Q & A in Internal Medicine
Associate Professor Wong Yin Onn
Clinical School, Johor Bahru,
This eBook is a collation of questions that I ask my medical students at my
Bedside teaching sessions. Dr Chok Yin Ling, a brilliant young doctor keen
on a career in Internal Medicine, was given these questions on a daily
basis. This was to help her to prepare for her post graduate examinations.
These questions and answers were edited and documented in her digital
diary; this eBook is the result. I hope that this work which is FREE to all
will help students at both undergraduate and post graduate levels.
I dedicate this eBook to all the teachers of this ancient art.
dr wong yin onn
MBBS(Mal), MRCP (UK), AM, FRCP(Glas)
22 March 2014
Foreword by Dr Ng Kian Seng, the founder of Aequanimitas
The Dear Yin Ling Series... The words are of course not to be taken
literally... "Dear" is the heart attitude that Prof Punna Wong brings to his
teaching, he loves his students...
Yin Ling is a real name but of course it is also a metaphor for the HO,
MO, Consultant, Medical student who is passionate for medicine and
patient... please do not allow overworked, underpaid Yin Ling to be the
sole person interacting with Prof Wong... think of that... I am also a Yin
Ling (older, male and fatter version) and Prof Wong is also addressing me
when he says, Dear Yin Ling...and Yin Ling should be proud that Prof
Wong has used her name...as a metaphor
I love the title and so do many of the people in Kluang and perhaps
around the world!
Dear Yin Ling,
Osler said that to succeed you must Have a Calling, The Calling to be the
BEST Physician that you can be, the most compassionate doctor available,
and the most dedicated student soaking up all that your seniors can
teach.
Even after he was well established in medicine, Osler was urged to
consider other career paths eg university presidency and politics, but he
always declined. Thank goodness for that. Politics would have killed him
off early.
In perhaps his greatest speech to a medical student body, titled
“Aequanimatus,” he spoke of having found his calling. You must have the
same calling that will push you to study till the wee hours, to see patients
till you drop from exhaustion, to learn like your life depends on it, and
hopefully to also teach your juniors like a woman possessed.
“To prevent disease, to relieve suffering, and to heal the sick—this is our
work. The profession in truth is a sort of guild or brotherhood, any
member of which can take up his calling in any part of the world and
find brethren whose language and methods and whose aims and ways
are identical with his own."
Questions
1) ON H.PYLORI Dear Yin Ling,
What can we use in HP resistant to Amox/clarythro/PPI combination treatment?
The issue is what to do with treatment failures. The success rate for the current combination is assumed to be over 85%. It is likely that the success rates are gradually decreasing as macrolide resistance becomes more prevalent. There is some cross-‐resistance to clarithromycin from the use of other macrolides.
After failure of a combination of PPI, amoxicillin and clarithromycin, a theoretically correct alternative would be the use, as second option, of other PPI-‐based triple therapy including amoxicillin (that does not induce resistance) and metronidazole (an antibiotic not used in the first trial). However in practice this approach as second-‐line treatment has proven to be disappointing (approx 50% eradication rate).
Levofloxacin-‐based 'rescue' therapy appears to be the best second-‐line strategy, representing a good alternative to quadruple therapy in patients with previous PPI-‐ clarithromycin-‐amoxicillin failure – this treatment has higher efficacy, simplicity of use (better compliance) and less adverse effects. Levofloxacin has, in vitro,
remarkable activity against H. pylori and primary resistance is relatively infrequent (when compared with metronidazole or clarithromycin).
A combination of a PPI, amoxicillin and levofloxacin, as first-‐line regimen, has mean eradication rates of about 90%. For patients with one previous eradication failure, H. pylori cures rates range from 60% to 94%. A recent systematic review showed a mean eradication rate with levofloxacin-‐based 'rescue' regimens
(combined with amoxicillin and a PPI in most studies) of 80%, which represents a relatively high figure when considering 'rescue' therapy will have have eradication rates lower than first-‐line treatments. A systematic review found higher H. pylori cure rates with 10-‐day than with 7-‐day regimens with the levofloxacin-‐amoxicillin-‐ PPI combination in particular (80% versus 68%), suggesting that the longer (10-‐ day) therapeutic scheme should be chosen. The daily dose is still unclear but 500mg daily may be as effective as 500mg bd.
Please check with Urea Breath Test post treatment for cure!
2) ON LIPIDS Dear yin ling,
High cholesterol plus high Triglycerides is common clinical problem. Statins alone often do not return one to normal physiology.
http://www.ncbi.nlm.nih.gov/m/pubmed/23324122/
Adverse events following statin-fenofibrate therapy versus statin alone: a meta-analysis of randomized controlled trials.
