ANAEMIA OF CHRONIC DISEASE

JATAU ED

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 OUTLINE
• INTRODUCTION
• DEFINITION
• PREVALENCE
• AETIOLOGY
• PATHOGENESIS
-ROLE OF CYTOKINES
-ROLE OF HEPCIDIN
- REDUCED LIFE SPAN OF RBC
• CLINICAL FEATURES
• DIAGNOSIS
• TREATMENT
• THE BIG QUESTION- TO TREAT OR NOT
• CONCLUSION
• REFERENCES
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 INTRODUCTION

- ANAEMIA OF CHRONIC DISEASE IS A HYPOPROLIFERATIVE

ANAEMIA RELATIVELY MILD THAT DEVELOPS IN RESPONSE TO
SYSTEMIC ILLNESS OR INFLAMMATION AND IS USUALLY
NORMOCYTIC , NORMOCHROMIC.

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 DEFINITION
• A MILD TO MODERATE ANAEMIA ASSOCIATED
WITH CHRONIC INFECTIONS AND
INFLAMMATORY DISORDERS AND SOME
MALIGNANCIES AS A RESULT OF
MACROPHAGE IRON RETENTION INDUCED BY
CYTOKINES AND THE MASTER REGULATOR
HEPCIDIN.

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 PREVALENCE

• HIGH PREVALENCE OF INFECTIOUS DISEASES

WORLDWIDE AND THE HIGH PREVALENCE OF
INFLAMMATORY AND MALIGNANT DISORDERS
TELLS THE PREVALENCE OF ACD AS THE SECOND
MOST COMMON CAUSE OF ANAEMIA AFTER IDA
• >130 MIL. AMERICANS LIVE WITH CHRONIC
CONDITIONS
• ACCOUNTS FOR 44.4% OF ANAEMIAS IN MEN
>85 YEARS
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COMMON CONDITIONS ASSOCIATED WITH
ACD
• INFECTION-AIDS/HIV, TUBERCULOSIS,
MALARIA, HEP C, OSTEOMYELITIS ,
CHRONIC ABSCESSES , SLE , SEPSIS
• INFLAMMATION- RHEUMATOID ARHTRITIS,
CROHNS DISEASE, ULCERATIVE COLITIS
• MALIGNANCY- CARCINOMAS, MYELOMA,
LYMPHOMAS
• OTHERS- DIABETTIS MELLITUS, CONGESTIVE
HEART DISEASE
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 AETIOLOGY/PATHOGENESIS

• CAUSE OF ACD IS MULTIFACTORIAL AND

COMPLEX INCLUDING:
* RED CELL DESTRUCTION
*DEREGULATED IRON ABSORPTION AND
TRANSPORT
*DIRECT INHIBITION OF HAEMOPOIESIS
*RELATIVE DEFICIENCY OF ERYTHROPOIETIN

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PATHOPHYSIOLOGY OF ACD

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ROLE OF CYTOKINES

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MOLECULAR MECHANISMS BY WHICH CYTOKINES DIRECTLY
OR INDIRECTLY AFFECT HAEMATOPOIESIS INCLUDE

CYTOKINE – INDUCED DECREASE IN RED CELL SURVIVAL –

(FEVER INDUCED RED CELL DESTRUCTION/ALTERATION OF
RED CELL KINETICS-ACTIVATION OF MACROPHAGE AND RES).
CYTOKINE INDUCED ABNORMALITIES IN IRON METABOLISM –
(CYTOKINES UP REGULATE HEPCIDIN ESPECIALLY IL-6).
CYTOKINES LEADING TO DIRECT INHIBITION OF
HAEMATOPOIESIS ESPECIALLY IFN-APOPTOSIS OF CD34 CELLS
CYTOKINES LEADING TO DECREASED ERYTHROPOIETIN
SECRETION.

