clinical pathology conference february 3, 2006 tresa mcneal, md combined internal...
TRANSCRIPT
Clinical Pathology Conference
February 3, 2006Tresa McNeal, MD
Combined Internal Medicine/Pediatrics
“In endeavoring to trace the clinical features of a given disease to their source, use is made of the physical signs and modern laboratory methods of investigating disease, as well as of all data relating to the anamnesis. The marks of disease are often decidedly obscure, and for their detection the diagnostician must call into requisition the various instruments of precision contributed by science, e.g., the microscope, stethoscope, hemomanometer, and many others, as well as the helps furnished from the laboratory expert.”
Anders, JM and Boston, LN. A Textbook of Medical Diagnosis. Saunders, 1911. p. 17.
Case Presentation
• 49 y/o WM referred to GI clinic for evaluation of elevated LFTs.
• History of abnormal LFTs back to 1998, but no records are available.
• c/o progressive fatigue and lower extremity edema to mid-calf for several weeks.
• Decreased appetite but no weight loss.• Syrup-colored, nonodorous urine for several
weeks.
Case Presentation
• Recently diagnosed with hypertension and treated with Maxzide for 1 week.
• No other medications.• Denies chronic use of OTC medications or
herbal products.• He works as a special education teacher, is
divorced, bisexual with unprotected intercourse, smokes ½ ppd for 20 years and denies illegal drug use.
• No recent travel outside of Central Texas.
Case Presentation
• Allergies: cipro causes a rash• PSH: Back surgery in 1990• ROS: Denies exertional dyspnea, paroxysmal
nocturnal dyspnea, chest pain, paresthesias, melena, hematochezia, fever, chills, nausea, vomiting, arthralgias, skin lesions, or jaundice.
Physical Examination
VS: BP – RUE 180/90, LUE 170/90, P 90, R 14, T 99.4, Wt. 88.4 kg.
Gen – Well-nourished, NAD, A&O.HEENT, Neck, CV – no significant findings.Lung – Diffuse vesicular breath sounds with slight decrease
on left posterior field.Abd – soft, no edema, active BS, no HSM or ascites.Ext – 1-2 mm pretibial edema on RLE, 2-3 mm ankle
edema on LLE.Musculo, derm – no significant findings.
Laboratory Data
• Alk phos – 112• Total bili – 0.3• AST 57 ALT 84• Albumin 2.3 total protein 4.6• UA – pH 5.5, sp gr 1.020,
protein >300 mg/dl, blood 3+ (>50 RBCs/hpf)
• ANA – negative• SPEP – IgG 544 , IgA 262,
IgM 168• SIFX – Alb 2.9, α-1 0.4, α-
21.0, β 1.1, 0.6• INR 1.1
Imaging studies
• CT scan of abdomen and pelvis with contrast – small non-obstructing right renal calculus, small left pleural effusion and normal size kidneys.
• Lower extremity doppler US – normal.
• Further diagnostic testing was performed.
Problem List
• Abnormal LFTs since 1998
• Progressive fatigue• New-onset LE edema• Decreased appetite• Syrup-colored urine for
several weeks• Newly-diagnosed HTN
• Unprotected bisexual intercourse
• Tobacco abuse• Renal failure• Mild anemia• Proteinuria• Hematuria• Small left pleural
effusion• hypoalbuminemia
Problem List
• Abnormal LFTs since 1998
• Progressive fatigue• New-onset LE edema• Decreased appetite• Syrup-colored urine for
several weeks• Newly-diagnosed HTN
• Unprotected bisexual intercourse
• Tobacco abuse• Renal failure• Mild anemia• Proteinuria• Hematuria• Hypoalbuminemia• Small left pleural effusion
Further Testing Wish List
• Hepatitis panel• HIV Ab• Renal biopsy• Urine sediment• ANCA levels• Complement levels• Cryoglobulins• VDRL
• Anti-GBM Ab• ASO titers• Anti-DNAse B Ab• 24-hour urine
collection
Condensed problem list
• Glomerulonephritis with probable nephrotic range proteinuria
• Chronically mildly elevated LFTs
• High-risk sexual behavior with concern for possible sexually transmitted disease
Azotemia
• Prerenal disease• Intrinsic renal disease
– Glomerular– tubulointerstitial
• Post-renal obstruction
Glomerular Disease
Glomerulopathies
Primarily nephritic syndromes Primarily nephrotic syndromesCan present as both nephritic
And nephrotic
