A 29 year old man presents with recurrent gout, in association with a very high uric acid level at over 800 umol/l. His blood tests show impaired renal function, with a creatinine of 180umol/l and an e-gfr of 28 ml/min. His father has also had gout from an early age with similarly high serum uric acid levels, but normal renal function. However, a brother had to have dialysis starting at age 36, leading to transplantation. This brother also suffered from gout.
The patient's only dietary risk factor for gout was a fondness for Coca-cola. He did not drink much alcohol and consumed little red meat, shellfish, prawn or offal.
What is the diagnosis?
Saturday 31 August 2013
Monday 26 August 2013
The Genius of Adolf Eugen Fick
Fick was a 19th century German physiologist. In 1870, he worked out that cardiac output could be measured from a subject's oxygen consumption, if the concentration of oxygen entering and leaving a given organ were known.
Thus, cardiac output= Oxygen consumption/Arterial O2 content-Venous O2 content
It is easy to calculate the arterial or venous oxygen content if you know the O2 saturation (SaO2) in arterial or venous blood, as almost all the O2 is carried by haemoglobin. Each gram of Hb carries 1.34 ml of O2.
Thus, Arterial oxygen content= 1.34*Hb concentration*SaO2
As cardiac output is expressed in l/min and Hb in g/dl, to make matters uniform, you have to multiply the denominator by 10.
Thus, cardiac output (l/min)= O2 consumption (l/min)/[10*1.34*Hb(g/dl)*SaO2]-[10*1.34*Hb(g/dl)*SvO2]
In practice, it is rarely necessary to determine the absolute cardiac output, but Fick's principle has been put to good use to determine the degree of left to right shunt by calculating the respective blood flow to pulmonary (Qp) and systemic circulation (Qs)in conditions such as ASD & VSD. In significant left to right shunt, Qp>Qs. If Qp is more than twice Qs, most authorities would recommend percutaneous closure of ASD or VSD with an Amplatzer device or a surgical closure if the shunt is very large, as with some VSDs.
It is easy to determine O2 saturation during cardiac catheterisation consecutively in the superior venna cava, right atrium, inferior vena cava, right ventricle and pulmonary artery. Pulmonary venous oxygen content is considered to be the same as the oxygen saturation of arterial blood measured during pulse oximetry, provided there is no right to left shunt. The latter can be detected by a drop off in O2 saturation while moving into the putative chamber, e.g decline in SO2 while moving from right atrium to right ventricle, suggests a right to left shunt from a VSD, while the same thing happening while moving down from the SVC to the RA indicates a right to left shunt via an ASD.
As the SVC normally has 3 times the flow as in the IVC, the systemic mixed venous O2 content is calculated as (3*SVC SO2+IVC SO2)/4.
Oxygen consumption can be be calculated by using a special spirometer with the subject rebreathing air and using a CO2 absorber.
Using the Fick principle, Qp/Qs can be written thus:
Qp/Qs= [Oxygen consumption/ 10*1.34*Hb*(Pulmonary venous SO2-Pulmonary arterial SO2)] divided by,
[Oxygen consumption/10*1.34*Hb*(Systemic arterial SO2-Systemic mixed venous SO2)]
or simply, Qp/Qs= Systemic arterial SO2-Systemic mixed venous SO2/Pulmonary venous SO2-Pulmonary arterial SO2
In practice, an alternative and non-invasive way to measure the pulmonary:systemic flow ratio in left to right shunts is to use Doppler Echo to find the area of the aortic and pulmonary outflow tracts and multiply them with their respective velocity time integral.
Thus, cardiac output= Oxygen consumption/Arterial O2 content-Venous O2 content
It is easy to calculate the arterial or venous oxygen content if you know the O2 saturation (SaO2) in arterial or venous blood, as almost all the O2 is carried by haemoglobin. Each gram of Hb carries 1.34 ml of O2.
Thus, Arterial oxygen content= 1.34*Hb concentration*SaO2
As cardiac output is expressed in l/min and Hb in g/dl, to make matters uniform, you have to multiply the denominator by 10.