Geng Q, et al. Journal Clin Exp Pharmacol Physiol. 2013 Mar;40(3):219-26. doi: 10.1111/1440-1681.12053.
Abstract
The combination of fenofibrate with statins is a beneficial therapeutic option for patients with mixed dyslipidaemia, but concerns about adverse events (AEs) make physicians reluctant to use this combination therapy. Medline, Embase and the Cochrane Library were searched to identify 13 randomized controlled trials,
involving 7712 patients, of statin-‐fenofibrate therapy versus statin alone for review. There were significant decreases in low-‐density lipoprotein-‐cholesterol, triglycerides and total cholesterol and increases in high-‐density lipoprotein-‐cholesterol in
patients receiving combination therapy compared with statin therapy alone. The incidence of aminotransferase elevations in the fenofibrate-‐statin therapy group was significantly higher than in the statin monotherapy group (odds ratio (OR), 1.66; 95% confidence interval (CI) 1.17-‐2.37; P < 0.05). The incidence of elevated creatine kinase levels (OR 0.88; 95% CI 0.63-‐1.23; P > 0.05), muscle-‐associated AEs (OR 0.98; 95% CI 0.88-‐1.09; P > 0.05) and withdrawals attributed to liver and muscle
dysfunction did not differ significantly between the two groups. The efficacy of fenofibrate + standard-‐dose statin and incidence of AEs in the fenofibrate +
standard-‐dose statin group were almost identical to those in the fenofibrate-‐statin group. In conclusion, combination therapy improves the blood lipid profile of
patients. Fenofibrate-‐statin combination therapy appears to be as well tolerated as statin monotherapy. Physicians should consider fenofibrate-‐statin combination therapy in patients but monitor aminotransferase levels to avoid hepatic
complications.
YL: i learnt that it's also important to realize that both alcohol and insulin resistance can give a high TG. insulin resistance caused the breakdown of triglycerides and release FFA. one dietary advice is to cut down simple carbs and sugars to control TG.
TG will also increase SMALL, DENSE LDL particle, aka LDL3, which is highly
atherogenic compared to LDL1 which is larger and less dense. we cannot measure both of them, hence the surrogate marker of high TG and low HDL reflects the
small and dense LDL3 particle. by controlling TG with a fibrate, we make the small dense LDL become bigger less dense LDL, and decrease the overall atherogenic risk, despite no change in LDL levels.
We rarely use gemfibrozil now.
Only fibrate and niacin increase one's HDL. but niacin makes one look like a crab-‐ flushing!!
We may combine with using a statin at night and fenofibrate in the morning.
PROF : Under what conditions will we still use gemfibrosil?
Many of our patients on follow up have renal impairment of various stages. They are commonly monitored by eGFR which is convenient vs 24h urine for CCl.
Fenofibrate increases creatinine levels significantly hence a calculated eGFR will be falsely lowered. Gemfibrosil avoids this effect.
http://www.ncbi.nlm.nih.gov/m/pubmed/12372935/
Fenofibrate increases creatininemia by increasing metabolic production of creatinine.
Hottelart C, et al. Journal Nephron. 2002;92(3):536-41.
Abstract
Fenofibrate is a potent hypolipemic agent, widely used in patients with renal insufficiency in whom dyslipidemia is frequent. A moderate reversible increase in creatinine plasma levels is an established side effect of fenofibrate therapy, which mechanism remains unknown. We have previously reported that in 13 patients with normal renal function or moderate renal insufficiency, two weeks of fenofibrate therapy increased creatininemia without any changes in renal plasma flow and glomerular filtration rate [1]. In 13 additional patients, muscular enzymes (AST, GPT, CPK, LDH) and myoglobin were measured before and after 2 weeks on fenofibrate, and the values of creatininemia obtained by the Jaffé technique and HPLC were compared. CPK and AST activity and plasma myoglobin increased in 2 patients with fenofibrate, but muscular enzymes remained unchanged in the population as a whole, and were not correlated to the changes in creatininemia. The changes in
creatininemia induced by fenofibrate measured by the Jaffé technique were strongly correlated to those measured by HPLC (r(2) = 0.675, p = 0.0006). Analysis of the pooled data of the two arms of the study showed in 26 patients that two weeks of fenofibrate therapy efficiently reduced total cholesterol and triglycerides plasma levels, and raised creatininemia from 139 +/-‐ 8 to 160 +/-‐ 10 micromol/l (p <
0.0001), but confirmed that creatininuria also increased to the extent that creatinine clearance remained unchanged (68 +/-‐ 6 vs. 67 +/-‐ 6 ml/min, n.s.). It is concluded that the increase in creatininemia induced by fenofibrate in renal patients does not reflect an impairment of renal function, nor an alteration of tubular creatinine
secretion, and is not falsely increased by a dosage interference. Fenofibrate-‐induced increase of daily creatinine production is neither readily explained by accelerated muscular cell lysis. It is proposed that fenofibrate increases the metabolic
production rate of creatinine.
