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