Histopathology of
Hepatitis C infection

        Laura Barisoni, MD
  Assistant professor in Pathology and Medicine,
    D...
Hepatitis C virus
•   First identified in 1989 by molecular cloning.

•   Small enveloped, single stranded RNA virus with ...
Several clinical syndromes follow
             exposure to HCV
•   Acute asymptomatic infection with recovery (serologic e...
Morphologic features of acute hepatitis

Parenchyma - Hepatocyte injury:
   - swelling – balloning degeneration
   - mild ...
Acute hepatitis




 Robbins: Pathologic basis of diseases 7th edition
Morphologic features of chronic hepatitis
Parenchyma - Hepatocyte injury:
   - swelling – balloning degeneration
   - mild...
Chronic hepatitis
Cirrhosis with hepatocellular
         carcinoma




                   Robbins: Pathologic basis of diseases 7th edition
Fulminant hepatitis

Small, soft, bile stained liver with   Portal tracts and terminal hepatic veins
wrinkled capsule     ...
Extra-hepatic manifestations of HCV
              infection
• Rheumatologic conditions     - arthritis,
                  ...
Renal manifestation associated with
              HCV infection

•   Membranoproliferative glomerulonephritis
•   Cryoglob...
MPGN & cryoglobulinemic nephropathy

• In 1992 a role for HCV infection in cryoglobulinemia was uncovered.

• In 1993 MPGN...
Pathologic features of
                   HCV-associated MPGN

                       Idiopathic MPGN                     ...
Evidence of HCV in renal tissue
Detection of viral particles in deposits                       Detection of HCV RNA in ren...
Spectrum of morphologic features of
  HCV-associated proliferative GN
Morphologic features of HCV-associated
    cryoglobulinemic nephropathy
HCV associated with fibrillary /
   immunotactoid glomerulopathy

FGP and ITG account for 0.6-1.6% of native kidney bx in ...
Clinical and pathologic features
•   Clinical presentation:
                              - proteinuria
                  ...
Fibrillary glomerulopathy in a pt with
         active HCV infection




                     Courtesy of Dr Glen Markowitz
Fibrillary glomerulopathy in a pt with
         active HCV infection




                          Courtesy of Dr Glen Mar...
Immunotactoid glomerulopathy in a
   pt with active HCV infection




                 Courtesy of Dr Glen Markowitz
Are HCV infection and FGP / ITG
  related or it is a coincidental
             finding?


   Renal function improves with
...
HCV and Membranous Glomerulopathy

•   Although MPGN is then most common association with Hep C infection, one
    of the ...
Pathologic features of
                   HCV-associated MGN


                       Idiopathic MGN                      ...
Morphologic features of MGN




Robbins: Pathologic basis of diseases 7th edition   Cao, Y. et al. NDT. 2009
IgA NP and HCV infection
Facts:      1. IgA NP is the most common glomerular disease worldwide
            2. HCV is the m...
HCV-associated IgA NP
Morphologic features      IgA




Mesangial proliferation   Evidence of HCV Ag in glomeruli




    ...
HCV & HIV co-infection
• Hep C and HIV infection often coexist = 250,000 in US
                                        = 1...
HCV & HIV: renal manifestations:


                 Total # pts    MPGN          MGN    Mesangio-   IC-NOS   CGP   Cryo
  ...
Summary and Conclusions
• HCV infection is a major public health concern mostly for its
  consequences on liver damage.
• ...
Upcoming SlideShare
Loading in …5
×

Barisoni Laura Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 Barisoni Laura

905 views
774 views

Published on

Published in: Health & Medicine
0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
905
On SlideShare
0
From Embeds
0
Number of Embeds
2
Actions
Shares
0
Downloads
6
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

Barisoni Laura Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 Barisoni Laura