3) ON CANTLIE’S LINE Dear Yin Ling,
Who is Sir James Cantlie and why is his contribution not only to medicine but also to Asia and the world?
Cantlie's line is named in his honour. What is this line and how is it so important to our understanding of the treatment of liver tumours? Everyday in my work I look out for diseases and carefully see if it is to the left or right of Cantlie's line and hence potentially treatable.
Dr James Cantlie was a Foundation Professor at the primordial College of Medicine in HongKong (later to become the Faculty of Medicine at the University of
HongKong). In his very first batch was a young brilliant Chinese lad named Sun Yat Sen. Teachers of old like some teachers today loved their students like their own children (following the Hippocratic oath the relationship is akin to a Father-‐ Son/Daughter bond).
It was also in HongKong that he did his seminal work on the liver. Years later when Dr Sun Yat Sen the revolutionary was kidnapped by the Manchurian regime in London and almost definitely headed back home for his head to be separated from his neck, it was Sir James Cantlie that Dr Sun turned to for help and he organised a
press campaign and much publicity that ultimately pressured the Manchurian
authorities to release Dr Sun, once again proving the power of the pen vs the sword.
Dr Sun subsequently went on to be the Father of Modern China.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2826664/
Thomas M van Gulik and Jacomina W van den Esschert
Abstract
As early as 1897, Sir James Cantlie published a series of observations of
extraordinary significance in the face of how we now look upon portal blood supply and the pre-‐resectional use of portal vein ligation or embolization to induce
hypertrophy of the part of the liver we intend to preserve. In the Proceedings of the Anatomical Society of Great Britain and Ireland, he describes performing an autopsy on a patient in which the right side of the liver was reduced to a mass of fibrotic tissue whereas the left side of the liver showed a marked hypertrophy.1* He noted ‘that the hypertrophy of the left side joined with the atrophied right side, at a line drawn through the fundus of the gallbladder to the center of the inferior vena cava at the back of the liver’. He assumed that an abscess had destructed the right lobe of the liver, and that this resulted in a compensatory hypertrophy of the contralateral part of the liver. Hence, he concluded that the line connecting the fundus of the gallbladder with the centre of the inferior vena cava indicated the mid-‐line of the liver, unlike common opinion at that time which considered the umbilical fissure as the division of the right and left liver lobes.
He corroborated his observations by performing experiments in which he injected the right and left divisions of the portal vein with coloured dyes showing that the injected areas met along a line connecting ‘the fundus of the gallbladder’ with ‘the spot where the inferior vena cava grooves the back of the liver’. This line we still refer to as Cantlie's line (Fig. 1) indicating the anatomical mid-‐line of the liver and defining the border between the right and left liver segments in the plane of the middle hepatic vein. As he realized that the right and left liver were perfused by two separate streams of the portal vein, he recognized the potential this phenomenon could have for hepatic surgery.
Cantlie's line represents the anatomical mid-‐line of the liver connecting the fundus of the gallbladder with the centre of the inferior vena cava.
He perceived the consequences the watershed between the right and left liver lobes could have for trauma of the liver by writing ‘The liver, when split or fissured by a blow, as between the buffers of railway-‐carriages, splits along the mid-‐line of the liver in preference to any other’. He also foresaw that this would not necessarily result in major bleeding as ‘haemorrhage has less to be dreaded as the liver is incised or torn in the neighborhood of that line (i.e the mid-‐line)’. Indeed in blunt abdominal trauma, the liver may be completely fractured along Cantlie's line
without any major bleeding from that plane. We were able to confirm this message recently in a patient admitted after blunt abdominal trauma who had fractured his liver along Cantlie's line (Fig. 2) and who had been successfully managed by
conservative treatment without the need for any blood transfusion.
Figure 2
Contrast enhanced abdominal computed tomography (CT) scan of a patient admitted after blunt abdominal trauma showing a fracture of the liver along
Cantlie's line, running between the medial borders of segment IV and segments V/ VIII.
