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Infantile Scurvy: still a relevant differential diagnosis in western medicine
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Infantile Scurvy: still a relevant differential diagnosis in western medicine D. Schwetje , A. Zillekens , JD. Kieback , S. Koob , R. Placzek PII: DOI: Reference:
S0899-9007(20)30009-5 https://doi.org/10.1016/j.nut.2020.110726 NUT 110726
To appear in:
Nutrition
Received date: Revised date: Accepted date:
30 January 2018 31 October 2019 11 January 2020
Please cite this article as: D. Schwetje , A. Zillekens , JD. Kieback , S. Koob , R. Placzek , Infantile Scurvy: still a relevant differential diagnosis in western medicine, Nutrition (2020), doi: https://doi.org/10.1016/j.nut.2020.110726
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Inc. All rights reserved.
Infantile Scurvy: still a relevant differential diagnosis in western medicine Authors: Schwetje D1, Zillekens A1, Kieback JD1, Koob S1, Placzek R1 1 University Hospital Bonn, Department of Orthopedics and traumatology, Bonn, Germany
Abstract Objective: Infantile Scurvy or Moller-Barlow’s disease appears to be of no further importance in western countries. This is a careless assumption. Especially with severely disabled children this malady manifests itself in a broad range of symptoms such as delayed or suppressed bone healing, minor traumatization leading to bruises/fractures and epiphyseolysis. Research Methods & Procedures: This article aims to present the required daily uptake of vitamin c and the biochemical pathways in the human body leading to the typical symptoms of scurvy. Two cases of chronic scurvy with prolonged bone healing and bleeding, epiphyseolysis and gingival hyperplasia are presented. Both patients were chronically ill with one having cerebral palsy (GMCSF-level IV) and the other a neuroblastoma of the adrenal gland. Results: After diagnosis, the substitution of vitamin via percutaneous endoscopic gastrostomy c in both patients had to be performed in order to treat them. Both patients quickly achieved a full recovery. Conclusion: The two patients presented show the importance of infantile scurvy in the daily medical care. Especially in the severely disabled or chronically ill children its prevalence is often underestimated. Keywords: Scurvy - Vitamin C – ascorbate – case report – orthopedics - pediatrics
Introduction Infantile Scurvy is a historically well-documented disease with is first description attributed to Hippocrates. A definitive report was written in the 18th century by James Lind who systematically observed the disease in sailors and was the first to recommend citrus juice as an effective treatment
[1]. After many contradictory publications, Thomas Barlow presented an anatomic study of infantile scurvy [2]. Even Johannes Möller after whom the infantile disease is named mistook many patients with acute rickets for patients with scurvy [3,3]. Vitamin C is water soluable and a strong chemical reducing agent [2], [4]. The human body cannot synthesise or store it like it can fat soluable vitamins. Regional differences (in the human body) in concentration show its organ specific use of the vitamin. The highest concentration of vitamin C can be found in the adrenal glands where ascorbate takes part in the catecholamin synthesis [2,3]. The uptake of vitamin C starts with its passage through the mouth and the absorption by the oral mucosa but mainly takes place in the jejunum and ileum. Transportation requires adenosintriphosphate because it is an active pathway and it is sodium-dependant. If the transportation capacity is exceeded during an excessive meal, the intake is passive via diffusion [5]. Below a concentration of 180 mg of vitamin C, the uptake is up to 80%. In food vitamin C exists as Lascorbate and dehydro-L-ascorbate. Mainly, vitamin C is resorbed in the form of dehydro-Lascorbate. Because only ascorbate works as a reducing agent and dehydro-L-ascorbate is an unstable construct, it is later reduced to ascorbate itself [6,7]. Differences regarding the uptake can be seen when high glucose concentrations are present: L-ascorbate, not dehydro-L-ascorbate, is blocked from resorption [7,8]. Vitamin C is renally eliminated when the uptake is below 1-3g. Therefore the most sensitive test for scurvy is a urinary sample [9]. Vitamin c deficiency appears to play a minor role in the western hemisphere due to its rich food supply because the required daily uptake of ascorbate is very low – as seen in the table below resulting in a low intestinal resorption rate. Table 1: Current Recommendations for daily vitamin c uptake in relation to age [10]
