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Haematology Group A. Patient X A 61 year old male A 61 year old male Presents with: Presents with: –generalised weakness & increasing dyspnoea on exertion.

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Presentation on theme: "Haematology Group A. Patient X A 61 year old male A 61 year old male Presents with: Presents with: –generalised weakness & increasing dyspnoea on exertion."— Presentation transcript:

1 Haematology Group A

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

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

4 Mr Xs Biochemistry - FBC Initial biochemistry: Initial biochemistry: PARAMETERVALUEREFERENCE RANGE Hb33 g/L (L) MCV125 fL (H) WCC2.4 x10 9 /L (L) x10 9 /L Neutrophils30% (L) 0.72 x10 9 /L x10 9 /L Monocytes5% (L) 0.12 x10 9 /L x10 9 /L Lymphocytes65% 1.56 x10 9 /L x10 9 /L Platelets49 x10 9 /L (L) x10 9 /L Blood flim: Marked anisocytosis (oval macrocytes +++) Poikilocytes (tear drop & fragmented cells ++) Red cells normochromatic Neutropenia with marked neutrophil hypersegmentation Thrombocytopenia.

5 Mr Xs Biochemistry - LFTs PARAMETERVALUEREFERENCE RANGE Serum bilirubin (total) μ 84 μmol/L (H)2-20 Conjugated bilirubin μ 44 μmol/L (H)1-4 AST420 U/L (H)10-45 GGT640 U/L (H)0-50 LD3162 U/L (H) Haptoglobins0.3 g/L Ferritin μ 442 μg/L (H) Serum B12138 pmol/L Serum folate0.7 nmol/L (L)7-45 Red cell folate125 nmol/L (L)

6 Portal Hypertension Pressure in the hepatic portal vein is increased Pressure in the hepatic portal vein is increased Most common cause is cirrhosis, but any liver disease can cause it Most common cause is cirrhosis, but any liver disease can cause it In cirrhosis, hepatocytes regenerate more slowly than scar-tissue forms 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: 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. 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 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 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 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 Also called steatosis Predominantly an asymptomatic condition that develops in response to a short duration (a few days) of alcohol abuse 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 Up to 15 drinks a day for 10 days Entirely reversible with abstinence Entirely reversible with abstinence

10 Alcoholic Hepatitis Prolonged alcohol abuse results in 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. 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. 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. 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 Reversible if patients stop drinking

11 Alcoholic Cirrhosis Alcoholic cirrhosis may occur before, concomitant with, after, or independent of a bout of alcoholic hepatitis 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 Characterized anatomically by widespread nodules in the liver combined with fibrosis Most common of specific organ damage in alcoholics 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 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 Bilirubin: A break-down product of haemoglobin Dying RBCs are engulfed & destroyed by macrophages Dying RBCs are engulfed & destroyed by macrophages Heme is split from globin & the iron core is salvaged Heme is split from globin & the iron core is salvaged The remaining heme molecule is degraded to bilirubin The remaining heme molecule is degraded to bilirubin

13 Bilirubin Unconjugated bilirubin is transported in the plasma bound to albumin Unconjugated bilirubin is transported in the plasma bound to albumin This free bilirubin is conjugated with glucuronic acid in the liver. 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 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 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 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 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 Hyperbilirubinemia: excess of bilirubin in the blood Visible jaundice occurs at ~20-30μmol/L Visible jaundice occurs at ~20-30μmol/L The patient has jaundice (scleral icterus) The patient has jaundice (scleral icterus) History of alcoholism History of alcoholism Mr X has mixed hyperbilirubinemia Mr X has mixed hyperbilirubinemia PARAMETERVALUE REFERENCE RANGE Serum bilirubin (total) μ 84 μmol/L (H)2-20 Conjugated bilirubin μ 44 μ mol/L (H)1-4

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

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

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

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

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

21 Haptoglobins Plasma proteins that carry free haemoglobin (i.e., Hb NOT in RBCs) Plasma proteins that carry free haemoglobin (i.e., Hb NOT in RBCs) Blood levels used to detect haemolysis (intravascular destruction of RBC) 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 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 Increased levels in certain chronic diseases and inflammatory disorders

22 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) 0.3g/L is boarder-line low for the normal range (0.3 – 2.0g/L) ParameterValue Reference Range Haptoglobin 0.3g/L g/L

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

24 Ferritin Two main functions: Two main functions: i.sequester potentially toxic iron into the apoferritin protein shell ii.provide a readily accessible store of iron Can be used to diagnose iron deficiency anaemia 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 Mr X – are his ferritin results consistent with alcoholic liver disease? 442μg/L is significantly higher than the upper normal range (33-330μg/L) 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 This suggests a high level of erythrophagocytosis, most likely due to severe inflammatory liver disease ParameterValue Reference Range Ferritin442μg/L (H)33-330μg/L

26 Folate (Vitamin B 9 ) Obtained from green, leafy vegetables Obtained from green, leafy vegetables Total body folate is ~70mg 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) 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 megaloblastic anemiamegaloblastic anemia

27 Folate–Deficient Anaemia Causes of the anaemia are poor dietary intake of folic acid as in chronic alcoholism Causes of the anaemia are poor dietary intake of folic acid as in chronic alcoholism Causes of folic acid depletion include: 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 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 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 Main causes: defective utilisation of folic acid or vitamin B12 deficiency; cytotoxic drugs; Di- Guliemo Syndrome

29 Mr X – are his results consistent with megaloblastic anaemia? The patients Hb is low, indicating anaemia, while his elevated MCV indicates macrocytic anaemia. The patients 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 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 Both of these results also support the diagnosis of megaloblastic anaemia due to folic acid deficiency. Parameter ValueReference Range Serum B12138 pmol/L Serum folate0.7 nmol/L (L) 7-45 Red cell folate125 nmol/L (L)

30 Mr Xs Biochemistry - FBC Initial biochemistry: Initial biochemistry: PARAMETERVALUEREFERENCE RANGE Hb33 g/L (L) MCV125 fL (H) WCC2.4 x10 9 /L (L) x10 9 /L Neutrophils30% (L) 0.72 x10 9 /L x10 9 /L Monocytes5% (L) 0.12 x10 9 /L x10 9 /L Lymphocytes65% 1.56 x10 9 /L x10 9 /L Platelets49 x10 9 /L (L) x10 9 /L 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 Xs neutrophils are below the normal range. Mr Xs 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 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. 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. Treatment for him is primarily supportive. He needs to improve his diet, and ideally, should cease alcohol intake. Corticosteroids may be indicated. Corticosteroids may be indicated.


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