HaematologyHaematology

Group AGroup A

Patient XPatient X

A 61 year old maleA 61 year old male Presents with: Presents with:

– generalised weakness & increasing dyspnoea generalised weakness & increasing dyspnoea on exertion for 3/52. on exertion for 3/52.

Medical History:Medical History:– AlcoholismAlcoholism

Social HistorySocial History– Divorced for 2 yearsDivorced for 2 years– Lives AloneLives Alone– Retrenched 6 years ago; has not worked sinceRetrenched 6 years ago; has not worked since

Mr X cont…Mr X cont…

On Examination:On Examination:

– Pallor and scleral icterus were notedPallor and scleral icterus were noted

– Clinical evidence of chronic alcoholic Clinical evidence of chronic alcoholic liver disease with portal hypertensionliver disease with portal hypertension

– Spleen was palpable (2cm).Spleen was palpable (2cm).

Mr X’s Biochemistry - FBCMr X’s Biochemistry - FBC Initial biochemistry:Initial biochemistry:

PARAMETER VALUE REFERENCE RANGE

Hb 33 g/L (L) 130-180

MCV 125 fL (H) 80-100

WCC 2.4 x109/L (L) 4.0-11.0 x109/L

Neutrophils 30% (L)0.72 x109/L

2.0-7.5 x109/L

Monocytes 5% (L)0.12 x109/L

0.2-0.8 x109/L

Lymphocytes 65%1.56 x109/L

1.5-4.0 x109/L

Platelets 49 x109/L (L) 150-400 x109/LBlood flim:

•Marked anisocytosis (oval macrocytes +++)•Poikilocytes (tear drop & fragmented cells ++)•Red cells normochromatic•Neutropenia with marked neutrophil hypersegmentation•Thrombocytopenia.

Mr X’s Biochemistry - LFTsMr X’s Biochemistry - LFTs

PARAMETER VALUEREFERENCE

RANGE

Serum bilirubin (total)

84 μμmol/L (H) 2-20

Conjugated bilirubin 44 μμmol/L (H) 1-4

AST 420 U/L (H) 10-45

GGT 640 U/L (H) 0-50

LD 3162 U/L (H) 110-230

Haptoglobins 0.3 g/L 0.3-2.0

Ferritin 442 μμg/L (H) 33-330

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

Portal HypertensionPortal Hypertension

Pressure in the hepatic portal vein is Pressure in the hepatic portal vein is increasedincreased

Most common cause is cirrhosis, but any Most common cause is cirrhosis, but any liver disease can cause itliver disease can cause it

In cirrhosis, hepatocytes regenerate more In cirrhosis, hepatocytes regenerate more slowly than scar-tissue forms slowly than scar-tissue forms – As the scar tissue shrinks, it obstructs blood As the scar tissue shrinks, it obstructs blood

flow through the hepatic portal systemflow through the hepatic portal system

Symptoms of Portal Symptoms of Portal HypertensionHypertension

Common portal hypertensive Common portal hypertensive complications include:complications include:

– Hepatic encephalopathyHepatic encephalopathy

– Bleeding esophageal varicesBleeding esophageal varices

– Ascites & spontaneous bacterial peritonitisAscites & spontaneous bacterial peritonitis

– Hepatorenal syndromeHepatorenal syndrome

Alcoholic Liver DiseaseAlcoholic Liver Disease A spectrum of clinical syndromes & pathologic A spectrum of clinical syndromes & pathologic

changes in the liver caused by alcohol. The spectrum changes in the liver caused by alcohol. The spectrum includes fatty liver, alcoholic hepatitis & alcoholic includes fatty liver, alcoholic hepatitis & alcoholic cirrohsis.cirrohsis.

