1. Training on Clinical Care of HIV, AIDS and Opportunistic Infections Unit 10 Haematologic, Hepatic and Renal Conditions

2. Haematologic, Hepatic and Renal Conditions- 2 Learning Objectives List causes of anaemia, low WBC counts, and platelet counts associated with HIV infection; Describe treatment for the common causes of HIV-associated haematologic conditions, and; Describe the evaluation of liver and kidney dysfunction. Training on Clinical Care of HIV, AIDS and Opportunistic Infections

3. Blood Disorders Haematologic, Hepatic and Renal Conditions- 3 Training on Clinical Care of HIV, AIDS and Opportunistic Infections

4. Haematologic, Hepatic and Renal Conditions- 4 Case Study Maggie, a 23 year old woman from Oshakati was diagnosed with HIV during her recent pregnancy. She and her baby each received a dose of nevirapine according to national guidelines. She is seen now, 2 months after the birth, to be assessed for HAART. Maggie reports little energy. When she carries her baby and other heavy items she is breathless and aware of her heart pounding. Training on Clinical Care of HIV, AIDS and Opportunistic Infections

5. Haematologic, Hepatic and Renal Conditions- 5 Case Study (2) Maggie has no fever, no night sweats, and no cough She is not on any medication Training on Clinical Care of HIV, AIDS and Opportunistic Infections

6. Haematologic, Hepatic and Renal Conditions- 6 Case Study: On Exam (3) T 37.5°C, Pulse 110, RR 24, BP 110/60 Pale mucous membranes & hand creases No jaundice No jugular venous distention 2/6 systolic ejection murmur Chest clear No hepatosplenomegaly No peripheral edema Training on Clinical Care of HIV, AIDS and Opportunistic Infections

7. Haematologic, Hepatic and Renal Conditions- 7 Case Study: On Exam (4) Hemoglobin 7.5 g/dl MCV 75 Reticulocyte count 0.3% White Blood Count 3,600 Platelet count 210,000 Creatinine normal ALT normal RPR negative Hepatitis B surface antigen negative CD4 lymphocyte count 110 cells/cu mm Training on Clinical Care of HIV, AIDS and Opportunistic Infections

8. Haematologic, Hepatic and Renal Conditions- 8 Degree of Anaemia Mild anaemia Hb > 10 g/dl to normal Moderate anaemia Hb 5 -10 g/dl Severe anaemia Hb < 5 g/dl Training on Clinical Care of HIV, AIDS and Opportunistic Infections

9. Haematologic, Hepatic and Renal Conditions- 9 Mild Anaemia Screen and investigate if: Bleeding Jaundice Fever Supportive treatment Re-enforce counselling on good nutrition Nutritional support with daily multivitamin/multimineral supplement Reassess for response in 1-2 months Training on Clinical Care of HIV, AIDS and Opportunistic Infections

10. Haematologic, Hepatic and Renal Conditions- 10 Moderate - Severe Anaemia Evaluate for severity and a specific cause History and physical Acute or chronic blood loss Chronic cough Weight loss Tachycardia, breathlessness, fatigue Fever Jaundice Lymphadenopathy Hepatosplenomegaly Liver or kidney disease Training on Clinical Care of HIV, AIDS and Opportunistic Infections

11. Haematologic, Hepatic and Renal Conditions- 11 Laboratory Evaluation Laboratory testing may include: FBC with RBC indices, reticulocytes HIV test (if not done already) In appropriate geographic regions Malaria smear Stool for ova and parasites (hookworm) Urine for Schistosoma eggs Chronic cough, fever or suspicion of TB Sputum for direct microscopy –Chest x-ray if smears for AFB negative Training on Clinical Care of HIV, AIDS and Opportunistic Infections