The symptoms of scurvy can easily be understood when considering the role of vitamin c in the human body: Ascorbate as a strong reducing agent induces hydroxylations of proline to hydroxyproline in the synthesis of collagen, which results in the stabilization of the molecule. Vitamin c causes the migration of long-chain fatty acids into the mitochondrial body during the biosynthesis of carnitine and therefore takes part in energy synthetization, particularly in the muscle. Ascorbate is associated with neurotransmitter biosynthesis (hydroxylation of dopamine to noradrenaline) as well as amidation of neuroendocrinal hormones such as gastrine, bombesine, CRH and TRH. It takes part in several detoxifications and increases the iron absorption by weakening the effect of phytates and other ligands. Vitamin c also supports the immune system through stabilization of the phagocyte membranes against oxidative self-destruction by the halogenide-peroxidase-system [4,5]. Without vitamin C, the resulting inefficient collagen synthesis leads to purpura, subperiostal and gingival bleeding, which causes substantial pain. Minor forms of the disease are characterized by lethargy and apathy, while major forms result in bleeding of the inner organs, inefficient bone metabolism and anemia (through reduced resorption and nutrient loss through bleeding). Due to this vulnerability of the immune system the children are characteristically prone to recurrent infections [5,11]. In 80% the scorbutic patients present an involvement of the musculoskeletal system in the form of arthralgies, myalgies, hemarthrosis and muscular hematomas [12,13]. Infantile scurvy is often underdiagnosed because of its unspecific range of symptoms, which frequently results in false diagnoses such as vasculitis or ulcerative gingivitis [14]. The main focus of current research lies on the prevention of delayed diagnosis and on re- establishing scurvy as a differential diagnosis. The two case reports presented are no exception, as the focus lies on the consequences of delayed diagnosis and the influence of the vitamin-c-substitution on patient reconvalescence.
First Case A six-year-old was admitted with bilateral knee pain and swelling of the left knee. The girl had been treated in our hospital for cerebral palsy (GMFCS-Level 4) sustained by postpartal hypoxia, paleness and for imminent hip luxation. The child was in a reduced general state and suffered of muscle as well as joint pain. The initial clinical and radiological examinations of both knees showed no pathological findings. The external laboratory results showed a mild hypochromic microcytic anemia. Over the course of several weeks the knee pain exacerbated, resulting in new X-ray images being taken in another department. After diagnosing a distal femoral epiphyseolysis in both legs without evidence of a high-energy traumatization or child abuse the patient was transferred back to our
hospital. Meanwhile, the parents recalled major bleeding and gingival swelling at the loss of one milk tooth. The child had also been refusing to eat or drink. The laboratory results showed an iron deficiency anemia (serum hemoglobin level 6.4 g/dl) and a positive Rumpel-Leede-test.
Figure 1: X-ray of a distal femoral epiphyseolysis, left knee in two planes
Figure 2: Photograph of swollen, inflamed gingiva
The clinical manifestation of hypochromic microcytic anemia in combination with bleeding, aforementioned symptoms and an atypical localization of the epiphyseolysis led us to suspect a chronic avitaminosis. Both knee joints were punctured and blood was evacuated (right: 6 ml; left: 7ml). Blood analysis confirmed a vitamin c serum level below 1 mg/l (reference level 5-15mg/l). A daily substitute of 50 mg ascorbate in combination with iron (5-6mg/kg body weight) was initiated and had to be administered via a stomach tube due to reduced overall ingestion of 900ml/d. Subsequently, a closed reposition of the epiphysiolysis was performed with immobilization of both legs in a cast for six weeks under sole mobilization with the physiotherapy. After five months, a stable bone situation and an almost free range of motion in both knees (extension/flexion 5-0-130°) was achieved.
Figure 3: X-ray of a distal femoral epiphyseolysis, right knee in two planes
Second Case The second six-year-old patient was transferred in our pediatric department in July 2015 after chemotherapy and haploid stem cell transplantation for neuroblastoma of the right adrenal gland. The girl showed delayed bone healing six weeks after sustaining femoral fractures of both legs and being treated with TEN (Titanium Elastic Nail) implantation in our traumatological department. Furthermore, the cachectic child complained of arthralgy and myalgia as well as malnourishment due to frequent vomiting. Her medical history revealed recurring infections. Despite several revisions including a change of osteosynthesis (double-TENS, plate osteosynthesis) and stabilization via plaster cast, satisfactory ossification could not be achieved. Follow-up X-ray imaging showed an osteopenia with major signs of bone demineralization as well as atraumatic epiphyseolysis capitis femoris in December 2016. Severe gastric bleeding and an anemic state of unknown origin were detected along with serum vitamin c levels below 1 mg/l (reference level 5-15 mg/l). In February 2016 a PEG (percutaneous endoscopic gastrostomy) and percutaneous endoscopic jejunostomy had to be performed to treat the patient’s cachexia. She received substitutions of 400mg of vitamin C intravenously twice a week in combination with other essential vitamins (vitamin D, folic acid et cetera). The patient improved markedly, as did the consolidation of her fractures.
