1. Gastroenterology Dr. JLeR Malherbe Prof. J Van Zyl
Paper Macrophages
Gastroenterology
Dr. JLeR Malherbe
Prof. J Van Zyl

2. Case Presentation
Mr. V is a 21 year old gentleman of Angolan descent, living in Kimberley and studying computer science
Long standing history of hepatosplenomegaly
Previously diagnosed as having cryptogenic liver cirrhosis with portal hypertension

3. Systemic Enquiry Only complaint is that of a painless enlarged liver
No abdominal pain, nausea or vomiting
Normal bowel habit
No melena or haematemesis
No cardiovascular or respiratory complaints
No nervous system complaints
No joint or bone pain. No other musculoskeletal complaints

4. Examination
Healthy looking young man. Normal growth and development. No dysmorphic features
Normal vital signs
j- a- c- c- o- l-
No nail abnormalities
CVS → 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

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

7. Special Investigations
U/E Na
144 K
3.7 Cl
103 Ur
2.3 Cr 78
Liver Functions
Total Bili 7
Conj Bili 2
Total Prot 82
Alb 41
AST 25
ALT 20
ALP 55
GGT 49
LDH
127
FBC
WCC
3.52
Neutro
1.90
Lympho
1.28 HB
14.2
MCV
80.1
PLT
190
CMP Mg
0.89 Ca
2.44
PO4
1.02
Coagulation PT 13
PTT
37 (2 seconds up)
INR
1.1
Inflammation
CRP 11
ESR 42

8. Special Investigations
Hepatitis A,B and C → Negative
HIV → Negative
Iron Studies → Normal
ANA and Anti-SMA → Negative
Caeruloplasmin → 0.4 (Normal)
Protein Electrophoresis → Polyclonal increase in gammaglobulins. No Beta-gamma bridging

9. 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

10. 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

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

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

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

14. Wrinkled Tissue Paper
Macrophages
GAUCHER’S DISEASE

15. Lysosomal Storage Disease
Inborn error of metabolism
Lysosomes 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

16. 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

17. Gauchers Disease Most common of lysosomal storage diseases
Deficiency → Glucocerebrosidase
Substrate → Glucocerebroside → Component of cell membranes
Accumulation in macrophage lysosomes (wrinkled tissue paper) → spleen, liver and bone marrow

18. 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

19. Clinical Type 1 Type 2 Type 3 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

20. Visceral Disease Splenomegaly Hepatomegaly 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

21. 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

22. Skeletal Disease Osteopenia Osteolytic lesions
Pathologic fractures
Vertebral compression
Osteolytic lesions
Painful 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

23. 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

24. Nervous System (T 2 and 3) Occulomotor dysfunction
Hypertonia and rigidity
Opisthotonus
Swallowing impairment
Seizures and Myoclonus
Dementia
Ataxia
Supranuclear gaze palzy

25. Clinical Course Spectrum of disease
Asymptomatic disease found incidentally in elderly → fulminant disease in children
Die from sequelae of severe bone disease, bleeding complications, infections, liver faliure or severe pulmonary disease

26. Diagnosis Reduced glucocerebrosidase activity in peripheral leukocytes
Mutational analysis
Gaucher cells → Bone marrow (not necessary for diagnosis)
ONCE DIAGNOSIS MADE INVESTIGATION FOCUS ON DETERMINING EXTENT AND SEVERITY OF DISEASE

27. Investigations Radiography DEXA
Fractures, Osteopenia, Lytic lesions
Erlenmeyer Flask deformity
DEXA
MRI femurs/axial skeleton → Bone marrow involvement
MRI/CT/Sonographic volumetric assesment of spleen and liver
FBC → ?Bone Marrow Aspiration/Trephine
S-ACE, TRAP, Chitotriosidase
CXR, Lung functions, Heartsonar

28. Investigations Mr V Skeletal survey reported as normal
DEXA 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 normal
Glucocerebrosidase activity pending

29. Treatment One of few IEM that’s treatable
Recombinant human enzyme → Imiglucerase and velaglucerase alfa → IV 15-60U/kg two weekly
Around R2.5 million/year → 70kg using 60U/kg
Indication
Symptomatic Children
Adults with severe disease → plt <60, liver >2.5x, spleen >15x, radiologic bone disease
Substrate reduction therapy (Miglustat)
Bisphosphonates for osteopenia
Pt need careful regular follow-up to assess disease activity and response

30. Mr V
Clinically Type 1 Gaucher’s disease with bone and visceral involvement
Confirmation with enzyme levels pending
Alendronate 10mg dly, Vit D 800iu dly, Calcium
Will 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

31. Take Home Very rare disease
Must be in differential of unexplained organomegaly → especially massive splenomegaly
Variable presentation/severity/clinical course
Treatment is expensive and requires specialized follow up

32. References Harrison’s Principles of Internal Medicine 17th ed
CM Eng. Genetics, clinical manifestations, and diagnosis of Gaucher disease. UpToDate 18.3
CM Eng. Initial assessment and routine monitoring of Gaucher disease. UpToDate 18.3
CM Eng. Treatment of Gaucher Disease. UpToDate 18.3
Guideline for Gaucher Disease South Africa. Dr. B Henderson