GASTROENTEROLOGYDR. JLER MALHERBE

PROF. J VAN ZYL

Paper Macrophages

Case Presentation

Mr. V is a 21 year old gentleman of Angolan descent, living in Kimberley and studying computer science

Long standing history of hepatosplenomegalyPreviously diagnosed as having cryptogenic

liver cirrhosis with portal hypertension

Systemic Enquiry

Only complaint is that of a painless enlarged liver

No abdominal pain, nausea or vomitingNormal bowel habitNo melena or haematemesisNo cardiovascular or respiratory complaintsNo nervous system complaintsNo joint or bone pain. No other

musculoskeletal complaints

Examination

Healthy looking young man. Normal growth and development. No dysmorphic features

Normal vital signsj- a- c- c- o- l- No nail abnormalitiesCVS → normal apex, normal jvp, normal heart

sounds, no added sounds or murmers, no signs of pulmonary hypertension

RESP→ normal chest expansion and air entry. No added sounds

Examination

ABD Hepatomegaly with span of 17cm. Spleen not palpable. No tenderness Normal bowel sounds No distended veins No spider naevi

Special Investigations

U/ENa 144K 3.7Cl 103Ur 2.3Cr 78

Liver FunctionsTotal Bili 7Conj Bili 2Total Prot 82Alb 41AST 25ALT 20ALP 55GGT 49LDH 127

CMPMg 0.89Ca 2.44PO4

1.02

FBCWCC 3.52Neutro 1.90Lympho 1.28HB 14.2MCV 80.1PLT 190CoagulationPT 13PTT 37 (2 seconds

up)INR 1.1Inflammation

CRP 11ESR 42

Special Investigations

Hepatitis A,B and C → NegativeHIV → NegativeIron Studies → NormalANA and Anti-SMA → NegativeCaeruloplasmin → 0.4 (Normal)Protein Electrophoresis → Polyclonal increase

in gammaglobulins. No Beta-gamma bridging

Special Investigations

Abdominal Sonar → Normal liver architecture, portal vein flow and size normal

Liver Spleen Scintography → Diffusely enlarged liver. Spleen moderately enlarged. Normal uptake

Liver Biopsy

H&E, 25 mag. Low power overview of liver biopsy shows expansion of the portal tracts and periportal regions with enlarged macrophages and Kupffer cells

H&E 100 mag. Periseptal and intra-lobular aggregates of enlarged Kupffer cells

H&E 400 mag. Closer view of enlarged periportal macrophages with striated wrinkled cytoplasm

PAS stain, 400mag. The cytoplasmic striations within the Kupffer cells are enhanced with a PAS stain.

GAUCHER’S DISEASE

Wrinkled Tissue PaperMacrophages

Lysosomal Storage Disease

Inborn error of metabolismLysosomes derived from fusion of trans-Golgi

network vesicles Synthesis of new membranes and membrane

constitutive proteins Complex hydrolyase enzyme system for processing

and degradation of proteins, nucleic acids, carbohydrates and lipids

Lysosomal Storage Disease

Mutation → Deficiency of specific enzyme → accumulation of substrate More than 30 diseases Mucopolysaccharidoses → Hurler GM2 Gangliosidoses → Tay-Sachs Neutral Lipids → Pompe Glycosphingolipidoses → Gaucher, Niemann-Pick,

Fabry

Gauchers Disease

Most common of lysosomal storage diseasesDeficiency → Glucocerebrosidase Substrate → Glucocerebroside → Component

of cell membranesAccumulation in macrophage lysosomes

(wrinkled tissue paper) → spleen, liver and bone marrow

Genetics

1 in 1000 Ashkenazi Jews<1 in 100 000 other populations> 250 mutations → 4 common in 85%

N370S, L44P, 84GG, IVS-2 Phenotypic/Genotypic linkage

Clinical

Type 1 Most common type → 90% N370S/N370S Visceral involvement, No neurology Variable severity

Type 2 Severe early neurological disease, die by 2 years

Type 3 Variable neurological and visceral disease

Visceral Disease

Splenomegaly Most common presenting sign Mild to Massive (5 to 75x normal size) Early satiety, abdominal discomfort, Hypersplenism Splenic infarct → Acute abdomen