Figure 4: X-ray of non- existent osseous consolidation of a distal femoral fracture with TENS in situ, left knee in two planes
Discussion Infantile Scurvy is an often- underdiagnosed disease. Common pathologies of the gastrointestinal anatomy associated with malabsorption, such as celiac disease [14], are a possible cause for avitaminosis. If a mothers serum vitamin C levels are adequate, the nursed baby is protected from such hypovitaminosis [12]. Vitamin C is characteristically unstable, though – it can easily be destroyed when cooked or simmered [15]. Therefore scurvy’s prevalence rose after the introduction of pasteurization and the new sense of hygiene in the United Kingdom accompanied by consuming the breast milk to reduce the bacterial load [16]. Literary research shows many reports of one-track fed children who were mistaken for having adequate access to fresh food [9,17–19]. A further risk factor is posed by vitamin loss in chronic renal failure, due to the major elimination pathway of ascorbate passing through urine [20]. Other possible causes are malassimilation, which results in decreased intestinal uptake, psychiatric disorders, cancer, AIDS and other consuming illnesses, inadequate parental nutrition or an increased nutritional demand [14], [21]. In both cases presented in this article the nutrition of the children with chronic diseases was neglected leading to percutaneous endoscopic gastrostomy/ jejunostomy being conducted to ensure adequate nourishment. In the daily (pediatric) orthopedic routine scurvy should be routinely considered a possible diagnosis, especially in children with spontaneous epiphyseolysis, which is frequently observed in the faster
growing epiphyses such as the proximal tibia, distal femur and proximal humerus [13,22]. In the first case the symmetric epiphyseolysis of the distal femora led to the diagnosis of infantile scurvy without prior knowledge of the patient´s underlying avitaminosis. This girl had cerebral palsy (GMFCS-Level 4), a risk factor for the disease, and showed a microcytic anemia correlating with a decrease in iron absorption as well as an increase in bleeding (after the loss of a tooth). Digestion was limited by cerebral palsy and missing nutrients had been previously substituted. Spontaneous fractures should also raise one´s suspicion of scurvy due to its resulting enhanced activity of the osteoclasts and diminished activity of the osteoblasts [13,23]. Furthermore, fracture healing is reduced in an avitaminotic state. In 1908, Frankel discovered in animal trials with guinea pigs that bone healing is repealed in scurvy [24]. The minimum required intake of vitamin C per day for lies around 0,5-1mg/d [4]. In the second clinical case, multiple spontaneous fractures were healing inadequately despite adequate surgical treatment. This prompted further examination leading to the diagnosis of infantile scurvy. The involvement of the musculoskeletal system can be observed in persistent and clinically manifested scurvy. Therefore, it is sensible to assume avitaminosis manifesting itself over a course of months [25]. Human and animal trials have shown avitaminosis to take 130 days on average to become symptomatic[26]. However, the reconvalescence after beginning substitution treatment is often seen after one week [21]. Vitamin C was administered as ascorbate as it is the only type of vitamin C on the market. Another issue is the lack of radiological experience with the disease due to its low occurence. The locations of skeletal manifestations correlate to their collagen production, so the faster growing epiphyses are classically the ones showing scorbutic changes (proximal humerus, distal radius and ulnae; distal femur, proximal tibia and fibula) [27]. These are the typical radiolocial findings in scurvy:
generalised demineralisation
Fraenkel line: zone of provisional calcification in the metathyseal endings [21]
Trummerfeld zone: translucent band caused by trabecular destruction and epiphyseal breaks, parallel to the joint lign and circular in epiphyseal bone cores [27], also known as the „scurvy line“ [28]
Wimberger’s ring: secondary ossification centres which show signs of osteoporosis and are embedded in a layer of mineralised cartilage in the growth periphery [29,30]
epiphyseolysis and epiphyseal dislocations or smaller fractures in the bone structure ([24]
Harris lines: compact zones of the metaphysis who demonstrate a discontinuity in bone growth by increased calcification after the resumption of growth [31]
„scorbutic pearls“: thickened rip-cartilage-borders, also known as the „scorbutic rosary“ [32]
„metaphyseal or Pelkan spurs“: lateral extension of the provisional calcification zone with stimulation of a periostal reaction [33]
In the second case many typical radiological signs were not detected in a second reevaluation of the X-rays. Though osteopenia had been described, scurvy had not been diagnosed. In combination with the observed decreased serum level of vitamin C, infantile scurvy could have been diagnosed.
