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Clinical Pathology Conference: A 39 y.o. male with jaundice

Goals of the talk. Model clinical reasoning and self directed learningEmphasize a mechanistic approach to understanding key findings Discuss the differential diagnosis for the key findingsShare some pearls along the way. Road Map. Review of the protocolDevelopment of a problem listDiscussion o

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Clinical Pathology Conference: A 39 y.o. male with jaundice

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    1. Clinical Pathology Conference: “A 39 y.o. male with jaundice” Stanford Massie M.D. October 20, 2009

    2. Goals of the talk Model clinical reasoning and self directed learning Emphasize a mechanistic approach to understanding key findings Discuss the differential diagnosis for the key findings Share some pearls along the way

    3. Road Map Review of the protocol Development of a problem list Discussion of key clinical findings Review and discussion of the differential Selection of the final diagnosis

    4. Wortmann RL. AmJMed. 1998 Apr;104:323-26. The sequential process of making a diagnosis

    5. Case: HPI 39 y.o. white male presents with: Generalized, progressive fatigue and 25 pound weight loss (1 year) Progressive dyspnea and decreased UOP (1-2 months) Abdominal Pain (vague, RUQ)/bloating (1 month) Abnormal HIDA scan ? Cholecystectomy Jaundice, gray stools (since surgery)

    6. Case: HPI He denies fever, chills, NS, cough, CP or dysuria ROS otherwise negative

    7. Case: PFSH PMH: GERD Social: Lives in Opp, AL, works as salesman, denies T/D, drinks ETOH once/month FH: several FMs with “slightly elevated bilirubin levels” Meds: Esomeprazole, Ursodiol

    8. Case: Physical Exam GEN: Obese, VSS, normal sats (RA) HEENT: Scleral and sublingual icterus Teeth marks on tongue CV/RESP: S4 present, lungs clear ABD: Mild to mod distention with shifting dullness Nontender, no Hepato-splenomegaly SKIN: Jaundice

    9. LFTs: AST- 56 ALT-68 AP- 144 Tbili- 29.6 DB- 19.8 TP 4.4/Alb 3.4 U/A: 2+Prot/3+Bld/21-25 RBC/hyaline & gran. casts Case: Basic Labs

    10. LFTs: AST- 56 ALT-68 AP- 144 Tbili- 29.6 DB- 19.8 TP 4.4/Alb 3.4 U/A: 2+Prot/3+Bld/21-25 RBC/hyaline & gran. casts Case: Basic Labs

    11. Case: More Labs TSH/CRP/ESR/NH4 all normal Ferritin 2347 Viral Hep panel/AMA/AMSA neg. SPEP: paraprotein present UPEP: negative IFE: Free lambda light chains

    12. Case: Additional Studies ECG: unremarkable RUQ U/S: Mild HSM, no IH/EH dilatation, moderate ascites CT Abd/Pelvis: HM (21cm) with heterogeneous enhancement, marked ascites TTE: IVS/LVPW 18mm, LVEDD 34 mm, Normal EFs

    13. Initial Problem List Progressive fatigue and weight loss (1 year) Progressive dyspnea (1-2 months) Active urinary sediment, proteinuria, ?Creatinine (duration ?), ?UOP Abd pain and bloating (1 month) Abnormal HIDA scan ? Cholecystectomy Family History of hyperbilirubinemia Jaundice and hyperbilirubinemia Gray stools Tooth marks on tongue Elevated Hgb/Hct S4, Echo with IVS hypertrophy/small LVEDD Heterogeneous hepatomegaly and ascites Paraproteinemia: Free Lambda light chains Markedly elevated Ferritin

    14. Wildner, M. Lancet 1999;354:2172. Occam’s razor William of Ockham (Occam) Born 1287 Surrey, England Fled to Bavaria after persecution because of his scholarly writings Philosophy of scientific economy “Pluralitas non est ponenda sine necessitate” (complexity should not be assumed unnecessarily)