  1. 1. Histopathology of Hepatitis C infection Laura Barisoni, MD Assistant professor in Pathology and Medicine, Director Nephropathology Clinical Service New York University New York, NY
  2. 2. Hepatitis C virus • First identified in 1989 by molecular cloning. • Small enveloped, single stranded RNA virus with a 9 kb genome. • Found to be responsible for most cases of sporadic or transfusion-associated hepatitis, previously referred as nonA - nonB hepatitis. • 170 Million persons are infected worldwide. • 40,000 new infections estimated annually in US • Major public health concern because - high rate of chronic infection - its association with cirrhosis - its association with hepatocellular carcinoma. - its association with immune-complex GN
  3. 3. Several clinical syndromes follow exposure to HCV • Acute asymptomatic infection with recovery (serologic evidence only). • Acute symptomatic hepatitis with recovery, with or without icterus. • Chronic hepatitis, with or without progression to cirrhosis. • Fulminant hepatitis: with massive or submassive hepatic necrosis. Robbins: Pathologic basis of diseases 7th edition
  4. 4. Morphologic features of acute hepatitis Parenchyma - Hepatocyte injury: - swelling – balloning degeneration - mild focal fatty changes - necrosis (isolated cells, clusters or bridging necrosis) - cytolysis (rupture) - apoptosis (shrinkage) - regenerative changes – proliferation - cholestasis Lobular disarray: loss of architecture Sinusoidal cell reactive changes - phagocytosed cellular debris in Kupffer cells - influx of mononuclear cells into sinusoids Portal tract changes - inflammation: predominantly mononuclear inflammatory spillover with periportal necrosis Robbins: Pathologic basis of diseases 7th edition
  5. 5. Acute hepatitis Robbins: Pathologic basis of diseases 7th edition
  6. 6. Morphologic features of chronic hepatitis Parenchyma - Hepatocyte injury: - swelling – balloning degeneration - mild focal fatty changes - necrosis (isolated cells, clusters or bridging necrosis) - cytolysis (rupture) - apoptosis (shrinkage) - regenerative changes – proliferation Sinusoidal cell reactive changes - phagocytosed cellular debris in Kupffer cells - influx of mononuclear cells into sinusoids Portal tract changes - inflammation: - confined - with spillover with hepatocyte necrosis (interface hepatitis). - bridging inflammation - lymphoid aggregates - fibrosis: - portal deposition - portal and periportal deposition - bridging fibrous septa - bile duct epithelial cell proliferation Robbins: Pathologic basis of diseases 7th edition
  7. 7. Chronic hepatitis
  8. 8. Cirrhosis with hepatocellular carcinoma Robbins: Pathologic basis of diseases 7th edition
  9. 9. Fulminant hepatitis Small, soft, bile stained liver with Portal tracts and terminal hepatic veins wrinkled capsule are closer together due to necrosis and collapse of intervening parenchyma Robbins: Pathologic basis of diseases 7th edition
  10. 10. Extra-hepatic manifestations of HCV infection • Rheumatologic conditions - arthritis, - vasculitis, - sicca syndrome • Dermatologic conditions - pruritus without evident skin lesions - Porphiria cutanea tarda - pigmented purpuric eruption - aphthous ulcer and lichen planus - leukocytoclastic vasculitis - erythema nodosum & erythema multiforme • Nephropathies - MPGN & others • Thyroid diseases - thyroiditis - thyroid carcinoma • Lung fibrosis • Sensory-motor neuropathy • B-cell lymphoproliferative diseases. - asymptomatic clonal B-cell expansions - cryoglobulinemia - B cell lymphoma
