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

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

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

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

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

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

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

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.

Wrinkled Tissue Paper Macrophages GAUCHER’S DISEASE

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

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 diseases Deficiency → Glucocerebrosidase Substrate → Glucocerebroside → Component of cell membranes Accumulation 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 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

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

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 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

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 dysfunction Hypertonia and rigidity Opisthotonus Swallowing impairment Seizures and Myoclonus Dementia Ataxia Supranuclear gaze palzy

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

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

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

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

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

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

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

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