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 MOLECULAR ASPECTS

• INCREASED SERUM LEVELS OF CYTOKINES – INTERLEUKIN (IL)-1,

IL-6, TUMOUR NECROSIS FACTOR (TNF), INTERFERON (IFN)-Α,
AND IFN-Β, HAVE BEEN OBSERVED IN MANY INFLAMMATORY
DISEASES INCLUDING AIDS, HEPATITIS C, TB,
BACTERIAL/FUNGAL INFECTIONS, RHEUMATOID ARTHRITIS,
INFLAMMATORY BOWEL DISEASES AND BOTH SOLID AND
HAEMATOLOGICAL MALIGNANCIES.
• ELEVATED LEVELS OF SEVERAL CYTOKINES HAVE BEEN FOUND
IN PATIENTS WITH MALARIAL INFECTION.
• ERYTHROCYTES INFECTED WITH VARIOUS STRAINS OF MALARIA
OR WITH PEPTIDES OF PLASMODIUM FALCIPARUM STIMULATE
MACROPHAGES TO SECRETE TNF.
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• HIGH LEVELS OF INFLAMMATORY CYTOKINES MAY BE
CONCENTRATED IN THE BONE MARROW MILIEU
• BONE MARROW OF PATIENTS WITH RHEUMATOID
ARTHRITIS HAS INCREASED LEVELS OF IL-6 AND TNF-
Α
* TRIALS OF CYTOKINE ANTAGONISTS (MONOCLONAL
ANTIBODIES AGAINST TNF-Α) IN INFLAMMATORY
DISEASES HAVE SHOWN THEM TO IMPROVE
ANAEMIA.

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 ROLE OF HEPCIDIN

ACD IS CHARACTERIZED BY DECREASE SERUM IRON,

DECREASE TIBC WITH NORMAL OR ELEVATED TOTAL IRON
STORES
ELEVATED LEVELS OF HEPCIDIN IN ACD
HEPCIDIN HAS A DIRECT EFFECT ON ERYTHROID
PROGENITOR PROLIFERATION AND SURVIVAL
ALTHOUGH RED CELL SURVIVAL IN ACD IS ONLY MILDLY
DECREASED, EVEN A SMALL DECREASE IN ERYTHROCYTE
HALF-LIFE MAY HAVE AN IMPACT ON HAEMOGLOBIN
CONCENTRATIONS WHEN ERYTHROPOIESIS IS
CONCOMITANTLY SUPPRESSED.
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Hepcidin

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 15
Fleming, R. E. et al. N Engl J Med 2005;352:1741-1744
 ABNORMAL IRON TURNOVER IN ACD OCCURS
VIA SEVERAL MECHANISMS
DECREASED TRANSFERRIN RECEPTORS IN THE SERUM AND
ON ERYTHROBLASTS OCCUR IN PATIENTS WITH ACD
INCREASED RELEASE OF LACTOFERIN FROM NEUTROPHILS
OR INCREASED SYNTHESIS OF APOFERRITIN LEADS TO A
POOL OF IRON TRAPPED IN STORAGE FORM UNAVAILABLE
FOR HEAMOGLOBIN SYNTHESIS.
HEPCIDIN BINDS, INTERNALISES AND DEGRADES THE IRON
EXPORT CHANNEL FERROPORTIN, THUS BLOCKING IRON
RELEASE FROM MACROPHAGES, HEPATOCYTES AND THE
DUODENUM, LEADING TO A DECREASE IN AVAILABLE IRON.

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 CLINICAL FEATURES
• USUALLY OBSCURED BY THE SIGNS AND
SYMPTOMS OF UNDERLYING DISEASE
• GENERALLY DEPENDANT ON;
-DEGREE OF ANAEMIA
-SPEED WITH WHICH THE ANAEMIA DEVELOPED
-EXISTENCE OF CO-MORBID DISEASES AND

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 DIAGNOSIS
• DIAGNOSIS IS OFTEN DIFFICULT AS ACD IS SEEN IN MANY CLINICAL SETTINGS.
• DIAGNOSIS IS PRIMARILY ONE OF EXCLUSION- THOROUGH SEARCH TO
DOCUMENT UNDERLYING ILLNESS
• MANY CHRONIC ILLNESSES ARE ASSOCIATED WITH OTHER FACTORS LEADING TO
ANAEMIA INCLUDING IRON AND NUTRITIONAL DEFICIENCY, BLEEDING,
HAEMOLYSIS, RENAL FAILURE WITH ABSOLUTE ERYTHROPOIETIN DEFICIENCY
AND MARROW FIBROSIS OR INFILTRATION.
* -ROLE OF FREQUENT PHLEBOTOMY IN HOSPITALISED PATIENTS CANNOT BE
RULED OUT.

 ACD IS OFTEN NOT DIAGNOSED.

