Accepted Manuscript Acute thiamine deficiency and refeeding syndrome: similar findings but different pathogenesis Arianna Maiorana, MD, PhD Gianluca Vergine, MD Valentina Coletti, MD Matteo Luciani, MD Cristiano Rizzo, MD Francesco Emma, MD Carlo Dionisi-Vici, MD PII:
S0899-9007(14)00124-5
DOI:
10.1016/j.nut.2014.02.019
Reference:
NUT 9237
To appear in:
Nutrition
Received Date: 26 December 2013 Revised Date:
18 February 2014
Accepted Date: 19 February 2014
Please cite this article as: Maiorana A, Vergine G, Coletti V, Luciani, M, Rizzo C, Emma F, DionisiVici, C, Acute thiamine deficiency and refeeding syndrome: similar findings but different pathogenesis, Nutrition (2014), doi: 10.1016/j.nut.2014.02.019. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. 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.
ACCEPTED MANUSCRIPT 1
Acute thiamine deficiency and refeeding syndrome: similar findings but different
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pathogenesis.
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Arianna Maiorana1, MD, PhD, Gianluca Vergine2, MD, Valentina Coletti3, MD, Matteo
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Luciani3,MD, Cristiano Rizzo1, MD, Francesco Emma2, MD, Carlo Dionisi-Vici1,MD.
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Department of Pediatric Medicine, Division of Metabolism and Research Unit of Metabolic
Biochemistry; 2
Department of Nephrology & Urology, Division of Nephrology and Dialysis;
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Department of Hematology and Oncology, Division of Hematology, Bambino Gesù
Children’s Hospital and Research Institute, Rome, Italy.
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Running head: Proximal tubular dysfunction in thiamine deficiency.
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Authors' contribution
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AM conceptualized and designed the study, carried out data collection and analyses, drafted
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the initial manuscript, reviewed and approved the final manuscript as submitted. GV carried
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out the initial analyses, drafted the initial manuscript, and approved the final manuscript as
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submitted. VC performed the data collection, participated in its design and coordination and
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helped to draft the manuscript. ML performed the data collection, participated in its design
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and coordination and approved the final manuscript as submitted. CR carried out the
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instrumental data analyses, participated to the interpretation of data and participated in its
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design. and coordination and helped to draft the manuscript. FE participated in its design and
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coordination and critically reviewed the manuscript and approved the final manuscript as
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submitted. CDV designed the data collection instruments, coordinated and supervised data
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collection, critically reviewed the manuscript and approved the final manuscript as submitted. All authors read and approved the final manuscript.
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Word count 2545
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Figures 3
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Tables 1
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Address correspondence to: Arianna Maiorana, Department of Pediatric Medicine, Division
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of Metabolism, Bambino Gesù Children’s Hospital, piazza S. Onofrio 4, 00165, Rome, Italy,
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phone number +390668592275, fax number +390668592791, email
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[email protected]
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Abstract Objective: Refeeding syndrome can occur in several contexts of relative malnutrition in which an overaggressive nutritional support is started. The consequences are life-threatening
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with multiorgan impairment, and severe electrolyte imbalances. During refeeding, glucose-
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involved insulin secretion causes abrupt reverse of lipolysis and a switch from catabolism to
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anabolism. This creates a sudden cellular demand of electrolytes (phosphate, potassium and
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magnesium) necessary for ATP synthesis, glucose transport and other synthesis reactions,
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resulting in decreased serum levels. Laboratory findings and multiorgan impairment similar to
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refeeding syndrome are also observed in acute thiamine deficiency.
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Methods: We describe two patients with leukemia who developed acute thiamine deficiency
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with an electrolyte pattern suggestive of refeeding syndrome, severe lactic acidosis and
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evidence of proximal renal tubular dysfunction.
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Results: A single thiamine administration led to rapid resolution of the tubular dysfunction
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and normalization of acidosis and electrolytes imbalance. This demonstrated that thiamine
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deficiency was responsible for the electrolyte imbalance, caused by tubular electrolytes losses.
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Conclusions: Our report indicates that, despite sharing many laboratory similarities, refeeding
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syndrome and acute thiamine deficiency should be viewed as separate entities in which the
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electrolyte abnormalities reported in cases of refeeding syndrome with thiamine deficiency
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and refractory lactic acidosis may be due to a renal tubular losses instead of a shifting from
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extracellular to intracellular compartment. In oncologic and malnourished patients, categories
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at particular risk of developing refeeding syndrome, in presence of these biochemical
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abnormalities, acute thiamine deficiency should be suspected and treated, because it promptly
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responds to thiamine administration.
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Key words: lactic acidosis, thiamine, methotrexate, renal tubular dysfunction,
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hypophosphatemia, refeeding syndrome.
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Introduction Thiamine deficiency can occur in anorexia nervosa, in leukemia/cancer [1], in patients
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receiving unsupplemented total parenteral nutrition (TPN) [2], in children fed with defective
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soy-based infant formulas [3], or in chronic alcohol abuse [4]. Clinical features of thiamine
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deficiency include neurological, cardiovascular and metabolic manifestations [2].