    15. Pruning the Problem List Progressive fatigue and weight loss Nonspecific, likely serious systemic illness Gray stools Lack of bilirubin in stool: obstruction? Progressive dyspnea (1-2 months) Not hypoxic, no findings on imaging of lungs or Echo to suggest Pulmonary source—Cardiac?? Abd pain and bloating (1 month) Likely due to hepatomegaly and ascites Abnormal HIDA scan?Cholecystectomy

    16. HIDA Scan: (Hepatic IminoDiacetic Acid) NM study to evaluate gall bladder fxn Often done if dx uncertain after U/S Technetium labeled HIDA given (IV) Taken up by hepatocytes/excreted in bile If GB not visualized, indicates cystic duct obstruction (stone or cholecystitis) Sens ~97%/Spec ~90% False positives: severe liver disease, hyperbilirubinemia, TPN+fasting Liver disease due to abnormal uptake and excretion of tracer. Hyperbilirubinemia largely avoided now with newer IDA compounds. TPN+ fasting can lead to GB already full due to prolonged lack of stimulation, unable to take up tracerLiver disease due to abnormal uptake and excretion of tracer. Hyperbilirubinemia largely avoided now with newer IDA compounds. TPN+ fasting can lead to GB already full due to prolonged lack of stimulation, unable to take up tracer

    17. Problem List: Version 2 Family History of hyperbilirubinemia Jaundice and hyperbilirubinemia Heterogeneous hepatomegaly and ascites Markedly elevated Ferritin Active urinary sediment, proteinuria, ?Creatinine (duration ?), ?UOP Tooth marks on tongue Elevated Hgb/Hct S4, Echo with IVS hypertrophy/small LVEDD Paraproteinemia: Free Lambda light chains

    18. Familial Hyperbilirubinemia Disclaimers in interpreting our case: Levels and associated clinical findings not known for family members Fractionation not known Assumption: mild, family members asymptomatic

    19. Asymptomatic Familial Hyperbilirubinemia: (Unconjugated) Gilbert’s Syndrome Genetic defect, impaired glucuronidation Mild, intermittent elevation of bilirubin, otherwise asymptomatic with NL LFTs Elevations precipitated by hemolysis, fasting, stress or infection No treatment required Crigler Najjar Type II Some research suggests a protective effect of the mutation ? Decreased atherogenesis or cancer Could have altered response to certain drugs, namely irinotecan (chemo) CJ Type I: congenital, severe jaundice and neurologic impairment due to bilirubin encephalopathy that can result in permanent neurologic sequelae, presents early in infancy (kernicterus) CJ II: less severe form of unconjugated hyperbilirubinemia. Usually have levels 8-18 but can rise to 40 with illness/fasting. May present as late as adulthood. Some research suggests a protective effect of the mutation ? Decreased atherogenesis or cancer Could have altered response to certain drugs, namely irinotecan (chemo) CJ Type I: congenital, severe jaundice and neurologic impairment due to bilirubin encephalopathy that can result in permanent neurologic sequelae, presents early in infancy (kernicterus) CJ II: less severe form of unconjugated hyperbilirubinemia. Usually have levels 8-18 but can rise to 40 with illness/fasting. May present as late as adulthood.

    20. Asymptomatic Familial Hyperbilirubinemia: (Conjugated) Dubin Johnson and Rotor’s syndromes Genetic defect, impaired excretion Mild, fluctuating elevation bilirubin, otherwise asymptomatic with NL LFTs Benign recurrent IH cholestasis (BRIC) Intermittent episodes with associated malaise, anorexia, pruritis, weight loss and malabpsorption BRIC starts in adolescence or early adulthood, labs show signs of cholestasis during episodes which can last for weeks to months with complete recovery. Not progressive. No treatment recommended for any of these conditions. Alk phos/GGT important to distinguish from other conditions. BRIC starts in adolescence or early adulthood, labs show signs of cholestasis during episodes which can last for weeks to months with complete recovery. Not progressive. No treatment recommended for any of these conditions. Alk phos/GGT important to distinguish from other conditions.