Thus, cardiac output (l/min)= O2 consumption (l/min)/[10*1.34*Hb(g/dl)*SaO2]-[10*1.34*Hb(g/dl)*SvO2]
In practice, it is rarely necessary to determine the absolute cardiac output, but Fick's principle has been put to good use to determine the degree of left to right shunt by calculating the respective blood flow to pulmonary (Qp) and systemic circulation (Qs)in conditions such as ASD & VSD. In significant left to right shunt, Qp>Qs. If Qp is more than twice Qs, most authorities would recommend percutaneous closure of ASD or VSD with an Amplatzer device or a surgical closure if the shunt is very large, as with some VSDs.
It is easy to determine O2 saturation during cardiac catheterisation consecutively in the superior venna cava, right atrium, inferior vena cava, right ventricle and pulmonary artery. Pulmonary venous oxygen content is considered to be the same as the oxygen saturation of arterial blood measured during pulse oximetry, provided there is no right to left shunt. The latter can be detected by a drop off in O2 saturation while moving into the putative chamber, e.g decline in SO2 while moving from right atrium to right ventricle, suggests a right to left shunt from a VSD, while the same thing happening while moving down from the SVC to the RA indicates a right to left shunt via an ASD.
As the SVC normally has 3 times the flow as in the IVC, the systemic mixed venous O2 content is calculated as (3*SVC SO2+IVC SO2)/4.
Oxygen consumption can be be calculated by using a special spirometer with the subject rebreathing air and using a CO2 absorber.
Using the Fick principle, Qp/Qs can be written thus:
Qp/Qs= [Oxygen consumption/ 10*1.34*Hb*(Pulmonary venous SO2-Pulmonary arterial SO2)] divided by,
[Oxygen consumption/10*1.34*Hb*(Systemic arterial SO2-Systemic mixed venous SO2)]
or simply, Qp/Qs= Systemic arterial SO2-Systemic mixed venous SO2/Pulmonary venous SO2-Pulmonary arterial SO2
In practice, an alternative and non-invasive way to measure the pulmonary:systemic flow ratio in left to right shunts is to use Doppler Echo to find the area of the aortic and pulmonary outflow tracts and multiply them with their respective velocity time integral.
Saturday 24 August 2013
Sunday 18 August 2013
A 65-Year Old Lady with Muscle Weakness and High CK
The lady presented with a 4-week history of increasing muscle weakness, resulting in a fall down the stairs on the day of admission. There was very little muscle pain.
Her background history included hyperetension & hypercholestrolaemia, and she was taking amlodipine 10 mg OD, bendroflumethiazide 2.5 mg OD and simvastatin 80 mg OD. She had been on these medications for ~2 years.
On admission, she had grade 4/5 muscle weakness proximally in both upper and lower limbs, without fasciculations or UMN signs. Cranial nerves were not involved.
Tests showed normal renal function, electrolytes & FBC. CK was elevated at 14000 U/l. Urine dipstick showed 4+ blood, but RBC within normal limits on microscopy.
ANA, ENA, dsDNA, Ig were all negative or within normal limits. ESR & CRP were not raised. MR scan of thigh muscles showed diffuse oedema and enhancement on T2 weighted images.
Thoughts?
Her background history included hyperetension & hypercholestrolaemia, and she was taking amlodipine 10 mg OD, bendroflumethiazide 2.5 mg OD and simvastatin 80 mg OD. She had been on these medications for ~2 years.
On admission, she had grade 4/5 muscle weakness proximally in both upper and lower limbs, without fasciculations or UMN signs. Cranial nerves were not involved.
Tests showed normal renal function, electrolytes & FBC. CK was elevated at 14000 U/l. Urine dipstick showed 4+ blood, but RBC within normal limits on microscopy.
ANA, ENA, dsDNA, Ig were all negative or within normal limits. ESR & CRP were not raised. MR scan of thigh muscles showed diffuse oedema and enhancement on T2 weighted images.
