A 31-year-old woman with chronic Hemolytic anemia and B12 deficiency with Coombs Positvity: Conversations
A 31 year old woman with chronic Hemolytic anemia and pancytopenia since 10 years and hypothyroidism since 6 months with current admission for severe anemia. There is a pansystolic murmur in mitral and tricuspid area as well as base of the heart (assumed to be an unusual hemic murmur) and there is no obvious organomegaly. She has sparse hair and generalized pallor with bipedal edema.
Lab investigations:
Patient physical exam findings:
Conversations:
Rakesh Dir: Sharing the above historical article for those who joined later
Rakesh Dir: Meenakshi please post a picture of the dorsum of her her both hands here taking care to deidentify herhttps://www.ncbi.nlm.nih.gov/pubmed/5302841
Ashwini BMJ: This is certainly an interesting case sir ! I have a couple of doubts- Could she have autoimmune disorders considering hemolytic anemia and hypothyroidism. Is it due to Hashimoto ? Was any workup for sle done ?
Is she a candidate for BMT ?
Rakesh Dir: Yes you are right Dr Ashwini. So do you feel she has an autoimmune Hemolytic anemia since the last 10 years? And yes in that vein it needs to be autoimmune thyroiditis too perhaps? What is the commonest cause of primary hypothyroidism otherwise? What ARA criterias of SLE will you look to rule out in this patient? What investigations already shared by Dr Meenakshi (our PGY1, aka intern) can you utilize to rule it out or rule it in?
Ashwini BMJ: Yes sir ! I think the common causes include autoimmune , aggressive treatment for hyperthyroidism, other drugs the patient could be taking.
For sle clinically look for hemolytic anemia, thrombocytopenia which matches. I don't remember the other ones. I'll just look it up and post it here. I think there's arthritis , neuropathy, renal diseases. For tests we could go for ana and ds dna.
Ashwini:
Here it is ! Hemolytic anemia, thrombocytopenia and Coombs test is done from the data given !
Rakesh Dir: Well done Dr Ashwini. So as this patient doesn't satisfy more than 4 criteria for SLE we aren't thinking more about it although again going by the fact that both are autoimmune diseases the management wouldn't be drastically different other than the differences that come with different organ involvement
Rakesh Dir: The case 3 in this quaint historical article is very similar to our case. What are your inputs on the dorsum of the hands in this patient? Let me know your thoughts once you also read case 3 in that article. Dr Ramesh please share an image of her treatment chart after deidentification.
Ashwini: Yes sir ! Understood. It would be steroids in that case. I just went through the iron profile actually. I had a couple of doubts. She's in iron overload which could be due to repeated blood transfusions on account of hemolytic anemia or does she have something like sideroblastic anemia ?What was the mcv for her sir ?
Ashwini: The ps says dimorphic anemia. So macrocytes and microcytes are there. Were there megaloblasts ? Case 3 is remarkably similar to case you'll have. What pointed the case to B12 deficiency ? Did she have loss of reflexes and neuropathy. Sorry sir I didn't understand what the dorsum of the hand signifies. It just looks edematous with thick skin. It is hyperpigmentation on the knuckles ? And the alopecia as well points to B12.
Rakesh Dir: Very good observation. Does this finding suggest anything? And the knuckles?
Ashwini BMJ: Yes that too ! Oh so then you started suspecting autoimmune B12 deficiency ! Wow ! I feel bad for the patient as she must be suffering and the risk of sounding a little insensitive, the process of forming the diagnosis is amazing ! It's like solving a puzzle with clues. Did the pernicious anemia cause heart damage ?
Rakesh Dir: Yes like Sherlock Holmes. But you are right we need a Sherlock Holmes with empathy.
Rakesh Dir: Well what does the previously shared Echo report tell you?
Answini BMJ: And now the patient is on B12 therapy ?
Rakesh Dir: Yes now we have started that but think if someone had done this 10 years back would it have changed her life?
Aswini BMJ: Absolutely ! It would have improved her quality of life. Echo's normal !
Answini: I am a huge Sherlock Holmes fan ! Fun fact: Sir Arthur Conan Doyle fashioned Sherlock Holmes on his mentor Dr Joseph Bell !