    21. Asymptomatic Familial Hyperbilirubinemia: Summary Possibilities: Gilbert’s Criggler-Najjar Type II Dubin-Johnson Rotor’s No systemic illnesses associated without earlier sequelae Could have exaggerated response to liver insults

    22. Problem List: Version 2 Family History of hyperbilirubinemia Jaundice and hyperbilirubinemia Heterogeneous hepatomegaly and ascites Markedly elevated Ferritin Active urinary sediment, proteinuria, ?Creatinine (duration ?), ?UOP Tooth marks on tongue Elevated Hgb/Hct S4, Echo with IVS hypertrophy/small LVEDD Paraproteinemia: Free Lambda light chains

    23. Markedly elevated Ferritin Storage form of iron (total body iron) Normal 40-200 (ng/mL) >300 (men) or >200 (women) should raise suspicion for iron overload Sources of error: Acute phase reactant (inflammation) Certain Liver Diseases: chronic viral hepatitis, alcoholic liver dz, NASH Obesity Malignancy Other reasons to have it, hemochromatosis would not explain all of his findingsOther reasons to have it, hemochromatosis would not explain all of his findings

    24. Problem List: Version 2 Family History of hyperbilirubinemia Jaundice and hyperbilirubinemia Heterogeneous hepatomegaly and ascites Markedly elevated Ferritin Active urinary sediment, proteinuria, ?Creatinine (duration ?), ?UOP Tooth marks on tongue Elevated Hgb/Hct S4, Echo with IVS hypertrophy/small LVEDD Paraproteinemia: Free Lambda light chains

    25. Elevated Hgb/Hct Decreased Plasma Volume Polycythemia—suspect if: Hgb> 18.5, Hct >52% (men) Hypoxia Cancers (renal cell, hepatocellular) Smoking Spurious Quick take---Not an exhaustive listQuick take---Not an exhaustive list

    26. Elevated Hgb/Hct Evaluation: Repeat the Hgb/Hct History and Physical Pulse Ox or ABG RBC mass Serum Epo

    27. Elevated Hgb/Hct: Our patient Decreased Plasma Volume Polycythemia ?? Hypoxia Cancers (renal cell, hepatocellular) Smoking Spurious

    28. Problem List: Version 2 Family History of hyperbilirubinemia Jaundice and hyperbilirubinemia Heterogeneous hepatomegaly and ascites Markedly elevated Ferritin Active urinary sediment, proteinuria, ?Creatinine (duration ?), ?UOP Tooth marks on tongue Elevated Hgb/Hct S4, Echo with IVS hypertrophy/small LVEDD Paraproteinemia: Free Lambda light chains

    29. Problem List: Version 3 Jaundice and hyperbilirubinemia Heterogeneous hepatomegaly and ascites Active urinary sediment, proteinuria, ?Creatinine (duration ?), ?UOP Paraproteinemia: Free Lambda light chains Tooth marks on tongue S4, Echo with IVS hypertrophy/small LVEDD

    30. Final Problem List Liver “trouble” Jaundice and hyperbilirubinemia Ascites Heterogeneous hepatomegaly on imaging Heart “trouble” S4, Echo with IVS hypertrophy/small LVEDD Kidney “trouble” Active urinary sediment, Proteinuria ,? Creat, ?UOP Tooth marks on tongue Paraproteinemia: Free Lambda light chains

    31. Approach to Jaundice Clinically apparent once Total Bilirubin >2-3 Reflects derangement in heme metabolic pathway or elimination Canalicular excretion of bilirubin is rate limiting step in bilirubin elimination. So… if liver function is normal: Total Bilirubin will not exceed 4 mg/dl Proportion of Conjugated Bilirubin remains normal (3-5% of total)