12. Haematologic, Hepatic and Renal Conditions- 12 Laboratory Evaluation (2) If liver or kidney disease suspected ALT / AST Urea or creatinine Suspected ulcer disease in older patients with iron deficiency Stool for occult blood Consider tests for Serum Iron / ferritin / TIBC Serum Folate Serum B12 levels Training on Clinical Care of HIV, AIDS and Opportunistic Infections

13. Haematologic, Hepatic and Renal Conditions- 13 Severe Anaemia In case of a negative initial evaluation of severe anaemia: Transfuse (if needed) after blood specimens obtained Bone marrow aspirate or biopsy TB or MOTT Disseminated fungal infection Malignancy Other bone marrow condition Training on Clinical Care of HIV, AIDS and Opportunistic Infections

14. Haematologic, Hepatic and Renal Conditions- 14 Anaemia Classification With Examples B12, folate deficiency haemolysisMacrocytic (MCV > 100) anaemia of chronic disease acute bleeding, haemolysis Normal size iron deficiency, chronic disease chronic blood loss Microcytic (MCV < 80) Inadequate Production (low retics) Loss or Destruction (high retics) RBC Size Process Training on Clinical Care of HIV, AIDS and Opportunistic Infections

15. Haematologic, Hepatic and Renal Conditions- 15 Case Study: How would you Classify Maggie’s Anaemia So Far? Moderate (Hb=7.5 g/dl, so between 5 and 10) Microcytic (MCV=75, so <80) Low reticulocyte count Could be: iron deficiency – multiple causes anaemia of chronic disease (nb: no indication from initial investigations) Training on Clinical Care of HIV, AIDS and Opportunistic Infections

16. Haematologic, Hepatic and Renal Conditions- 16 Microcytic Anaemia Chronic iron loss Normal menstruation Pregnancy Hookworm Schistosomiasis Non-infectious GI tract bleeding Ulcer, gastritis, colon cancer Anaemia of Chronic Disease Nutritional deficiency Thalassaemia Congenital due to abnormal Hb synthesis Training on Clinical Care of HIV, AIDS and Opportunistic Infections

17. Haematologic, Hepatic and Renal Conditions- 17 Comparison of Iron-deficiency and Anaemia of Chronic Disease Laboratory parameters Iron deficiency Anaemia of chronic disease MCVlowusually normal; 15-25% low Serum ironlowlow (or low normal) TIBChighlow (or low normal) Serum ferritinlowHigh or normal RDW = (MCV/RBC) highNormal (11-14.5%) Training on Clinical Care of HIV, AIDS and Opportunistic Infections

18. Haematologic, Hepatic and Renal Conditions- 18 Normocytic Anaemia haemolysis – (before response activated) Malaria Autoimmune hemolytic anaemia Early iron deficiency anaemia Chronic renal failure Decreased erythropoietin causes decreased RBC production Chronic liver disease Endocrine disorders Bone marrow disorders Training on Clinical Care of HIV, AIDS and Opportunistic Infections

19. Haematologic, Hepatic and Renal Conditions- 19 Normocytic Anaemia (2) Anaemia of Chronic Disease Reduced iron utilization for hemoglobin production despite adequate iron stores Chronic infections Advanced HIV TB and MOTT Chronic inflammatory disease Rheumatoid arthritis Collagen-vascular disease Malignancy Training on Clinical Care of HIV, AIDS and Opportunistic Infections

20. Haematologic, Hepatic and Renal Conditions- 20 Macrocytic Anaemia haemolysis Young RBCs are large Malaria Autoimmune hemolytic anaemia Folate or B12 deficiency Bone marrow disorders Aplastic anaemia Myelodysplastic syndrome Some leukaemias Note: AZT and d4T cause macrocytosis. If there is no anemia, it does not need to be evaluated. Training on Clinical Care of HIV, AIDS and Opportunistic Infections