Approximately 15% to 20% of those who abuse Approximately 15% to 20% of those who abuse alcohol develop alcoholic hepatitis and/or cirrhosis, alcohol develop alcoholic hepatitis and/or cirrhosis, which may develop in succession or exist which may develop in succession or exist concomitantlyconcomitantly

The level of alcohol consumption necessary for the The level of alcohol consumption necessary for the development of these advanced forms of alcoholic development of these advanced forms of alcoholic liver disease is probably 80 g of alcohol per day, the liver disease is probably 80 g of alcohol per day, the equivalent to 6 to 8 drinks daily for several yearsequivalent to 6 to 8 drinks daily for several years

BUT, the threshold of alcohol necessary for the BUT, the threshold of alcohol necessary for the development of advanced alcoholic liver disease development of advanced alcoholic liver disease varies substantially among individualsvaries substantially among individuals

Alcoholic Fatty LiverAlcoholic Fatty Liver

Also called steatosisAlso called steatosis Predominantly an asymptomatic Predominantly an asymptomatic

condition that develops in response condition that develops in response to a short duration (a few days) of to a short duration (a few days) of alcohol abusealcohol abuse

Up to 15 drinks a day for 10 daysUp to 15 drinks a day for 10 days Entirely reversible with abstinenceEntirely reversible with abstinence

Alcoholic HepatitisAlcoholic Hepatitis Prolonged alcohol abuse results in alcoholic Prolonged alcohol abuse results in alcoholic

hepatitis.hepatitis. Patients with this condition have various Patients with this condition have various

constitutional symptoms, such as fatigue, constitutional symptoms, such as fatigue, anorexia, weight loss, nausea and vomiting. anorexia, weight loss, nausea and vomiting.

Severe alcoholic hepatitis may be evident by Severe alcoholic hepatitis may be evident by advanced symptoms due to portal advanced symptoms due to portal hypertension, including gastrointestinal (GI) hypertension, including gastrointestinal (GI) bleeding, ascites, and hepatic encephalopathy. bleeding, ascites, and hepatic encephalopathy.

Other findings depend on the severity of liver Other findings depend on the severity of liver insult and may include jaundice, splenomegaly, insult and may include jaundice, splenomegaly, hepatic bruits, collateral vessels, and ascites. hepatic bruits, collateral vessels, and ascites.

Reversible if patients stop drinkingReversible if patients stop drinking

Alcoholic CirrhosisAlcoholic Cirrhosis Alcoholic cirrhosis may occur before, concomitant Alcoholic cirrhosis may occur before, concomitant

with, after, or independent of a bout of alcoholic with, after, or independent of a bout of alcoholic hepatitishepatitis

Characterized anatomically by widespread nodules Characterized anatomically by widespread nodules in the liver combined with fibrosisin the liver combined with fibrosis

Most common of specific organ damage in alcoholicsMost common of specific organ damage in alcoholics

The clinical history is similar to that of alcoholic The clinical history is similar to that of alcoholic hepatitis, & symptoms are similar to those observed hepatitis, & symptoms are similar to those observed with other forms of end-stage liver diseasewith other forms of end-stage liver disease

BilirubinBilirubin

Bilirubin:Bilirubin: A break-down product of A break-down product of haemoglobinhaemoglobin

Dying RBCs are engulfed & Dying RBCs are engulfed & destroyed by macrophagesdestroyed by macrophages

Heme is split from globin & the iron Heme is split from globin & the iron core is salvagedcore is salvaged

The remaining heme molecule is The remaining heme molecule is degraded to degraded to bilirubinbilirubin

BilirubinBilirubin

Unconjugated bilirubin is transported in Unconjugated bilirubin is transported in the plasma bound to albuminthe plasma bound to albumin

This free bilirubin is conjugated with This free bilirubin is conjugated with glucuronic acid in the liver. glucuronic acid in the liver.