Answini: I do agree, a doctor patient relationship is the crux of it. There's a good book on it by Danielle Ofri- what patients say and what doctors hear. Do give it a read !
Abhishek Choudhary: Great discussion and a lot of learning. Thank you Drs. It's wonderful to see empathy in the professional setting.
Rakesh Dir: If only we could develop a mechanism to share it more vividly so that more and more people can touch the lives of the patients we are privileged to experience so that our patients get helped by more and more people. Would an empathy EHR be the answer. Avinash, Vivek, Madhava, Shrija and team have taken some steps to create an Immersive EHR and will be presenting it in Cuttack this month.
Abhishek Choudhary: Wow! Look forward to hearing more about this. Anything that improves user interface in healthcare is a step forward ... and this sounds like a major leap
Rakesh Dir: Dr Ashwini there is another issue here where we need your help. This patient was initially begun on prednisone in the view of autoimmune Hemolytic anemia seeing her coombs positive state (that you may have seen in the attached reports). However if you have read the 1963 article you may have found that vitamin b12 anemia can itself cause coombs positivity. So perhaps there is no role of steroids here? In fact no role of anything other than vitamin b12 for her Addisonian pernicious anemia? Speaking of Addisonian I am reminded of another question. Why does pigmentation happen in b12 deficiency? Is there an Addisonian connection if any?
Vivek Podder: "the predominant mechanism of hyper pigmentation in vitamin B12 is hypothesised as 1) Deficiency of vitminB12 decreases the level of reduced glutathione, which activate tyrosinase and thus leads to transfer to melanosomes. 2) Defect in the melanin transfer between melanocytes and keratinocytes, resulting in pigmentary incontinence. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3830324/
Vivek Podder: But in this case report, they think the dominant mechanism of hyper pigmentation is not a defect in melanin transport but is rather an increase in melanin synthesis.
Rakesh Dir: Thanks for sharing this Vivek. Yes we were discussing this patient with our 9th semester students yesterday and one of them did manage to fish out this article but we couldn't discuss it further due to time (which is always scarce in offline interactions). So why does the synthesis increase? Vivek can you find a recent paper that documents coombs positivity in vitamin b 12 deficiency?
Ashwini: Ooh that is very intriguing ! I don't know about this ! I'll try to look up papers on the same.
Vivek Podder: This is another case report of both Pernicious Anemia with Autoimmune Hemolytic Anemia. a direct antiglobin test (Coombs) with IgG was found to be positive which was suggestive of AIHA. Further anemia workup also revealed a vitamin B12 deficiency at 60 pg/mL (250–950), folate 7.26 ng/mL (5.9–24.8), and normal thyroid profile. As the management of anemia due to pernicious anemia with hemolysis is different from patients presenting with autoimmune hemolytic anemia (AIHA) with a positive direct Coombs test, differentiating these two conditions early on is important. Although it has been reported that patients with pernicious anemia can transiently have a positive Coombs test which becomes negative on treatment with vitamin B12 supplementation, patients with true AIHA would not respond to vitamin B12 supplementation unless they are treated with steroids [6]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983393/
Rakesh Dir: Thanks Vivek. Great find that will help the patient. Any leads on when (how many days after vitamin b12 supplementation) to repeat her coombs to see if it is negative?
Vivek Podder: "On her subsequent clinic visits, we continued her on prednisone 40 mg daily and monthly subcutaneous vitamin B12 supplementation until her hemoglobin and hematocrit stabilized. After the direct Coombs test became negative at six months (?), with a stable hemoglobin more than 10 g/dL, normal LDH, and reticulocyte count < 100,000, the steroids were gradually tapered off over two months while she was continued on subcutaneous vitamin B12 supplements."
Rakesh Dir: hanks so they have gone our way. We too are continuing the steroids. But is it really necessary? How do we find the answer? 🙂
Vivek Podder: Sir, if we can rule out AIHA earlier then we may consider not using steroids? As in the same case, Managing their patient was challenging as she presented with a severe normocytic anemia and hemolytic picture, none of which were suggesting vitamin B12 deficiency. Further evaluation for causes of anemia revealed a diagnosis of vitamin B12 deficiency due to deficiency of intrinsic factor and subsequently a diagnosis of pernicious anemia was made. As no alloantibodies were detected on further workup, a delayed hemolytic transfusion reaction as a cause for her hemolysis was ruled out.
