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\begin{document}

\title{Vitamin B12 Malabsorption and Pseudo-Thrombotic Microangiopathy in an
Adolescent.}



\author[1]{Simone Chang}%
\author[2]{Mercia Gondim}%
\author[3]{Michael Angelo Huang}%
\affil[1]{University of Louisville School of Medicine}%
\affil[2]{Norton Children's Hospital}%
\affil[3]{University of Louisville}%


\vspace{-1em}



  
  \date{May 05, 2024}


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\begin{abstract}
Thrombotic microangiopathies (TMAs) are a group of rare disorders that
can be considered life threatening. The hallmark of this disease is a
microangiopathic hemolytic anemia with an associated thrombocytopenia
which could be congenital or acquired. Acquired vitamin B12 deficiency
is overlooked in developed countries but can mimic a TMA. We report the
case of 17-year-old male with malabsorption of vitamin B12 with
development of pseudo-TMA. When faced with a clinical presentation of a
TMA in a child or an adolescent patient, physicians must be aware of the
possibility of vitamin B12 deficiency especially in patients at risk for
malabsorption.%
\end{abstract}%



\sloppy


\textbf{Abstract}

Thrombotic microangiopathies (TMAs) are a group of rare disorders that
can be considered life threatening. The hallmark of this disease is a
microangiopathic hemolytic anemia with an associated thrombocytopenia
which could be congenital or acquired. Acquired vitamin B12 deficiency
is overlooked in developed countries but can mimic a TMA. We report the
case of 17-year-old male with malabsorption of vitamin B12 with
development of pseudo-TMA. When faced with a clinical presentation of a
TMA in a child or an adolescent patient, physicians must be aware of the
possibility of vitamin B12 deficiency especially in patients at risk for
malabsorption.

\textbf{Introduction}

Thrombotic microangiopathies (TMAs) are a group of rare disorders that
are characterized by microangiopathic hemolytic anemia and
thrombocytopenia with thrombosis of the microvasculature. This is often
associated with organ dysfunction and encompass congenital and acquired
etiologies{[}1{]}. Distinguishing between these disorders is important,
as many TMAs are life-threatening.

Acquired B12 deficiency is overlooked because of its rarity in developed
countries{[}2{]}. Hematologic manifestations of B12 deficiency can
include pancytopenia because of ineffective hematopoiesis. Defective red
blood cells (RBCs) undergo phagocytosis in the marrow and as a result
mimic an intravascular hemolytic process.

We describe the case of a 17- year-old male who had a history of
intestinal resection and celiac disease which lead to a pseudo -- TMA
through malabsorption of vitamin B12.

\textbf{Case Description}

A 17-year-old male with history of intestinal resection secondary to
gastroschisis at birth was referred to the emergency room for shortness
of breath, fatigue, and lightheadedness for a week. His history was
significant for celiac disease, iron and B12 deficiency with symptomatic
anemia in the past, requiring transfusions. It had been at least a year
since he had taken his last supplements and he had not adhered to a
gluten-free diet. He denied constitutional symptoms, fevers, bleeding,
or recurrent illnesses. His physical examination was significant for
weight below the third percentile, pallor, mildly icteric sclerae and
hepatosplenomegaly. He was alert and oriented with no noticeable
neurological deficits.

His complete blood count (CBC) was significant for pancytopenia with a
WBC: 2.42 x 10\^{}3/uL, Hb: 5.9 g/dL, MCV: 95.4 fL, Plt: 111 x
10\^{}3/uL and a reticulocytopenia of 0.6\%. Review of his peripheral
smear was significant for anisocytosis, microcytosis, poikilocytosis and
schistocytes. Routine chemistries were suggestive of hemolysis with an
elevated LDH of \textgreater{}50 000 U/L, an unconjugated
hyperbilirubinemia of 3.7 mg/dL and an undetectable haptoglobin. His
synthetic liver function was unremarkable with normal coagulation
studies despite a notable transaminitis. A liver ultrasound showed
diffuse echogenicity with likely fatty infiltration but no evidence of
portal hypertension. He had a negative direct coombs, iron studies were
unremarkable and a B12 \textless{}109 pg/mL. His renal function was also
unremarkable. He was transfused two units of packed red blood cells,
which allowed for stabilization of his hemoglobin and he was started on
oral iron and B12 supplementation.