    32. Approach to Jaundice First step: Fractionation of the Bilirubin Primarily unconjugated (indirect) Ex. hemolysis, inherited disorders, Wilson’s Both conjugated (direct) and unconjugated Ex. biliary obstruction, HC injury, IH cholestasis Then, look at the “LFT pattern” Cholestatic pattern (alk phos, GGT) Hepatocellular injury (AST, ALT) Then, measures of true liver function PT/INR, Albumin

    33. Our patient Mixed hyperbilirubinemia Tbili-29.6, Dbili 19.8 Mild transaminitis w/o obstruction AP 144 (Nl <117), AST 56, ALT 68 Liver function relatively preserved PT 16.8 (Nl 12-15), Alb 3.4 Imaging also rules out obstruction

    37. Final Problem List Liver “trouble” Jaundice and hyperbilirubinemia Ascites Heterogeneous hepatomegaly on imaging Heart “trouble” S4, Echo with IVS hypertrophy/small LVEDD Kidney “trouble” Active urinary sediment, Proteinuria ,? Creat, ?UOP Tooth marks on tongue Paraproteinemia: Free Lambda light chains

    38. Tooth marks on the tongue Macroglossia: a resting tongue that protrudes beyond the teeth or alveolar ridge (long term, painless) True macroglossia Hypertrophy/hyperplasia of tongue muscles Infiltration of the tongue Pseudo macroglossia (small mandible)

    39. Macroglossia: Causes Amyloidosis is the most common cause of macroglossia in adults Others: Acromegaly Angioedema Lymphoma Space occupying lesions under tongue Chronic inflammatatory—TB, syphilis

    41. Final Problem List Liver “trouble” Jaundice and hyperbilirubinemia Ascites Heterogeneous hepatomegaly on imaging Heart “trouble” S4, Echo with IVS hypertrophy/small LVEDD Kidney “trouble” Active urinary sediment, Proteinuria ,? Creat, ?UOP Tooth marks on tongue Paraproteinemia: Free Lambda light chains

    42. Monoclonal Proteins Immunoglobulin protein produced by a single clone of plasma cells Usually composed of paired heavy chains (G, A, M, D, E) and two light chains either kappa or lambda Causes: Malignancy (myeloma, plasmacytoma) MGUS Interestingly, the paraprotein can affect other lab tests by interfering with the assays (including bilirubin) Interestingly, the paraprotein can affect other lab tests by interfering with the assays (including bilirubin)

    43. Monoclonal Proteins: Testing Protein Electropheresis (SPEP/UPEP) Serum proteins classified by final position after electropheresis Heavier bands suggest monoclonal protein Can quantitate monoclonal protein

    44. Monoclonal Proteins: Testing Immunofixation or IFE (serum/urine) Serum electropheresed into 5 or more lanes, then overlaid with antibodies to immunoglobulin components Confirms monoclonal protein and type More sensitive than SPEP Does not quantitate amount

    45. FIGURE 1 Panel B: A dense, localized band (red asterisk) representing a monoclonal protein of gamma mobility is seen on serum protein electrophoresis on agarose gel (anode on left). Panel A: Densitometer tracing of these findings reveals a tall, narrow-based peak (red asterisk) of gamma mobility and a reduction in the normal polyclonal gamma band. The monoclonal band has a densitometric appearance similar to that of albumin (alb), and has been likened to a church spire. FIGURE 2 This figure shows the serum protein electrophoretic pattern (SPEP) and immunofixation pattern of a single serum sample with antisera to heavy chain determinants of IgG, IgA, and IgM, and to kappa and lambda light chains. It shows a discrete band on SPEP (red asterisk) and a band (seen as a dark column) with similar mobility reacting only with the antisera to IgG (blue asterisk) and the kappa light chain (black asterisk), indicative of an IgG kappa monoclonal protein. FIGURE 1 Panel B: A dense, localized band (red asterisk) representing a monoclonal protein of gamma mobility is seen on serum protein electrophoresis on agarose gel (anode on left). Panel A: Densitometer tracing of these findings reveals a tall, narrow-based peak (red asterisk) of gamma mobility and a reduction in the normal polyclonal gamma band. The monoclonal band has a densitometric appearance similar to that of albumin (alb), and has been likened to a church spire. FIGURE 2 This figure shows the serum protein electrophoretic pattern (SPEP) and immunofixation pattern of a single serum sample with antisera to heavy chain determinants of IgG, IgA, and IgM, and to kappa and lambda light chains. It shows a discrete band on SPEP (red asterisk) and a band (seen as a dark column) with similar mobility reacting only with the antisera to IgG (blue asterisk) and the kappa light chain (black asterisk), indicative of an IgG kappa monoclonal protein.

