extra-hepatic manifestations of hepatitis c: what the …/media/images/swedish/cme... · extra...

MA Dirac MD PhDJune 2, 2017Swedish Fam Med

EXTRA-HEPATIC MANIFESTATIONS OF HEPATITIS C:

WHAT THE PCP NEEDS TO KNOW

Context Sample cases Pathophysiology and epidemiology Course and treatment

Cryoglobulinemic vasculitis Other EHMs by system Care for HCV-infected and HCV-unknown

OUTLINE

27yo man establishing care Incarceration, construction, new girlfriend Concerns: Inattention, impulsivity Back pain Ankle pain Hep C

CASE 1: MR. G

Sx No N/V, abd pain, jaundice

Exam Nml abd, no stigmata

Labs Mild transaminitis, nml CBC Genotype, VL Fib 4 = 0.56

Referred to Hepatology

CASE 1: MR. G

*Mental health and MSK first*

CASE 1: MR. G

New rash Feet and legs Itchy, hard to sleep

“red papules and plaques, some excoriated, others violaceous” Punch biopsy

CASE 1: MR. G

56yo woman, resident transition Problem list: MDD, GAD Multiple pain complaints H/o EtOH Methadone maintenance Chronic rhinitis Hypertension LVH CKD2

HLD GERD Hep C

CASE 2: MS. S

Previously referred to HMC Hepatology “Not bad enough to treat ” Repeated labs and re-referred

CASE 2: MS. S

*Focus on pain, mental health, SSI*

CASE 2: MS. S

2015: HTN: well-controlled CKD 2

CASE 2: MS. S

2016: Winter: Microalbuminuria 15 400 Fall: Nephrotic syndrome and worsening GFR Referred to Neph

CASE 2: MS. S

2017: Renal biopsy

CASE 2: MS. S

Complex patients Hep C on radar, but back-burner Role of PCP; multi-system dx

CASES

Hepatotropic and lymphotropic virus U.S. prevalence 1.0% HCV RNA+

CONTEXT: ETIOLOGY AND EPIDEMIOLOGY

Life expectancy shorter by 15y Liver-related etiologies Risk-factors EHMs

CONTEXT: COURSE OF INFECTION

1990s: interferon (IFN) and ribavarin Pro-inflammatory

2011: first-generation of direct antivirals Often combined

2014: second-generation of direct antivirals

CONTEXT: TREATMENT

EHM may Be prevented Remit or improve Create urgency Require other tx

CONTEXT: HCV TREATMENT

Context Sample cases Etiology and epidemiology Course and treatment

Cryoglobulinemic vasculitis Other EHMs by system Care for HCV-infected and HCV-unknown

OUTLINE

*HCV is lymphotropic!*

CRYOGLOBULINEMIA

CRYOGLOBULINEMIA

Image credit Gianfranco Lauletta, DOI: 10.5772/55474

In HCV-infected persons 40-60% produce cryoglobulins (CG) 5-30% develop cryoglobulinemic vasculitis (CV)

In patients with CV 70 to >90% have HCV

CRYOGLOBULINEMIA

Palpable purpura

CRYOGLOBULINEMIC VASCULITIS

CRYOGLOBULINEMIC VASCULITIS

CRYOGLOBULINEMIC VASCULITIS

CRYOGLOBULINEMIC VASCULITIS

CRYOGLOBULINEMIC VASCULITIS

Palpable purpuraLower legs , feet, thighs, abdomen, buttocks, Ues

CRYOGLOBULINEMIC VASCULITIS

CRYOGLOBULINEMIC VASCULITIS

Palpable purpuraLower legs , feet, thighs, abdomen, buttocks, UesUlceration, bullae, necrosis

CRYOGLOBULINEMIC VASCULITIS

Palpable purpura Fatigue, arthralgias

CRYOGLOBULINEMIC VASCULITIS

Palpable purpura Fatigue, arthralgias Nephrotic syndrome and renal failure

CRYOGLOBULINEMIC VASCULITIS

Type 1 membrano-proliferative glomerulonephritis (MPGN) Microscopic hematuria Proteinuria Nephrotic in 20%