Figure 5: X-ray of non- existent osseous consolidation of a distal femoral fracture with TENS in situ, left knee in two planes with Anteroposterior radiograph of the left knee shows osteopenia, dense bands along the metaphyseal side of the epiphyses in the zone of provisional calcification (Frankel line [red arrow]) with an adjacent lucent line called the Trummerfeld zone, or “scurvy line” (white arrow).
Conclusion Infantile Scurvy is a majorly under- or tardily diagnosed disease. In countries with apparent adequate food supply, one-sided nutrition as well as several concomitant maladies (chronic renal failure, consuming (oncological) diseases, malabsorption and psychiatric disorders) are relevant risk factors. Aside from unspecific clinical symptoms, delay in fracture healing is an indicator of infantile scurvy. Determination of serum/urine levels of vitamin C and X-ray analysis can be used to confirm the diagnosis. Infantile Scurvy remains an important differential diagnosis in modern clinical practice. Conflict of Interest None
References [1] J. Lind, A treatise on the scurvy. In three parts. Containing An Inquiry into the Nature, Causes, and Cure, of that Disease. Together with A Critical and Chronological View of what has been published on this subject, A. Millar in the Strand, London, 1757. [2] T. Barlow, “On Cases described as „Acute Rickets” which are probably a Combination of Scurvy and Rickets: The Scurvy being an essential, and the Rickets a variable, element,” Med Chir Trans, no. 66, pp. 159–221, 1883. [3] J. O. L. Möller, “Acute Rachitis,” in Königsberger medicinische Jahrbücher, pp. 377–379, 1859. [4] G. H. Bourne, The Biochemistry and Physiology of Bone: Volume II, Academic Press, New York, 1972. [5] H. K. Biesalski, S. C. Bischoff, and C. Puchstein, Ernährungsmedizin: Nach dem Curriculum Ernährungsmedizin der Bundesärztekammer und der DGE, Thieme, Stuttgart, 2010. [6] K. Pietrzik, I. Golly, and D. Loew, Handbuch Vitamine: Für Prophylaxe, Beratung und Therapie ; mit 94 Tabellen, Elsevier Urban & Fischer, München, 2008. [7] J. Mandl, A. Szarka, and G. Bánhegyi, “Vitamin C: Update on physiology and pharmacology,” British journal of pharmacology, vol. 157, no. 7, pp. 1097–1110, 2009. [8] C. Malo and J. X. Wilson, “Glucose modulates vitamin C transport in adult human small intestinal brush border membrane vesicles,” The Journal of nutrition, vol. 130, no. 1, pp. 63–69, 2000. [9] J. D. Akikusa, D. Garrick, and M. C. Nash, “Scurvy: Fogotten but not gone,” J Paediatr Child Health, vol. 2003, no. 39, pp. 75–77. [10] “New Reference Values for Vitamin C Intake,” Annals of nutrition & metabolism, vol. 67, no. 1, pp. 13–20, 2015. [11] M. Linnemann and M. Kühl, Biochemie für Mediziner, Springer, Berlin, 2002. [12] O. Fain, “Musculoskeletal manifestations of scurvy,” Joint Bone Spine, vol. 2005, no. 72, pp. 124–128. [13] H. Hamperl, Lehrbuch der Allgemeinen Pathologie und der Pathologischen Anatomie, Springer, Berlin, 1944. [14] R. L. Allgaier, K. Vallabh, and S. Lahri, “Scurvy: A difficult diagnosis with a simple cure,” African Journal of Emergency Medicine, vol. 2, no. 1, pp. 20–23, 2012. [15] A. Hirsch, Handbuch der geographischen und historischen Pathologie: Band 2: Die chronischen Infektions- und Intoxikationskrankheiten, parasitäre Wundkrankheiten und chronische Ernährungs-Anomalien vom Historisch-Geographischen Standpunkte aus und mit besonderer Berücksichtigung der Ætiologie, Verlag von Ferdinand Enke, Stuttgart, 1883. [16] A. F. Hess, Scurvy Past and Present, J.B. Lippincott Company, Philadelphia, 1920. [17] D. Hafez, S. Saint, J. Griauzde et al., “CLINICAL PROBLEM-SOLVING. A Deficient Diagnosis,” The New England journal of medicine, vol. 374, no. 14, pp. 1369–1374, 2016. [18] I. Vitoria, B. Lopez, J. Gomez et al., “Improper Use of a Plant-Based Vitamin C-Deficient Beverage Causes Scurvy in an Infant,” Pediatrics, vol. 137, no. 2, e20152781, 2016. [19] M. Seya, A. Handa, D. Hasegawa et al., “Scurvy: From a Selective Diet in Children with Developmental Delay,” The Journal of pediatrics, vol. 177, p. 331, 2016. [20] K. Kittisakmontri, N. Swangtrakul, W. Padungmaneesub et al., “Gingival Bleeding and Bloody Dialysate: A Case Report of Scurvy in a Child With End-Stage Renal Disease Receiving Peritoneal Dialysis,” Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation, vol. 26, no. 6, pp. 407–411, 2016. [21] Y. Tamura, D. C. Welch, A. Z. John et al., “Scurvy presenting as painful gait with bruising in a young boy,” Arch Pediatr adoles med, vol. 154, pp. 732–735, 2000. [22] J. P. Weinmann and H. Sicher, Bone and bones: Fundamentals of Bone Physiology, The C.V. Mosby Company, St. Louis, 1947.
