MEDICAL GRANDROUNDS

1. MEDICAL GRANDROUNDS Michelle B. Moreno, M.D.

2. Objectives • To present a case of a young patient with hypertension • To discuss hepatitis C, its prevalence, diagnosis, evaluation, prevention and extrahepatic manifestations • To present the treatment option for this case

3. Patient’s Data • G.P. • 29 year old male • Filipino • Elevated blood pressure

4. History of Present Illness 4 months PTA Hypertension Imidapril + HCTZ 10/12.5 OD with good compliance BP persistently elevated (150/80 – 180/90) Admission

5. Review of Systems No headache, blurring of vision No skin lesions No chest pain, palpitations, difficulty of breathing, easy fatigability No cough, colds, fever, night sweats No abdominal pain, dysuria (+) grade 2 bipedal edema 3 weeks ago

6. Past Medical History No Diabetes Mellitus No Asthma (+) Allergy to Ibuprofen No previous surgery or hospitalization No history of blood transfusion

7. Family History (+) Hypertension – mother No Diabetes Mellitus No Asthma No hepatitis

8. Personal / Social History Smoker 7 pack years At present, consumes 8-10 sticks per day Occasional alcoholic drinker 1 sexual partner (+) tattoo on left leg and arm x 1 year No illicit drug use

9. Physical Examination Conscious, coherent, not in respiratory distress BP 160/110 HR 86 RR 17 T 36.9 Good skin turgor, no skin lesions, Anicteric sclerae, pink palpebral conjunctivae, no lymphadenopathy, no masses, no neck vein distention, JVP 8, no carotid bruit Symmetrical chest expansion, no intercostal retractions, clear breath sounds

10. Adynamic precordium, PMI at 5th ICS LMCL, no heaves, no thrills, normal rate, regular rhythm, distinct S1 and S2, no murmurs, no S3, no S4 Flat, normoactive bowel sounds, no bruit, soft, no tenderness, no organomegaly, no masses, Pulses full and equal, no edema, (+) tattoo on left leg and arm

11. Salient Features • 29,M • uncontrolled blood pressure • Known Hypertensive • BP 160/110 HR 86 • (+) grade 2 bipedal edema 3 weeks ago

12. Admitting Impression Hypertension stage II R/O Secondary causes

13. Differential Diagnosis • Secondary Hypertension • Renal artery stenosis • Primary renal disease • Pheochromocytoma • Primary Aldosteronism • Coarctation of aorta • Hypothyroidism • Primary Hyperparathyroidism

14. Upon admission • BP 160/110 150/80 Clonidine (Catapres) 75 mcg SL • Normal CBC, chest xray

16. 1st Hospital Day

18. Proteinuria, • Hypoalbuminemia • Hyperlipidemia • Active urinary sediments • History of edema • Nephrology referral Impression: Nephrotic syndrome Acute GN vs chronic GN R/O RPGN

19. KUB ultrasound 24 hour urine collection ESR, CRP, ASO, ANA, C3, HbsAg, Anti Hbs, Anti HCV, anti HIV

20. KUB Ultrasound: Bilateral renal parenchymal disease. Normal urinary bladder. • 24 hour urine collection Urine Creatinine: 105.4 mgs% = 1370.20 mgs/24hrs Urine protein: 740.2 mgs% = 9622.60 mgs/24hrs Total volume 1300ml/24hrs Sp.gr. 1.020

21. ESR 60 • CRP negative • ASO less than 200 • ANA negative • C3 normal • Anti HIV negative

22. 4th Hospital Day • CT scan guided kidney biopsy • (+) Anti HCV GI referral • Ultrasound of upper abdomen Minimal ascites. Gallbladder polyp. Normal liver, biliary tree, pancreas and spleen.