Chronic renal impairment Acute renal failure

CRYOGLOBULINEMIC VASCULITIS: RENAL

*Potentially fatal, dialysis-dependent*

CRYOGLOBULINEMIC VASCULITIS: RENAL

Palpable purpura Fatigue, arthralgias Nephrotic syndrome and renal failure (MPGN) Neurologic disease

CRYOGLOBULINEMIC VASCULITIS

Vasculitis of vaso nervorum Distal extremities Symmetric Sensory-predominant

CRYOGLOBULINEMIC VASCULITIS: PERIPHERAL NEUROPATHY

Palpable purpura Fatigue, arthralgias Nephrotic syndrome and renal failure (MPGN) Neurologic disease Peripheral neuropathy CNS vasculitis

CRYOGLOBULINEMIC VASCULITIS

Palpable purpura Fatigue, arthralgias Nephrotic syndrome and renal failure (MPGN) Neurologic disease Peripheral neuropathy CNS vasculitis

Raynaud’s phenomenon

CRYOGLOBULINEMIC VASCULITIS

Palpable purpura Fatigue, arthralgias Nephrotic syndrome and renal failure (MPGN) Neurologic disease Peripheral neuropathy CNS vasculitis

Raynaud’s phenomenon Sicca symptoms

CRYOGLOBULINEMIC VASCULITIS

History and clinical f indings Nonspecific lab abnml hypocomplementemia elevated RF spurious leukocytosis or thrombocytosis normocytic anemia elevated ESR and CRP

Detection of cryoglobulins (negative in 30-40%) Tissue biopsy Skin Kidney

HCV RNA (or other viral etiology)

CRYOGLOBULINEMIC VASCULITIS: DIAGNOSIS

HCV-infected patient Monitor for signs and symptoms Annual urinalysis and creatinine Note non-specific labs Low threshold to biopsy

CRYOGLOBULINEMIC VASCULITIS: APPROACH TO PATIENT

HCV-unknown patient HCV in ddx for new hematuria kidney injury peripheral neuropathy appropriate rashes

CRYOGLOBULINEMIC VASCULITIS: APPROACH TO PATIENT

More data for IFN than direct anti-virals Complete/partial remission of CV in SVR No improvement in CV if no SVR

CRYOGLOBULINEMIC VASCULITIS: RESPONSE TO HCV TREATMENT

Scenarios Acute, life-threatening Incomplete remission with antiviral tx

Treatments Rituximab Apheresis Immunosuppression Low-Ag diet

CRYOGLOBULINEMIC VASCULITIS: OTHER TREATMENTS

Context Sample cases Etiology and epidemiology Course and treatment

Cryoglobulinemic vasculitis Other EHMs by system Care for HCV-infected and HCV-unknown

OUTLINE

MPGN due to Cryoglobulinemic Vasculitis Membranous nephropathy Polyarteritis nodosa +/- Crescentic glomerulonephritis Others: focal segmental glomerulosclerosis, proliferative

glomerulonephritis, f ibril lary glomerulopathy

RENAL

Improved creatinine and proteinuria in SVR

RENAL: TREATMENT

Purpura due to Cryoglobulinemic Vasculitis

DERMATOLOGIC

Purpura due to Cryoglobulinemic Vasculitis Porphyria cutanea tarda

DERMATOLOGIC

DERMATOLOGIC: PCT

DERMATOLOGIC: PCT

DERMATOLOGIC: PCT

DERMATOLOGIC: PCT

DERMATOLOGIC: PCT

DERMATOLOGIC: PCT

DERMATOLOGIC: PCT

DERMATOLOGIC: PCT

Purpura due to Cryoglobulinemic Vasculitis Porphyria cutanea tarda In HCV-infected patients: up to 20% with porphyria cutanea tarda

DERMATOLOGIC

Purpura due to Cryoglobulinemic Vasculitis Porphyria cutanea tarda (acquired) In HCV-infected patients: up to 20% with porphyria cutanea tarda