    47. Monoclonal Proteins: Testing Serum Free Light Chains (FLC) SPEP/IFE may still miss some Light chains only or low concentrations 16% of Myeloma pts had only light chain AL amyloid: only light chain production Immunoassay to detect low conc. of monoclonal Free Light Chains More sensitive than urine IFE Replace urine testing in initial screening?

    49. Final Problem List Liver “trouble” Jaundice and hyperbilirubinemia Ascites Heterogeneous hepatomegaly on imaging Heart “trouble” S4, Echo with IVS hypertrophy/small LVEDD Kidney “trouble” Active urinary sediment, Proteinuria ,? Creat, ?UOP Tooth marks on tongue Paraproteinemia: Free Lambda light chains

    50. Classical features of Amyloidosis Waxy skin, easy bruising Enlarged muscles (tongue/deltoids) CHF/conduction abnormalities Hepatomegaly Heavy proteinuria or nephrotic synd. Neuropathy (peripheral or autonomic) Impaired coagulation

    51. Amyloidosis Pathologic deposition of protein Protein fibrils: polymers composed of LMW subunit proteins Conformational changes render them insoluble so they precipitate in tissues Causing progressive tissue damage >25 molecule precursors in humans

    52. Amyloidosis Clinical manifestations determined by: Type of precursor protein Tissue distribution Amount Localized or systemic Hereditary or acquired

    53. Amyloidosis: Types AL Amyloidosis Light chain (L) Plasma cell dyscrasia Deposition of Ig light chain fragments AA Amyloidosis Serum Amyloid A (A)- acute phase reactant Secondary to chronic inflammation RA, SNSA, Chronic infections

    54. Amyloidosis: Types Dialysis related Hereditary (transthyretin etc.) Age related (senile) Organ specific (skin, eye, heart, pancreas, GU tract)

    55. Amyloidosis: Diagnosis Tissue biopsy with Congo red stain Fat pad aspiration (SQ) Safest, yield higher in multi-organ illnesses 57-85% sensitive, 92-100% specific (AA/AL) Rectal/salivary gland biopsy Clinically involved site Additional evaluation: Testing for monoclonal protein Testing for plasma cell dyscrasia

    57. Amyloid purpura This image shows palpebral and periorbital purpura in a patient with amyloidosis. Reproduced Amyloid purpura This image shows palpebral and periorbital purpura in a patient with amyloidosis. Reproduced

    58. Light Chain (AL) Amyloidosis Aka “Primary Systemic Amyloidosis” Most common type of systemic amyloidosis 5-12/million cases per year Incidence similar to Hodgkin’s or CML Clonal population of plasma cells producing light chain (?>? , ratio 3:1)

    59. Light Chain (AL) Amyloidosis Kidneys: nephrotic syndrome Heart: restrictive CM Liver: hepatomegaly Neuro: orthostatic hypotension, distal sensory neuropathy Soft tissue: Purpura, Macroglossia Macroglossia is hallmark finding of dz. Kidney and heart are most frequently involved organs, but virtually any tissue other than brain can be affected. 10% can have associated myeloma (most have <5% plasma cells in BM).Kidney and heart are most frequently involved organs, but virtually any tissue other than brain can be affected. 10% can have associated myeloma (most have <5% plasma cells in BM).

