Hepatitis infectious disease in medicine

Hepatitis

1. Level 4 Semester 8 Module (Infectious Diseases)

2. Viral Hepatitis

3. Name: prof. Raghda El- sayed Farag Department: Tropical Medicine Department Official e-mail: [email protected] Office hours: Available time : S unday 09:00 AM – 02:00 PM INSTRUCTOR INFORMATION

4. Mission and Vision of Faculty رسالة الكلية: تلتزم كلیة الطب البشري – جامعة الدلتا للعلوم والتكنولوجیا بتقدیم برنامج تعلیمي تكاملي متمیز یقوم على المھـارة والمعرفـة ویھـدف الى تخریج أطبـاء قـادرین على الوفـاء بواجبـاتھم المھنیـة والأخلاقیـة، والتعلیم الطبي المستمر والمشاركة الفعالة في البحث العلمي وخدمة المجتمع. رؤية الكلية : تسعى كلیة الطب البشري - جامعة الدلتا للعلوم والتكنولوجیا من خلال تطبیق برنامج التعلم القائم على اكتســاب الجدارات أن تكون في مقدمة المؤسسات الطبیة التعلیمیة المتمیزة على المستوى المحلي والقومى والعالمي .

5. Learning Outcomes By the end of the lecture, the students will learn: Definition of hepatitis Causes of hepatitis (viral , bacterial, fungal, autoimmune others) C lassification : A cute viral hepatitis C hronic viral hepatitis Different Clinical presentation & complications Diagnosis Mangments

6. Case Scenario Ahmed, 19 years old male, presents to the clinic with complaints of yellowish discoloration of eyes, fatigue, generalized weakness and malaise. He also reports nausea and elevation of body temperature for the previous 2 days. By drop of fever he get dark urine and yellowish discoloration of his eyes. He also reported decreased appetite, pruritus, light colored stool and occasional episodes of vomiting. Ahmed used to eat fast food outdoors, no past history of recent surgery , blood transfusion or any interventional procedures.

7. Physical Examination Vital Signs: Blood pressure: 120/80 mmHg, Heart rate: 82 beats per minute, Respiratory rate: 16 breaths per minute, Temperature: 98.6°F (37°C). General Appearance: The patient appears fatigued , jaundiced and moderately pale. Abdominal Examination: Inspection: No visible abdominal distension or scars. Palpation: Mild tenderness in the right upper quadrant of the abdomen. The liver was soft, is palpable 2 cm below the right costal margin.

8. Definition Hepatitis a general term referring to inflammation of the liver. May result from various causes, both infectious ( ie , viral, bacterial, fungal, and parasitic organisms ) and noninfectious ( eg , alcohol, drugs, autoimmune diseases, and metabolic diseases)

9. Classification Acute hepatitis Infections Viral hepatitis: A, B, C, D, E Other viruses: EBV, CMV, HSV, Yellow fever Bacterial hepatitis : leptospira ecterus haemorrhgica , Neisseria meningitidis and gonorrhea, salmonella, brucella, campylobacter Drugs and toxins: Alcohol Halothane, isoniazid Paracetamol Metabolic: Wilson's disease

10. 2. Chronic hepatitis: Inflammation of the liver lasting for at least six months Viral Hepatitis: B, C, D Autoimmune hepatitis Drugs and toxins: Alcohol, isoniazid (INH), methyldopa Metabolic: Wilson's disease, 𝛼 -1 antitrypsin deficiency

11. Acute Viral Hepatitis ETIOLOGY Viral hepatitis: A, B, C, D, E Other viruses causing hepatitis: EBV, CMV, HSV, Yellow fever   HAV HBV HCV HDV HEV Genome RNA DNA RNA RNA RNA Transmission Oral Blood Blood Blood Oral IP 2-6w 1-6 m 1-6 m 1-6 m 2-6 w Incidence Sporadic or epidemic Sporadic Sporadic Sporadic Sporadic or epidemic Age Young Any Any Any Young

12. HAV HBV HCV HDV HEV Acute attack Mild Severe Mild Severe Mild (except in pregnant) Sequelae After acute hepatitis No chronicity + no relation to HCC Chronicity +cirrhosis+ HCC Chronicity +cirrhosis+ HCC Chronicity +cirrhosis+ HCC No chronicity + no relation to HCC Prophylaxis (active) Vaccine Vaccine ---------- Prevented by HBV vaccine ---------- Prophylaxis (Passive) Immuno-globulins Immuno- globulin ---------- ----------

