Histopathology of Hepatitis C infection

Laura Barisoni, MD

Assistant professor in Pathology and Medicine,Director Nephropathology Clinical Service

New York UniversityNew York, NY

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

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

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 mononuclearinflammatory spillover with periportal necrosis

Robbins: Pathologic basis of diseases 7th edition

Acute hepatitis

Robbins: Pathologic basis of diseases 7th edition

Morphologic features of chronic hepatitisParenchyma - 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- 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 proliferationRobbins: Pathologic basis of diseases 7th edition

Chronic hepatitis

Cirrhosis with hepatocellular carcinoma

Robbins: Pathologic basis of diseases 7th edition

Fulminant hepatitis

Small, soft, bile stained liver with

wrinkled capsule

Portal tracts and terminal hepatic veins are closer together due to necrosis and collapse of intervening parenchyma

Robbins: Pathologic basis of diseases 7th edition

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- 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

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

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)

Pathologic features ofHCV-associated MPGN

Idiopathic MPGN HCV-associated MPGN

Light microscopy•Thickening of the GBM•Double contours•Mesangial expansion/hypercellularity•Lobulation of the tuft

•Thickening of the GBM•Double contours•Mesangial expansion/hypercellularity•Lobulation of the tuft•Intraluminal thrombi•Cryoglobulinemic vasculitis

•C3 in mesangium granular •segmental IgM, IgG, kappa and lambda

Immunofluorescence•C3 in mesangium granular•C3 in GBM, semilinear•IgG and C1q occasionally present

•segmental IgM, IgG, kappa and lambda light chains in GBM and mesangium•IgM, IgG and kappa and lambda light chains in intralumial thrombi•C3 in GBM and mesangium- inconstant

Electron microscopy•Subendothelial electron dense deposits•Subepithelial electron dense deposits•Mesangial deposits•Double contours•Mesangial cell proliferation

•Subendothelial electron dense deposits•Subepithelial electron dense deposits•Mesangial deposits•Double contours•Mesangial cell proliferation•Intracapillary deposits•Organized deposits•Viral particles

Immunohistochemistry •HCV core antigen can be demonstrated in deposits in some cases

Evidence of HCV in renal tissueDetection of viral particles in deposits Detection of HCV RNA in renal tissue

Sabry et al. Int Urol Nephrol. 2005

Detection of HCV Ag in glomeruli

Detection of HCV RNA in micro-dissected glomeruli

Sansonno et al Clin Exp Immunol. 2009 Sansonno et al Clin Exp Immunol. 2009

Sabry et al. Int Urol Nephrol. 2005

Sabry et al. Int Urol Nephrol. 2005

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 USOrganized deposits with negative congo red reactivityPathogenesis is unknown for idiopathic forms, probably similar to cryoglobulinemic nephropathy in HCV infected patients.

FGP : 12-30nm randomly organized fibrills in mesangium and GBMFGP : 12-30nm randomly organized fibrills in mesangium and GBMITG : 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 & HCV2 cases Markowitz et al (JASN 1998)

Clinical and pathologic features• Clinical presentation:

- proteinuria- hematuria- renal insufficiency- hypocomplementemia- new onset of HTN

• Patterns of glomerular injury by LM are:• 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

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 Markowitz

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?finding?

Renal function improves with interferon therapy

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- 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 extrahepaticimmunological abnormalities following HCV infection

Pathologic features ofHCV-associated MGN

Idiopathic MGN HCV-associated MGN

Light microscopy •Thickening of the GBM•Spikes and holes

•Thickening of the GBM•Spikes and holes•Mesangial expansion/hypercellularity•Segmental sclerosis (rare)

Immunofluorescence •Granular IgG in GBM•Granular C3 in GBM

•Granular IgG in GBM•Granular C3 in GBM - inconstant

Electron microscopy •Subepithelial electron dense deposits•Remodeling of the GBM

•Subepithelial electron dense deposits•Remodeling of the GBM (spikes)•Mesangial deposits (rare)•Viral particles

Immunohistochemistry •Antibodies against phospholipase A2 receptor are positive in some cases

•HCV core antigen can be demonstrated in GBM in some cases

Morphologic features of MGN

Cao, Y. et al. NDT. 2009Robbins: Pathologic basis of diseases 7th edition

IgA NP and HCV infection

Facts: 1. IgA NP is the most common glomerular disease worldwide2. HCV is the major couse of liver disease worldwide

What is the relationship between IgA NP and HCV infection?

Possible scenarios

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.

Possible scenarios1. IgA NP and HCV infections are so common - coincidental finding2. Indirect relationship secondary to liver dysfunction3. Direct: immune-mediated pathogenetic mechanism

HCV-associated IgA NP

Morphologic features IgA

Evidence of HCV Ag in glomeruli

Cao, Y. et al. NDT. 2009

Mesangial proliferation

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

HCV & HIV: renal manifestations:

Total # pts MPGN(type 1 & 3)

MGN Mesangio-

prolif.IC-NOS CGP Cryo

vasculitis

Gonzalo et alNephron 1994

1 / 1 / / / /

Stokes et al AJKD 1997

12 5 1 5 1* 1* /

Chen et alJASN 1999

14 6 + 5 3~^* 1~ 1^ 1* /

Saadoun et alAIDS 2006

11 / / / / / 2 + 9

Izzedine et alAIDS 2009

30 15 ? ? ? ? /

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 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.