21. Haematologic, Hepatic and Renal Conditions- 21 HIV-Associated Anaemia Anaemia is: the most frequent haematological abnormality seen in patients with HIV an independent predictor of all-cause mortality and AIDS-related mortality; also associated with a more rapid decline in CD4 counts* often multifactorial in HIV patients *study in women with HIV in Tanzania: J. Acquir Immune Defic Syndr 2005;40:219-225 Training on Clinical Care of HIV, AIDS and Opportunistic Infections

22. Haematologic, Hepatic and Renal Conditions- 22 HIV-Associated Anaemia (2) Nutritional deficiencies complicated by malabsorption Iron, Folate, B12 (?) Protein Anaemia of chronic disease HIV, OIs, Malignancies Reduced erythropoietin production Disordered iron utilization Cytokine production decreases marrow output Training on Clinical Care of HIV, AIDS and Opportunistic Infections

23. Haematologic, Hepatic and Renal Conditions- 23 HIV-Associated Anaemia (3) Specific OI Parvovirus B19 Marrow invasion MOTT, TB, CMV, EBV, Lymphoma Medications Reduced production AZT, (d4T) Amphotericin Trimethoprim, pyrimethamine albendazole haemolysis in G6PD deficiency (Sulfa, dapsone) Training on Clinical Care of HIV, AIDS and Opportunistic Infections

24. Haematologic, Hepatic and Renal Conditions- 24 Case Study (5) Factors likely to contribute to Maggie’s anaemia Pregnancy Reduced iron stores Possible reduced folate Intra –partum or post-partum bleeding Possible role of parasitic infection Malaria during pregnancy Hookworm Advanced immunosuppression CD4 110 Mild leucopoenia Training on Clinical Care of HIV, AIDS and Opportunistic Infections

25. Haematologic, Hepatic and Renal Conditions- 25 Case Study: Maggie’s Lab Test Results Malaria smear: negative Stool parasite exam Positive for hookworm Measuring serum iron and folate may be useful if available Iron low, RDW high, serum ferritin low Folate normal Training on Clinical Care of HIV, AIDS and Opportunistic Infections

26. Haematologic, Hepatic and Renal Conditions- 26 Case Study: Treatment Maggie is treated for her hookworm with albendazole She receives supplemental iron & folate She begins OI prophylaxis with cotrimoxazole 960 mg daily She begins isoniazid preventive therapy She begins first line HAART with stavudine, lamivudine and nevirapine NB: treating HIV patients with iron in the absence of iron deficiency is not recommended Training on Clinical Care of HIV, AIDS and Opportunistic Infections

27. Haematologic, Hepatic and Renal Conditions- 27 Case Study: Follow-up After 3 months of combined therapy, Maggie’s haemoglobin is 11 grams/dl Training on Clinical Care of HIV, AIDS and Opportunistic Infections

28. Haematologic, Hepatic and Renal Conditions- 28 Summary: Management of Anaemia In Patients with HIV Classify the type of anaemia Correct the cause of the anaemia If iron deficiency, give iron after correcting the underlying problem Give HAART if anaemia is due to HIV Unexplained anaemia <8 g/dl is a WHO Clinical Stage 3 condition Avoid AZT Training on Clinical Care of HIV, AIDS and Opportunistic Infections

29. Haematologic, Hepatic and Renal Conditions- 29 HIV-Associated Leukopaenia and Neutropaenia Common with advanced immunosuppression Direct bone marrow suppression in advanced HIV disease CMV, EBV, parvovirus B19 Hypersplenism (TB, MAC) Low lymphocyte count reflects reduction in CD4 cells Drug toxicity a common cause of leukopaenia Zidovudine, tenofovir Sulfa, trimethoprim, pyrimethamine Ganciclovir 20-34% of HIV-infected will experience neutropaenia Unexplained neutropaenia < 0.5 x 10 9 /L is a WHO Clinical Stage 3 condition Training on Clinical Care of HIV, AIDS and Opportunistic Infections

