Haematology

1. Haematology Group A

2. Patient X • A 61 year old male • Presents with: • generalised weakness & increasing dyspnoea on exertion for 3/52. • Medical History: • Alcoholism • Social History • Divorced for 2 years • Lives Alone • Retrenched 6 years ago; has not worked since

3. Mr X cont… • On Examination: • Pallor and scleral icterus were noted • Clinical evidence of chronic alcoholic liver disease with portal hypertension • Spleen was palpable (2cm).

4. Mr X’s Biochemistry - FBC • Initial biochemistry: • Blood flim: • Marked anisocytosis (oval macrocytes +++) • Poikilocytes (tear drop & fragmented cells ++) • Red cells normochromatic • Neutropenia with marked neutrophil hypersegmentation • Thrombocytopenia.

5. Mr X’s Biochemistry - LFTs

6. Portal Hypertension • Pressure in the hepatic portal vein is increased • Most common cause is cirrhosis, but any liver disease can cause it • In cirrhosis, hepatocytes regenerate more slowly than scar-tissue forms • As the scar tissue shrinks, it obstructs blood flow through the hepatic portal system

7. Symptoms of Portal Hypertension • Common portal hypertensive complications include: • Hepatic encephalopathy • Bleeding esophageal varices • Ascites & spontaneous bacterial peritonitis • Hepatorenal syndrome

8. Alcoholic Liver Disease • A spectrum of clinical syndromes & pathologic changes in the liver caused by alcohol. The spectrum includes fatty liver, alcoholic hepatitis & alcoholic cirrohsis. • Approximately 15% to 20% of those who abuse alcohol develop alcoholic hepatitis and/or cirrhosis, which may develop in succession or exist concomitantly • The level of alcohol consumption necessary for the development of these advanced forms of alcoholic liver disease is probably 80 g of alcohol per day, the equivalent to 6 to 8 drinks daily for several years • BUT, the threshold of alcohol necessary for the development of advanced alcoholic liver disease varies substantially among individuals

9. Alcoholic Fatty Liver • Also called steatosis • Predominantly an asymptomatic condition that develops in response to a short duration (a few days) of alcohol abuse • Up to 15 drinks a day for 10 days • Entirely reversible with abstinence

10. Alcoholic Hepatitis • Prolonged alcohol abuse results in alcoholic hepatitis. • Patients with this condition have various constitutional symptoms, such as fatigue, anorexia, weight loss, nausea and vomiting. • Severe alcoholic hepatitis may be evident by advanced symptoms due to portal hypertension, including gastrointestinal (GI) bleeding, ascites, and hepatic encephalopathy. • Other findings depend on the severity of liver insult and may include jaundice, splenomegaly, hepatic bruits, collateral vessels, and ascites. • Reversible if patients stop drinking

11. Alcoholic Cirrhosis • Alcoholic cirrhosis may occur before, concomitant with, after, or independent of a bout of alcoholic hepatitis • Characterized anatomically by widespread nodules in the liver combined with fibrosis • Most common of specific organ damage in alcoholics • The clinical history is similar to that of alcoholic hepatitis, & symptoms are similar to those observed with other forms of end-stage liver disease

12. Bilirubin • Bilirubin: A break-down product of haemoglobin • Dying RBCs are engulfed & destroyed by macrophages • Heme is split from globin & the iron core is salvaged • The remaining heme molecule is degraded to bilirubin

13. Bilirubin • Unconjugated bilirubin is transported in the plasma bound to albumin • This free bilirubin is conjugated with glucuronic acid in the liver. • The conjugated bilirubin is then secreted in the bile as an orange-yellow pigment

14. Bilirubin & Liver Disease • Generally, liver disease leads to mixed hyperbilirubinemia, i.e., high levels of both circulating (unconjugated) and conjugated bilirubin. (Total=84, range: 2-20) and conjugated 44 micro mol/L, range: 1-4 • This is due to impaired liver uptake of unconjugated, and impaired excretion of conjugated bilirubin from bile duct perhaps due to gallstones, hepatitis, trauma or long term alcohol abuse • Also, an increase in bilirubin may mean too many RBC are getting destroyed

15. Mr X – are his bilirubin results consistent with alcoholic liver disease? • Hyperbilirubinemia: excess of bilirubin in the blood • Visible jaundice occurs at ~20-30μmol/L • The patient has jaundice (scleral icterus) • History of alcoholism • Mr X has mixed hyperbilirubinemia

16. Lactate Dehydrogenase (LD) • Cytoplasmic enzyme • Its function is to catalyze the oxidation of L-lactate to pyruvate • Assayed as a measure of anaerobic carbohydrate metabolism • Present in heart, liver, kindey, lungs, skeletal muscle and brains • Used as a diagnostic marker for MI, muscular disorders, malignancy and liver disease • Not a specific marker

17. Increased Levels Indicate: • MI • Stroke • Anaemia • Hypotension • Liver disease • Megaloblastic anaemia • Perniciour anaemia