NB- ANAEMIA OF RENAL FAILURE IS THOUGHT TO BE AN ANAEMIA OF

ABSOLUTE ERYTHROPOIETIN DEFICIENCY AND NOT NECESSARILY ACD BUT
EFFICIENT DIALYSIS LEADS TO IMPROVED RESPONSE TO ERYTHROPOIETIN; ??
OTHER FACTORS INCLUDING CYTOKINES MAY PLAY A ROLE
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 BEST WAY TO DIAGNOSE ACD

• DOCUMENT AN ANAEMIA OF UNDERPRODUCTION

*LOW RETICULOCYTE INDEX
*LOW SERUM IRON AND TRANSFERRIN LEVELS
*ELEVATED SERUM FERRITIN LEVELS IN A SETTING OF A SYSTEMIC, USUALLY
INFLAMMATORY ILLNESS.
• RULE OUT OTHER POSSIBLE CAUSES OF ANAEMIA SUCH AS:
*HAEMOLYSIS
*NUTRITIONAL DEFICIENCY
*SEQUESTRATION ETC.
 A COMPONENT OF IRON DEFICIENCY SHOULD BE HIGHLY CONSIDERED IN A
PATIENT WITH SYSTEMIC INFLAMMATION AND A LOW OR “NORMAL” SERUM
FERRITIN CONCENTRATION
 TIBC SHOULD BE HIGH IN IRON DEFICIENCY ANAEMIA WHILE IT IS LOW OR
NORMAL IN ACD
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• BONE MARROW EXAMINATION
URINARY HEPCIDIN LEVELS
(Assessment of Hepcidin levels )
CELLULAR EXPRESSION OF FERROPORTIN (when feasible)
may be a useful diagnostic tool.
DIAGNOSIS OF ACD REMAINS A CLINICAL ONE

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SERUM LEVELS THAT DIFFERENTIATE ACD &
IDA

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ALGORITHM FOR ACD DIFFERENTIALS

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 TREATMENT

• IDEAL TREATMENT – TREAT THE CHRONIC DISEASE.

• TRANSFUSION IN MORE SEVERE CASES.
• ERYTHROPOIETIN( EPOIETIN ΑLPHA /ΒETA,
DARBOPOIETIN) IN SOME CIRCUMSTANCES.
• IRON REPLACEMENT THERAPY.
NB-MAY BE COSTLY AND DANGEROUS.

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 QUESTION

• TO TREAT OR NOT TO TREAT ?

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 ACD: HARMFUL DISORDER OR AN ADAPTIVE
BENEFICIAL RESPONSE?
PREVAILING OPINION-WEISS AND
GOODNOUGH:

• ANAEMIA OF CHRONIC DISORDER IS AN

ADVERSE CONSEQUENCE OF SYSTEMIC
ILLNESS.
• PATIENTS WOULD BE BETTER OFF WITHOUT IT
• SHOULD BE TREATED

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 ACD AS DELETERIOUS – 2 NOTIONS

• REDUCTION IN RED BLOOD CELL MASS IS

PRESUMED TO COMPROMISE OXYGEN
DELIVERY TO TISSUES THUS OBLIGATE THE
ORGANISM TO COMPENSATE FOR REDUCED
OXYGEN – CARRYING CAPACITY.
CF :ANAEMIA IS ASSOCIATED WITH A POOR
PROGNOSIS IN MANY CLINICAL DISORDERS.
• IN CONCLUSION – TREATMENT OF ACD IS
BENEFICIAL.
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HYPOTHESIS – RYAN ZARYCHAUSKI & DONALD HOUSTON.

• ACD IS A BENEFICIAL AND ADAPTIVE RESPONSE TO

AN UNDERLYING DISEASE STATE.
• THAT ANAEMIA IS ASSOCIATED WITH A POOR
PROGNOSIS IN MANY DISORDERS IS NOT SUFFICIENT
REASON TO ATTRIBUTE CAUSATION.
• TREATMENT OF MILD TO MODERATE ANAEMIA OF
CHRONIC DISEASE APPEARS TO INCREASE
MORTALITY.