In patients with porphyria cutanea tarda: 20-85% have HCV infection

DERMATOLOGIC

Purpura due to Cryoglobulinemic Vasculitis Porphyria cutanea tarda

DERMATOLOGIC

Purpura due to Cryoglobulinemic Vasculitis Porphyria cutanea tarda Lichen planus

DERMATOLOGIC

Purpura due to Cryoglobulinemic Vasculitis Porphyria cutanea tarda Lichen planus

DERMATOLOGIC

DERMATOLOGIC: LP

DERMATOLOGIC: LP

DERMATOLOGIC: LP

DERMATOLOGIC: LP

DERMATOLOGIC: LP

DERMATOLOGIC: LP

DERMATOLOGIC: LP

DERMATOLOGIC: LP

DERMATOLOGIC: LP

DERMATOLOGIC: LP

Purpura due to Cryoglobulinemic Vasculitis Porphyria cutanea tarda Lichen planus

DERMATOLOGIC

Purpura due to Cryoglobulinemic Vasculitis Porphyria cutanea tarda Lichen planus In HCV-infected patients: ~5% develop LP

DERMATOLOGIC

Purpura due to Cryoglobulinemic Vasculitis Porphyria cutanea tarda Lichen planus In HCV-infected patients: ~5% develop LP

In patients with lichen planus: 0-60% are HCV-infected

DERMATOLOGIC

Purpura due to Cryoglobulinemic Vasculitis Porphyria cutanea tarda Lichen planus Necrolytic acral erythema

DERMATOLOGIC

Purpura due to Cryoglobulinemic Vasculitis Porphyria cutanea tarda Lichen planus Necrolytic acral erythema

DERMATOLOGIC

DERMATOLOGIC: NECROLYTIC ACRAL ERYTHEMA

DERMATOLOGIC: NECROLYTIC ACRAL ERYTHEMA

Purpura due to Cryoglobulinemic Vasculitis Porphyria cutanea tarda Lichen planus Necrolytic acral erythema In HCV-infected patients: 1-2% develop NAE

DERMATOLOGIC

Purpura due to Cryoglobulinemic Vasculitis Porphyria cutanea tarda Lichen planus Necrolytic acral erythema In HCV-infected patients: 1-2% develop NAE

In patients with NAE Nearly all HCV-infected

DERMATOLOGIC

Purpura due to Cryoglobulinemic Vasculitis Skin biopsy

Porphyria cutanea tarda Urine uroporphyrin levels

Lichen planus Skin biopsy

Necrolytic acral erythema Skin biopsy

DERMATOLOGIC: DIAGNOSIS

HCV-infected patient Monitor skin exam and have low threshold to biopsy

DERMATOLOGIC: APPROACH TO PATIENT

HCV-unknown patient Test for HCV in any new PCT, LP or NAE

DERMATOLOGIC: APPROACH TO PATIENT

Purpura due to Cryoglobulinemic Vasculitis Responds to SVR

Porphyria cutanea tarda Responds to SVR, sometimes VL suppression RBV-based : new or worsening

Lichen planus Direct antivirals: theoretical benefit IFN-based: new or worsening

Necrolytic acral erythema Antiviral: Limited data suggest benefit

DERMATOLOGIC: RESPONSE TO ANTI-VIRAL TREATMENT

Purpura due to Cryoglobulinemic Vasculitis Rituximab, aphoresis, immunosuppression, diet

Porphyria cutanea tarda Phlebotomy, antimalarial, sun protection

Lichen planus Immunosuppressive therapies

Necrolytic acral erythema Immunosuppression: Mixed data

DERMATOLOGIC: OTHER TREATMENTS

Thyroid Auto-antibodies Dysfunction Papillary cancer

Diabetes mellitus type 2 and insulin resistance

ENDOCRINOLOGIC

Sjogren/sicca (with or without Cryoglobulinemic Vasculitis) In HCV-infected: 20-30% have sicca In sicca: ~5% are HCV-infected

Arthritis In HCV-infected: ~5% RA-like Oligoarthritis

RHEUMATOLOGIC

Peripheral neuropathy and CNS vasculitis in CV Fatigue and deficits in concentration and working memory

NEUROLOGIC

Cryoglobulinemic vasculitis Non-B-cell lymphomas Monoclonal gammopathies Immune thrombocytopenia Autoimmune hemolytic anemia VTE?

