,spleen,and peripheral blood of marrow,spleen,and peripheral blood of abnormal mononuclear cells with hairy abnormal mononuclear cells with hairy cytoplasmic projections and best detected cytoplasmic projections and best detected by phase contrast microscopy.by phase contrast microscopy.

Males affected more than femalesMales affected more than females Marked by splenomegaly , however Marked by splenomegaly , however

lymphadenopathy is unusual lymphadenopathy is unusual Splenectomy is usually regarded as Splenectomy is usually regarded as

treatment of choicetreatment of choice Long term use of injections of alpha Long term use of injections of alpha

interferon cause regression of hairy cellsinterferon cause regression of hairy cells

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

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

SymptomsSymptoms

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

Hematologic Disorders Causing Massive Splenomegaly Polycythemia VeraPolycythemia Vera Multiple MyelomaMultiple Myeloma POEMS SyndromePOEMS Syndrome Waldenström's MacroglobulinemiaWaldenström's Macroglobulinemia chronic lymphocytic leukemiachronic lymphocytic leukemia non-Hodgkin lymphomanon-Hodgkin lymphoma chronic myelocytic leukemiachronic myelocytic leukemia malaria (hyper-reactive malarial malaria (hyper-reactive malarial

splenomegaly)splenomegaly)