[23] E. A. Park, “Bone Growth in Health and Disease,” Archives of Disease in Childhood, vol. 29, pp. 269–281, 1954. [24] E. Fraenkel, Die Möller-Barlowsche Krankheit, Lucas Gräfe & Stillem, Hamburg, 1908. [25] H. L. Jaffe, Metabolic, Degenerative, and Inflammatory Diseases of Bones and Joints, Urban and Schwarzenberg, München, 1972. [26] O. Fain and M. Thomas, “Le scorbut actuellement,” Cahiers de nutrition et de diététique, vol. 1997, no. 32, pp. 300–305. [27] H. Wimberger, “Zur Diagnose des Säuglingsskorbuts,” Zeitschrift für Kinderheilkunde, vol. 36, 45, pp. 279–285, 1923. [28] C. Y. Chang, D. I. Rosenthal, D. M. Mitchell et al., “Imaging Findings of Metabolic Bone Disease,” Radiographics : a review publication of the Radiological Society of North America, Inc, vol. 36, no. 6, pp. 1871–1887, 2016. [29] D. J. Ortner and W. G. J. Putschar, Identification of Pathological Conditions in Human Skeletal Remains, Smithsonian Institution Press, Washington, 1997. [30] H. Wimberger, “V. Klinisch-Radiologische Diagnostik von Rachitis, Skorbut und Lues Congenita im Kindesalter,” Ergebnisse der Inneren Medizin und Kinderheilkunde, vol. 28, pp. 264–370, 1925. [31] P. Carli-Thiele and M. Schultz, “Wechselwirkungen zwischen Mangel- und Infektionskrankheiten des Kindesalters bei neolithischen Populationen,” in Mensch und Umwelt während des Neolithikums und der Frühbronzezeit in Mitteleuropa. Ergebnisse interdisziplinärer Zusammenarbeit zwischen Archäologie, Klimatologie, Biologie und Medizin. Internationaler Workshop vom 9. - 12. November 1995, Institut für Ur- und Frühgeschichte der Universität Wien, pp. 273–285. [32] J. T. Cassidy and R. E. Petty, Textbook of Pediatric Rheumatology, Churchill Livingstone, New York, 1991. [33] T. Waldron, Paleopathology, Cambride University Press, New York, 2009.
Infantile Scurvy: still a relevant differential diagnosis in western medicine D. Schwetje , A. Zillekens , JD. Kieback , S. Koob , R. Placzek PII: DOI: Reference:
S0899-9007(20)30009-5 https://doi.org/10.1016/j.nut.2020.110726 NUT 110726
To appear in:
Nutrition
Received date: Revised date: Accepted date:
30 January 2018 31 October 2019 11 January 2020
Please cite this article as: D. Schwetje , A. Zillekens , JD. Kieback , S. Koob , R. Placzek , Infantile Scurvy: still a relevant differential diagnosis in western medicine, Nutrition (2020), doi: https://doi.org/10.1016/j.nut.2020.110726
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Inc. All rights reserved.
