Clinical Case Conference David Goldberg February 16, 2011.
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Transcript of Clinical Case Conference David Goldberg February 16, 2011.
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Clinical Case Conference
David Goldberg
February 16, 2011
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History
• Cc: Ascites and increased LAEs• 64 year-old male with PMH
– Transfusion dependent CMML for several years – S/p 1 cycle chemo (decitabine)– Tongue cancer s/p chemo/xrt 2004
• 1 month increased abdominal distention– Difficulty breathing– Decreased appetite– Abdominal discomfort
• (+) jaundice (unclear time course)• Diarrhea x 1 month
– Frequent loose BMs
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History, cont’d
• Reports testing “positive” for hepatitis B in 1980s• Other PMH: HTN, hyperlipidemia, PTSD• PSH: None• Meds: Amicar, Levoxyl, Flagyl, Ativan• ROS: (+) SOB• Social History: (+) 40 pack years of tobacco,
“social” EtOH• Family History: No FH liver disease
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Physical Exam
• Vitals: BP-113/65, P-79, T-97.4• Gen: Appeared older than stated age• HEENT: Icteric sclerae• CV: RRR, nl s1/s2, no m/r/g• Pulm: CTABl• Abd: Distended abdomen with normal bowel
sounds, (+) fluid wave, (+) shifting dullness, no tenderness
• Neuro: No asterixis• Skin: No palmar erythema or spider angiomata
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Laboratory Values• Uric acid-7.4• LDH-348• CBC: WBC-4.9, Hb-10.4, Plt-28• Chem-7: Normal, Cr-0.93• Alk phos-716• AST-37• ALT-28• Bilirubin-6.2 (3.6 direct)• Hepatitis B: SAg(-), SAb(+), CAb(+), EAb(+)• HCV Ab (-)• Ascites: 120 WBCs, 16,000 RBCs, Albumin-1.1 (serum-2.6)• INR-1.9
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Questions
• What is in your differential?
• What would you do next in his evaluation?
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Ultrasound
1. Mild hepatomegaly and splenomegaly.
2. Uncomplicated cholelithiasis.
3. Altered phasicity of the middle hepatic vein, likely secondary to diffuse infiltrative liver disease.
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TJ Liver Biopsy
• RA pressure: 11/0 (mean 6) mm Hg
• Free hepatic vein pressure: 15/9 (mean 12) mm Hg
• Wedged right hepatic vein pressure: 45/28 (mean 37) mm Hg
• Corrected sinusoidal pressure: 25 mm Hg
• Tryptase 582
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Outline
• Briefly define mastocytosis
• Discuss mastocytosis of the gastrointestinal tract
• Focus on hepatic complications of mastocytosis
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Background
• 1869: Urticaria pigmentosa decribed
• 1877: Mast cells first decribed– Mastzellen: distended with cytoplasmic
granules
• 1949: First description of mastocytosis
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Mastocytosis• Excessive mast cell accumulation
– Cutaneous• Urticaria pigmentosa• Telangiectasia macularis eruptiva perstans (TMEP) • Diffuse cutaneous mastocytosis (DCM) • Solitary mastocytoma
– Systemic (extracutaneous tissues)• Indolent systemic mastocytosis (ISM)• Smoldering systemic mastocytosis (SSM)
– High mast cell burden– Liver or spleen enlargement but no dysfunction– Subtle signs myelodysplasia
• Isolated bone marrow mastocytosis (BMM• Systemic mastocytosis with an associated hematologic non-mast cell lineage disorder (SM-AHNMD)
– Associated disorder may be myeloproliferative, myelodysplastic, or lymphoproliferative. • Aggressive systemic mastocytosis (ASM)
– Tissue dysfunction» Hepatic fibrosis and portal hypertension» Malabsorption» Cytopenia due to aggressive tissue infiltration
• Mast cell leukemia (MCL)– Immature blasts in bone marrow or blood smear
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Mastocytosis
• Mast cells– Protects body from microbes and other insults– Generates inflammatory responses– Releases
• histamine, heparin, leukotrienes, prostaglandins, platelet activating factor, proteases, and cytokines, including tumor necrosis factor (TNF)
– Response from release• Allergic• Anaphylactic
• Disease– Episodic mast cell mediator release– Chronic release– Tissue infiltration by mast cells– Associated non-mast cell clonal hematologic disease
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Skin findings
• Darier’s sign– Urticaria and erythema within 5 minutes of
scratching, rubbing, or stroking skin or skin lesions that are heavily infiltrated with mast cells
Urticaria Pigmentosa: Reddish brown spots that will turn into hives when they are rubbed hard or scratched
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Triggers for disease
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Diagnosis
• One major and one minor or three minor• Major criteria
– Presence in bone marrow or extracutaneous organ of multifocal dense aggregates of greater than 15->tryptase or other special stains
• Minor criteria– Atypical morphology or spindle shapes in >25 percent of the
mast cells in bone marrow sections, bone marrow aspirate, or other extracutaneous tissues
– Mutational analysis of KIT showing a codon 816 mutation (eg, Asp816Val) in bone marrow, blood, or extracutaneous organs
– Bone marrow or other extracutaneous mast cells expressing the surface markers CD2, CD25, or both
– Serum tryptase levels (when the patient is in a baseline state) >20 ng/mL.