30. Haematologic, Hepatic and Renal Conditions- 30 Thrombocytopenia About 11% of HIV-infected patients will develop a low platelet count (<100,000) Up to 25-45% with advanced immunosuppression May be part of marrow suppression in advanced HIV with anaemia and leukopaenia Autoimmune Immune thrombocytopenic purpura (ITP) With haemolysis Malaria Thrombotic thrombocytopenic purpura (TTP) Disseminated intravascular coagulation (DIC) Drug toxicity: Ganciclovir, Ranitidine Viral: Parvovirus B19 Training on Clinical Care of HIV, AIDS and Opportunistic Infections

31. Haematologic, Hepatic and Renal Conditions- 31 Immune Thrombocytopaenic Purpura (ITP) Antibodies against platelets or megakaryocytes Bone marrow aspirate / trephine may help with diagnosis Monitor platelet counts closely if >75,000 If <75,000 (certainly < 20,000) and spontaneous bleeding consider treating: HAART if proven ITP Unexplained chronic platelets <50,000 is WHO Stage 3 Avoid AZT – marrow suppressive If does not remit, consider prednisone 30-60 mg/day Intravenous immune globulin (IVIG) if available Platelet transfusions in emergencies; most transfused platelets will be destroyed so this is not a lasting solution Training on Clinical Care of HIV, AIDS and Opportunistic Infections

32. Haematologic, Hepatic and Renal Conditions- 32 Thrombotic Thrombocytopenic Purpura (TTP) Rare but more common in HIV infected than in non-HIV infected Disseminated platelet aggregation Syndrome Haemolytic anemia Thrombocytopenia (thrombotic microangiopathy) Fever Acute renal failure Altered mental status Many precipitating factors HIV infection Pregnancy Medications Bacterial toxins Training on Clinical Care of HIV, AIDS and Opportunistic Infections

33. Haematologic, Hepatic and Renal Conditions- 33 Treatment HAART Support with platelet-depleted FFP for up to 3 weeks Avoid platelet transfusions – may increase thrombotic risk Corticosteroids Consider splenectomy if refractory Daily plasmapheresis Not currently available in Namibia Vincristine for relapse Thrombotic Thrombocytopenic Purpura (TTP) (2) Training on Clinical Care of HIV, AIDS and Opportunistic Infections

34. Liver Disease Haematologic, Hepatic and Renal Conditions- 34 Training on Clinical Care of HIV, AIDS and Opportunistic Infections

35. Haematologic, Hepatic and Renal Conditions- 35 Patterns of Liver Abnormalities 1.Haemolysis/Indirect Bilirubin 2.Acute hepatocellular necrosis 3.Chronic hepatocellular disorders 4.Alcoholic hepatitis & cirrhosis 5.Infiltrative Disease 6.Cholestasis Training on Clinical Care of HIV, AIDS and Opportunistic Infections

36. Haematologic, Hepatic and Renal Conditions- 36 Liver Function Tests As An Aid In diagnosis See Handout 11.1 Training on Clinical Care of HIV, AIDS and Opportunistic Infections

37. Haematologic, Hepatic and Renal Conditions- 37 Case 1 45 year old man presents to the clinic with jaundice, abdominal complaints and feeling “unwell”. He is HIV positive and has a CD4 count of 180. Laboratory test results: Elevated direct > indirect bilirubin AST=360 U/L, ALT=180 U/L GGT=235 U/L Alkaline phosphatase normal Albumin = 25 g/L PT prolonged Training on Clinical Care of HIV, AIDS and Opportunistic Infections

38. Haematologic, Hepatic and Renal Conditions- 38 Case 1 (2) What is the most likely cause of his jaundice? Alcoholic hepatitis Training on Clinical Care of HIV, AIDS and Opportunistic Infections

39. Haematologic, Hepatic and Renal Conditions- 39 Case 2 28 year old woman on HAART (d4T/3TC/NVP) presents very unwell with jaundice, high fever (39°C) and right-sided abdominal pain. Laboratory test results: Elevated direct > indirect bilirubin AST=405 U/L, ALT=650 U/L GGT=normal Alkaline phosphatase = 200 U/L Albumin = normal PT normal Training on Clinical Care of HIV, AIDS and Opportunistic Infections