Infantile Scurvy: still a relevant differential diagnosis in western medicine Authors: Schwetje D1, Zillekens A1, Kieback JD1, Koob S1, Placzek R1 1 University Hospital Bonn, Department of Orthopedics and traumatology, Bonn, Germany
Abstract Objective: Infantile Scurvy or Moller-Barlow’s disease appears to be of no further importance in western countries. This is a careless assumption. Especially with severely disabled children this malady manifests itself in a broad range of symptoms such as delayed or suppressed bone healing, minor traumatization leading to bruises/fractures and epiphyseolysis. Research Methods & Procedures: This article aims to present the required daily uptake of vitamin c and the biochemical pathways in the human body leading to the typical symptoms of scurvy. Two cases of chronic scurvy with prolonged bone healing and bleeding, epiphyseolysis and gingival hyperplasia are presented. Both patients were chronically ill with one having cerebral palsy (GMCSF-level IV) and the other a neuroblastoma of the adrenal gland. Results: After diagnosis, the substitution of vitamin via percutaneous endoscopic gastrostomy c in both patients had to be performed in order to treat them. Both patients quickly achieved a full recovery. Conclusion: The two patients presented show the importance of infantile scurvy in the daily medical care. Especially in the severely disabled or chronically ill children its prevalence is often underestimated. Keywords: Scurvy - Vitamin C – ascorbate – case report – orthopedics - pediatrics
Introduction Infantile Scurvy is a historically well-documented disease with is first description attributed to Hippocrates. A definitive report was written in the 18th century by James Lind who systematically observed the disease in sailors and was the first to recommend citrus juice as an effective treatment
[1]. After many contradictory publications, Thomas Barlow presented an anatomic study of infantile scurvy [2]. Even Johannes Möller after whom the infantile disease is named mistook many patients with acute rickets for patients with scurvy [3,3]. Vitamin C is water soluable and a strong chemical reducing agent [2], [4]. The human body cannot synthesise or store it like it can fat soluable vitamins. Regional differences (in the human body) in concentration show its organ specific use of the vitamin. The highest concentration of vitamin C can be found in the adrenal glands where ascorbate takes part in the catecholamin synthesis [2,3]. The uptake of vitamin C starts with its passage through the mouth and the absorption by the oral mucosa but mainly takes place in the jejunum and ileum. Transportation requires adenosintriphosphate because it is an active pathway and it is sodium-dependant. If the transportation capacity is exceeded during an excessive meal, the intake is passive via diffusion [5]. Below a concentration of 180 mg of vitamin C, the uptake is up to 80%. In food vitamin C exists as Lascorbate and dehydro-L-ascorbate. Mainly, vitamin C is resorbed in the form of dehydro-Lascorbate. Because only ascorbate works as a reducing agent and dehydro-L-ascorbate is an unstable construct, it is later reduced to ascorbate itself [6,7]. Differences regarding the uptake can be seen when high glucose concentrations are present: L-ascorbate, not dehydro-L-ascorbate, is blocked from resorption [7,8]. Vitamin C is renally eliminated when the uptake is below 1-3g. Therefore the most sensitive test for scurvy is a urinary sample [9]. Vitamin c deficiency appears to play a minor role in the western hemisphere due to its rich food supply because the required daily uptake of ascorbate is very low – as seen in the table below resulting in a low intestinal resorption rate. Table 1: Current Recommendations for daily vitamin c uptake in relation to age [10]
The symptoms of scurvy can easily be understood when considering the role of vitamin c in the human body: Ascorbate as a strong reducing agent induces hydroxylations of proline to hydroxyproline in the synthesis of collagen, which results in the stabilization of the molecule. Vitamin c causes the migration of long-chain fatty acids into the mitochondrial body during the biosynthesis of carnitine and therefore takes part in energy synthetization, particularly in the muscle. Ascorbate is associated with neurotransmitter biosynthesis (hydroxylation of dopamine to noradrenaline) as well as amidation of neuroendocrinal hormones such as gastrine, bombesine, CRH and TRH. It takes part in several detoxifications and increases the iron absorption by weakening the effect of phytates and other ligands. Vitamin c also supports the immune system through stabilization of the phagocyte membranes against oxidative self-destruction by the halogenide-peroxidase-system [4,5]. Without vitamin C, the resulting inefficient collagen synthesis leads to purpura, subperiostal and gingival bleeding, which causes substantial pain. Minor forms of the disease are characterized by lethargy and apathy, while major forms result in bleeding of the inner organs, inefficient bone metabolism and anemia (through reduced resorption and nutrient loss through bleeding). Due to this vulnerability of the immune system the children are characteristically prone to recurrent infections [5,11]. In 80% the scorbutic patients present an involvement of the musculoskeletal system in the form of arthralgies, myalgies, hemarthrosis and muscular hematomas [12,13]. Infantile scurvy is often underdiagnosed because of its unspecific range of symptoms, which frequently results in false diagnoses such as vasculitis or ulcerative gingivitis [14]. The main focus of current research lies on the prevention of delayed diagnosis and on re- establishing scurvy as a differential diagnosis. The two case reports presented are no exception, as the focus lies on the consequences of delayed diagnosis and the influence of the vitamin-c-substitution on patient reconvalescence.
