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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 • • • • • • • • • 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 • • • • • • • • 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 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 • • • • • 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 • • • • • • • 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 • • • • • • • 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 • • • • 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 • • • • • • 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 • • • • 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 • • • • • • • • • • • • • • 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 • • • • Chronic hepatitis Mild activity, grade 1 Mild fibrosis, stage 1 Mild steatosis The End • • • • 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:_____________________