Lab investigations:
Patient physical exam findings:
Conversations:
Rakesh Dir: Sharing the above historical article for those who joined later
Rakesh Dir: Meenakshi please post a picture of the dorsum of her her both hands here taking care to deidentify herhttps://www.ncbi.nlm.nih.gov/pubmed/5302841
Ashwini BMJ: This is certainly an interesting case sir ! I have a couple of doubts- Could she have autoimmune disorders considering hemolytic anemia and hypothyroidism. Is it due to Hashimoto ? Was any workup for sle done ?
Is she a candidate for BMT ?
Rakesh Dir: Yes you are right Dr Ashwini. So do you feel she has an autoimmune Hemolytic anemia since the last 10 years? And yes in that vein it needs to be autoimmune thyroiditis too perhaps? What is the commonest cause of primary hypothyroidism otherwise? What ARA criterias of SLE will you look to rule out in this patient? What investigations already shared by Dr Meenakshi (our PGY1, aka intern) can you utilize to rule it out or rule it in?
Ashwini BMJ: Yes sir ! I think the common causes include autoimmune , aggressive treatment for hyperthyroidism, other drugs the patient could be taking.
For sle clinically look for hemolytic anemia, thrombocytopenia which matches. I don't remember the other ones. I'll just look it up and post it here. I think there's arthritis , neuropathy, renal diseases. For tests we could go for ana and ds dna.
Ashwini:
Here it is ! Hemolytic anemia, thrombocytopenia and Coombs test is done from the data given !
Rakesh Dir: Well done Dr Ashwini. So as this patient doesn't satisfy more than 4 criteria for SLE we aren't thinking more about it although again going by the fact that both are autoimmune diseases the management wouldn't be drastically different other than the differences that come with different organ involvement
Rakesh Dir: The case 3 in this quaint historical article is very similar to our case. What are your inputs on the dorsum of the hands in this patient? Let me know your thoughts once you also read case 3 in that article. Dr Ramesh please share an image of her treatment chart after deidentification.
Ashwini: Yes sir ! Understood. It would be steroids in that case. I just went through the iron profile actually. I had a couple of doubts. She's in iron overload which could be due to repeated blood transfusions on account of hemolytic anemia or does she have something like sideroblastic anemia ?What was the mcv for her sir ?
Ashwini: The ps says dimorphic anemia. So macrocytes and microcytes are there. Were there megaloblasts ? Case 3 is remarkably similar to case you'll have. What pointed the case to B12 deficiency ? Did she have loss of reflexes and neuropathy. Sorry sir I didn't understand what the dorsum of the hand signifies. It just looks edematous with thick skin. It is hyperpigmentation on the knuckles ? And the alopecia as well points to B12.
Rakesh Dir: Very good observation. Does this finding suggest anything? And the knuckles?
Ashwini BMJ: Yes that too ! Oh so then you started suspecting autoimmune B12 deficiency ! Wow ! I feel bad for the patient as she must be suffering and the risk of sounding a little insensitive, the process of forming the diagnosis is amazing ! It's like solving a puzzle with clues. Did the pernicious anemia cause heart damage ?
Rakesh Dir: Yes like Sherlock Holmes. But you are right we need a Sherlock Holmes with empathy.
Rakesh Dir: Well what does the previously shared Echo report tell you?
Answini BMJ: And now the patient is on B12 therapy ?
Rakesh Dir: Yes now we have started that but think if someone had done this 10 years back would it have changed her life?
Aswini BMJ: Absolutely ! It would have improved her quality of life. Echo's normal !
Answini: I am a huge Sherlock Holmes fan ! Fun fact: Sir Arthur Conan Doyle fashioned Sherlock Holmes on his mentor Dr Joseph Bell !
Answini: I do agree, a doctor patient relationship is the crux of it. There's a good book on it by Danielle Ofri- what patients say and what doctors hear. Do give it a read !