First Case A six-year-old was admitted with bilateral knee pain and swelling of the left knee. The girl had been treated in our hospital for cerebral palsy (GMFCS-Level 4) sustained by postpartal hypoxia, paleness and for imminent hip luxation. The child was in a reduced general state and suffered of muscle as well as joint pain. The initial clinical and radiological examinations of both knees showed no pathological findings. The external laboratory results showed a mild hypochromic microcytic anemia. Over the course of several weeks the knee pain exacerbated, resulting in new X-ray images being taken in another department. After diagnosing a distal femoral epiphyseolysis in both legs without evidence of a high-energy traumatization or child abuse the patient was transferred back to our
hospital. Meanwhile, the parents recalled major bleeding and gingival swelling at the loss of one milk tooth. The child had also been refusing to eat or drink. The laboratory results showed an iron deficiency anemia (serum hemoglobin level 6.4 g/dl) and a positive Rumpel-Leede-test.
Figure 1: X-ray of a distal femoral epiphyseolysis, left knee in two planes
Figure 2: Photograph of swollen, inflamed gingiva
The clinical manifestation of hypochromic microcytic anemia in combination with bleeding, aforementioned symptoms and an atypical localization of the epiphyseolysis led us to suspect a chronic avitaminosis. Both knee joints were punctured and blood was evacuated (right: 6 ml; left: 7ml). Blood analysis confirmed a vitamin c serum level below 1 mg/l (reference level 5-15mg/l). A daily substitute of 50 mg ascorbate in combination with iron (5-6mg/kg body weight) was initiated and had to be administered via a stomach tube due to reduced overall ingestion of 900ml/d. Subsequently, a closed reposition of the epiphysiolysis was performed with immobilization of both legs in a cast for six weeks under sole mobilization with the physiotherapy. After five months, a stable bone situation and an almost free range of motion in both knees (extension/flexion 5-0-130°) was achieved.
Figure 3: X-ray of a distal femoral epiphyseolysis, right knee in two planes
Second Case The second six-year-old patient was transferred in our pediatric department in July 2015 after chemotherapy and haploid stem cell transplantation for neuroblastoma of the right adrenal gland. The girl showed delayed bone healing six weeks after sustaining femoral fractures of both legs and being treated with TEN (Titanium Elastic Nail) implantation in our traumatological department. Furthermore, the cachectic child complained of arthralgy and myalgia as well as malnourishment due to frequent vomiting. Her medical history revealed recurring infections. Despite several revisions including a change of osteosynthesis (double-TENS, plate osteosynthesis) and stabilization via plaster cast, satisfactory ossification could not be achieved. Follow-up X-ray imaging showed an osteopenia with major signs of bone demineralization as well as atraumatic epiphyseolysis capitis femoris in December 2016. Severe gastric bleeding and an anemic state of unknown origin were detected along with serum vitamin c levels below 1 mg/l (reference level 5-15 mg/l). In February 2016 a PEG (percutaneous endoscopic gastrostomy) and percutaneous endoscopic jejunostomy had to be performed to treat the patient’s cachexia. She received substitutions of 400mg of vitamin C intravenously twice a week in combination with other essential vitamins (vitamin D, folic acid et cetera). The patient improved markedly, as did the consolidation of her fractures.