Thoughts?
Wednesday 7 August 2013
T-cell Receptor Rearrangement- unravelled
Cells of the adaptive immune system, i.e. B- and T-cells are amazingly diverse. They have to be to deal with myriad antigens that the body is exposed to. This diversity is achieved by rearrangement of the receptors on B and T cells during development. While I was aware of this, there was one unanswered question that had always puzzled me...until today. I'll share this shortly.
It is common knowledge that B cell "receptors" are comprised of immunoglobulins, which consist of heavy and light chains. Both have invariant constant (C) regions and variable regions. It is obviously the latter that contribute to their diversity and specificity. In the heavy chains, the variable regions are further comprised of V, D, and J regions ( stand for variable, diversity and joining). The light chain variable chains lack a D region and only consist of V & J regions. Each V, D or J domain has numerous alleles- up to 60, 70 or even more. Thus there are a high number of combinations possible, remembering that a given Ig chain will contain only one each of V, D or J. (Figure 1). These regions are flanked by signal sequences that allow their recognition in order that recombination may occur. These recognition sites undergo further changes -mutations- on exposure to antigens, a process called somatic hypermutation, resulting in increased affinity of the antibody for its antigen- affinity maturation.
Now we come to the reason for this post. T cells, instead of having immunoglobulins on their cell surface, have dimeric receptor chains- either a combination of alpha and beta or a combination of gamma and delta. alpha-beta T cells make up ~95% of all T cells, while the gamma-delta T cells are in a minority. It was therefore puzzling for me to note that in haematological malignancies such as leukaemias and lymphomas, it was usual to test for rearrangement of receptor chains in gamma chains, which are present in only 5% of T cells, rather than in alpha or beta chains, which make up the other 95%.
Here's why. Using standard methods such as Southern blotting, or increasingly now, PCR, you need a much smaller number of probes if were looking for clonality in T-gamma chains, than if you employed T-alpha or T-beta chains. Firstly, T-gamma chains only have V & J region and lack a D region, unlike T-alpha or T-beta. More importantly, the T-gamma chain has far less recombination-capable segments than either T-alpha or T-beta chains. For example, T-alpha has 70 V segments and at least 61 J segments spread over a large area (thus increasing the difficulty of Southern blotting). On the other hand the T-gamma chain has only 14 V segments and 5 J segments, and is therefore much easier to probe.
BTW, the same enzymes- RAG 1 and RAG 2, are responsible for splicing and rejoining of the various V, D and J regions in both B and T cells, which is the basis of severe combined immunodeficiency when there is a problem with RAG. However, unlike B cells, somatic hypermutation and affinity maturation does not occur in T cells. Nevertheless, further diversity is introduced by an enzyme called Terminal deoxynucleotidyl transferase (TdT) which randomly makes changes in the junctions between V, D and J chains. As the enzyme TdT is only present in immature lymphocytes, its presence or absence can inform the stage in lymphocyte ontogeny at which a lymphoid neoplasm arose.
Figure 1. Germline organisation of the T cell receptor genes
It is common knowledge that B cell "receptors" are comprised of immunoglobulins, which consist of heavy and light chains. Both have invariant constant (C) regions and variable regions. It is obviously the latter that contribute to their diversity and specificity. In the heavy chains, the variable regions are further comprised of V, D, and J regions ( stand for variable, diversity and joining). The light chain variable chains lack a D region and only consist of V & J regions. Each V, D or J domain has numerous alleles- up to 60, 70 or even more. Thus there are a high number of combinations possible, remembering that a given Ig chain will contain only one each of V, D or J. (Figure 1). These regions are flanked by signal sequences that allow their recognition in order that recombination may occur. These recognition sites undergo further changes -mutations- on exposure to antigens, a process called somatic hypermutation, resulting in increased affinity of the antibody for its antigen- affinity maturation.