The conjugated bilirubin is then The conjugated bilirubin is then secreted in the bile as an orange-yellow secreted in the bile as an orange-yellow pigmentpigment

Bilirubin & Liver DiseaseBilirubin & Liver Disease Generally, liver disease leads to mixed Generally, liver disease leads to mixed

hyperbilirubinemia, i.e., high levels of both hyperbilirubinemia, i.e., high levels of both circulating (unconjugated) and conjugated circulating (unconjugated) and conjugated bilirubin. (Total=84, range: 2-20) and bilirubin. (Total=84, range: 2-20) and conjugated 44 micro mol/L, range: 1-4conjugated 44 micro mol/L, range: 1-4

This is due to impaired liver uptake of This is due to impaired liver uptake of unconjugated, and impaired excretion of unconjugated, and impaired excretion of conjugated bilirubin from bile duct perhaps conjugated bilirubin from bile duct perhaps due to gallstones, hepatitis, trauma or long due to gallstones, hepatitis, trauma or long term alcohol abuse term alcohol abuse

Also, an increase in bilirubin may mean too Also, an increase in bilirubin may mean too many RBC are getting destroyedmany RBC are getting destroyed

Mr X – are his bilirubin results Mr X – are his bilirubin results consistent with alcoholic liver consistent with alcoholic liver

disease? disease? Hyperbilirubinemia:Hyperbilirubinemia: excess of excess of

bilirubin in the bloodbilirubin in the blood Visible jaundice occurs at ~20-30μmol/LVisible jaundice occurs at ~20-30μmol/L The patient has jaundice (scleral icterus)The patient has jaundice (scleral icterus)

History of alcoholismHistory of alcoholism Mr X has mixed Mr X has mixed hyperbilirubinemiahyperbilirubinemia

PARAMETER

VALUEREFERENCE

RANGE

Serum bilirubin (total)

84 μμmol/L (H) 2-20

Conjugated bilirubin

44 μμmol/L (H) 1-4

Lactate Dehydrogenase (LD)Lactate Dehydrogenase (LD)

Cytoplasmic enzymeCytoplasmic enzyme

Its function is to catalyze the oxidation of L-lactate to Its function is to catalyze the oxidation of L-lactate to pyruvatepyruvate– Assayed as a measure of anaerobic carbohydrate metabolismAssayed as a measure of anaerobic carbohydrate metabolism

Present in heart, liver, kindey, lungs, skeletal muscle Present in heart, liver, kindey, lungs, skeletal muscle and brainsand brains

UUsed as a diagnostic marker for MI, sed as a diagnostic marker for MI, muscular disorders, malignancy and liver muscular disorders, malignancy and liver disease disease

Not a specific markerNot a specific marker

Increased Levels Indicate:Increased Levels Indicate:

MIMI StrokeStroke AnaemiaAnaemia HypotensionHypotension Liver diseaseLiver disease Megaloblastic anaemiaMegaloblastic anaemia Perniciour anaemiaPerniciour anaemia

When is LD testing When is LD testing PerformedPerformed

Possible diagnosis:Possible diagnosis:– Anaemia of Vitamin B12 deficiencyAnaemia of Vitamin B12 deficiency– Megaloblastic anaemiaMegaloblastic anaemia– Perniciour anaemiaPerniciour anaemia

LD isoenzyme levels may be LD isoenzyme levels may be requestedrequested

Lactate Dehydrogenase & Lactate Dehydrogenase & Liver DiseaseLiver Disease

LD has several isoenzymes (LD-1 to LD has several isoenzymes (LD-1 to LD-5)LD-5)

LD-1 and 2LD-1 and 2– MI, Renal infarction, megaloblastic MI, Renal infarction, megaloblastic

anaemiaanaemia LD-2 and 3LD-2 and 3

– Acute leukaemiaAcute leukaemia LD-5LD-5

– Liver and skeletal muscle damageLiver and skeletal muscle damage

What this tells us:What this tells us:

Tissue damageTissue damage Possible liver diseasePossible liver disease Possible anaemiaPossible anaemia Muscle injuryMuscle injury MIMI

HaptoglobinsHaptoglobins Plasma proteins that carry “free” haemoglobin Plasma proteins that carry “free” haemoglobin

(i.e., Hb NOT in RBCs)(i.e., Hb NOT in RBCs) Blood levels used to detect haemolysis Blood levels used to detect haemolysis