13. Hepatitis A Virus (HAV) RNA virus Fecal – oral transmission 2 - 6 weeks incubation period Children and young adults affected Acute attack is usually mild but may complicated with relapse or presented with severe cholestatic form. Not complicated with chronicity or HCC Prophylaxis with vaccination or immunoglobulin

14. Hepatitis B Virus (HBV) DNA virus Blood, sexual, or vertical (from mother to child) transmission 1 - 6 months incubation period Affects any age Acute attack is usually severe specially if acquired in older age Complicated with both chronicity and HCC Prophylaxis with vaccination or immunoglobulins

15. Hepatitis C Virus (HCV) RNA virus Transmitted by blood and community acquired (unknown etiology) 1 - 6 months incubation period Any age affected, but more commonly in adults Acute attack is usually mild or may go unnoticed Associated with both chronicity and HCC No prophylaxis

16. Hepatitis D Virus (HDV) Weak incomplete RNA virus "Delta agent" dependent on HBsAg (affects only those infected with HBV ) Forms of infection: Co-infection: Infection with HBV and HDV occurs simultaneously. Gives the picture of acute hepatitis (may be fulminant ) Super-infection: Occurs when a chronic HBV carrier becomes additionally infected with HDV. Causes activation of hepatitis in a previously stable patient.

17. Blood, sexual, and vertical 1 - 6 months incubation period Sporadic incidence Occurs at any age. Acute attack is usually severe. Associated with chronicity. Prophylaxis is vaccination against HBV. Hepatitis D Virus (HDV)

18. Hepatitis E Virus (HEV) RNA virus Fecal – oral transmission 2 - 6 weeks incubation period Children and young adults affected Acute attack is usually mild except in pregnant females . Not associated with chronicity or HCC No prophylaxis

19. Clinical Picture of acute Hepatitis Anicteric Hepatitis They are mild cases with no jaundice They present with influenza - like symptoms They are usually missed in diagnosis (most cases of acute HCV infection) Icteric Hepatitis Pre - icteric stage (3 days-2 weeks) Symptoms Acute onset fever Marked anorexia / nausea / vomiting Dull aching pain in the right hypochondrium / epigastrium Signs Fever Nonspecific skin rash Enlarged, tender, soft liver

20. Icteric stage (1 - 4 weeks) Symptoms Drop of fever / improvement of the general condition Dark urine occurs first with or without pale stools then jaundice Anorexia / nausea / vomiting markedly improve or disappear Signs Absent fever Liver is enlarged, tender, soft Spleen is slightly enlarged (20% of cases) LN are slightly enlarged (10% of cases)

21. Convalescence stage Symptoms and signs gradually improve, then disappear Complete recovery of the liver (clinical, biochemical & histological) may take up to 6 months.

22. Sequelae after acute infection COMPLETE RECOVERY Most cases: HAV and HEV Many cases: HBV and HDV (up to 90%) Few cases: HCV (only 15-25%) COMPLICATIONS Hepatic complications Relapse ( especially with HAV) Original attack recurs / jaundice reappears Serum bilirubin / enzymes  once again

23. Cholestatic Hepatitis (especially with HAV) Prolonged cholestasis (pruritus, jaundice,  alkaline phosphatase ALP) Persistent jaundice for 8-28 weeks followed by complete recovery Fulminant Hepatitis Massive hepatic necrosis (features of acute liver failure BUT rare)

24. Post-Hepatitis Syndrome Transaminitis p resents with fatigue, anorexia, pain in right hypochondrium (all investigations are normal EXCEPT mild  of transaminases) Chronic sequelae (Only in HBV, HCV, HDV) Chronic hepatitis Cirrhosis Hepatocellular Carcinoma Carrier state

25. Extrahepatic complications Arthritis Aplastic anemia Guillain - Barré syndrome Glomerulonephritis (only with HBV and HCV) Polyarteritis nodosa / cryoglobulinemia (only with HBV and HCV)