Figure 4: X-ray of non- existent osseous consolidation of a distal femoral fracture with TENS in situ, left knee in two planes
Discussion Infantile Scurvy is an often- underdiagnosed disease. Common pathologies of the gastrointestinal anatomy associated with malabsorption, such as celiac disease [14], are a possible cause for avitaminosis. If a mothers serum vitamin C levels are adequate, the nursed baby is protected from such hypovitaminosis [12]. Vitamin C is characteristically unstable, though – it can easily be destroyed when cooked or simmered [15]. Therefore scurvy’s prevalence rose after the introduction of pasteurization and the new sense of hygiene in the United Kingdom accompanied by consuming the breast milk to reduce the bacterial load [16]. Literary research shows many reports of one-track fed children who were mistaken for having adequate access to fresh food [9,17–19]. A further risk factor is posed by vitamin loss in chronic renal failure, due to the major elimination pathway of ascorbate passing through urine [20]. Other possible causes are malassimilation, which results in decreased intestinal uptake, psychiatric disorders, cancer, AIDS and other consuming illnesses, inadequate parental nutrition or an increased nutritional demand [14], [21]. In both cases presented in this article the nutrition of the children with chronic diseases was neglected leading to percutaneous endoscopic gastrostomy/ jejunostomy being conducted to ensure adequate nourishment. In the daily (pediatric) orthopedic routine scurvy should be routinely considered a possible diagnosis, especially in children with spontaneous epiphyseolysis, which is frequently observed in the faster
growing epiphyses such as the proximal tibia, distal femur and proximal humerus [13,22]. In the first case the symmetric epiphyseolysis of the distal femora led to the diagnosis of infantile scurvy without prior knowledge of the patient´s underlying avitaminosis. This girl had cerebral palsy (GMFCS-Level 4), a risk factor for the disease, and showed a microcytic anemia correlating with a decrease in iron absorption as well as an increase in bleeding (after the loss of a tooth). Digestion was limited by cerebral palsy and missing nutrients had been previously substituted. Spontaneous fractures should also raise one´s suspicion of scurvy due to its resulting enhanced activity of the osteoclasts and diminished activity of the osteoblasts [13,23]. Furthermore, fracture healing is reduced in an avitaminotic state. In 1908, Frankel discovered in animal trials with guinea pigs that bone healing is repealed in scurvy [24]. The minimum required intake of vitamin C per day for lies around 0,5-1mg/d [4]. In the second clinical case, multiple spontaneous fractures were healing inadequately despite adequate surgical treatment. This prompted further examination leading to the diagnosis of infantile scurvy. The involvement of the musculoskeletal system can be observed in persistent and clinically manifested scurvy. Therefore, it is sensible to assume avitaminosis manifesting itself over a course of months [25]. Human and animal trials have shown avitaminosis to take 130 days on average to become symptomatic[26]. However, the reconvalescence after beginning substitution treatment is often seen after one week [21]. Vitamin C was administered as ascorbate as it is the only type of vitamin C on the market. Another issue is the lack of radiological experience with the disease due to its low occurence. The locations of skeletal manifestations correlate to their collagen production, so the faster growing epiphyses are classically the ones showing scorbutic changes (proximal humerus, distal radius and ulnae; distal femur, proximal tibia and fibula) [27]. These are the typical radiolocial findings in scurvy:
generalised demineralisation
Fraenkel line: zone of provisional calcification in the metathyseal endings [21]
Trummerfeld zone: translucent band caused by trabecular destruction and epiphyseal breaks, parallel to the joint lign and circular in epiphyseal bone cores [27], also known as the „scurvy line“ [28]
Wimberger’s ring: secondary ossification centres which show signs of osteoporosis and are embedded in a layer of mineralised cartilage in the growth periphery [29,30]
epiphyseolysis and epiphyseal dislocations or smaller fractures in the bone structure ([24]
Harris lines: compact zones of the metaphysis who demonstrate a discontinuity in bone growth by increased calcification after the resumption of growth [31]
„scorbutic pearls“: thickened rip-cartilage-borders, also known as the „scorbutic rosary“ [32]
„metaphyseal or Pelkan spurs“: lateral extension of the provisional calcification zone with stimulation of a periostal reaction [33]
In the second case many typical radiological signs were not detected in a second reevaluation of the X-rays. Though osteopenia had been described, scurvy had not been diagnosed. In combination with the observed decreased serum level of vitamin C, infantile scurvy could have been diagnosed.
Figure 5: X-ray of non- existent osseous consolidation of a distal femoral fracture with TENS in situ, left knee in two planes with Anteroposterior radiograph of the left knee shows osteopenia, dense bands along the metaphyseal side of the epiphyses in the zone of provisional calcification (Frankel line [red arrow]) with an adjacent lucent line called the Trummerfeld zone, or “scurvy line” (white arrow).
Conclusion Infantile Scurvy is a majorly under- or tardily diagnosed disease. In countries with apparent adequate food supply, one-sided nutrition as well as several concomitant maladies (chronic renal failure, consuming (oncological) diseases, malabsorption and psychiatric disorders) are relevant risk factors. Aside from unspecific clinical symptoms, delay in fracture healing is an indicator of infantile scurvy. Determination of serum/urine levels of vitamin C and X-ray analysis can be used to confirm the diagnosis. Infantile Scurvy remains an important differential diagnosis in modern clinical practice. Conflict of Interest None
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