40. Haematologic, Hepatic and Renal Conditions- 40 Case 2 (2) What is the most likely diagnosis? Acute hepatocellular necrosis, probably infectious in origin (fever) What is the role of nevirapine in this case? Training on Clinical Care of HIV, AIDS and Opportunistic Infections

41. Haematologic, Hepatic and Renal Conditions- 41 Case 3 36 year old woman on HAART presents with vague abdominal complaints. On examination she has hepatomegaly. Laboratory test results: Bilirubin normal AST and ALT normal GGT=100 U/L Alkaline phosphatase = 300 U/L Albumin normal PT normal Training on Clinical Care of HIV, AIDS and Opportunistic Infections

42. Haematologic, Hepatic and Renal Conditions- 42 Case 3 (2) What pattern of liver injury does this probably represent? Infiltrative Disease Training on Clinical Care of HIV, AIDS and Opportunistic Infections

43. Haematologic, Hepatic and Renal Conditions- 43 Case 4 25 year old man with malaise, fever and jaundice. Laboratory test results: Indirect bilirubin high AST = 65 U/L, ALT normal All other liver tests normal Training on Clinical Care of HIV, AIDS and Opportunistic Infections

44. Haematologic, Hepatic and Renal Conditions- 44 Case 4 (2) What is the most likely explanation for the jaundice? Haemolysis Training on Clinical Care of HIV, AIDS and Opportunistic Infections

45. Haematologic, Hepatic and Renal Conditions- 45 Case 5 48 year old man with jaundice which he first noticed a few weeks ago. Laboratory test results: Elevated direct > indirect bilirubin AST=240 U/L, ALT=215 U/L GGT=normal Alkaline phosphatase = 200 U/L Albumin = 26 g/L PT mildly prolonged Training on Clinical Care of HIV, AIDS and Opportunistic Infections

46. Haematologic, Hepatic and Renal Conditions- 46 Case 5 (2) What could be the cause of his jaundice? Chronic hepatocellular disorders Training on Clinical Care of HIV, AIDS and Opportunistic Infections

47. Haematologic, Hepatic and Renal Conditions- 47 Case 6 30 year old man with jaundice, fever, and right upper quadrant pain. He has HIV and his CD4 count is 24. Laboratory test results: Elevated direct bilirubin AST=230 U/L, ALT=250 U/L GGT=115 U/L Alkaline phosphatase = 400 U/L Albumin = normal PT normal Training on Clinical Care of HIV, AIDS and Opportunistic Infections

48. Haematologic, Hepatic and Renal Conditions- 48 Case 6 (2) What could be the cause of his jaundice? Cholestasis cholangitis Training on Clinical Care of HIV, AIDS and Opportunistic Infections

49. Haematologic, Hepatic and Renal Conditions- 49 Cholestasis IntrahepaticExtrahepatic Acute hepatitis (A, B, C, alcohol, EBV, CMV) Cancer: pancreas, gall bladder, etc CirrhosisEnlarged portal lymph nodes 1° biliary cirrhosis Anabolic and contraceptive steroids antibiotics Sclerosing cholangitis Training on Clinical Care of HIV, AIDS and Opportunistic Infections

50. Renal Disorders Haematologic, Hepatic and Renal Conditions- 50 Training on Clinical Care of HIV, AIDS and Opportunistic Infections

51. Haematologic, Hepatic and Renal Conditions- 51 Kidney Disease HIV-associated renal disease HIV-associated nephropathy Drug toxicity Kidney Stones Glomerulonephritis Acute renal failure Chronic renal failure Training on Clinical Care of HIV, AIDS and Opportunistic Infections