Coming back to his initial observation at the autopsy, he noted the ‘almost elephantine’ hypertrophy of the left side of the liver at the expense of a greatly atrophied right side ‘which looked like, and practically was, a mere appendage to the left side of the organ’. On dissection of the liver he found the veins, artery and duct of the right side of the liver to be obliterated whereas those to the left side were proportionally increased in diameter. From this observation he conceived that by eliminating blood supply to one side of the liver, a functional advantage for the spared half of the liver could be created resulting in hypertrophy of that part of the liver. He then wrote ‘It is theoretically possible to tie the vessels of one side at the gate of the liver, supplying an abnormal growth in one or other of the liver lobes, leaving the other side to do the work’. Realizing the importance this phenomenon could have for resecting the liver, he continued ‘I commend this subject to all those who are working at the surgery of the liver; and I believe that if, in the hands of future observers, the statements I have made receive closer investigation, the
surgery of the liver will be advanced a step’. The foresight he had was amazing, with the first formal right hemihepatectomy being performed 55 years later in Beaujon
Hospital in Paris and the first clinical portal vein embolization being performed in Japan 85 years after his report.
Sir James Cantlie (Fig. 3) was born in 1851 in Banffshire, Scotland. After finishing his
medical studies at Aberdeen University, he trained as a surgeon at Charing Cross Hospital in London. He became a fellow of the Royal College of Surgeons in 1877 and went on to work as a surgeon at Charing Cross. Interestingly, in 1887 he moved to Hong Kong where he became a co-‐founder of a new medical school, the Hong Kong College of Medicine for Chinese, the forerunner of the Faculty of Medicine of the University of Hong Kong. In this institution, of which he led the surgical department, Cantlie carried out the autopsy described above. One of his students was SunYat Sen who would later become the first provisional president of the Republic of China. When this Chinese leader was detained at the Chinese Legation in London in 1896, Cantlie played a key role in his release. In 1897 Cantlie returned to practice in London.
Figure 3 Sir James Cantlie (1851–1926)
The division of the portal vein into a right and left branch at the liver hilum was already reported by the anatomists of the 17thcentury. Francis Glisson (1598–1677)
in his textbook Anatomia Hepatis described cannulating the portal vein and making casts of the portal venous system. Cantlie, however, showed that by the separate
portal vasculature, the liver could be functionally divided into an anatomically
distinct right and left half. The potential of one half of the liver to hypertrophy when the other half is deprived of its blood supply was further confirmed in experimental studies by Rous and Larimore in 1920 and Schalm and colleagues in 1956. The latter authors from Arnhem, the Netherlands, made reference to Cantlie's work and ideas on unilateral occlusion of the portal vein. Surprisingly, portal vein occlusion found its way to clinical application only in 1982, when Makuuchi and later, Kinoshita,
published their first experiences with portal vein embolization in patients. Hence, although the credit for the first clinical portal vein occlusions goes to these
colleagues in Japan, it should be remembered that in 1897, James Cantlie from Scotland had already laid down the concept of pre-‐operative portal vein occlusion.
YL: Cantlie's Line delineates the SURGICAL anatomy of the liver, a line connecting the fundus of the GB and the IVC, separating the liver into the surgical Left and surgical Right lobe. while, the Falciform Ligament we see from the anterior aspect of the liver is just the anatomical line, nothing to do with its function nor help with surgery.
You often look for the hepatic veins on USG while placing your probe subcostally. It's the one with thin walls as opposed to the thicker walls of the portal veins. The
middle and right hepatic vein join the IVC, showing us the 'Playboy Sign'. A thin playboy if its normal. When you see lesions suspicious of HCC/mets, if they are on one side of the Cantlie's line, there is hope of tumour resection for the patient. if it crosses both lobes, unfortunately we will have to prepare the patient for the worst.
4) ON THALASSEMIA Dear yin ling,
Yesterday a student told me that her mother has heavy menses and is chronically anaemic. Low ferritin confirmed. The student herself looked a bit pale too.
I asked if she has any family history of Thalassemia. And she replied that Screening for Thalasaemia for her mother was done at the same time. And it is 'normal'.
YL: Thalassemia cannot be screened when there is concurrent iron deficiency anemia.. HbA2 will be FALSELY NORMAL. We have to correct the iron deficiency first. Repeat ferritin-‐ normal range only then we can do a thalassemia screening. Prof : Iron deficiency is common in adult women. It is a serious potential
complicating factor when testing for a thalassaemia carrier state. Both iron
deficiency and a thalassaemia carrier state may result in a low MCV and MCH. But the MCV in thalasaemia is generally very low. Erythrocytosis is more likely to be caused by thalassaemia, but it is not a diagnostic finding.
The diagnostic criterion for beta thalassemia trait (BTT) is elevated Hb-‐A2 levels.
Iron deficiency anemia (IDA) reduces the synthesis of Hb-‐A2, resulting in reduced Hb-‐A2 levels, so patients with co-‐pathological conditions BTT with IDA, may have a normal level of Hb-‐A2.
Many socio-‐economic factors like worm infestation, poor diet, multiple pregnancies, doctor unawareness result in interpretation of these subjects as simply iron
deficiency anaemia or worse as normal.
