Unknown case Unknown case conferenceconference

May 2008May 2008

Chief complaint and Chief complaint and historyhistory

59 year old woman59 year old woman Worsening abdominal pain, Weight loss Worsening abdominal pain, Weight loss

((↓30 lb) past 4 months↓30 lb) past 4 months Pain: right sided, no radiation, dull, Pain: right sided, no radiation, dull,

constant, eating worsens, also nausea, constant, eating worsens, also nausea, vomiting and “bloating”.vomiting and “bloating”.

ROS: Fatigue, loss of appetite, short of ROS: Fatigue, loss of appetite, short of breath, frequent urination, ear pain.breath, frequent urination, ear pain.

Seen in 2003 for pain.Seen in 2003 for pain. CT showed kidney cystsCT showed kidney cysts

Exam and testingExam and testing PAST MEDICAL HISTORY: PAST MEDICAL HISTORY: RefluxReflux

Chronic knee painChronic knee painHistory of breast cystHistory of breast cyst

EXAM:EXAM: RUQ tenderness.  Liver is palpated at the RUQ tenderness.  Liver is palpated at the costal edge. costal edge.

CT:CT: Complex mass in the left ovary (4.7 x 6.9 x Complex mass in the left ovary (4.7 x 6.9 x 4.9 cm)4.9 cm)

Left and right kidneys with simple cysts.Left and right kidneys with simple cysts.Liver is “fatty”Liver is “fatty”

U/S: left hypoechoic ovarian mass, no free fluid in pelvis, U/S: left hypoechoic ovarian mass, no free fluid in pelvis, normal endometriumnormal endometrium

LABS:LABS: Hyperlipidemia with LDL of 332, triglycerides 294, Hyperlipidemia with LDL of 332, triglycerides 294,

and total cholesterol 410 and total cholesterol 410 Microscopic hematuria. Microscopic hematuria. Proteinuria 3+ on UA Proteinuria 3+ on UA CA-125 was 13 U/mL (0-35)CA-125 was 13 U/mL (0-35)

PATH: Pap smear was negativePATH: Pap smear was negative

Colonoscopy: Colonoscopy: Patchy erythema right Patchy erythema right

colon near IC valvecolon near IC valve Patchy changes seen Patchy changes seen

throughout the remainder throughout the remainder of the colon, extending of the colon, extending down into the sigmoid down into the sigmoid colon.  colon. 

2 diminutive colon polyps 2 diminutive colon polyps in sigmoid colonin sigmoid colon

EGD: EGD: Moderate to severe antral Moderate to severe antral

erythema and erosions erythema and erosions and friability.  Mostly pre-and friability.  Mostly pre-pyloricpyloric

TAH-BSOTAH-BSO

Large fibroid and..

ContrControlol

Liver Liver biopsybiopsy

Congo Congo redred

Liver Liver biopsybiopsy

What’s Amyloid?What’s Amyloid?

Amorphous, eosinophilic, Amorphous, eosinophilic, hyaline, extracellular substancehyaline, extracellular substance Congo red stainCongo red stain Apple green birefringenceApple green birefringence Pathologic misfolded proteinPathologic misfolded protein

Intrinsic property to assume pathologic Intrinsic property to assume pathologic configurationconfiguration

Replacement of amino acidReplacement of amino acid Proteolytic remodeling of protein Proteolytic remodeling of protein

precursorprecursor

““Apple Green Apple Green Birefringence”Birefringence”

What you needWhat you need Polarized lightPolarized light Congo red stained slideCongo red stained slide

Merlini G, Bellotti V. Molecular Mechanisms of Amyloidosis. N Engl J Med Merlini G, Bellotti V. Molecular Mechanisms of Amyloidosis. N Engl J Med

2003;349:583-96.2003;349:583-96.

Amyloid typesAmyloid types 21 biochemically distinct forms21 biochemically distinct forms Amyloid light chain (AL)Amyloid light chain (AL)

Most are composed of Most are composed of λλ light chains light chains Associated with monoclonal B cell Associated with monoclonal B cell

proliferation.proliferation. Amyloid associated (AA)Amyloid associated (AA)

Non-immunoglobulin protein made by liverNon-immunoglobulin protein made by liver Circulates in association with HDL3 subclass Circulates in association with HDL3 subclass

of lipoproteinsof lipoproteins Reactive to chronic infection or inflammationReactive to chronic infection or inflammation

AAββ amyloid amyloid Alzheimer’sAlzheimer’s Cerebral plaques and blood vessel wallsCerebral plaques and blood vessel walls Derived from amyloid precursor proteinDerived from amyloid precursor protein

Biochemical-clinical Biochemical-clinical classificationclassification

Merlini G, Bellotti V. Molecular Mechanisms of Amyloidosis. N Engl J Med Merlini G, Bellotti V. Molecular Mechanisms of Amyloidosis. N Engl J Med 2003;349:583-96.2003;349:583-96.