26. Investigations Liver function tests  serum bilirubin, transaminases, ALP, gamma globulins Normal albumin Abdominal ultrasound Hepatomegaly Splenomegaly (20% of cases) Urine analysis Dark, frothy urine due to the presence of bilirubin and bile salts  urobilinogen Slight proteinuria and hematuria (due to glomerulonephritis) Stool analysis Pale stool (cholestatic types)  stercobilinogen Blood picture Leucopenia with relative lymphocytosis Hepatitis markers in blood  may still negative very early in acute infection PCR HBV DNA (most sensitive index for viral replication) HCV RNA (detected after 2weeks of infection) HDV RNA

27. Hepatitis Markers In Blood Hepatitis A Markers ( Anti HAV antibodies ) IgM = recent infection IgG = old infection Hepatitis B Markers HBsAg (Hepatitis B surface antigen) Appears 6 weeks after infection Disappears after 3 months Persistence > 6 months = carrier state OR chronic active infection state Anti-HBs antibodies Appear after 3 months and persists Indicate either recovery OR immunity

28. HBc Ag (Hepatitis B core antigen) not detectable in the blood (only detected in liver biopsy) Anti-HBcAg IgM = acute hepatitis ( persistence > 6 months = chronic active hepatitis ) IgG = carrier OR old infection IgM + IgG = chronic active hepatitis HBeAg Presence =  infectivity Persistence > 3 m = chronicity Anti- HBe AB presence =  infectivity

29. Hepatitis B M arkers

30. Hepatitis C Markers: Anti - HCV antibodies Detected after 6 weeks of infection Hepatitis D Markers Anti - HDV antibodies IgM = recent infection IgG = old infection HBsAg positive Hepatitis E Markers : Anti - HEV antibodies IgM = recent infection IgG = old infection

31. Treatment of acute hepatitis Bed rest until: Patient is symptom-free. Liver is no longer tender. Serum bilirubin is less than 1.5 mg/dl. Diet Fats are restricted because they aggravate nausea. Protein is given freely BUT restricted if liver failure develops High carbohydrate diet Symptomatic treatment Nausea: anti-emetic. Pruritus: ursodeoxycholic acid, Cholestyramine. Treatment of complications, e.g. corticosteroids in cholestatic hepatitis

32. Chronic A ctive H epatitis ETIOLOGY Viral Hepatitis: B, C, D Autoimmune hepatitis Drugs and toxins: Alcohol, isoniazid (INH), methyldopa Metabolic: Wilson's disease, 𝛼 -1 antitrypsin deficiency

33. Clinical picture Symptoms Asymptomatic Accidental discovery Non-specific symptoms Fatigue, anorexia, general ill health Hepatic symptoms Pain in the Rt hypochondrium Jaundice Liver failure occurs late Extra-Hepatic symptoms Symptoms of cryoglobulinemia, glomerulonephritis, arthritis , etc., especially in autoimmune cases

34. Signs Hepatic signs Liver is enlarged and firm Spleen is enlarged Signs of complications: Liver cirrhosis  shrunken liver. Liver cell failure and portal hypertension (late) Hepatocellular carcinoma Extra-Hepatic signs Signs of cryoglobulinemia, glomerulonephritis, arthritis, etc., especially in autoimmune cases

35. Investigations Liver function tests  serum bilirubin (direct + indirect), transaminases, ALP, globulin  albumin Prothrombin time prolonged Abdominal ultrasound Hepatomegaly / cirrhosis / HCC Splenomegaly

36. Liver biopsy Typical pathology of chronic hepatitis (necroinflammation + fibrosis) Specific pathology of the cause: HBV (ground-glass appearance, positive orcein stain) HCV (lymphocyte deposits, fatty changes [steatosis]) Investigations for the cause Hepatitis markers: for B, C, D. Auto-antibodies for autoimmune hepatitis (total IgG, anti-nuclear antibody ANA, anti-smooth muscle antibody ASMA, anti-liver kidney microsomal antibody ALKMA).

37. Treatment Treatment of chronic HBV hepatitis Immune modulator Drugs I nterferon-type drugs, e.g. 𝛼-interferon and pegylated interferon (long-acting interferon) G iven IM over 6 months to 1 year S ide effects in clude: F atigue D epression B one marrow suppression

38. Antiviral Drugs ( nucleoside analogues): I nclude: Entecavir (Baraclude) Tenofovir (Viread) Lamivudine (Epivir) Stop or slow down reproduction of HBV (reduces liver inflammation and damage) Taken orally once a day until seroconversion (which is very rare) and usually for li fe .