Abhishek Choudhary: Great discussion and a lot of learning. Thank you Drs. It's wonderful to see empathy in the professional setting.
Rakesh Dir: If only we could develop a mechanism to share it more vividly so that more and more people can touch the lives of the patients we are privileged to experience so that our patients get helped by more and more people. Would an empathy EHR be the answer. Avinash, Vivek, Madhava, Shrija and team have taken some steps to create an Immersive EHR and will be presenting it in Cuttack this month.
Abhishek Choudhary: Wow! Look forward to hearing more about this. Anything that improves user interface in healthcare is a step forward ... and this sounds like a major leap
Rakesh Dir: Dr Ashwini there is another issue here where we need your help. This patient was initially begun on prednisone in the view of autoimmune Hemolytic anemia seeing her coombs positive state (that you may have seen in the attached reports). However if you have read the 1963 article you may have found that vitamin b12 anemia can itself cause coombs positivity. So perhaps there is no role of steroids here? In fact no role of anything other than vitamin b12 for her Addisonian pernicious anemia? Speaking of Addisonian I am reminded of another question. Why does pigmentation happen in b12 deficiency? Is there an Addisonian connection if any?
Vivek Podder: "the predominant mechanism of hyper pigmentation in vitamin B12 is hypothesised as 1) Deficiency of vitminB12 decreases the level of reduced glutathione, which activate tyrosinase and thus leads to transfer to melanosomes. 2) Defect in the melanin transfer between melanocytes and keratinocytes, resulting in pigmentary incontinence. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3830324/
Vivek Podder: But in this case report, they think the dominant mechanism of hyper pigmentation is not a defect in melanin transport but is rather an increase in melanin synthesis.
Rakesh Dir: Thanks for sharing this Vivek. Yes we were discussing this patient with our 9th semester students yesterday and one of them did manage to fish out this article but we couldn't discuss it further due to time (which is always scarce in offline interactions). So why does the synthesis increase? Vivek can you find a recent paper that documents coombs positivity in vitamin b 12 deficiency?
Ashwini: Ooh that is very intriguing ! I don't know about this ! I'll try to look up papers on the same.
Vivek Podder: This is another case report of both Pernicious Anemia with Autoimmune Hemolytic Anemia. a direct antiglobin test (Coombs) with IgG was found to be positive which was suggestive of AIHA. Further anemia workup also revealed a vitamin B12 deficiency at 60 pg/mL (250–950), folate 7.26 ng/mL (5.9–24.8), and normal thyroid profile. As the management of anemia due to pernicious anemia with hemolysis is different from patients presenting with autoimmune hemolytic anemia (AIHA) with a positive direct Coombs test, differentiating these two conditions early on is important. Although it has been reported that patients with pernicious anemia can transiently have a positive Coombs test which becomes negative on treatment with vitamin B12 supplementation, patients with true AIHA would not respond to vitamin B12 supplementation unless they are treated with steroids [6]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983393/
Rakesh Dir: Thanks Vivek. Great find that will help the patient. Any leads on when (how many days after vitamin b12 supplementation) to repeat her coombs to see if it is negative?
Vivek Podder: "On her subsequent clinic visits, we continued her on prednisone 40 mg daily and monthly subcutaneous vitamin B12 supplementation until her hemoglobin and hematocrit stabilized. After the direct Coombs test became negative at six months (?), with a stable hemoglobin more than 10 g/dL, normal LDH, and reticulocyte count < 100,000, the steroids were gradually tapered off over two months while she was continued on subcutaneous vitamin B12 supplements."
Rakesh Dir: hanks so they have gone our way. We too are continuing the steroids. But is it really necessary? How do we find the answer? 🙂
Vivek Podder: Sir, if we can rule out AIHA earlier then we may consider not using steroids? As in the same case, Managing their patient was challenging as she presented with a severe normocytic anemia and hemolytic picture, none of which were suggesting vitamin B12 deficiency. Further evaluation for causes of anemia revealed a diagnosis of vitamin B12 deficiency due to deficiency of intrinsic factor and subsequently a diagnosis of pernicious anemia was made. As no alloantibodies were detected on further workup, a delayed hemolytic transfusion reaction as a cause for her hemolysis was ruled out.
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