Focal proliferative GNDiffuse proliferative GNRapidly progressive GN
Membranous GNMinimal change disease
Focal segmentalglomerulosclerosis
Membranoproliferative GNDeposition disease
Thrombotic microangiopathyIgA nephropathy
Condensed problem list
• Glomerulonephritis with probable nephrotic range proteinuria
• Chronically mildly elevated LFTs
• High-risk sexual behavior with concern for possible sexually transmitted disease
Elevated LFTs
• Can be nonspecific• Often found incidentally• Need thorough history of symptoms • Need thorough social history• Physical exam to look for stigmata of liver
disease• Consider the pattern of LFT abnormalities• Consider other lab data critical in assessing liver
function
Elevated LFTs
• ALT – mainly from liver
• AST – heart, skeletal muscle, kidney, brain
• Absolute levels of enzymes correlate poorly with the extent of liver injury or involvement
Differential Diagnosisof chronic mild liver enzyme elevation
• Medications• EtOH• Infectious – Hepatitis B/C• Hereditary hemochromatosis• Steatohepatitis• Nonhepatic causes of enzyme elevation• Rare causes
– Autoimmune hepatitis– Wilson’s– Alpha-1-antitrypsin deficiency
Differential Diagnosisof chronic mild enzyme elevation
• Medications• EtOH• Infectious – Hepatitis B/C• Hereditary hemochromatosis• Steatohepatitis• Nonhepatic causes of enzyme elevation• Rare causes
– Autoimmune hepatitis– Wilson’s– Alpha-1-antitrypsin deficiency
Condensed problem list
• Glomerulonephritis with probable nephrotic range proteinuria
• Chronically mildly elevated LFTs
• High-risk sexual behavior with concern for possible sexually transmitted disease
Mechanisms of viral-induced renal disease
• Circulating immune complexes– Viral antigen and host antiviral antibodies– Endogenous antigens modified by viral injury and host auto-
antibodies• In situ immune-mediated mechanisms• Expression of viral proteins or abnormal host proteins in
tissue inducing:– Cell death through necrosis or apoptosis or cell dysfunction.– Increased cell matrix synthesis and/or decreased matrix
degradation– Release of cytokines, chemokines and adhesion molecules, and
growth factors• Direct cytopathogenic effect on glomerular cells; undefined
mechanism
di Belgiojoso BG, Ferrario F, Landriani N. Virus-related glomerular diseases: Histological and clinical aspects. J Nephro 2002; 15: 469-79.
HIV and Renal Disease
• HIV Associated Nephropathy– Focal segmental glomerulosclerosis– Mesangial hyperplasia
• Immune complex glomerulonephritis– Membranoproliferative GN– IgA nephropathy– Membranous nephropathy
• Various Glomerulonephritides– Amyloidosis– Minimal change disease– Diabetic nephropathy
di Belgiojoso BG, Ferrario F, Landriani N. Virus-related glomerular diseases: Histological and clinical aspects. J Nephro 2002; 15: 469-79.
Hepatitis C Associated Renal Disease
• Mixed cryoglobulinemia associated with MPGN
• Membranoproliferative glomerulonephritis
• Membranous nephropathy
Hepatitis B Associated Renal Disease
• Membranous nephropathy
• Membranoproliferative glomerulonephritis
• IgA nephropathy
• Polyarteritis nodosa with associated diffuse proliferative GN, mesangial proliferative GN, MPGN or membranous GN
Glomerular DiseaseGlomerulopathies
Primarily nephritic syndromes Primarily nephrotic syndromesCan present as both nephritic
And nephrotic
Focal proliferative GNDiffuse proliferative GNRapidly progressive GN
Membranous GNMinimal change disease
Focal segmentalglomerulosclerosis
Membranoproliferative GNDeposition disease
Thrombotic microangiopathyIgA nephropathy
Membranous nephropathy
• Most typically presents with nephrotic syndrome
• Idiopathic vs. secondary– Autoimmune– Infection– Drugs– Malignancy
Membranous NephropathyPathogenesis
• Capillary wall subepithelial deposits• Immune complex formation with induction of
autoantibodies against intrinsic glomerular antigens in idiopathic form
• Circulating immune complex formation in secondary forms deposits within the mesangium as well as subepithelial area.