Now we come to the reason for this post. T cells, instead of having immunoglobulins on their cell surface, have dimeric receptor chains- either a combination of alpha and beta or a combination of gamma and delta. alpha-beta T cells make up ~95% of all T cells, while the gamma-delta T cells are in a minority. It was therefore puzzling for me to note that in haematological malignancies such as leukaemias and lymphomas, it was usual to test for rearrangement of receptor chains in gamma chains, which are present in only 5% of T cells, rather than in alpha or beta chains, which make up the other 95%.
Here's why. Using standard methods such as Southern blotting, or increasingly now, PCR, you need a much smaller number of probes if were looking for clonality in T-gamma chains, than if you employed T-alpha or T-beta chains. Firstly, T-gamma chains only have V & J region and lack a D region, unlike T-alpha or T-beta. More importantly, the T-gamma chain has far less recombination-capable segments than either T-alpha or T-beta chains. For example, T-alpha has 70 V segments and at least 61 J segments spread over a large area (thus increasing the difficulty of Southern blotting). On the other hand the T-gamma chain has only 14 V segments and 5 J segments, and is therefore much easier to probe.
BTW, the same enzymes- RAG 1 and RAG 2, are responsible for splicing and rejoining of the various V, D and J regions in both B and T cells, which is the basis of severe combined immunodeficiency when there is a problem with RAG. However, unlike B cells, somatic hypermutation and affinity maturation does not occur in T cells. Nevertheless, further diversity is introduced by an enzyme called Terminal deoxynucleotidyl transferase (TdT) which randomly makes changes in the junctions between V, D and J chains. As the enzyme TdT is only present in immature lymphocytes, its presence or absence can inform the stage in lymphocyte ontogeny at which a lymphoid neoplasm arose.
Figure 1. Germline organisation of the T cell receptor genes
Sunday 4 August 2013
The Lady With Microcytic Anaemia...Revisited
Shonkus, I wanted to revist this case we discussed some time ago, as I learnt something that could throw further light on the diagnosis. To begin with, here's the discussion so far. You are in bold and I am in italics.
Tnx....!!.Hope Ur in Gr8 spirits...FJS reported to me c/o Cough 2 mths, & occasional SOB with Fatigue.She is a housewife nd apparently looks healthy. Took t/t in 2010 for GERD & All.Rhinitis provided by then Physicain Dr Jagdish MD(Int.Med).Reports 2010 depict a normal AEC, ESR as 34mm/1st hr. Hb% was not done at tht time. on 18th instant upon detecting Pallor Inv.were ordered. Hb% was 7.5gm/dl, ESR 50 mm/1st hr, AEC 250, TLC 14,300/cmm, N-73%,RBC count 4.59mill./cmm, RBC indices :MCV 58.6 um3 (82-93),MCH 16.3pg (28-32), MCHC 27.9 g/l(32-36), RBS 95mg/dl, Throat C/s indicate Normal Flora. CXR PA Normal. She was surprised nd her husband attending to her complained of her irregular dietary habits. Upon , gentle prodding she gave a further h/o Bleeding PR since last yr on & off few episodes which she attributed to Piles,one episode 15 days back which stood controlled. Asked for, Thallasemia Profile, a stool Examination, Endoscopy, including proctosigmoido & Colonoscopy at a higher center. Ur discussion on this is solicited....Tnx....
SRL report is in hand FJS f/37 : Hb% 7.7g/dl , Hematocrit 27.4 , RBC 4.45mil/muL, MCV 61.6 fl, MCH 17.2pg, MCHC 27.9g/dl , Red Cell distribution width 21.4% , Platelet count 429thou/muL , Mean platelet vol 9.2 fl ,WBC count 13thou/muL , N 69% , RBC- Marked anisocytosis, mild poikilicytosis, microcytic hypochromic, with elliptocytes & ovalocytes. Serum Iron 97mic.gm/dl , TIBC 435 micgm/dl , % saturation 22 . Hb Variant Analysis : HbA 95.6% , Hb A2 2% , Hb F 0.3% , HbS,D,C 0%. Unknown Unidentified peak 2.1 (0.00 - 2.00 )....yes platelets here are high with raised total count....