18. When is LD testing Performed • Possible diagnosis: • Anaemia of Vitamin B12 deficiency • Megaloblastic anaemia • Perniciour anaemia • LD isoenzyme levels may be requested

19. Lactate Dehydrogenase & Liver Disease • LD has several isoenzymes (LD-1 to LD-5) • LD-1 and 2 • MI, Renal infarction, megaloblastic anaemia • LD-2 and 3 • Acute leukaemia • LD-5 • Liver and skeletal muscle damage

20. What this tells us: • Tissue damage • Possible liver disease • Possible anaemia • Muscle injury • MI

21. Haptoglobins • Plasma proteins that carry “free” haemoglobin (i.e., Hb NOT in RBCs) • Blood levels used to detect haemolysis (intravascular destruction of RBC) • Normally ~10% of haemolysis is handled by haptoglobins and haemopexin • Haemolysis > Haptoglobin synthesis  decrease in serum haptoglobin • Lower than normal levels may indicate chronic liver disease, haemolytic anaemia, primary liver disease, AMI and some cancers • Increased levels in certain chronic diseases and inflammatory disorders

22. Parameter Value Reference Range Haptoglobin 0.3g/L 0.3-2.0g/L Mr X – are his haptoglobin results consistent with alcoholic liver disease? • 0.3g/L is boarder-line low for the normal range (0.3 – 2.0g/L)

23. Ferritin • An iron compound synthesised in response to erythrophagocytosis • Ferritin is stored in the liver, spleen & bone marrow for eventual encorporation into haemoglobin • Ferritin iron is the principle form of iron storage therefore serum ferritin levels indicate the body’s iron stores

24. Ferritin • Two main functions: • sequester potentially toxic iron into the apoferritin protein shell • provide a readily accessible store of iron • Can be used to diagnose iron deficiency anaemia • In combination with serum iron and total iron-binding capacity tests, it can differentiate and classify different types of anaemia's

25. Parameter Value Reference Range Ferritin 442μg/L (H) 33-330μg/L Mr X – are his ferritin results consistent with alcoholic liver disease? • 442μg/L is significantly higher than the upper normal range (33-330μg/L) • This suggests a high level of erythrophagocytosis, most likely due to severe inflammatory liver disease

26. Folate (Vitamin B9) • Obtained from green, leafy vegetables • Total body folate is ~70mg • 1/3 of this is stored in the liver • In folate deficiency anaemia, the red cells are abnormally large (“megalocytes”) • Precursors, in the bone marrow are “megaloblasts” • Thus, this anaemia is referred to as megaloblastic anemia

27. Folate–Deficient Anaemia • Causes of the anaemia are poor dietary intake of folic acid as in chronic alcoholism • Causes of folic acid depletion include: • Poor intake (e.g., chronic alcoholism, diet lacking in fresh vegetables) • Inadequate absorption/malabsorption syndrome (e.g, drug-induced by phenytoin, primidone, barbiturates; celiac disease) • Inadequate utilisation via antagonists such as methotrexate and trimethoprim • Alcohol also interferes with its intestinal absorption, intermediate metabolism & entero-hepatic salvage

28. Megaloblastic Anemia • Results from defective DNA synthesis. RNA synthesis continues  increased cytoplasmic mass & maturation • I.e., All cells have dyspoiesis: cytoplasmic maturity > nuclear maturity  production of megaloblasts • Dyspoiesis  increased intramedullary cell death  hyperbilirubinemia & hyperuricemia • All cell lines are affected, so leukopenia & thrombocytopenia may occur • Main causes: defective utilisation of folic acid or vitamin B12 deficiency; cytotoxic drugs; Di-Guliemo Syndrome

29. Parameter Value Reference Range Serum B12 138 pmol/L 120-680 Serum folate 0.7 nmol/L (L) 7-45 Red cell folate 125 nmol/L (L) 360-1400 Mr X – are his results consistent with megaloblastic anaemia? • The patient’s Hb is low, indicating anaemia, while his elevated MCV indicates macrocytic anaemia. • The patient has a serum folate of 0.7nmol/L, & a RBC folate level of 125nmol/L which are well below the normal ranges. His serum B12 is within the normal range • Normal serum B12 assay with a low RBC folate level are consistent with alcoholism • Both of these results also support the diagnosis of megaloblastic anaemia due to folic acid deficiency.

30. Mr X’s Biochemistry - FBC • Initial biochemistry: • Blood flim: • Marked anisocytosis (oval macrocytes +++) • Poikilocytes (tear drop & fragmented cells ++) • Red cells normochromatic • Neutropenia with marked neutrophil hypersegmentation • Thrombocytopenia.

31. Mr X – are his results consistent with megaloblastic anaemia? • Mr X’s neutrophils are below the normal range. • This tends to occur in chronic disease states and megaloblastic anaemias • Hypersegmentation of neutrophils occurs in 91% of cases megaloblastic anaemia

32. Conclusions • Mr X is experiencing multiple biochemical changes due to his chronic alcohol intake. • Treatment for him is primarily supportive. He needs to improve his diet, and ideally, should cease alcohol intake. • Corticosteroids may be indicated.