• Associated with chronic Hep B and Hep C.• Disease may reflect an interaction between the
virus and immunologically vulnerable individuals
4 ultrastructural stage of membranous nephropathyBrenner & Rector's The Kidney, 7th ed., Copyright © 2004 Saunders, An Imprint of Elsevier
The Internet Pathology Laboratory for Medical Education Florida State University College of Medicine
http://155.100.78.12/WebPath/webpath.html#MENU
Membranous NephropathyClinical Presentation
• More common in children and Asian population
• Nephrotic syndrome• Hypertension• Often resolves spontaneously in children• Progression to chronic renal failure in 25%
of adults• May be asymptomatic especially if
subnephrotic proteinuria
Hypothesis for pathogenetic mechanism of development of Hep B MN
Bhimma, R. Hepatitis B Virus-Associated Nephropathy. Am J Nephro. 24(2). 2004.
Differences in clinical presentation of HBV MN between children and adults
Bhimma, R. Hepatitis B Virus-Associated Nephropathy. Am J Nephro. 24(2). 2004.
Membranous NephropathyTreatment
• Corticosteroids – not proven useful
• Chlorambucil/prednisone
• Cyclosporine
• Mycophenolate
• Monoclonal antibody against C5
• Rituximab
Hep B Associated Membranous Nephropathy
Treatment• Corticosteroids – ineffective; promote active viral
replication with disease progression which becomes evident after stopping steroids
• Interferon-alpha – multiple small studies in early to mid-1990s showing response to anti-viral treatment
• Some studies suggest interferon combined with lamivudine
• If untreated, 29% progress to renal failure with 10% requiring hemodialysis
Membranoproliferative Glomerulonephritis
• Majority of patients diagnosed between ages 8 and 30 years in its idiopathic form
• Identified in about 10% of renal biopsies
Membranoproliferative Glomerulonephritis
• Type I– Diffuse capillary wall thickening and
endocapillary hypercellularity– Doubling or complex replication of GBMs
seen on specialized GBM stains– Immune complex disease – infection,
neoplasm, hereditary disease, autoimmune disease
– Inflammation affects mesangial and endothelial cells
Membranoproliferative Glomerulonephritis
• Type II– “dense deposit disease”– Spherical, irregular mesangial dense deposits
with subendothelial and subepithelial deposits– Difficult to distinguish on light microscopy– C3 nephritic factor
The Internet Pathology Laboratory for Medical Education Florida State University College of Medicine
http://155.100.78.12/WebPath/webpath.html#MENU
Membranoproliferative GlomerulonephritisClinical Presentation
Nephrotic syndrome
• Microscopic or gross hematuria
• Hypertension in 50%
• Renal insufficiency in 30%
• Hypocomplementemia
• Associated with many secondary causes
Membranoproliferative GlomerulonephritisAssociated Diseases
• Mixed cryoglobulinemia– Associated with hepatitis C in 90%– Vasculitis, glomerulonephritis, proteinuria,
palpable purpura, hypocomplementemia, arthralgias, peripheral neuropathy
– Can be subclinical
Membranoproliferative GlomerulonephritisAssociated Diseases
-Polyarteritis nodosa
-40-50% have hepatitis B
-fever, anemia, LFT abnormalities, nephrotic syndrome, low serum complement, polyarthritis, hypertension, LE purpura, CHF, CNS involvement
Membranoproliferative GlomerulonephritisTreatment
• For type I – – treat underlying disease– Prednisone?– ASA, dipyridamole, warfarin?
