Clinical Case Conference
David Goldberg
February 16, 2011
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
History, cont’d
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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
Physical Exam
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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
Laboratory Values
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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
Questions
• What is in your differential?
• What would you do next in his evaluation?
Ultrasound
1. Mild hepatomegaly and splenomegaly.
2. Uncomplicated cholelithiasis.
3. Altered phasicity of the middle hepatic
vein, likely secondary to diffuse infiltrative
liver disease.
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
Outline
• Briefly define mastocytosis
• Discuss mastocytosis of the
gastrointestinal tract
• Focus on hepatic complications of
mastocytosis
Background
• 1869: Urticaria pigmentosa decribed
• 1877: Mast cells first decribed
– Mastzellen: distended with cytoplasmic
granules
• 1949: First description of mastocytosis
Mastocytosis
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Excessive mast cell accumulation
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Cutaneous
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Urticaria pigmentosa
Telangiectasia macularis eruptiva perstans (TMEP)
Diffuse cutaneous mastocytosis (DCM)
Solitary mastocytoma
Systemic (extracutaneous tissues)
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Indolent systemic mastocytosis (ISM)
Smoldering systemic mastocytosis (SSM)
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Isolated bone marrow mastocytosis (BMM
Systemic mastocytosis with an associated hematologic non-mast cell lineage disorder (SM-AHNMD)
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Associated disorder may be myeloproliferative, myelodysplastic, or lymphoproliferative.
Aggressive systemic mastocytosis (ASM)
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High mast cell burden
Liver or spleen enlargement but no dysfunction
Subtle signs myelodysplasia
Tissue dysfunction
» Hepatic fibrosis and portal hypertension
» Malabsorption
» Cytopenia due to aggressive tissue infiltration
Mast cell leukemia (MCL)
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Immature blasts in bone marrow or blood smear
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
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Episodic mast cell mediator release
Chronic release
Tissue infiltration by mast cells
Associated non-mast cell clonal hematologic disease
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
Triggers for disease
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.
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
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
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
Flushing
• Carcinoid
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Patchy
Violaceous
Lasts few minutes
Postprandial
Not associated with hemodynamic changes
• Systemic mastocytosis
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Bright red
Pruritic
Burning
Other symptoms of mast cell degranulation
Lee et al. World J Gastro 2008
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
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
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.
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
Treatment
• H2 blockers (gastric acid hypersecretion)
– Dyspeptic pain
– Diarrhea
– Malabsorption
– Higher dose
• Cromolyn sodium
– Mast cell membrane stabilizer
– Diarrhea
– Abdominal pain
– Cramps
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