39. Treatment of chronic HCV hepatitis Direct-acting anti-viral therapy Goal of therapy: Prevent the complications, e.g. cirrhosis, HCC, and extrahepatic complications Improve quality of life Prevent transmission of HCV

40. HCV treated with fixed combinations of either: Sofosbuvir / velpatasvir (Epclusa) 12w Sofosbuvir / ledipasvir (Harvoni) 12w Sofosbuvir/daclatasvir 12 weeks Side effects: Nausea Fatigue Headache Disturbed sleep (insomnia)

41. Endpoint of therapy is undetectable HCV RNA in serum by sensitive assay (lower limit of detection <15 IU/ml) 12 weeks or 24 weeks after the end of treatment. Patients with advanced fibrosis and cirrhosis must continue surveillance for HCC every 4 months by assessment of levels of AFP and detection of focal hepatic lesions by US.

42. Treatment of complications , e.g., eosophageal varices (band ligation), HCC (ablations, resection, systemic therapy) .

43. Case Discussion/reflection What are further investigation What is the diagnosis of our case? How to manage?

44. Laboratory investigations Bilirubin : total 8 g/dl , direct :5.2 g/dl ALT: 840/38 AST: 618/ 45 GGT: 410/39 Alkaline phosphatase : 35/13 Urine examination: bilirinuria

45. HBsAg: - ve Anti HCV ab :- ve HAV IgM: + ve IgG total: 1200/1600

46. Diagnosis Acute hepatitis A

47. Treatment of acute hepatitis Bed rest until: Patient is symptom-free. Liver is no longer tender. Serum bilirubin is less than 1.5 mg/dl. Diet Fats are restricted because they aggravate nausea. Protein is given freely BUT restricted if liver failure develops High carbohydrate diet Symptomatic treatment Nausea: anti-emetic. Pruritus: ursodeoxycholic acid, Cholestyramine. Treatment of complications, e.g. corticosteroids in cholestatic hepatitis

48. Summary and wrap up In fectious hepatitis can caused by viral, bacterial, fungal, and parasitic organisms Non-infectious causes ( eg , alcohol, drugs, autoimmune diseases, and metabolic diseases) should be included in differential diagnosis . Acute disease symptoms include: fever, nausea, abdominal pain, fatigue, malaise, and jaundice. Acute infection with HBV and HCV can lead to chronic infection. Chronic infection may be complicated with cirrhosis and hepatocellular carcinoma (HCC). Furthermore, chronic hepatitis carriers remain infectious and may transmit the disease for many years. There is available drug therapy for both HCV and HBV.

49. Questions What are common virus causing hepatitis? What are common causes of bacterial hepatitis?

50. Questions After needle stick injury infected with HBV you can detect transmission of infection as early as first week by: Core IgG Core Ag PCR for HBV DNA HBs Ag HB e Ag

51. Questions After needle stick injury infected with HBV you can detect transmission of infection as early as first week by: Core IgG Core Ag PCR for HBV DNA HBs Ag HB e Ag

52. Questions HBV marker responsible for high infectivity is: HBV s Ag HBV e Ag HBV c Ag HBV c IgM HBV c IgG

53. Questions HBV marker responsible for high infectivity is: HBV s Ag HBV e Ag HBV c Ag HBV c IgM HBV c IgG

54. Questions The percentage of acute HCV infection becoming chronic is: 70 - 75 % 25 - 30 % 80 - 85 % 90 - 95 % 40 - 45 %

55. Questions The percentage of acute HCV infection becoming chronic is: 70 - 75 % 25 - 30 % 80 - 85 % 90 - 95 % 40 - 45 %

56. Any Questions??

57. References & recommended readings Handbooks: Davidson, R., Brent, A., Seale, R., & Seale, Anna. (2014). Oxford handbook of tropical medicine (4th ed., Oxford medical publications). Oxford: Oxford University Press (Textbook) Manson's Tropical Diseases. Edition: 23rd. Elsevier. (Textbook) http://www.dpd.cdc.gov/dpdx