The differential included a pancytopenia secondary to B12 deficiency
with a superimposed hemolytic process as well as concern for a malignant
bone marrow infiltrative process given his pancytopenia and
hepatomegaly. Paroxysmal nocturnal hemogobinuria testing was negative. A
bone marrow biopsy and aspirate displayed no changes consistent with
myelodysplasia or malignancy. There was evidence of erythroid
hyperplasia and megaloblastic maturation along with hypersegmented
neutrophils consistent with his B12 deficiency as shown in Fig. 1. His
liver biopsy showed non-alcoholic steatohepatitis attributed to his
uncontrolled celiac disease and the decision was made to convert his
oral B12 to an intramuscular formulation.

Repeat B12 and LDH were 525 pg/mL and 503 U/L respectively showing
resolution of his symptoms. Despite not being included in the initial
differential, a hemolytic anemia in the presence of a progressive
thrombocytopenia warrants the consideration of a TMA. However, given the
resolution of his symptoms with B12 supplementation the diagnosis of
pseudo-TMA secondary to B12 deficiency was made.

\textbf{Discussion}

B12 deficiency is the leading cause of megaloblastic anemia and in
developed countries is often overlooked. It is more common in the
elderly but the estimated prevalence is around 6\% in people younger
than 60 years in the United Kingdom and United States {[}2{]}. Causes of
severe of B12 deficiency generally involve disruption of some aspect of
the physiologic pathway for B12 absorption comprising intrinsic factor
and the cubam receptor in the terminal ileum {[}3{]}. In the reported
case, there are several factors that could have contributed to B12
deficiency, his history of intestinal resection and his uncontrolled
celiac disease. Despite not being frequently reported, B12 deficiency in
patients with celiac disease has a prevalence of between 8\% and 41\%
{[}4, 5{]}.

Hematologic manifestations consist of all blood elements being affected
by this ineffective megaloblastic hematopoiesis. Initially, the cell
content and size of RBC usually precede the onset of anemia. Nuclear
hypersegmentation of neutrophils is another common early manifestation.
Neutropenia and thrombocytopenia can infrequently follow as late
features with a resulting pancytopenia that can ultimately become severe
enough to mimic a severe aplastic anemia.

Hematopoietic precursor cells produced in the bone marrow are defective
in B12 deficiency. As a result, they undergo cell death in the marrow
and are phagocytosed before they can exit into the blood as
reticulocytes. This intramedullary hemolysis manifests itself with
increased markers of cell turnover such as LDH and markers of increased
hemoglobin breakdown such as indirect hyperbilirubinemia and decreased
or absent haptoglobin. As a means of compensating, erythropoietin levels
rise and the bone marrow becomes more hypercellular (as shown in Fig.
1), however the reticulocyte count fails to rise {[}6{]}.

In our case, his pancytopenia and reticulocytopenia were evident and
consistent with a megaloblastic picture. However, his LDH seemed to be
elevated out of proportion to the degree of hemolysis he experienced.
When compared to patients with thrombotic thrombocytopenic purpura
(TTP), No\selectlanguage{ngerman}ël et al showed that patients who had pseudo-TMA had
significantly higher LDH levels, platelet counts and lower reticulocyte
counts in the adult population {[}7{]}. Hyperhomocysteinemia has also
been implicated (not checked in our patient) in increasing the risk of
hemolysis in vitamin B12 in vitro in addition to causing endothelial
damage leading to intravascular hemolysis and RBC fragmentation {[}8{]}.
This combination of intramedullary and intravascular hemolysis could
potentially account for the degree of LDH elevation seen in this case.

There have been three other cases of reported pediatric pseudo- TMA
secondary to B12 in the literature {[}9-12{]}. These cases all occurred
because of decreased intake and our case highlights the need to follow
patients with malabsorptive syndromes. Because many of the cases were
initially thought to have thrombotic thrombocytopenic purpura (TTP),
they received plasma exchange with gradual improvement of their
symptoms. This improvement is thought to be due to B12 contained in the
infused plasma during the exchange{[}13{]}.

The PLASMIC score has served as prediction tool for severe ADAMTS13
deficiency{[}14{]} but has not been evaluated in differentiating TTP
from a pseudo-TMA. While it is well recognized as a helpful adjunct in
the adult population, few studies have looked at its utility in children
and adolescents. Linder et al showed retrospectively that the PLASMIC
score was able to accurately identify pediatric patients at highest risk
for severe ADAMTS13 deficiency with a sensitivity of 100\% and a
specificity of 78.1\% {[}15{]}. In evaluating the PLASMIC scores of
pediatric cases in the literature; 75\% of the patients with B12 induced
pseudo-TMA would have been placed in a low risk category (TABLE 1). This
may prove to be a helpful adjunct to physicians when faced with this
clinical presentation.