52. Haematologic, Hepatic and Renal Conditions- 52 Quantify Renal Insufficiency Measure creatinine clearance with a serum creatinine and 24-hour urine collection for creatinine Estimate creatinine clearance with a serum creatinine and the formula: =(140-age) x Lean Body Wt (kg) x 1.22 plasma creatinine (umol/l) For women, multiply above by 0.85 Normal values: men 97-137 ml/min; women 88-128 ml/min Training on Clinical Care of HIV, AIDS and Opportunistic Infections

53. Haematologic, Hepatic and Renal Conditions- 53 HIV-Associated Nephropathy (HIVAN) Rapidly progressive RF in HIV+ men Rare in women Moderate-severe proteinuria Normal blood pressure, no edema No cells or casts in urine Enlarged, echogenic kidneys Pathology: Focal Segmental Sclerosing Glomerulonephritis (FSGN) Training on Clinical Care of HIV, AIDS and Opportunistic Infections

54. Haematologic, Hepatic and Renal Conditions- 54 Treatment of HIVAN Avoid nephrotoxins May respond to HAART Use doses of NRTIs adjusted for renal insufficiency Progression may slow with treatment of proteinuria Analogous to diabetic FSGN ACE-inhibitors, calcium channel blockers Training on Clinical Care of HIV, AIDS and Opportunistic Infections

55. Haematologic, Hepatic and Renal Conditions- 55 Renal Drug Toxicity A wide variety of drugs may injure the kidney via different mechanisms NSAIDS Aminoglycosides Iodine containing contrast dye Tenofovir Amphotericin B Training on Clinical Care of HIV, AIDS and Opportunistic Infections

56. Haematologic, Hepatic and Renal Conditions- 56 Membranoproliferative Glomerulonephritis Associated with Hepatitis C, HIV, and other conditions Presents as: Nephritic syndrome with urinary RBC, RBC casts, proteinuria, renal insufficiency, hypertension, edema Nephrotic syndrome with high grade proteinuria, low serum albumin, high cholesterol, edema Progresses to renal failure No known therapy Training on Clinical Care of HIV, AIDS and Opportunistic Infections

57. Haematologic, Hepatic and Renal Conditions- 57 Acute Renal Failure Often reversible Many etiologies Decreased renal blood flow Toxic injury Urinary tract obstruction Immediate management Ensure adequate blood volume and blood pressure Ensure bladder drainage Training on Clinical Care of HIV, AIDS and Opportunistic Infections

58. Haematologic, Hepatic and Renal Conditions- 58 Acute Renal Failure (2) Evaluation BUN, creatinine, electrolytes Urine analysis Review history for potential insults including hypotension and drug or toxin exposure Renal ultrasound? Ongoing management Manage fluids and electrolytes Minimize protein load Avoid nephrotoxins Dialysis Training on Clinical Care of HIV, AIDS and Opportunistic Infections

59. Haematologic, Hepatic and Renal Conditions- 59 Chronic Renal Failure Irreversible Many etiologies Diabetes Hypertension Glomerulonephritis Common syndrome Azotemia, anaemia, acidosis, high phosphate Mild proteinuria Hypertension common Small shrunken kidneys Training on Clinical Care of HIV, AIDS and Opportunistic Infections

60. Haematologic, Hepatic and Renal Conditions- 60 Renal Stones Many etiologies Calcium Urate Indinavir stones Stones are crystals of precipitated drug Occurs with high blood levels or dehydration Stones often pass spontaneously with fluids and analgesics Intervention is rarely needed Training on Clinical Care of HIV, AIDS and Opportunistic Infections

61. Haematologic, Hepatic and Renal Conditions- 61 Key Points HIV-associated anaemia is often multifactorial. Simultaneous treatment of factors contributing to anaemia is very effective. Characterizing the pattern of liver injury helps guide the workup and treatment of liver disease. HIV itself is one cause of renal insufficiency which may respond to HAART. Training on Clinical Care of HIV, AIDS and Opportunistic Infections