HEMATOLOGIC

Ocular disorders Hepatic osteodystrophy HCV-associated osteosclerosis Cardiovascular disease

OTHER

Evidence of harm or no benefit for autoimmune-mediated Thyroid, Sjogren/sicca, +/- arthritis

Evidence of benefit in lymphoma Lymphoma response in 73% overall, 83% in SVR

OTHER EHM: RESPONSE TO IFN TREATMENT

Benefits in preventing: Decreases incidence of thyroid disease or DM

Benefits in reversing: Some cases of improved glycemic control or improved insulin response Limited data suggest lymphoma response

No observed or theoretical benefit where autoimmune destruction has occurred

OTHER EHM: RESPONSE TO DIRECT ANTIVIRALS

Usual treatments appropriate and compatible with antivirals: Thyroid disorders Diabetes mellitus Sjogren/sicca (with or without Cryoglobulinemic Vasculitis) Arthritis ASCVD risk

Lymphoma Increased remission with dual therapy Increased toxicity

OTHER EHM: EHM-SPECIFIC TREATMENTS

Context Sample cases Etiology and epidemiology Course and treatment

Cryoglobulinemia Other EHMs by system Care for HCV-infected and HCV-unknown

OUTLINE

Lichen planus Approved anti-viral therapy Lost to follow up

CASE 1: MR. G

Amyloidosis! (not an EHM) Other s/s of EHM Eventually approved anti-viral therapy Improved energy, mood, myalgias, engagement

CASE 2: MS. S

Patients without HCV diagnosis When to test for HCV?

Patients with known HCV Monitoring and testing Response to treatments

EXTRA-HEPATIC MANIFESTATIONS

EHM HCV unknown

Cryoglobulinemic vasculitis Test for HCV if CV diagnosis considered

Renal disease Include HCV in Ddx of new renal disease

Dermatologic conditions Test for HCV if PCT, LP or NAE found

Endocrine disorders Routine screening

Rheumatologic disorders Routine screening

Neurologic disorders Include HCV in Ddx of peripheral neuropathy (and CNS vasculitis)

SUMMARY

EHM HCV known

Cryoglobulinemic vasculitis Monitor Cr, urinalysis, signs and symptomsLow threshold to refer or biopsy

Renal disease Monitor Cr, urinalysisLow threshold to refer

Dermatologic conditions Monitor examLow threshold to biopsy

Endocrine disorders Monitor signs and symptoms

Rheumatologic disorders Monitor signs and symptoms

Neurologic disorders Monitor signs and symptoms

SUMMARY

EHM Response to anti-viral txCryoglobulinemic vasculitis Favorable

May also need EHM-specific therapies

Renal disease Favorable

Dermatologic conditions Possible harm with IFN, RBVFavorable or unknown with directMay also need EHM-specific therapies

Endocrine disorders Possible harm with IFNPossible decrease new cases with direct Possible improvement DM with directRequire EHM-specific therapy

Rheumatologic disorders Possible harm with IFNSicca too late: sx tx onlyPossible favorable in arthritis, but may also need EHM-specific

Neurologic disorders Less studied

SUMMARY

Drs. Brown, Fu, Sadacharan, and Tidwell for their feedback on this presentation

Ms. Croghan, Drs. Kowdley and Wang for their support of my hepatology elective

ACKNOWLEDGEMENTS

A m e r i c a n A s s o c i a t i o n f o r t h e S t u d y o f L i v e r D i s e a s e s / I n f e c t i o u s D i s e a s e s S o c i e t y o f A m e r i c a . H C V G u i d a n c e : R e c o m m e n d a t i o n s f o r T e s t i n g , M a n a g i n g , a n d T r e a t i n g H e p a t i t i s C h t t p : / / w w w . h c v g u i d e l i n e s . o r g / P u b l i s h e d 2 0 1 7 . A c c e s s e d A p r i l 2 4 , 2 0 1 7 .

C h o p r a S . E p i d e m i o l o g y a n d t r a n s m i s s i o n o f h e p a t i t i s C v i r u s i n f e c t i o n . I n : P o s t , T W , e d . U p T o D a t e .W a l t h a m , M A ; 2 0 1 7 .

C h o p r a S , F l a m m S . E x t r a h e p a t i c m a n i f e s t a t i o n s o f h e p a t i t i s C v i r u s i n f e c t i o n . I n : P o s t , T W , e d . U p T o D a t e . W a l t h a m , M A ; 2 0 1 7 .