PROF : What is the danger of just giving iron to patients undiagnosed or misdiagnosed as iron deficiency? Tell me about Hepcidin and its role in iron physiology. What happens in Thalasaemia carriers?
YL : Hepcidin regulates the iron absorption in our body. Hepcidin inhibits iron absorption. Low hepcidin encourage iron absorption and vice versa. When there is increase erythropoiesis.. hepcidin will be low so that absorption of iron is increased, and vice versa. During inflammation, hepcidin also an acute phase reactant is high, iron absorption is less so contributing further to anemia of chronic diseases.
Beta thal carriers do not have severe anemia but they have increase in
erythropoiesis and low hepcidin levels. They can have iron overload from all the increased iron absorption.
When we have not diagnosed iron deficiency anemia, giving iron to pt who has other diseases such as beta thal trait may cause iron overload! More so with their tendency to have an increased iron absorption. We are doing more harm than good to them
PROF : It is uncommon to transfuse patients with BTT unless their Hb is unacceptably low. Most of them adapt very well to the chronic anaemia.
Furthermore blood transfusion also transfuses iron besides the risk of blood borne diseases. Having said that I am aware of some BTT female patients who require blood transfusion. They likely have beta thalasaemia intermedia
The term "thalassemia" is derived from the Greek root words for "anemia" and "sea" because the thalassemia syndromes were initially believed to be restricted to populations around the Mediterranean Sea
In most adults, 97% of the hemoglobin produced is hemoglobin A (HbA), which has two alpha-‐globin chains and two beta-‐globin chains. The remaining 2% to 3% of adult hemoglobin is hemoglobin A2, which is composed of a pair of alpha-‐globin chains and a pair of delta-‐globin chains. In some adults, fetal hemoglobin HbF, which is composed of two alpha-‐ and two gamma-‐globins, may continue to be produced, but it does not typically exceed 2% of the hemoglobin production
Thalassemia intermedia is a term to describe patients with beta-‐thalassemia in whom the clinical severity falls between the minor and major forms. The minor forms, tend to be clinically mild, if not asymptomatic
There are two beta-‐globin genes controlling the production of beta-‐globin, one on each copy of chromosome 11. The beta-‐globin gene may have a mutation that results in the production of no beta-‐globin, noted as [beta]0, or it may have a mutation that results in reduced production of beta-‐globin, noted as [beta]+. Beta-‐ thalassemia trait occurs when a person acquires a normal beta-‐globin gene and a thalassemic beta-‐globin gene, or two thalassemic beta-‐globin genes that still produce minimal to moderate amounts of beta-‐globin chains
Survival advantage
The RBC in a patient with beta-‐thalassemia trait is more rigid and dehydrated than a normal RBC.
Due to similarities in the distributions of malaria and the thalassemias, it was
hypothesized that the development of thalassemia traits offered some protection in malarial infection. Alpha-‐thalassemia may offer some general protection against severe malaria. Beta-‐thalassemic patients may be protected from malaria by an enhanced phagocytosis of the early intraerythrocytic form of malaria, called rings, in beta-‐thalassemic cells.
Thalassemia trait may be manifested by pallor, fatigue, or other nonspecific
complaints associated with anemia. There may be a family history of anemia; often it has been mistakenly diagnosed as iron deficiency. The family's ethnic origin may be suggestive of a thalassemia trait if they are from the Mediterranean region, or Southeast Asia. There is frequently a marked microcytosis, with a LOW mean corpuscular volume, and mild to moderate hypochromia of the RBCs. The
characteristic RBC count index findings for beta-‐thalassemia trait are a high RBC count, mild anemia, and microcytic, hypochromic cells. The mean corpuscular hemoglobin concentration (MCHC) tends to remain in the normal range of values. Mild splenomegaly may be found in people with beta-‐thalassemia trait
Diagnosing the thalassemia traits can be difficult because the lab values may mimic iron deficiency; there may even be concurrent iron deficiency. If a patient has a low MCV, a serum ferritin level should be obtained.
If the ferritin is low, the iron deficiency should be corrected, and the MCV
reinterpreted afterward. If the ferritin is normal, a hemoglobin electrophoresis will identify hemoglobins A, F, and a number of other hemoglobin variants, along with the estimation of the HbA2 level. People with an elevated level of HbA2 along with hypochromic, microcytic RBCs have a beta-‐thalassemia trait . If the HbA2 is
borderline high to normal, it is likely that they have alpha-‐thalassemia or a
combination of alpha-‐beta thalassemia. Alpha-‐thalassemia trait is often regarded as a diagnosis of exclusion because the hemoglobin electrophoresis does not definitively prove it is an alpha-‐thalassemia trait. The definitive testing for alpha-‐ thalassemia traits would be genetic testing that can determine the exact number of deletions of the alpha-‐globin genes. These tests, however, are expensive and not readily available.
