A 38 year old woman keeps returning to your clinic with tiredness, myalgia, a feeling of lightheadedness, and has almost fainted several times. She has a poor appetite and is losing weight. She has night sweats and has been doing volunteer work with an NGO caring for refugees with chronic ill health. She is in charge of distributing the medicines in a DOTS program for TB. She has malaise in the evenings but has not noted any fever. She has no cough, breathlessness or chest pain.
Her menstrual periods are scanty but regular. Her youngest child (of 5 pregnancies) is 10 years old. She is not on oral contraceptives. Her diet is not lacking in red meat, vegetables, fish, eggs, milk or legumes.She is clinically anemic and has not responded to oral iron, folic acid and B-complex tablets you have been giving her for a month.
What should she be investigated for?
This woman has been in contact with patients with tuberculosis. Some of them may be coughing up the mycobacterium. She should have an X ray chest at once. Pulmonary tuberculosis may nay not produce any respiratory symptoms while the lesions are small and fibronodular. Disseminated tuberculosis may never produce respiratory symptoms and the lesions the size of a millet seed are seen after they have had time to calcifie i.e. 3-6 weeks time.. Tuberculosis may be hidden away in hilar lymph nodes. Extrapulmonary tuberculosis is even more difficult to catch as we are all expecting the patient to cough. Vague abdominal pain with a doughy abdomen or an irregular abdominal mass especially in the right iliac fossa should rouse suspicion of abdominal TB. A B12 deficiency anemia should make you investigate the lower end of the ileum where B12-intrinsic factor complex is absorbed. An ESR is too non-specific. A tuberculin test is difficult to interpret unless she was known to be negative in the past, and how do you work in the factor that she received the BCG vaccine in childhood. There is no material available for mycobacterial culture as blood culture is highly unlikely to yield a positive result . A blood test for PCR for mycobacteria may help.
Why is she not responding to hematinic therapy? She has anemia of chronic disease which we will discuss below.
Should she be given IV iron therapy? Until her chronic disease is treated she will not respond to any therapy for the correction of anemia.
A 28 year old ex-soldier has developed pain in his left ankle, right knee and two fingers on his left hand for the past 6 months. The latter was initially diagnosed as carpal tunnel syndrome but two of the proximal interphalangeal joints became swollen and tender so the diagnosis was changed. He was a long distance runner in the army and won several trophies and has kept up his intense training even after leaving the army. 3 months ago he had pain in the left foot attributed to a hairline fracture in a metatarsal bone. He dislikes hospital visits and has been dosing himself with over the counter NSAIDs. he is also feeling tired and finds it difficult to carry on his running and heavy exercise. He did go to a doctor and had some tests done. His serum ferritin level is 60 ng/l, Tsat is less than 20%, hemoglobin is 10.5gm/dl and the anemia is normocytic, normochromic with a normal white cell count and platelet count and no abnormal cell in the blood. His occult blood test is negative.
He has not responded to oral iron, folic acid, vitamin C and prophylactic PPI.
Why is he anemic?
You should ask him about his diet. He says he still eats a high protein diet which his professional athletic trainer had laid out for him. Ask him about any symptoms of dyspepsia or heartburn. He has none. He has not passed black tarry stools nor does he have hemorrhoids. He has no abnormal cells in his blood and the iron studies show iron deficiency.
What is his disease? From the history the possibilities are RA, NSAID induced dyspepsia, trauma from his 5-8 kilometer running. He has or should be investigated for rheumatoid arthritis. The history is not suggestive of gout and if his uric acid is raised he should have his renal functions investigated, The NSAIDs may have contributed to loss of renal function as well as a GI bleed. The other reason for a non-responsive iron deficiency is repeated trauma as seen in the intense running program he undertakes.
Should you check renal functions? Yes his renal functions should be carefully looked at. He has an autoimmune disease which can affect the kidneys. He is on drugs which can affect the kidneys.
How will you treat his anemia? This appears to be anemia of chronic disease. It will respond to hematinics once the inflammation is under control.
A 56 year old man is being managed for Type 2 diabetes. He is grossly overweight with a BMI of 35. His fasting blood sugar ranges between 180-130 mg/dl. and his HbA1c is usually 9. He is a businessman and has a sedentary lifestyle. He makes no effort to walk, joint a gym but usually does not go there and goes to his golf club only for a meal. He is on metformin 1000 mg twice a day and sitagliptin 50 mg twice a day. He is not hypertensive. His resting ECG is normal and he can perform suboptimally ETT on a treadmill for not more than 5 minutes, because he gets both tired and breathless. His echocardiogram was done and shows an ejection fraction of 56. His cardiologist does not think his symptoms are caused by IHD. The TSH levels are normal.