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 ANAEMIA AND OXYGEN DELIVERY

SEVERE ANAEMIA IS ASSOCIATED WITH IMPAIRED OXYGEN

DELIVERY; HOWEVER,
IN PATIENTS WITH ACD, THE ANAEMIA IS GENERALLY MILD TO
MODERATE.
OXYGEN CONSUMPTION IN THE RESTING HUMAN BODY IS
APPROXIMATELY 4 TIMES LESS THAN OXYGEN DELIVERY TO THE
TISSUES.
INCREASED EXTRACTION OF OXYGEN FROM THE TISSUES
COMBINED WITH A RIGHTWARD SHIFT IN THE OXYGEN –
HAEMOGLOBIN DISSOCIATION CURVE IS SUFFICIENT TO
MAINTAIN NORMAL OXYGEN DELIVERY IN THE PRESENCE OF
MILD TO MODERATE ANAEMIA.
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ANAEMIA AS A MARKER OF POOR PROGNOSIS

ANAEMIA HAS BEEN ASSOCIATED WITH MORTALITY IN MANY

DISORDERS – RENAL FAILURE, CHF, CANCER ETC.
ASSOCIATION WITH INCREASED MORTALITY IS NOT
EVIDENCE OF CAUSATION.
BOTH THE DEGREE OF ANAEMIA AND THE PROGNOSIS LIKELY
REFLECT THE SEVERITY OF THE UNDERLYING DISEASE.
EXCESS DEATHS AMONG CHRONICALLY ILL PATIENTS WITH
ANAEMIA ARE GENERALLY NOT DUE DIRECTLY TO THE
ANAEMIA OR TO PROCESSES ON WHICH THE ANAEMIA
WOULD BE EXPECTED TO HAVE A MAJOR IMPACT.

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• TREATMENT OF THE ANAEMIA WOULD NOT BE
EXPECTED TO IMPROVE A PATIENT’S OVERALL
PROGNOSIS IF THE ANAEMIA IS SIMPLY A MARKER
OF A SERIOUS, AND POSSIBLY UNDIAGNOSED,
UNDERLYING CONDITION.
NB- TREATMENT OF ANAEMIA HAS REPEATEDLY
BEEN FOUND TO WORSEN RATHER THAN IMPROVE
CLINICAL OUTCOMES.

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 ANAEMIA AS AN ADAPTIVE PHYSIOLOGIC
RESPONSE
• ACD IS A HIGHLY COORDINATED AND GENETICALLY
CONSERVED RESPONSE TO SYSTEMIC DISEASE.
• HAS FEATURES OF A BIOLOGICALLY ADAPTIVE
RESPONSE
• EFFECTORS OF THIS RESPONSE SUCH AS HEPCIDIN IS
A MAJOR REGULATOR OF IRON METABOLISM.
• SEQUESTRATION OF IRON WITHIN MACROPHAGES
AS SEEN IN ACD COULD HAVE SEVERAL BENEFICIAL
EFFECTS.

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IRON IS AN ESSENTIAL NUTRIENT REQUIRED FOR THE GROWTH
OF MANY MICROORGANISMS.
IRON LOADING PROMOTES INFECTION AND FACILITATES THE
GROWTH OF MALIGNANT CELLS.
PLASMA ITSELF DEMONSTRATES ANTIMICROBIAL PROPERTIES
THAT ARE ATTENUATED BY THE ADDITION OF IRON.
INHIBITION OF BACTERIAL GROWTH OCCURS IN IRON
DEFICIENT CONDITIONS.
HYPOFERREMIA IS THEREFORE THOUGHT TO BE AN INNATE
ANTIMICROBIAL STRATEGY.
CF – INCREASED RATES OF INFECTION SEEN AMONG PATIENTS
WITH ΒETA-THALASSEMIA MAJOR WITH IRON OVERLOAD.
FREE IRON IS TOXIC AND ITS CONCENTRATION TIGHTLY
REGULATED.

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 OTHER ADAPTIVE MEASURES IN ACD

DECREASED BONE MARROW PRODUCTION REDUCES

NUTRIENT UTILIZATION IN TIMES OF STRESS.
MODERATE ANAEMIA AND COMPENSATORY EXPANSION
OF PLASMA VOLUME REDUCES BLOOD VISCOSITY –
DECREASED LEFT VENTRICULAR STROKE WORK AND MAY
IMPROVE MICROVASCULAR PERFUSION.
DECREASED MARGINATION OF PLATELETS AND DECREASED
SCAVENGING OF NITRIC OXIDE MAY ALSO REDUCE
THROMBOSIS.
* ABOVE HYPOTHESES ARE YET TO BE PROVEN AND THE
RELATIVE IMPORTANCE OF EACH POTENTIAL MECHANISM
REMAINS UNKNOWN.
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 POTENTIAL HARMS OF TREATMENT