Whenever I deal with RBC Indices the tall fair complexioned bespectaled ,well dressed Dr SB Pandey Asso.Prof Patho. who used to churn out these with monotonous regularity with a pronunciation as bland as it could be......nd believe me it seems as it is just yestday only I left the class...!!!....Golam case will post eve.....
The lady with the anaemia doesn't look as straightforward as it looks. While the tests would on the face of it, suggest iron deficiency, notice that while the TIBC is raised, the serum iron is in the normal range and that transferrin saturation is only slightly low, discordant with the severity of anaemia. Yet, it is almost certain that she has a degree of iron deficiency, as such marked anisocytosis & high RDW is not seen in pure thal trait.
However, notice the extremely low MCV and the very low haematocrit, and the relatively normal RBC count despite the severe anaemia. These are all features of thal minor. Yet, HbA2 is not raised. How do you reconcile this?
I believe this lady has a combination of iron deficiency anaemia and delta-beta thalassemia trait. Since delta chains are a component of HbA2, the latter has failed to rise. Thal traits are quite common among Asians.
I'd investigate the iron deficiency anaemia exactly as you have, but be aware that the response to iron therapy may not be as impressive as you'd otherwise expect.
To start from where we left off, I am convinced because of the reasons described above that this lady has a combination of thal trait and iron deficiency anaemia. But this time, I'd like to provide a bit more information, and perhaps a rider.
Firstly, I have learnt that iron deficiency anaemia (IDA) can calse false normalisation of the HbA2 in subjects with thal trait. When you treat the IDA, the HbA2 may rise above the upper limit of normal in these subjects. Although this lady's HbA2 is far below the threshold of around 3.2% considered diagnostic of beta thal trait, I'd repeat her Hb and HbA2 after a three week course of iron, say FeSO4 200 mg tds. The Hb should rise by at least 2 g/l in pure IDA, which I expect not to happen in this case because of concurrent thal trait. However, I'd expect the HbA2 to rise considerably- above 3.2%, confirming coincident beta thal trait besides her IDA.
There is however, one other possibility. The HbA2 would not be expected to rise in alpa-thal traits because the alpha globin chain is a component of HbA2. Alpha thal is coded by 4 genes, i.e. 2 paired genes on chromosome 16. If one or two genes are deleted, the patient hardly has any anaemia, but may have slight microcytosis. However, if 3 genes are deleted, the patient can have severe microcytic anaemia resembling beta thal.
Here's where her ethnicity comes in. Although alpha thal traits are well documented in Asians, particularly the alpha 1 trait or cis-deletion (--/alpha, alpha), beta thal trait is far more common in this population. In fact 8% of Bangladeshis carry the beta thal trait (4% among Pakistanis and 3.5% among indians, compared with only 0.1% in white British). On balance therefore, I feel this lady has a combination of IDA and either beta thal trait or beta-delta thal trait. You should get the answer if you repeat her HbA2 levels after a month on iron replacement therapy.
Tnx....!!.Hope Ur in Gr8 spirits...FJS reported to me c/o Cough 2 mths, & occasional SOB with Fatigue.She is a housewife nd apparently looks healthy. Took t/t in 2010 for GERD & All.Rhinitis provided by then Physicain Dr Jagdish MD(Int.Med).Reports 2010 depict a normal AEC, ESR as 34mm/1st hr. Hb% was not done at tht time. on 18th instant upon detecting Pallor Inv.were ordered. Hb% was 7.5gm/dl, ESR 50 mm/1st hr, AEC 250, TLC 14,300/cmm, N-73%,RBC count 4.59mill./cmm, RBC indices :MCV 58.6 um3 (82-93),MCH 16.3pg (28-32), MCHC 27.9 g/l(32-36), RBS 95mg/dl, Throat C/s indicate Normal Flora. CXR PA Normal. She was surprised nd her husband attending to her complained of her irregular dietary habits. Upon , gentle prodding she gave a further h/o Bleeding PR since last yr on & off few episodes which she attributed to Piles,one episode 15 days back which stood controlled. Asked for, Thallasemia Profile, a stool Examination, Endoscopy, including proctosigmoido & Colonoscopy at a higher center. Ur discussion on this is solicited....Tnx....