The treating team deduced that his initial pancytopenia had been
secondary to his B12 deficiency given his history. This case posed a
diagnostic challenge and highlights to pediatric hematologists this
unusual presentation of B12 induced TMA and that it should be considered
in the differential with a patient presenting with a TMA syndrome.

References

1. Kottke-Marchant, K., \emph{Diagnostic approach to microangiopathic
hemolytic disorders.} Int J Lab Hematol, 2017. \textbf{39 Suppl 1} : p.
69-75.

2. Hunt, A., D. Harrington, and S. Robinson, \emph{Vitamin B12
deficiency.} Bmj, 2014. \textbf{349} : p. g5226.

3. Green, R., \emph{Vitamin B(12) deficiency from the perspective of a
practicing hematologist.} Blood, 2017. \textbf{129} (19): p. 2603-2611.

4. Dahele, A. and S. Ghosh, \emph{Vitamin B12 deficiency in untreated
celiac disease.} Am J Gastroenterol, 2001. \textbf{96} (3): p. 745-50.

5. García-Manzanares, A. and A.J. Lucendo, \emph{Nutritional and dietary
aspects of celiac disease.} Nutr Clin Pract, 2011. \textbf{26} (2): p.
163-73.

6. Orkin, S.H., D.E. Fisher, and D. Ginsburg, \emph{Nathan and Oski's
hematology and oncology of infancy and childhood} . 2015, Philadelphia
(Pa.): Elsevier Saunders.

7. Noël, N., et al., \emph{Hemolysis and schistocytosis in the emergency
department: consider pseudothrombotic microangiopathy related to vitamin
B12 deficiency.} Qjm, 2013. \textbf{106} (11): p. 1017-22.

8. Ventura, P., et al., \emph{A role for homocysteine increase in
haemolysis of megaloblastic anaemias due to vitamin B(12) and folate
deficiency: results from an in vitro experience.} Biochim Biophys Acta,
2004. \textbf{1739} (1): p. 33-42.

9. Asano, T., et al., \emph{Neglect-induced pseudo-thrombotic
thrombocytopenic purpura due to vitamin B12 deficiency.} Pediatr Int,
2015. \textbf{57} (5): p. 988-90.

10. Delbet, J.D. and T. Ulinski, \emph{Thrombotic microangiopathy and
breastfeeding: where is the link? Answers.} Pediatr Nephrol,
2018.\textbf{33} (6): p. 987-989.

11. Delbet, J.D. and T. Ulinski, \emph{Thrombotic microangiopathy and
breastfeeding: where is the link? Questions.} Pediatr Nephrol,
2018.\textbf{33} (6): p. 985-986.

12. Dimond, A., J.N. George, and C. Hastings, \emph{Severe vitamin B-12
deficiency in a child mimicking thrombotic thrombocytopenic
purpura.}Pediatr Blood Cancer, 2009. \textbf{52} (3): p. 420-2.

13. Green, R., \emph{Anemias beyond B12 and iron deficiency: the buzz
about other B's, elementary, and nonelementary problems.} Hematology,
2012. \textbf{2012} (1): p. 492-498.

14. Bendapudi, P.K., et al., \emph{Derivation and external validation of
the PLASMIC score for rapid assessment of adults with thrombotic
microangiopathies: a cohort study.} Lancet Haematol, 2017.\textbf{4}
(4): p. e157-e164.

15. Linder, G.E., et al., \emph{Assessment of the Plasmic Score Utility
for Classification of Pediatric Thrombotic Microangiopathies.} Blood,
2019. \textbf{134} (Supplement\_1): p. 1075-1075.

Figure Legend

Table 1: WBC: white blood cell count, Hb: hemoglobin, MCV: mean
corpuscular volume, Plt: platelet count,

ANC: Absolute Neutrophil Count, Retic: reticulocyte count, LDH: lactate
dehydrogenase.

\textbf{Hosted file}

\verb`Table 1.docx`  available at \url{https://authorea.com/users/346736/articles/472627-vitamin-b12-malabsorption-and-pseudo-thrombotic-microangiopathy-in-an-adolescent}\selectlanguage{english}
\begin{figure}[H]
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\includegraphics[width=0.70\columnwidth]{figures/Bone-marrow-aspirate-showing-erythroid-hyperplasia-and-megaloblastic-changes-of-nuclei/Bone-marrow-aspirate-showing-erythroid-hyperplasia-and-megaloblastic-changes-of-nuclei}

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