STUDIES HAVE SHOWN ADVERSE CONSEQUENCES ON

USING RED BLOOD CELL TRANSFUSION OR USE OF
ERYTHROPOIESIS – STIMULATING AGENTS IN
MANAGING ACD ESPECIALLY IN CRITICALLY ILL
PATIENTS, PATIENTS WITH RENAL FAILURE AND IN
CANCER PATIENTS.
AMONG PATIENTS WHO RECEIVED RED BLOOD CELL
TRANSFUSIONS, PREDICTED PROBABILITY OF DEATH
WAS HIGHER AMONG THOSE WITH A PRETRANSFUSION
HAEMATOCRIT ABOVE 0.25 – 0.30 THAN AMONG
THOSE WITH A LOWER HAEMATOCRIT.
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• TRANSFUSION APPEARED TO BE MORE HARMFUL IN
PATIENTS WITH MILD TO MODERATE ANAEMIA BUT
SEEMED TO BE BENEFICIAL TO PATIENTS WITH MORE
SEVERE ANAEMIA.
• IN ANOTHER CONTROLLED TRIAL, ADMINISTRATION OF
ERYTHROPOIETIN TO CRITICALLY ILL PATIENTS
INCREASED HAEMOGLOBIN LEVELS BUT DID NOT
REDUCE THE FREQUENCY OF TRANSFUSION OR
OVERALL MORTALITY.
• THUS IT MAY NOT BE THE RED BLOOD CELLS
TRANSFUSED BUT, RATHER, THE ACHIEVED
HAEMOGLOBIN LEVEL THAT CONFERS RISK IN
CRITICALLY ILL PATIENTS WITH ACD.
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 CONCLUSION
- IN CONCLUDING, THE AUTHORS ARE OF THE OPINION THAT
ACD IS AN ADAPTIVE RESPONSE AND COULD BE BENEFICIAL TO
PATIENTS WITH INFLAMMATORY DISEASE.
ANY ADAPTIVE RESPONSE MAY AT TIMES BE EXCESSIVE OR
INSUFFICIENT AND THUS MALADAPTIVE .
THEY ADVOCATE RESTRAINT REGARDING TREATMENT OF MILD TO
MODERATE ACD.
* RISKS OF TREATMENT, INCLUDING DEATH, SHOULD BE WEIGHED
CAREFULLY AGAINST THE POTENTIAL BENEFITS OF LESS FATIGUE
AND OTHER IMPROVEMENTS IN QUALITY OF LIFE BEFORE THERAPY
TO OVERRIDE THE ACD IS CONSIDERED.
THEY ADVOCATE FUTURE THERAPEUTIC TRIALS TO ATTEMPT TO
CHARACTERIZE THE CAUSE OF ANAEMIA IN PATIENTS AND TO
DETECT DIFFERENCES IN MORTALITY BETWEEN TREATMENT
GROUPS. 36
 REFERENCES
• GUENTER W, GOODNOUGH L T. ACD :REVIEW ARTICLE. N ENGL J MED
2005;352: 1011-1023
• BERTERO M T, CAPPIO F C. ACD IN SYSTEMIC AUTOIMMUNE DISEASES.
HAEMATOLOGICA 1997; 82:375-381
• CHEN B H, GANDHI S. ACD:MAKING THE RIGHT CALL. THE CANADIAN J CME
2004; 61-62
• MEHTA A B, HOFFBRAND A V. HAEMATOLOGICAL ASPECTS OF SYSTEMIC
DISEASES. IN: HOFFBRAND A V, LEWIS S M, TUDDENHAM E G D(EDS). 5TH
EDITION. POSTGRADUATE HAEMATOLOGY. LONDON: ARNOLD 2005; 965-66.
• GANZ T. ANAEMIA OF CHRONIC DISEASES. IN: BEUTLER E, COLLER B S,
LITCHMAN M A, KIPPS T J, SELIGSOHN U (EDS). WILLIAMS HEMATOLOGY 8TH
EDITION. NEWYORK: MCGRAW HILL 2010: 503-7.
• WAKAMA T T. ANAEMIA OF CHRONIC DISORDER. FACULTY OF PATHOLOGY
NPMCN 2012 UPDATE COURSE

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THANK YOU

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