  11. 11. Renal manifestation associated with HCV infection • Membranoproliferative glomerulonephritis • Cryoglobulinemic NP • Cryoglobulinemic vasculitis • Mesangioproliferative glomerulonephritis • Membranous glomerulopathy • Acute proliferative/exudative glomerulonephritis • Focal segmental glomerulosclerosis • Fibrillary/immunotactoid glomerulopathy • IgA nephropathy • Amyloid nephropathy • Diabetic nephropathy
  12. 12. MPGN & cryoglobulinemic nephropathy • In 1992 a role for HCV infection in cryoglobulinemia was uncovered. • In 1993 MPGN with organized deposits was described in pts with HCV-associated cryoglobulinemia. • MPGN type 1 is responsible for approximately 80% of all renal lesions in type II cryoglobulinemic nephropathy. • Cryoglobulinemic nephropathy occurs almost exclusively in connection with type II cryoglobulinemia (monoclonal IgM and polyclonal IgG)
  13. 13. Pathologic features of HCV-associated MPGN Idiopathic MPGN HCV-associated MPGN •Thickening of the GBM •Thickening of the GBM •Double contours •Double contours Light microscopy •Mesangial expansion/hypercellularity •Mesangial expansion/hypercellularity •Lobulation of the tuft •Lobulation of the tuft •Intraluminal thrombi •Cryoglobulinemic vasculitis •C3 in mesangium granular •segmental IgM, IgG, kappa and lambda •C3 in GBM, semilinear light chains in GBM and mesangium Immunofluorescence •IgG and C1q occasionally present •IgM, IgG and kappa and lambda light chains in intralumial thrombi •C3 in GBM and mesangium- inconstant •Subendothelial electron dense •Subendothelial electron dense deposits deposits •Subepithelial electron dense deposits Electron microscopy •Subepithelial electron dense deposits •Mesangial deposits •Mesangial deposits •Double contours •Double contours •Mesangial cell proliferation •Mesangial cell proliferation •Intracapillary deposits •Organized deposits •Viral particles •HCV core antigen can be Immunohistochemistry demonstrated in deposits in some cases
  14. 14. Evidence of HCV in renal tissue Detection of viral particles in deposits Detection of HCV RNA in renal tissue Sabry et al. Int Urol Nephrol. 2005 Detection of HCV RNA in micro- dissected glomeruli Sabry et al. Int Urol Nephrol. 2005 Detection of HCV Ag in glomeruli Sansonno et al Clin Exp Immunol. 2009 Sansonno et al Clin Exp Immunol. 2009
  15. 15. Spectrum of morphologic features of HCV-associated proliferative GN
  16. 16. Morphologic features of HCV-associated cryoglobulinemic nephropathy
  17. 17. HCV associated with fibrillary / immunotactoid glomerulopathy FGP and ITG account for 0.6-1.6% of native kidney bx in US Organized deposits with negative congo red reactivity Pathogenesis is unknown for idiopathic forms, probably similar to cryoglobulinemic nephropathy in HCV infected patients. FGP : 12-30nm randomly organized fibrills in mesangium and GBM ITG : 50 nm microtubules, organized in parallel bundles. FGP & HCV: 1 case Coroneos et al in 1997 (AJKD) 4 cases Markowitz et al (JASN 1998) 1 case Ray et al (Renal Failure 2008) ITG & HCV 2 cases Markowitz et al (JASN 1998)
  18. 18. Clinical and pathologic features • Clinical presentation: - proteinuria - hematuria - renal insufficiency - hypocomplementemia - new onset of HTN • Patterns of glomerular injury by LM are: - Mesangioproliferative - Membranoproliferative (type 1 or 3) - Membranous - Crescents • Immunofluroescence: IgG and complement (C3 and C1q) • Electron microscopy: indistinguishable from idiopathic FGP and ITG
  19. 19. Fibrillary glomerulopathy in a pt with active HCV infection Courtesy of Dr Glen Markowitz
  20. 20. Fibrillary glomerulopathy in a pt with active HCV infection Courtesy of Dr Glen Markowitz
  21. 21. Immunotactoid glomerulopathy in a pt with active HCV infection Courtesy of Dr Glen Markowitz
  22. 22. Are HCV infection and FGP / ITG related or it is a coincidental finding? Renal function improves with interferon therapy
