Paper Macrophages

1. 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

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 • GM2Gangliosidoses → 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, liverand 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 • 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 • 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 • 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 • 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 diaphysisintramedullary → 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 velaglucerasealfa → 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 17thed 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