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GI tract and SM
• 16 consecutive patients with systemic mastocytosis– 9 w/ DU or duodenitis– Gastric acid hypersecretion in 6
• Mean BAO 20.7 mEq/h
– Increase plasma histamine• Correlated with BAO• Decreased gastrin
– Abdominal pain or diarrhea• 80% patients
– PUD: 15-44%
Cherner et al. Gastroenterology 1988
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GI tract and SM
• 14-85% cases– 16 series– Since 1985: 60-80%
• GI symptoms– Abdominal pain (51%)– Diarrhea (43%)– Nausea/vomiting (28%)
• Secondary to mast cell mediators
Lee et al. World J Gastro 2008
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GI tract and SM
• Abdominal pain– Epigastric: Ulcer disease and acid hypersecretion– Lower abdominal: Cramping due to motility
• Diarrhea– Gastric acid hypersecretion
• Volume of gastric acid• Mucosal injury/ulceration->secretory diarrhea• Inhibits pancreatic enzymes
– Steatorrhea->lipase– Altered bowel motility– Malabsorption
• Mucosal injury• Edema
Lee et al. World J Gastro 2008
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Flushing
• Carcinoid– Patchy – Violaceous– Lasts few minutes– Postprandial– Not associated with hemodynamic changes
• Systemic mastocytosis– Bright red– Pruritic– Burning– Other symptoms of mast cell degranulation
Lee et al. World J Gastro 2008
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Liver disease and SM
• Hepatomegaly– 41-72%– More commonly seen in more advanced/aggresisive
disease• Cirrhosis
– 4% patients• LAE abnormalities
– Alk phos more common– Correlates with severity of disease, degree of fibrosis,
and mast cell load• Portal venopathy or VOD
Lee et al. World J Gastro 2008
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Portal Hypertension
• Portal hypertension– Intrahepatic venous obstruction
• Fibrosis in portal areas or hepatic sinusoids– Pre- and post-sinusoidal blockage secondary to mast
cell infiltration and/or fibrosis– Increased splenic vein blood flow
• AV shunts in spleen->vasodilators– Hepatic venous outflow obstruction– Occurs in 10-40% of patients– Ascites common
Jensen R et al. Hematology/Oncology Clinics of North America 2000
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Liver disease and SM
• 182 patients with generalized mastocytosis– 52 own cases 130 from literature– 131 (72%) with hepatomegaly– 25 (14%) with periportal fibrosis– 7 (4%) with cirrhosis– 77 (42%) with confirmed mast cell infiltration
histologically• Predominantly in portal tracts• Loosely scattered throughout sinusoids
Horny et al. Cancer 1989.
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Liver disease and SM• Portal hypertension
– 4 cases SM, 3 with portal HTN and ascites1
• No cirrhosis on liver biopsy• Lab findings c/w autoimmune cholangitis• Non-cirrhotic portal HTN->erroneous diagnosis of cirrhosis
– 49 F p/w 6 weeks ascites• Liver biopsy w/ periportal fibrosis• Sinusoidal infiltrate suggestive of myeloid leukaemia• Centrilobular cell loss and congestion c/w hepatic venous outflow
obstruction• Initially diagnosed with CMML• Toluidine blue stain showed mast cells in portal tracts
• Intrahepatic cholestasis– 35 F w/ mast cells in portal tracts and centrizonal cholestasis3
• Nl ERCP• Cholestatic labs resolved with chemo
1-Kyriakou et al. Am J Gastro 1998; 2-Naryanan Post Grad Med Journal 1989; 3-Safyan et al. Am J Gastro 1997
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Treatment
• H2 blockers (gastric acid hypersecretion)
– Dyspeptic pain– Diarrhea– Malabsorption– Higher dose
• Cromolyn sodium– Mast cell membrane stabilizer– Diarrhea – Abdominal pain– Cramps
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Conclusions
• Mastocytosis is a rare disorder resulting from excessive mast cell accumulation
• GI tract can be involved, leading to PUD and diarrhea
• Liver commonly involved in SM, and can result in portal hypertension, cirrhosis, and associated complications