• For type II– No good form of therapy– Recurs invariably in transplant patients
• Therapy indicated for moderate to severe disease– Nephrotic syndrome, hypertension, or fibrosis on
biopsy– Progressive disease
Hepatitis AssociatedMembranoproliferative Glomerulonephritis
Treatment• For hepatitis B-associated disease
– Most early studies are combined MN/MPGN patients– Majority of nonresponders to interferon had MPGN
• For hepatitis C-associated disease– Combination interferon plus ribavirin has shown some
success.– Resistant to treatment with interferon alone– PEG-IFN, ribavirin, +/- steroids, +/- cyclophosphamide
for more severe vasculitic processes– Plasmapheresis plus rituximab for refractory cases
Proposed Diagnoses
• Hepatitis B• Hepatitis C
• Membranoproliferative glomerulonephritis
• Membranous nephropathy
References• Altric L, Plaisler E, et. al. Influence of antiviral therapy in hepatitis C virus-associated
cryoglobulinemic MPGN. Am J Kidney Dis 2004; 43( 4) : 617-23.• Anders JM and Boston LN. A Textbook of Medical Diagnosis. Saunders, 1911. p. 17.• Brenner and Rector. The Kidney. 2004. pp. 1314-40.• di Belgiojoso BG, Ferrario F, Landriani N. Virus-related glomerular diseases: Histological and
clinical aspects. J Nephro 2002; 15: 469-79.• Bhimma R, Coovadia HM. Hepatitis B Virus-Associated Nephropathy. Am J Nephro 2004; 24(2).• Fauci AS, et al. Harrison’s Principles of Internal Medicine. 14th ed. 1998. • Han SB. Extrahepatic manifestations of chronic hepatitis B. Clinic Liver Dis 2004; 8(2). • Kim JD, Averell HS. Antiviral therapy: role in the management of extrahepatic diseases. Gastro
Clinic N Am 2004; 33: 693-708.• Meyers CM, Seeff LB, et. al. Hepatitis C and renal disease: an update. Am J of Kidney Dis
2003; 42 (4).• Robbins and Cotran. Pathologic Basis of Disease. 7th ed. 2005: 966-93.• Sabry AA, Sobh MA, et. al. Effect of combination therapy (ribavirin and interferon) in HCV-
related glomerulopathy. Nephro Dial Transpl 2002; 17: 1924-30.• The Internet Pathology Laboratory for Medical Education. Florida State University College of
Medicine. http://155.100.78.12/WebPath/webpath.html#MENU• UpToDate.com• Yun EJ, Meng MV, Carroll PR. Evaluation of the patient with hematuria. Med Clinic N Am 2004;
88(2).
Internal Medicine Clinical Pathology
Conference James T. Sing, Jr., D.O.
Department of Internal Medicine
Division of Gastroenterology
CPC• Abnormal LFTs due to chronic hepatitis B
viral infection(+) HBs-Ag
(+) HBe-Ag
(-) HBe-Ab
Viral load 387,000 x 103
(-) HDV-Ab
(-) HIV
(-) HCV
CPC• Chronic HBV infection
– Liver Biopsy – grade I, stage I disease– Declined pegylated interferon therapy– Lamivudine (Epivir®)
• Conversion to (+) HBe-Ab
– Adefovir (Hepsera®)
CPC• Membranoproliferative glomerulonephritis
– Furosemide 80mg BID– Plendil® 10mg Q day– Prinivil® 10mg Q day– Stabilization of Scr 1.4– Proteinuria improved– HTN controlled
CPC• Renal diseases associated with viral
hepatitis– HBV
• Membranoproliferative glomerulonephritis • Membranous nephropathy• Polyarteritis nodosa
– HCV• Membranoproliferative glomerulonephritis• Membranous nephropathy• Mixed cryoglobulinemia
• Enlarged glomeruli
• Thickened membranes
• Glomerular scarring, synechiae
• Mesangial hypercellularity
• Fibrocellular crescents in 5 of 15 glomeruli• No completely sclerosed glomeruli• Scattered tubular atrophy
Diagnosis
• Membranous glomerulonephritis
• Stage II-III
• Mesangial proliferation and deposits more common in secondary disease
DDx for secondary membranous glomerulonephritis
• Infectious: hep B and C, syphilis, endocarditis, some parasites
• Neoplastic: carcinomas, seminoma, lymphoma, leukemia, melanoma
• Autoimmune: SLE, RA, Hash/Graves, primary biliary cirrhosis, others
• Medications: gold, mercury, lithium, captopril• Miscellaneous: sclerosing cholangitis, renal vein
thrombosis, diabetes, sickle cell
• Primarily lymphocytic infiltrate
• No definite bile duct destruction
• Mild activity at limiting plate
The End
• Proceed to post test
• Print post test
• Complete post test
• Return post test to– Dr. Sandra Oliver– 407i TAMUII