Please always remember that Iron deficiency may obscure the results of the hemoglobin electrophoresis if thalassemia trait is present as it falsely normalize the level of HbA2
Dear Yin Ling
are you aware of experimental treatments in Thalassaemia offering a possible cure. The experimental treatments include inducing the body to produce fetal
hemoglobin again as opposed to adult hemoglobin, and the introduction of gene therapy. The treatments currently being tried are bone marrow or umbilical stem cell transplants.
Fetal hemoglobin changes to adult hemoglobin later in childhood. It was noted that infants born with sickle cell anemia showed no signs of sickling until the fetal
hemoglobin was replaced. It was extrapolated that if a child with thalassemia could have their adult hemoglobin replaced by fetal hemoglobin once again, this would be beneficial. A search began to find a drug that could reverse the neonatal switch in hemoglobins. This would need to be a drug that changed gene regulation called a hypomethylator.
A drug was found (5-‐azacyidine) that worked well but caused severe side effects. We await new drugs.
It is hoped that eventually thalassemia will be treated by replacing the defective globin gene with a normally working gene
Presently the treatment of choice is stem cell transplant. Healthy stem cells sources include bone marrow and umbilical cord blood from healthy donors. Umbilical cord blood is a more readily available source of stem cells. The recent movement of umbilical stem cell collection at births is building up banks of possible tissue
matches. The goal of stem cell transplantation is similar to gene therapy, ie replace the defective blood cells found in thalassemia with healthy normal blood cells.
As far as exams is concerned, no discussion will be complete without mention of treatment BEFORE conception. This is particularly important in high prevalence regions.
Both parental genetic screening and preimplantation diagnosis from a single blastomere in in-‐vitro fertilization have totally changed the way of life in some countries with previously high numbers of children with thalassemia. Throughout the Mediterranean, education campaigns have taken place for entire countries, especially targeting secondary school teens. Education and free thalassemia clinics provide choices about birth control, mate selection, adoption, fetal testing, artificial
insemination by donor, and abortion. Even the conservative Greek Orthodox Church agreed to require that all couples applying for a marriage certificate be pretested for thalassemia carrier trait. Abortion, which was previously illegal, has become legal in pregnancies diagnosed with thalassemia.
Needless to say such steps have their proponents and opponents.
5) Yin Ling,
A 25-‐year-‐old Chinese woman was referred for review of her anaemia. She is pregnant – about 12 weeks gestation at the time of presentation. G1P0 Asymptomatic. Planned pregnancy.
She was noted by her GP to be pale when she went for her UPT. She does not recall any family members who are pale or require regular transfusion. Her
menses prior to pregnancy was unremarkable. She eats like a true Malaysian with a "see food, eat food" diet. No bleeding noted.
Clinically she appears pale but no koilonychia or glossitis is noted. She is not jaundiced or sallor or have any abnormal facies. No splenomegaly.
Her initial full blood count from her GP showed a microcytic, hypochromic
anaemia (MCH, 25.6 pg/cell, MCV 68) with a haemoglobin of 10.2 g/dL. The GP had started ferrous sulphate tablets at 200 mg three times daily for 4 weeks and asked for a repeat full blood count when the tablets had finished. The repeat full blood count results show a deterioration of the anaemia as below.
Haemoglobin 9.8: Platelets: 384
White cell count: 10100 MCH: 26 MCV 65
At this point the GP asked for a consult.
Questions
• Why did the iron tablets not help? • What is the significance of this result?
• How might you explain the different results for the two full blood counts?
Prof : Dear yin ling,
dietary iron comes in different forms, the percentage of dietary iron absorbed depends on the type of food we eat and what other foods are being eaten at the same time. For example, iron from meat is easier for the body to absorb than iron from vegetable.
In addition, iron absorption can be greatly increased or decreased by various factors. Chemicals called polyphenols in tea, coffee, cocoa, spinach inhibit iron absorption as well. Eating more ascorbic acid, which is common in fruits, vegetables and fortified foods, can improve iron absorption. But Calcium inhibits the absorption of iron by an unknown mechanism. This is probably why there is a correlation between high milk intake and iron deficiency.
If indeed this patient or any patient has Fe def, then they should have iron supplementation both to correct anaemia and replenish body stores. This is
achieved most simply and cheaply with ferrous sulphate 200 mg three times daily although ferrous gluconate and ferrous fumarate are as effective.
Elemental iron is the iron available in the supplement for absorption
Ascorbic acid enhances iron absorption and can be given together.