    60. Light Chain (AL) Amyloidosis Diagnosis requires: Demonstration of amyloid in tissue Demonstration of plasma cell dyscrasia Demonstration of free light chain Serum FLC >10X more sensitive than IFE

    61. Light Chain (AL) Amyloidosis Treatment: Early diagnosis is the key Goal of therapy is to rapidly stop LC production by suppressing the plasma cell dyscrasia Regimens include melphalan/dexamethasone High dose melphalan/Stem cell transplant

    62. Amyloid Cardiomyopathy Definition: Signs of myocardial or conduction system involvement Seen in 50% of AL pts, <5% AA pts Transthyretin variants strongly associate d with cardiac involvement AL pts tend to have rapid progression Median survival 11 vs. 75 mos in one series Light chains may have direct toxic effects Compared with systemic senile amyloidosis (only 18 pts)Compared with systemic senile amyloidosis (only 18 pts)

    63. Amyloid Cardiomyopathy Clinical features: Asymptomatic to major symptoms (1/3) Right sided CHF prominent Syncope/PreSyncope EKG: Low voltage in limb leads Echo: restrictive CM, “sparkling” BNP: sensitive marker for AL associated cardiac dysfunction Periph edema and hepatomegaly prominent *Can mimic Hypetrophic CM (rare) Periph edema and hepatomegaly prominent *Can mimic Hypetrophic CM (rare)

    64. The M-mode echocardiogram in a patient with amyloid cardiomyopathy shows a small left ventricular (LV) cavity, brightly reflective myocardium, and markedly reduced systolic function. IVS: interventricular septum; PWLV: posterior wall of the LV. The M-mode echocardiogram in a patient with amyloid cardiomyopathy shows a small left ventricular (LV) cavity, brightly reflective myocardium, and markedly reduced systolic function.IVS: interventricular septum; PWLV: posterior wall of the LV.

    66. Hepatic Amyloidosis 70% of pts with primary systemic amyloidosis had liver involvement (autopsy) Yet deposition of amyloid in liver rarely causes clinical manifestations Associated with poor prognosis

    67. Hepatic Amyloidosis Retrospective review Systemic amyloidosis with biopsy proven liver involvement Mayo 1975-1997

    68. Hepatic Amyloidosis 98 patients (mean age 58, 69% male) Presenting symptoms/signs: Involuntary weight loss (72%) Fatigue (60%) Abdominal Pain (53%) Hepatomegaly (81%) Ascites (42%)

    69. Hepatic Amyloidosis Lab findings: Proteinuria (89%) Elevated Alk Phos (86%) AP >500 (61%) Hypogammaglobulinemia (28%) Median Survival: 8.5 months

    70. Hepatic Amyloidosis

    71. Final Problem List Liver “trouble” Jaundice and hyperbilirubinemia Ascites Heterogeneous hepatomegaly on imaging Heart “trouble” S4, Echo with IVS hypertrophy/small LVEDD Kidney “trouble” Active urinary sediment, Proteinuria, ? Creat, ?UOP Tooth marks on tongue Paraproteinemia: Free Lambda light chains

    72. Final Diagnosis AL Amyloidosis with: Renal involvment: nephrotic syndrome? Cardiac involvement: Restrictive CM Liver involvement: hepatomegaly, ascites and IH cholestasis Soft tissue involvement: macroglossia Lambda light chain production

    73. Final Diagnosis Diagnostic tests: Abdominal fat pad biopsy (most likely) Liver biopsy (less likely) Bone marrow biopsy

    74. Selected References Light-Chain (AL) Amyloidosis: Diagnosis and Treatment. Sanchorawala V. Clin J Am Soc Nephrol 2006(1):1331–1341. Primary (AL) Hepatic Amyloidosis: Clinical Features and Natural History in 98 Patients. Park MA et al. Medicine 2003;82:291–8. Molecular Mechanisms of Amyloidosis. Merlini G and Bellotti V. NEJM 2003;349:583-596. The Systemic Amyloidoses. Falk RH et al. NEJM 1997;337:898-909. Up-To-Date. Online version 17.2. Numerous cards!

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