(intravascular destruction of RBC)(intravascular destruction of RBC)– Normally ~10% of haemolysis is handled by Normally ~10% of haemolysis is handled by

haptoglobins and haemopexinhaptoglobins and haemopexin– Haemolysis > Haptoglobin synthesis Haemolysis > Haptoglobin synthesis decrease in decrease in

serum haptoglobinserum haptoglobin Lower than normal levels may indicate chronic Lower than normal levels may indicate chronic

liver disease, haemolytic anaemia, primary liver liver disease, haemolytic anaemia, primary liver disease, AMI and some cancersdisease, AMI and some cancers

Increased levels in certain chronic diseases and Increased levels in certain chronic diseases and inflammatory disordersinflammatory disorders

Mr X – are his haptoglobin Mr X – are his haptoglobin results consistent with results consistent with alcoholic liver disease?alcoholic liver disease?

0.3g/L is boarder-line low for the 0.3g/L is boarder-line low for the normal range (0.3 – 2.0g/L)normal range (0.3 – 2.0g/L)

Parameter ValueReference

Range

Haptoglobin0.3g/L 0.3-2.0g/L

FerritinFerritin

An iron compound synthesised in An iron compound synthesised in response to erythrophagocytosisresponse to erythrophagocytosis

Ferritin is stored in the liver, spleen Ferritin is stored in the liver, spleen & bone marrow for eventual & bone marrow for eventual encorporation into haemoglobinencorporation into haemoglobin

Ferritin iron is the principle form of Ferritin iron is the principle form of iron storage therefore serum ferritin iron storage therefore serum ferritin levels indicate the body’s iron storeslevels indicate the body’s iron stores

FerritinFerritin

Two main functions:Two main functions:i.i. sequester potentially toxic iron into the sequester potentially toxic iron into the

apoferritin protein shellapoferritin protein shellii.ii. provide a readily accessible store of provide a readily accessible store of

ironiron Can be used to diagnose iron Can be used to diagnose iron

deficiency anaemiadeficiency anaemia– In combination with serum iron and In combination with serum iron and

total iron-binding capacity tests, it can total iron-binding capacity tests, it can differentiate and classify different types differentiate and classify different types of anaemia'sof anaemia's

Mr X – are his ferritin results Mr X – are his ferritin results consistent with alcoholic liver consistent with alcoholic liver

disease?disease?

442μg/L is significantly higher than 442μg/L is significantly higher than the upper normal range the upper normal range (33-330μg/L)(33-330μg/L)

This suggests a high level of This suggests a high level of erythrophagocytosis, most likely due erythrophagocytosis, most likely due to severe inflammatory liver diseaseto severe inflammatory liver diseaseParameter Value

Reference Range

Ferritin 442μg/L (H) 33-330μg/L

Folate (Vitamin BFolate (Vitamin B99))

Obtained from green, leafy vegetablesObtained from green, leafy vegetables

Total body folate is ~70mgTotal body folate is ~70mg– 1/3 of this is stored in the liver1/3 of this is stored in the liver

In folate In folate deficiency anaemia, the red cells deficiency anaemia, the red cells are abnormally large (“megalocytes”)are abnormally large (“megalocytes”)– Precursors, in the bone marrow are Precursors, in the bone marrow are

“megaloblasts”“megaloblasts”– Thus, this anaemia is referred to as Thus, this anaemia is referred to as

megaloblastic anemiamegaloblastic anemia

Folate–Deficient AnaemiaFolate–Deficient Anaemia Causes of the anaemia are poor dietary Causes of the anaemia are poor dietary

intake of folic acid as in chronic alcoholismintake 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 Poor intake (e.g., chronic alcoholism, diet lacking in fresh vegetables) in fresh vegetables)

– Inadequate absorption/malabsorption syndrome Inadequate absorption/malabsorption syndrome (e.g, drug-induced by phenytoin, primidone, (e.g, drug-induced by phenytoin, primidone, barbiturates; celiac disease)barbiturates; celiac disease)

– Inadequate utilisation via antagonists such as Inadequate utilisation via antagonists such as methotrexate and trimethoprimmethotrexate and trimethoprim