Organ involvementOrgan involvement Nephrotic syndromeNephrotic syndrome Restrictive cardiomyopathyRestrictive cardiomyopathy HepatomegalyHepatomegaly Autonomic nervous systemAutonomic nervous system

Orthostatic hypotensionOrthostatic hypotension Early satiety as a result of delayed Early satiety as a result of delayed

gastric emptyinggastric emptying Erectile dysfunctionErectile dysfunction Intestinal motility issuesIntestinal motility issues

Peripheral nervous systemPeripheral nervous system Painful, bilateral, symmetric, distal Painful, bilateral, symmetric, distal

sensory neuropathysensory neuropathy Progresses to motor neuropathyProgresses to motor neuropathy

Other soft tissue involvementOther soft tissue involvement MacroglossiaMacroglossia Carpal tunnel syndromeCarpal tunnel syndrome Skin nodulesSkin nodules ArthropathyArthropathy AlopeciaAlopecia Nail dystrophyNail dystrophy Submandibular gland enlargementSubmandibular gland enlargement Periorbital purpuraPeriorbital purpura Hoarseness of voice. Hoarseness of voice.

Merlini G, Bellotti V. Molecular Mechanisms of Merlini G, Bellotti V. Molecular Mechanisms of Amyloidosis.Amyloidosis.

N Engl J Med 2003;349:583-96.N Engl J Med 2003;349:583-96.

Mechanism of damageMechanism of damage

The deposition of large amounts of The deposition of large amounts of fibrillar material can subvert the fibrillar material can subvert the tissue architecture tissue architecture

Interacting with local receptors, Interacting with local receptors, leading to an inflammatory responseleading to an inflammatory response

Precursors mediate cellular toxicity Precursors mediate cellular toxicity through a mechanism that causes through a mechanism that causes oxidative stress and activates the oxidative stress and activates the apoptotic pathway.apoptotic pathway.

Amyloid light chainAmyloid light chain In our population, multiple myeloma should be at In our population, multiple myeloma should be at

the top of your list when you find amyloid in a the top of your list when you find amyloid in a biopsy.biopsy.

Plasma cell burden can be low 5-10%Plasma cell burden can be low 5-10% 12-15% of patients with myeloma12-15% of patients with myeloma Fat pad biopsy (FNAFP)Fat pad biopsy (FNAFP)

Often not considered clinically conclusiveOften not considered clinically conclusive Followed by further invasive procedures to detect amyloidFollowed by further invasive procedures to detect amyloid Estimated sensitivity 75% and specificity 92%Estimated sensitivity 75% and specificity 92% Overall, the reliance on the results depended on the Overall, the reliance on the results depended on the

degree of clinical suspicion. degree of clinical suspicion. Recent diagnostic and prognostic advancesRecent diagnostic and prognostic advances

Serum free light-chain assaySerum free light-chain assay Cardiac magnetic resonance imagingCardiac magnetic resonance imaging Serologic cardiac biomarkers. Serologic cardiac biomarkers.

Ansari-Lari MA, Ali SZ. Fine-needle aspiration of abdominal fat pad for amyloid detection: Ansari-Lari MA, Ali SZ. Fine-needle aspiration of abdominal fat pad for amyloid detection: a clinically useful test? Diagn Cytopathol. 2004 Mar;30(3):178-81.a clinically useful test? Diagn Cytopathol. 2004 Mar;30(3):178-81.

KappaLambda

Control

Further IHC

showed Kappa > Lambda

Abnormal plasma cell population Abnormal plasma cell population Abnormal expressionAbnormal expression

CD19(absent)CD19(absent) CD45 (variable)CD45 (variable) Monoclonal kappa cytoplasmic Monoclonal kappa cytoplasmic

light chain restrictionlight chain restriction SPE: IgA kappa Monoclonal Est. SPE: IgA kappa Monoclonal Est.

1.9 g/dL 1.9 g/dL Monoclonal component Monoclonal component

characterized as free kappa light characterized as free kappa light chain too small to quantitate. chain too small to quantitate.

Normal gammaglobulins are Normal gammaglobulins are depressed. depressed.

Bone marrow biopsy

and flow cytometry

were done:

References:References:

Ansari-Lari MA, Ali SZ. Fine-needle aspiration of Ansari-Lari MA, Ali SZ. Fine-needle aspiration of abdominal fat pad for amyloid detection: a abdominal fat pad for amyloid detection: a clinically useful test? Diagn Cytopathol. 2004 clinically useful test? Diagn Cytopathol. 2004 Mar;30(3):178-81. Mar;30(3):178-81.

Robbins and Cotran Pathologic Basis of Disease Robbins and Cotran Pathologic Basis of Disease (7(7thth ed.) ed.)

Merlini G, Bellotti V. Molecular Mechanisms of Merlini G, Bellotti V. Molecular Mechanisms of Amyloidosis. N Engl J Med 2003;349:583-96.Amyloidosis. N Engl J Med 2003;349:583-96.

Sanchorawala V. Light-Chain (AL) Amyloidosis: Sanchorawala V. Light-Chain (AL) Amyloidosis: Diagnosis and Treatment Clin J Am Soc Nephrol, Diagnosis and Treatment Clin J Am Soc Nephrol, Nov 2006;1:1331-1341. Nov 2006;1:1331-1341.