Transcript Clinical Pathology Conference

Clinical Pathology Conference
February 3, 2006
Tresa 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
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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, α21.0, 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
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Hepatitis panel
HIV Ab
Renal biopsy
Urine sediment
ANCA levels
Complement levels
Cryoglobulins
VDRL
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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 syndromes
Can present as both nephritic
And nephrotic
Focal proliferative GN
Diffuse proliferative GN
Rapidly progressive GN
Membranous GN
Minimal change disease
Focal segmental
glomerulosclerosis
Membranoproliferative GN
Deposition disease
Thrombotic microangiopathy
IgA 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
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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 Diagnosis
of chronic mild liver enzyme elevation
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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 Diagnosis
of chronic mild enzyme elevation
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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
High-risk Sexual Behavior
Hepatitis B
Hepatitis C
HIV
Syphilis
Mechanisms of viral-induced renal
disease
• Circulating immune complexes
– Viral antigen and host antiviral antibodies
– Endogenous antigens modified by viral injury and host autoantibodies
• 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
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Membranous nephropathy
Membranoproliferative glomerulonephritis
IgA nephropathy
Polyarteritis nodosa with associated
diffuse proliferative GN, mesangial
proliferative GN, MPGN or membranous
GN
Glomerular Disease
Glomerulopathies
Primarily nephritic syndromes
Primarily nephrotic syndromes
Can present as both nephritic
And nephrotic
Focal proliferative GN
Diffuse proliferative GN
Rapidly progressive GN
Membranous GN
Minimal change disease
Focal segmental
glomerulosclerosis
Membranoproliferative GN
Deposition disease
Thrombotic microangiopathy
IgA nephropathy
Membranous nephropathy
• Most typically presents with nephrotic
syndrome
• Idiopathic vs. secondary
– Autoimmune
– Infection
– Drugs
– Malignancy
Membranous Nephropathy
Pathogenesis
• 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 nephropathy
Brenner & 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#M
ENU
Membranous Nephropathy
Clinical 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 Nephropathy
Treatment
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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
MPGN type 2
MPGN type 1
The Internet Pathology Laboratory
for Medical Education
Florida State University College of Medicine
http://155.100.78.12/WebPath/webpath.html#
MENU
Membranoproliferative Glomerulonephritis
Clinical Presentation
Nephrotic syndrome
• Microscopic or gross hematuria
• Hypertension in 50%
• Renal insufficiency in 30%
• Hypocomplementemia
• Associated with many secondary causes
Membranoproliferative Glomerulonephritis
Associated Diseases
• Mixed cryoglobulinemia
– Associated with hepatitis C in 90%
– Vasculitis, glomerulonephritis, proteinuria,
palpable purpura, hypocomplementemia,
arthralgias, peripheral neuropathy
– Can be subclinical
Membranoproliferative Glomerulonephritis
Associated 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 Glomerulonephritis
Treatment
• 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 Associated
Membranoproliferative 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
Most useful tests
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Hepatitis panel
Urine sediment
Renal biopsy
Complement levels
Proposed Diagnoses
• Hepatitis B
• Hepatitis C
• Membranoproliferative
glomerulonephritis
• Membranous
nephropathy
Special Thanks
• Dr. Tommy Sing
• Dr. Stephen Sibbitt
• Dr. Don Chaffer
References
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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
Mild interstitial lymphocytic infiltrate, periglomerular fibrosis, unremarkable
vessels
• Enlarged glomeruli
• Thickened membranes
• Glomerular scarring,
synechiae
• Mesangial hypercellularity
• Fibrocellular crescents in 5 of
15 glomeruli
• No completely sclerosed
glomeruli
• Scattered tubular atrophy
Thickened membranes, suggestion of subepithelial spikes
• Electron dense subepithelial and intramembranous deposits
• Thickened membranes
Mesangial hypercellularity and electron dense deposits
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
Mild periportal inflammation, mild steatosis
• Primarily lymphocytic infiltrate
• No definite bile duct destruction
• Mild activity at limiting plate
• Minimal collagen fibrosis in trichrome stain
• No viral inclusions detected in our case
Diagnosis
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Chronic hepatitis
Mild activity, grade 1
Mild fibrosis, stage 1
Mild steatosis
The End
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Proceed to post test
Print post test
Complete post test
Return post test to
– Dr. Sandra Oliver
– 407i TAMUII
Post test 1
• List 1 renal disease associated with viral
hepatitis B and 1 renal disease associated
with viral hepatitis C.
– HBV:_____________________
– HCV:_____________________