Alcohol also interferes with its intestinal Alcohol also interferes with its intestinal absorption, intermediate metabolism & absorption, intermediate metabolism & entero-hepatic salvageentero-hepatic salvage

Megaloblastic AnemiaMegaloblastic Anemia Results from defective DNA synthesis. RNA Results from defective DNA synthesis. RNA

synthesis continues synthesis continues increased cytoplasmic increased cytoplasmic mass & maturationmass & maturation– I.e., All cells have dyspoiesis: cytoplasmic maturity I.e., All cells have dyspoiesis: cytoplasmic maturity

> nuclear maturity > nuclear maturity production of megaloblasts production of megaloblasts– Dyspoiesis Dyspoiesis increased intramedullary cell death increased intramedullary cell death

hyperbilirubinemia & hyperuricemia hyperbilirubinemia & hyperuricemia– All cell lines are affected, so leukopenia & All cell lines are affected, so leukopenia &

thrombocytopenia may occurthrombocytopenia may occur Main causes: defective utilisation of folic acid Main causes: defective utilisation of folic acid

or vitamin B12 deficiency; cytotoxic drugs; Di-or vitamin B12 deficiency; cytotoxic drugs; Di-Guliemo SyndromeGuliemo Syndrome

Mr X – are his results Mr X – are his results consistent with megaloblastic consistent with megaloblastic

anaemia?anaemia? The patient’s Hb is low, indicating anaemia, while his The patient’s Hb is low, indicating anaemia, while his

elevated MCV indicates macrocytic anaemia. elevated MCV indicates macrocytic anaemia.

The patient has a serum folate of 0.7nmol/L, & a RBC The patient has a serum folate of 0.7nmol/L, & a RBC folate level of 125nmol/L which are well below the normal folate level of 125nmol/L which are well below the normal ranges. His serum B12 is within the normal range ranges. His serum B12 is within the normal range – Normal serum B12 assay with a low RBC folate level are Normal serum B12 assay with a low RBC folate level are

consistent with alcoholismconsistent with alcoholism

Both of these results Both of these results

also support the diagnosis ofalso support the diagnosis of

megaloblastic anaemia due megaloblastic anaemia due

to folic acid deficiency.to folic acid deficiency.

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’s Biochemistry - FBCMr X’s Biochemistry - FBC Initial biochemistry:Initial biochemistry:

PARAMETER VALUE REFERENCE RANGE

Hb 33 g/L (L) 130-180

MCV 125 fL (H) 80-100

WCC 2.4 x109/L (L) 4.0-11.0 x109/L

Neutrophils 30% (L)0.72 x109/L

2.0-7.5 x109/L

Monocytes 5% (L)0.12 x109/L

0.2-0.8 x109/L

Lymphocytes 65%1.56 x109/L

1.5-4.0 x109/L

Platelets 49 x109/L (L) 150-400 x109/LBlood flim:

•Marked anisocytosis (oval macrocytes +++)•Poikilocytes (tear drop & fragmented cells ++)•Red cells normochromatic•Neutropenia with marked neutrophil hypersegmentation•Thrombocytopenia.

Mr X – are his results Mr X – are his results consistent with megaloblastic consistent with megaloblastic

anaemia?anaemia? Mr X’s Mr X’s neutrophils are below the neutrophils are below the

normal range.normal range.– This tends to occur in chronic disease This tends to occur in chronic disease

states and megaloblastic anaemiasstates and megaloblastic anaemias Hypersegmentation of neutrophils Hypersegmentation of neutrophils

occurs in 91% of cases megaloblastic occurs in 91% of cases megaloblastic anaemiaanaemia

ConclusionsConclusions

Mr X is experiencing multiple Mr X is experiencing multiple biochemical changes due to his biochemical changes due to his chronic alcohol intake. chronic alcohol intake.

Treatment for him is primarily Treatment for him is primarily supportive. He needs to improve his supportive. He needs to improve his diet, and ideally, should cease diet, and ideally, should cease alcohol intake.alcohol intake.

Corticosteroids may be indicated.Corticosteroids may be indicated.