His current problem is tiredness and somnolence during the day. His wife says he snores heavily and is very restless at night. Sleep studies show episodes of sleep apnoea lasting 2-3 minutes at least 34 times in the night. His Hb is 12 gm/dl, serum ferritin 100 ng/dl and Tsat is <15%. The anemia is normocytic, normochromic. He is advised to use a CPAP machine during sleep.
Why is he iron deficient? A workup should be done for a source of blood loss, poor dietary intake, poor iron absorption.
Is he likely to respond to iron therapy?
Why does chronic disease cause anemia and a lack of response to hematinics?
Chronic diseases often associated with anemia include any long standing infection like tuberculosis, brucellosis, osteomyelitis etc, inflammatory conditions like rheumatoid arthritis, SLE, polymyalgia rheumatica, inflammatory bowel disease etc and the more modern definition includes heart disease, diabetes mellitus and severe trauma.
Anemia of chronic disease is characterized primarily by the following:
- Decreased availability of iron
- Relatively decreased levels of erythropoietin
- Mild decrease in the lifespan of RBCs to 70-80 days (normally 120 days)
What factors regulate the availability of usable iron in the body?
- Hepcidin, is an endogenous antimicrobial peptide secreted by the liver. It controls the level of plasma iron by regulating the intestinal absorption of dietary iron, as well as the release of iron from macrophages and the transfer of iron stored in the hepatocytes. Increase in hepcidin level in the course of inflammatory disease may be a significant mediator of the accompanying anemia.
- Another proposed mechanism for anemia of chronic illness involves cytokines, such as interleukins (IL-1 and IL-6) and tumor necrosis factor (TNF-alpha). These are believed to cause the destruction of RBC precursors and decrease the number of erythropoietin receptors on progenitor cells.
- Loss of renal function. The severity of anemia of CKD is directly related to the degree of loss of renal function, as the kidneys are responsible for approximately 90% of erythropoietin production. Whereas hypoxia in an individual with normally functioning kidneys leads to erythropoietin gene transcription, and hence increased RBC production, CKD results in primary deficiency of erythropoietin production by the interstitial fibroblasts, also known as type I interstitial cells.
Why are people with CKD anemic?
In individuals with advanced stages of CKD, the etiology of anemia tends to be multifactorial and include the following:
Decreased RBC production due to lack of erythropoietin
Increased RBC destruction due to hemolysis (intravascular or extravascular)
Increased blood loss due to multiple venipunctures for an array of indications
In general, anemia is more common in women, in particular, those in their childbearing years. In the latter decades of life, anemia tends to occur without any particular sex predilection. However, in patients with chronic kidney disease (CKD), the risk of developing anemia is 30% higher in males than in females. Although males have higher hemoglobin values, they also have higher rates of advanced CKD. The prevalence of anemia is lower in current smokers, which has been attributed to secondary erythrocytosis.
Anemia is common in patients with CKD. The landmark study by Obrador et al showed that among predialysis patients, 68% of those with advanced CKD who required renal replacement therapy had a hematocrit of less than 30%; of those, 51% had a hematocrit less than 28%.Furthermore, although anemia is not as common in earlier stages of CKD, the prevalence of concurrent anemia was 5.2% in patients with stage III disease, rising to 44.1% in those with stage IV disease. The prevalence of anemia of CKD is also greater in those older than 60 years, as compared with those age 46 to 60 years. This is probably secondary to the greater rate of CKD in older individuals, as well as the lower estimated glomerular filtration rates (GFRs) that are associated with aging.
Clinicians must be wary of the tendency to dismiss the non-specific symptoms as insignificant—for example, as being due to old age—when in fact they should serve as alarming signals of disease or pathology.
Patients with anemia of chronic disease or CKD may present with the following symptoms:
Generalized weakness or malaise, easy fatigability
Generalized body aches, or myalgias
Orthostatic symptoms (eg, lightheadedness, dizziness)
Syncope or near-syncope
Decreased exercise tolerance
Inability to concentrate
Loss of appetite
The following physical findings may be noted:
Neurovascular; Decreased cognitive ability
Eyes; Pale conjunctivae
Cardiovascular; Orthostatic hypotension, tachyarrhythmias
I have already dealt with the treatment of iron deficiency in chronic diseases in my last blog so I am not repeating it. What is important is to identify the increase in symptoms caused by anemia and iron deficiency and the lack of release of iron from macrophages. Once erythropoietin is started in CKD patients iron deficiency develops quickly as they are usually on a very restricted diet.