SRL report is in hand FJS f/37 : Hb% 7.7g/dl , Hematocrit 27.4 , RBC 4.45mil/muL, MCV 61.6 fl, MCH 17.2pg, MCHC 27.9g/dl , Red Cell distribution width 21.4% , Platelet count 429thou/muL , Mean platelet vol 9.2 fl ,WBC count 13thou/muL , N 69% , RBC- Marked anisocytosis, mild poikilicytosis, microcytic hypochromic, with elliptocytes & ovalocytes. Serum Iron 97mic.gm/dl , TIBC 435 micgm/dl , % saturation 22 . Hb Variant Analysis : HbA 95.6% , Hb A2 2% , Hb F 0.3% , HbS,D,C 0%. Unknown Unidentified peak 2.1 (0.00 - 2.00 )....yes platelets here are high with raised total count....
Whenever I deal with RBC Indices the tall fair complexioned bespectaled ,well dressed Dr SB Pandey Asso.Prof Patho. who used to churn out these with monotonous regularity with a pronunciation as bland as it could be......nd believe me it seems as it is just yestday only I left the class...!!!....Golam case will post eve.....
The lady with the anaemia doesn't look as straightforward as it looks. While the tests would on the face of it, suggest iron deficiency, notice that while the TIBC is raised, the serum iron is in the normal range and that transferrin saturation is only slightly low, discordant with the severity of anaemia. Yet, it is almost certain that she has a degree of iron deficiency, as such marked anisocytosis & high RDW is not seen in pure thal trait.
However, notice the extremely low MCV and the very low haematocrit, and the relatively normal RBC count despite the severe anaemia. These are all features of thal minor. Yet, HbA2 is not raised. How do you reconcile this?
I believe this lady has a combination of iron deficiency anaemia and delta-beta thalassemia trait. Since delta chains are a component of HbA2, the latter has failed to rise. Thal traits are quite common among Asians.
I'd investigate the iron deficiency anaemia exactly as you have, but be aware that the response to iron therapy may not be as impressive as you'd otherwise expect.
To start from where we left off, I am convinced because of the reasons described above that this lady has a combination of thal trait and iron deficiency anaemia. But this time, I'd like to provide a bit more information, and perhaps a rider.
Firstly, I have learnt that iron deficiency anaemia (IDA) can calse false normalisation of the HbA2 in subjects with thal trait. When you treat the IDA, the HbA2 may rise above the upper limit of normal in these subjects. Although this lady's HbA2 is far below the threshold of around 3.2% considered diagnostic of beta thal trait, I'd repeat her Hb and HbA2 after a three week course of iron, say FeSO4 200 mg tds. The Hb should rise by at least 2 g/l in pure IDA, which I expect not to happen in this case because of concurrent thal trait. However, I'd expect the HbA2 to rise considerably- above 3.2%, confirming coincident beta thal trait besides her IDA.
There is however, one other possibility. The HbA2 would not be expected to rise in alpa-thal traits because the alpha globin chain is a component of HbA2. Alpha thal is coded by 4 genes, i.e. 2 paired genes on chromosome 16. If one or two genes are deleted, the patient hardly has any anaemia, but may have slight microcytosis. However, if 3 genes are deleted, the patient can have severe microcytic anaemia resembling beta thal.
Here's where her ethnicity comes in. Although alpha thal traits are well documented in Asians, particularly the alpha 1 trait or cis-deletion (--/alpha, alpha), beta thal trait is far more common in this population. In fact 8% of Bangladeshis carry the beta thal trait (4% among Pakistanis and 3.5% among indians, compared with only 0.1% in white British). On balance therefore, I feel this lady has a combination of IDA and either beta thal trait or beta-delta thal trait. You should get the answer if you repeat her HbA2 levels after a month on iron replacement therapy.
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