Hepatomegaly Universal Usually less severe than splenomegaly (2 to 3x normal) Hepatic fibrosis common → Hepatic failure, cirrhosis,

portal HPT uncommon

Skeletal Disease

Two pathologic processes in bone: Bone marrow encroachment by lipid-laden

macrophages Anemia Thrombocytopaenia Bleeding

Decreased mineral density → Osteopenia Uncertain mechanism Abnormal osteoclast regulation or overproduction of cytokines by activated

macrophages

Skeletal Disease

Osteopenia Pathologic fractures Vertebral compression

Osteolytic lesionsPainful crises → Osteonecrosis (AVN/Bone

infarction) Proximal and distal femur, proximal tibia and humerus

94% radiological evidence, 63% Bone pain, 33% bone crises, 8% joint pain

Other Manifestations

Growth retardation in children → Most catch up later

Interstitial Lung disease → Infiltration of alveolar spaces and interstitium

Pulmonary hypertension → Occlusion of pulmonary capillaries

Increased risk of haematologic malignancies especially myeloma

Nervous System (T 2 and 3)

Occulomotor dysfunctionHypertonia and rigidityOpisthotonusSwallowing impairmentSeizures and MyoclonusDementiaAtaxiaSupranuclear gaze palzy

Clinical Course

Spectrum of disease Asymptomatic disease found incidentally in elderly →

fulminant disease in childrenDie from sequelae of severe bone disease,

bleeding complications, infections, liver faliure or severe pulmonary disease

Diagnosis

Reduced glucocerebrosidase activity in peripheral leukocytes

Mutational analysisGaucher cells → Bone marrow (not necessary

for diagnosis)

ONCE DIAGNOSIS MADE INVESTIGATION FOCUS ON DETERMINING EXTENT AND SEVERITY OF DISEASE

Investigations

Radiography Fractures, Osteopenia, Lytic lesions Erlenmeyer Flask deformity

DEXAMRI femurs/axial skeleton → Bone marrow

involvementMRI/CT/Sonographic volumetric assesment of

spleen and liverFBC → ?Bone Marrow Aspiration/TrephineS-ACE, TRAP, ChitotriosidaseCXR, Lung functions, Heartsonar

Investigations Mr V

Skeletal survey reported as normalDEXA scan → AP spine Z score -2.7

Metabolic screen (Calcium, PTH, Vit D, Testosterone, Prolactin) negative for other causes

MRI femurs → Small areas of low signal intensity in metaphysis and diaphysis intramedullary → Early bone marrow involvement

CXR, Lung Functions, Heartsonar normalGlucocerebrosidase activity pending

Treatment

One of few IEM that’s treatable Recombinant human enzyme → Imiglucerase and

velaglucerase alfa → IV 15-60U/kg two weeklyAround R2.5 million/year → 70kg using 60U/kgIndication

Symptomatic Children Adults with severe disease → plt <60, liver >2.5x, spleen

>15x, radiologic bone diseaseSubstrate reduction therapy (Miglustat) Bisphosphonates for osteopeniaPt need careful regular follow-up to assess disease

activity and response

Mr V

Clinically Type 1 Gaucher’s disease with bone and visceral involvement

Confirmation with enzyme levels pendingAlendronate 10mg dly, Vit D 800iu dly,

CalciumWill be followed by Dr. Henderson of Human

Genetics Decision on possible low dose enzyme replacement

will be made after discussion with Gaucher’s disease committee

Take Home

Very rare diseaseMust be in differential of unexplained

organomegaly → especially massive splenomegaly

Variable presentation/severity/clinical courseTreatment is expensive and requires

specialized follow up

References

1. Harrison’s Principles of Internal Medicine 17th ed2. CM Eng. Genetics, clinical manifestations, and diagnosis of Gaucher

disease. UpToDate 18.33. CM Eng. Initial assessment and routine monitoring of Gaucher

disease. UpToDate 18.34. CM Eng. Treatment of Gaucher Disease. UpToDate 18.35. Guideline for Gaucher Disease South Africa. Dr. B Henderson