Patients often ask for injections instead! But Parenteral iron should only be used when there is true intolerance to oral preparations. It is painful (when given intramuscularly), expensive, cause the bum to have a BLACK spot and may cause anaphylactic reactions. AND The rise in haemoglobin is no quicker than with oral preparations!!! So why take the risk! The haemoglobin concentration should rise by 2 g/dl after 3–4 weeks.
Iron from meat, poultry, and fish (i.e., heme iron) is absorbed two to three times more efficiently than iron from plants (i.e., non-‐heme iron).
The amount of iron absorbed from plant foods (non-‐heme iron) depends on the other types of foods eaten at the same meal. Thats why we eat a mixture of
dishes.Foods containing heme iron (meat, poultry, and fish) enhance iron absorption from foods that contain non-‐heme iron (e.g., fortified bread, spinach).
Foods containing vitamin C also enhance non-‐heme iron absorption when eaten at the same meal. Fruits at end of meal is important.
Substances (such as polyphenols, phytates, or calcium) that are part of some foods or drinks such as tea, coffee, whole grains, legumes and milk or dairy products can decrease the amount of non-‐heme iron absorbed at a meal. Drink Chinese tea in small amounts during your meal, good tea is sipped right?! Not gulped.
Calcium decrease the amount heme-‐iron absorbed at a meal. However, for healthy individuals who consume a variety of food, the amount of iron inhibition from these substances is usually not of concern.
Vegetarian diets are low in heme iron.
Medicines for peptic ulcer disease and acid reflux taken long term like some poor teachers here for chronic stress induced gastritis reduce the amount of acid in the stomach and the iron absorbed and cause iron deficiency. Thats the price we pay for teaching!
This case scenario is complicated by the facts that
1. She is pregnant
2. She is not menstruating
Because of rapid growth, infants and toddlers need more iron than older children. A student above is worried about the parasite called Ancylostoma duodenale. I am more concerned about a MUCH2 bigger parasite called FOETUS! Women who are pregnant have higher iron needs because of this. To get enough, most women must take an iron supplement in pregnancy.
Serum iron. This test measures the amount of iron in the blood. BUT The level of iron in the blood may be normal even if the total amount of iron in the body is low. For this reason, a serum iron test is not adequate.
that sticks many Fe molecules but its also an inflammation associated molecule. Remember Cytokine storm in Dengue and what we must measure? Se FERRITIN!!!! A measure of this protein in the serum helps find out how much of the body's stored iron has been used or left. Se ferritin reflects the total body ferritin values.
Transferrin level, and total iron-‐binding capacity. Transferrin is a protein that carries iron in the blood. Its like the lorries that carry this heavy metal round and round without it falling off and damaging all the roads. Total iron-‐binding capacity
measures how much is the total capacity of the transferrin in the blood is there to carry iron. If the patient has iron-‐deficiency anemia, he/she will have a high level of transferrin, a high Total Fe carrying capacity aka TIBC that has ironically no iron. (hehe IRONically)
So what should we use for screening, and what do we use when trying to diagnose a cause of anaemia?
For GP screening, se ferritin is easily available and affordable. For diagnostic work up, the iron studies PLUS Folic acid levels PLUS Vit B12 and TSH is needed. The most useful Ix at workup is actually a PBF read by a competent haematologist. The answer is almost always there.
Hemosiderin is an abnormal microscopic pigment composed of iron oxide and can accumulate in different organs in various diseases. Iron is toxic when not properly stored. Humans store iron within ferritin. The form of iron in ferritin is Iron(III) oxide-‐ hydroxide. By complexing with ferritin, the iron is made water soluble!
Several diseases result in deposition of Iron(III) oxide-‐hydroxide in tissues in an insoluble form. These deposits of iron is hemosiderin! These deposits often cause no symptoms, but they lead to organ damage.
Hemosiderin often forms after bleeding into an organ. When blood leaves a ruptured blood vessel, the hemoglobin of the red blood cells is released into the extracellular space. The macrophages phagocytose the hemoglobin to degrade it, producing hemosiderin and porphyrin. The iron in haemosiderin cannot be released for use. Its stuck!
YL: after a month's treatment with iron supplement and assuming she is taking her iron tablets, she is still having microcytic hypochromic anemia with an MCV of 65, MCH of 26, low normal MCHC, normal RBC and normal RDW! We don't know the Se Ferritin and TIBC nor serum iron so far.
production is haywired and a high RDW reflects a nutritional anemia. RDW helps us differentiate thalassemia and IDA for microcytic anemia; and vitamin B12/folate deficiency (megaloblastic anemia) from other macrocytic but NON megaloblastic anemia, hence its importance. in thalassemia the production of RBC is generally still OKAY, although they are abit small, hence the normal RDW.
In this patient, a normal RBC and low normal MCHC, coupled on with a normal RDW, we really couldn't strike thalasemia off, moreover she's pregnant!