  23. 23. HCV and Membranous Glomerulopathy • Although MPGN is then most common association with Hep C infection, one of the first cases reported of immune-complex mediated GN was MGN (Rollino, Rocatello et al., Nephron 1991). • Clinical features: - Proteinuria - nephrotic range - Microscopic hematuria – sometimes - Generally negative Cryo - Generally normal renal function (mild renal insufficiency reported in 2 cases) - Mild hepatic dysfunction at the time of renal manifestation - Liver biopsies have shown chronic active hepatitis • Pathogenesis is unclear - immune complex deposition involving HCV proteins - autoimmune mechanism due to extrahepatic immunological abnormalities following HCV infection
  24. 24. Pathologic features of HCV-associated MGN Idiopathic MGN HCV-associated MGN •Thickening of the GBM •Thickening of the GBM •Spikes and holes Light microscopy •Spikes and holes •Mesangial expansion/hypercellularity •Segmental sclerosis (rare) •Granular IgG in GBM •Granular IgG in GBM Immunofluorescence •Granular C3 in GBM •Granular C3 in GBM - inconstant •Subepithelial electron dense deposits •Subepithelial electron dense deposits •Remodeling of the GBM (spikes) Electron microscopy •Remodeling of the GBM •Mesangial deposits (rare) •Viral particles •Antibodies against phospholipase A2 •HCV core antigen can be Immunohistochemistry receptor are positive in some cases demonstrated in GBM in some cases
  25. 25. Morphologic features of MGN Robbins: Pathologic basis of diseases 7th edition Cao, Y. et al. NDT. 2009
  26. 26. IgA NP and HCV infection Facts: 1. IgA NP is the most common glomerular disease worldwide 2. HCV is the major couse of liver disease worldwide What is the relationship between IgA NP and HCV infection? Possible scenarios 1. IgA NP and HCV infections are so common - coincidental finding 2. Indirect relationship secondary to liver dysfunction 3. Direct: immune-mediated pathogenetic mechanism Clinical presentation -cryoglobulinemia (vasculitis and arthralgias), - microscopic hematuria, - non-nephrotic proteinuria, - mild renal insufficiency - elevated transaminases. Liver biopsy with chronic active hepatitis and micronodular cirrhosis. Renal biopsy with IgA NP, with mesangial deposits of IgA and mesangial proliferation with segmental sclerosis.
  27. 27. HCV-associated IgA NP Morphologic features IgA Mesangial proliferation Evidence of HCV Ag in glomeruli Cao, Y. et al. NDT. 2009
  28. 28. HCV & HIV co-infection • Hep C and HIV infection often coexist = 250,000 in US = 10 Millions Worldwide - 25-30% of HIV pts have coexisting HCV infection - 8% of HCV pts have coexisting HIV infection • HCV- GD in HIV pts is rare - HIV pts are immunossuppressed - HIVAN precedes development of HCV-GD • Rapid progression to renal failure • Kidney biopsy is recomanded
  29. 29. HCV & HIV: renal manifestations: Total # pts MPGN MGN Mesangio- IC-NOS CGP Cryo (type 1 & 3) prolif. vasculitis Gonzalo et al 1 / 1 / / / / Nephron 1994 Stokes et al 12 5 1 5 1* 1* / AJKD 1997 Chen et al 14 6+5 3~^* 1~ 1^ 1* / JASN 1999 Saadoun et al 11 / / / / / 2+9 AIDS 2006 Izzedine et al 30 15 ? ? ? ? / AIDS 2009
  30. 30. Summary and Conclusions • HCV infection is a major public health concern mostly for its consequences on liver damage. • HCV infection is also cause, directly or indirectly, of glomerular disease. • Large spectrum of renal damage associated with HCV infection, but most common and known association is MPGN/cryoglobulinemic nephropathy. • HCV infection may coexists with other infections such as HIV and is a poor prognostic feature. • Because of potential therapeutic implication a renal biopsy is required to investigate the nature of the renal disease.

×