23. Hepatitis C Virus (HCV) • RNA virus • WHO, the global prevalence averages 3%, 170M worldwide • 6 genotypes • Genotype 1: longer duration of treatment

24. Transmission • Intravenous drug use / needle stick injury • Blood transfusion • Intranasal cocaine use • Hemodialysis • HCV-positive mother • Sexual transmission • History of tattooing and/or body piercing

25. HCV genotype

26. Exposure Acute Infection Spontaneous resolution (20-50%) Chronic hepatitis C (50-80%)

27. Chronic hepatitis C Extrahepatic Cirrhosis Hepatocellular carcinoma (1-4% per year)

28. Extrahepatic Hematologic diseases Autoimmune disorders Renal disease Dermatologic condition Diabetes Mellitus

29. Renal Manifestations • There is a strong and likely causal association between chronic hepatitis C virus (HCV) infection and glomerular disease • 3 types: • Mixed Cryoglobulinemia • Membranoproliferative glomerulonephritis (MPGN) • Membranous nephropathy

30. 7th Hospital Day • Discharged • Pending kidney biopsy, HCV RNA, and HCV genotype results • Home meds: Atorvastatin 20 mg daily at bedtime Amlodipine 10 mg daily Prednisone 10 mg 3 x day

31. Pathology

32. On Follow up (after 1 week) • BP 140/90 • (+) grade 2 bipedal edema • Repeat SGPT: normal • Creatinine 2.3 • Proteinuria +3, Hematuria +3 • HCV RNA: 9,737,233 IU/mL • HCV genotype: genotype 1

33. Electron Microscopy • The presence of subepithelial electron-dense deposits and tubuloreticular structure in this biopsy with strong C1q staining in glomeruli suggests a diagnosis of lupus nephritis. Other conditions with tubuloreticular structures include viral infections (hepatitis and HIV) and alpha-interferon treatment.

34. (1) Membranous Glomerulopathy, stage I (2) Acute and chronic tubulointerstitial nephritis

35. Salient Features • 29, M • Hypertension • Hepatitis C glomerulonephritis • HCV RNA: 9,737,233 IU/mL • HCV genotype: genotype 1 • Normal SGPT • Estimated creatinine clearance 31 ml/min

36. Treatment options • Pegylated Interferon • influenza like symptoms • thrombocytopenia • leukopenia • depression • thyroiditis • Ribavirin • anemia • gout • nasal congestion • itchiness

37. Treatment • Goal: viral clearance

38. Pegylated Interferon • Pegylation refers to the cross-linking of polyethylene glycol (PEG) molecules to the interferon molecule, which delays renal clearance. • Advantage of pegylation is that it permits less frequent dosing (once weekly versus three times a week with non-pegylated interferon)

39. Ribavirin • Nucleoside analog which has a broad spectrum of antiviral activity. • It inhibits the replication of RNA viruses in cell culture. It appears to decrease hepatitis C virus infectivity in a dose-dependent manner

40. Pt M 29 GN, NS Negative

41. Pt Membranous nephropathy

42. Pt 1 Peginf-alfa-2b + ribavirin

43. 6 patients became HCV RNA PCR negative and 4 of 7 have maintained both virological and renal remission. • 1 of 7 has maintained virological and partial renal remission • 1 patient did not tolerate interferon, but is in renal remission with low dose ribavirin Bruchfeld, A. et al. Interferon and ribavirin treatment in patients with hepatitis C-associated renal disease and renal insufficiency. Nephrol Dial Transplant (2003) 18: 1573-1580

44. 1 vasculitis patient responded with complete remission but relapsed virologically and had a minor vasculitic flare after 9 months • 1 patient with vasculitis had low dose immunosuppresion in addition to antiviral therapy

48. Before Treatment • serum HCV RNA • HCV genotype • Baseline liver biochemistry, renal function, CBC, thyroid function • Psychiatric evaluation • Pregnancy test

49. During treatment • Blood counts and aminotransferases: weeks 1, 2, and 4 and at 4- to 8-week intervals thereafter.

50. At 24 weeks: aminotransferase levels and HCV RNA. • If HCV RNA still present, stop therapy. • In patients with genotype 1, stop therapy if HCV RNA is still positive. Continue therapy for a total of 48 weeks if HCV RNA is negative, and retesting for HCV RNA at the end of treatment.