So in view of a microcytic hypochromic anemia that is not correctable and also a FBC components which suggest something other than IDA, i would run iron panel tests to correct whatever iron deficiency anemia there is, and proceed to work her up for thalasemia. Beta Thalassemia trait can be easily pick up by Hb electrophoresis, while alpha thal needs a molecular diagnosis (as all Hb has an alpha component, on
electrophoresis one low all low!)
it is important to pick up alpha thal, a disease that is caused by gene deletion. if this patient happened to be a carrier/ minor, it is even more important to screen her husband too! the scariest thing about alpha thal is for the mother to have an aa/-‐ -‐ gene makeup which have the likelihood to couple up with a similar aa/-‐ -‐ gene makeup carried by her husband...and produce a hydrops in her pregnancy.
Prof : The normal physiological increase in plasma volume in pregnancy causes haemodilution and can give an artificially low haemoglobin level. However, haemoglobin levels should not fall below 11.0g/dL and less than 10.5g/dL is abnormal.
We often ASSUME that a microcytic, hypochromic anaemia esp in pregnancy is caused by a lack of iron. However, this patient is not iron deficient. Her se ferritin when tested is normal. Thalassaemia carriers are well, normal looking people but in females with heavy menses or during pregnancy are often anaemic, sharing the features of iron deficiency of microcytosis and hypochromia. A careful look beyond the FBC at the PBF will tell us the answer because the PBF is very characteristic. Another distinguishing element is the erythrocyte count which is reduced with iron deficit, but often increased in thalassaemia carriers.
Her partner/husband/boyfriend needs urgent testing for haemoglobinopathies in order to estimate the risk to the fetus. If the partner tests positive the couple can be offered fetal testing to determine how the child might be affected, as for the fetus there is a one in two chance of being a carrier of haemoglobinopathy and a one in four chance of being either affected by the disease or free of the genetic disposition. Excluding the possibility that the baby’s father is a carrier of a haemoglobinopathy allows everyone to relax.
A very low MCV/MCH must trigger testing for haemoglobinopathies.
KEY POINTS
• Watch out: not all microcytic, hypochromic anaemias as seen in the FBC is caused by iron deficiency.
• Test results in pregnancy have a different significance compared with tests for those not pregnant.
For one you the doctor is dealing with a few lives!
Prof : The pathogenesis of anemia of chronic disease is multifactorial and is related to hypo-‐activity of the bone marrow, with relatively inadequate production of erythropoietin or a poor response to erythropoietin, as well as slightly shortened red blood cell survival.
The hallmark ferrokinetic profile of anemia of chronic disease is decreased serum iron level, decreased transferrin level, or normal or elevated ferritin levels, all of which result in iron being present but inaccessible for use.
Do not forget Endocrine deficiency states, including hypothyroidism, adrenal or pituitary insufficiency, and hypogonadism, which may cause secondary bone marrow failure because of reduced stimulation of erythropoietin secretion. Hyperthyroidism may also cause normocytic anemia.
Anemia occurs in acute and chronic renal failure. The anemia is usually normocytic but may be microcytic. In renal failure, anemia occurs in part because uremic metabolites decrease the lifespan of circulating red blood cells and reduce erythropoiesis.
Anemia secondary to uremia is characterized by inappropriately low erythropoietin levels, in contrast to the normal or high levels that occur with most other causes of anemia. To further confuse the presentation, serum iron levels and the percentage of iron saturation are often low. Furthermore, the serum creatinine level and the degree of anemia may not correlate well.
And never forget abt RETICULOCYTES! ! They falsely increase mcv.
Remember that the role of the consultant is TO BE CONSULTED WHEN OTHERS HAVE DIFFICULTY SOLVING A PUZZLE. So one must think laterally. When the HO or MO is stuck it is usually because they are thinking along one line and NOT SEEING THE FOREST. JUST THE TREE
Prof: Yin Ling,
You know that in thalassemia minor/trait, patients tend to have elevated RBC count (>5.5) with low mcv and mch.
What is the pathophysiology behind this? What does this lead to clinically? When a patient has a type of thalassemia, there is an excess production and accumulation of globin chains produced by genes that are not effected by the thalassemia deletion. This is a compensation mechanism that the body utilizes to maintain hemoglobin production.
For eg In alpha thalassemia, the body can produce excess gamma chains as a compensatory mechanism. This can lead to the production of gamma chain tetramers (hemoglobin Bart's) in the unborn child and as beta chain tetramers (hemoglobin H) in adults. This subsequent tetramer accumulation in response to thalassemia often leads to red blood cell damage and hemolytic anemia.
The normal or high RBC count results from MASSIVE FACTORIES in bone marrow producing RBCs desperately in response to chronic anaemia.