E s m a t S , E l g e n d y D , A l i M , E s m a t S , E l - N a b a r a w y E A , M a h m o u d S B , S h a k e r O . P r e v a l e n c e o f p h o t o s e n s i t i v i t y i n c h r o n i c h e p a t i t i s C v i r u s p a t i e n t s a n d i t s r e l a t i o n t o s e r u m a n d u r i n a r y p o r p h y r i n s . L i v e r I n t . 2 0 1 4 ; 3 4 ( 7 ) : 1 0 3 3 - 9 .

F e r v e n z a F , S e t h i S , K y l e R A , F l a m m S . C l i n i c a l m a n i f e s t a t i o n s a n d d i a g n o s i s o f t h e m i x e d c r y o g l o b u l i n e m i a s y n d r o m e ( e s s e n t i a l m i x e d c r y o g l o b u l i n e m i a ) . I n : P o s t , T W , e d . U p T o D a t e . W a l t h a m , M A ; 2 0 1 7 .

H e i m M H . 2 5 y e a r s o f i n t e r f e r o n - b a s e d t r e a t m e n t o f c h r o n i c h e p a t i t i s C : a n e p o c h c o m i n g t o a n e n d . N a t u r e R e v i e w s I m m u n o l o g y . 2 0 1 3 ; 1 3 : 5 3 5 – 4 2 .

K a m a r N , R o s t a i n g L . O v e r v i e w o f r e n a l d i s e a s e a s s o c i a t e d w i t h h e p a t i t i s C v i r u s i n f e c t i o n . I n : P o s t , T W , e d . U p T o D a t e . W a l t h a m , M A ; 2 0 1 7 .

M a h a j a n R , X i n g J , L i u S J , L y K N , M o o r m a n A C , R u p p L , X u F , H o l m b e r g S D , C h r o n i c H e p a t i t i s C o h o r t S t u d y ( C H e C S ) I n v e s t i g a t o r s . M o r t a l i t y a m o n g p e r s o n s i n c a r e w i t h h e p a t i t i s C v i r u s i n f e c t i o n : t h e C h r o n i c H e p a t i t i s C o h o r t S t u d y ( C H e C S ) , 2 0 0 6 - 2 0 1 0 . C l i n I n f e c t D i s . 2 0 1 4 ; 5 8 ( 8 ) : 1 0 5 5 - 6 1 .

P i n c h o f f J , D r o b n i k A , B o r n s c h l e g e l K , B r a u n s t e i n S , C h a n C , V a r m a J K , F u l d J . D e a t h s A m o n g P e o p l e W i t h H e p a t i t i s C i n N e w Y o r k C i t y , 2 0 0 0 – 2 0 1 1 . C l i n I n f e c t D i s . 2 0 1 4 ; 5 8 ( 8 ) : 1 0 4 7 - 5 4 .

W o r l d H e a l t h O r g a n i z a t i o n . G u i d e l i n e s f o r t h e s c r e e n i n g , c a r e a n d t r e a t m e n t o f p e r s o n s w i t h c h r o n i c h e p a t i t i s C i n f e c t i o n . h t t p : / / w w w . w h o . i n t / h i v / p u b / h e p a t i t i s / h e p a t i t i s - c - g u i d e l i n e s / e n / P u b l i s h e d 2 0 1 4 . A c c e s s e d A p r i l 2 4 , 2 0 1 7 .

Z i g n e g o A L , R a m o s - C a s a l s M , F e r r i C , S a a d o u n D , A r c a i n i L , R o c c a t e l l o D , A n t o n e l l i A , D e s b o i s A C , C o m a r m o n d C , G r a g n a n i L , C a s a t o M , L a m p r e c h t P , M a n g i a A , T z i o u f a s A G , Y o u n o s s i Z M , C a c o u b P ; I n t e r n a t i o n a l S t u d y G r o u p o f E x t r a h e p a t i c M a n i f e s t a t i o n s r e l a t e d t o H C V . E v i d e n c e - b a s e d r e c o m m e n d a t i o n s o n t h e m a n a g e m e n t o f e x t r a h e p a t i c m a n i f e s t a t i o n s o f c h r o n i c h e p a t i t i s C v i r u s i n f e c t i o n A u t o i m m u n R e v 2 0 1 7 ; 1 6 ( 5 ) : 5 2 3 - 4 1

REFERENCES