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Furthermore, acute thiamine deficiency has been considered a component of the refeeding
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syndrome (RS), a potentially lethal condition characterized by severe electrolyte and fluid
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imbalance [5]. RS was originally described in grossly malnourished prisoners released from
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concentration camps during the Second World War who presented heart failure, neurological
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complications with convulsions and coma following refeeding [5,6]. RS characteristically
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occurs when malnourished and starved subjects receive high carbohydrate feeding causing a
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sudden change of the energy sources, from fat to carbohydrates, which causes a sustained
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increase in insulin secretion. The insulin action induces a sudden shift of salt from
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extracellular to intracellular compartment. The laboratory hallmark of RS is
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hypophosphatemia; additional features include reduced plasma potassium and magnesium
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levels, hyperglycemia, metabolic acidosis, along with sodium and water retention causing
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fluid overload [4,7,8]. The consequences of these severe changes can be life-threatening.
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Conditions at high risk include recent weight loss, secondary to poor caloric intake or nutrient
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losses [8]. Patients with malignancy are at particular risk of developing RS because they
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frequently develop malnutrition and are depleted of micronutrients and electrolytes as a
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consequence of their treatment. An excessive parenteral carbohydrate supply may act as a
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trigger for RS, especially if glucose supply is not adequately supplemented with vitamins and
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oligoelements [4,9]. Interestingly, laboratory findings similar to RS are also observed in
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acute thiamine deficiency [1]. We report on two children with leukemia who developed acute
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thiamine deficiency and showed an electrolyte pattern of RS, whose pathogenetic mechanism
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was due to a severe proximal renal tubular dysfunction which promptly responded to thiamine
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administration.
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Case reports
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Case 1
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This female patient presented at 5 months of age with intestinal bleeding, severe anemia, and
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thrombocytopenia leading to the diagnosis of B-cell leukemia. She was enrolled in the
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International Collaborative Treatment Protocol for Children under one year of age
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(INTERFANT 2006). During consolidation phase, few days after the first administration of
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i.v. high dose Methotrexate 5000 mg/m2, the child presented with diarrhea and vomiting
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treated by parenteral hydration with 5% glucose saline solution for a week. A complete
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parenteral nutrition support (TPN) with glucose concentration of 33% was started on the
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following day (day 0), when a second dose of i.v. Methotrexate 5000 mg/m2 was
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administered. Feeding difficulties persisted and TPN was continued. On day 19th, clinical
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conditions further deteriorated with appearance of tachypnoea and lethargy. Blood gas
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analysis revealed severe metabolic acidosis (pH 6.9, normal value 7.32-7.48; BE –25
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mEq/L, nv -2/+3; HCO3- 5 mEq/L), high anion gap (21mEq/L), hyperlactatemia (13.3
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mMol/L, nv 0.4-2.2, 120 mg/dl, nv 4-20 ), and moderate hyperglycemia (158 mg/dl). Further
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laboratory findings showed severe hypophosphatemia (0.9 mg/dl), hypokalemia (2.5 mEq/L)
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and hypomagnesemia (1.4 mg/dl). As shown in Table 1, mineral and electrolyte imbalance
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was consistent with a proximal tubular dysfunction with renal loss of phosphate, magnesium
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and potassium. Despite intravenous administration of large dose bicarbonate, up to 10
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mEq/kg, and electrolyte supplementation, clinical conditions and severe metabolic acidosis
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and electrolyte imbalance further deteriorated. Continuous veno-venous hemofiltration
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(CVVH) was started on day 20th but caused only slight improvement. On day 21st,
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ACCEPTED MANUSCRIPT examination of urinary organic acids showed a characteristic pattern as seen in thiamine
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deficiency [1] (Figure 1). Soon after 300 mg thiamine administration, we observed an almost
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immediate improvement of clinical conditions with complete normalization of metabolic
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acidosis within 3 hours (Figure 2). In the following 24-48 hours, blood electrolyte
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abnormalities fully recovered with normalization of blood lactate and of urine organic acid
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profile. Proximal tubular dysfunction completely resolved in the following days (Table 1).
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Case 2
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Acute myeloid leukemia was diagnosed at the age of 9 years in this male patient who was
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enrolled in the Italian Protocol AIEOP LAM 2002. During the first chemotherapy course, he
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developed persistent vomiting requiring TPN with a 33% glucose concentration (day 0). On
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day 19th, he suddenly developed mental status changes, hypothermia, hypotension and
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tachypnoea. Cerebral magnetic resonance imaging (MRI) showed bilateral high-intensity
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signals of basal ganglia. Blood gas analysis revealed severe metabolic acidosis (pH 6.8, BE
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–29 mEq/L, HCO3- 3 mEq/L, anion gap 35 mEq/L), hyperlactatemia (15.5 mMol/L, 140
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mg/dl), and hyperglycemia (270 mg/dl). Further laboratory findings showed
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hypophosphatemia (1.2 mg/dl), hypokalemia (2.4 mEq/L) and hypomagnesemia (1.2 mg/dl).
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Similarly to patient 1, urinary investigation showed evidence of proximal renal tubular
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dysfunction (Table 1). Attempts to correct metabolic acidosis with iv sodium bicarbonate
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were ineffective. Reviewing of TPN prescription showed that vitamin supplementation was
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missed. Thiamine deficiency was confirmed by analysis of plasma levels (30 nmol/L, normal
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66.5-200) and by analysis of urinary organic acids which showed a characteristic profile.
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Three hours after administration of 300 mg thiamine, metabolic acidosis disappeared;
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electrolyte abnormalities and renal tubular dysfunction fully recovered within 5 days (Table
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1).
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ACCEPTED MANUSCRIPT Discussion
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Malnourished patients presenting with acute illnesses receiving parenteral hydration with
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high concentration glucose solutions or treated with enteral or parenteral nutrition without
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adequate vitamin supplementation, are at high risk for developing the RS [1,5,7,10,11].
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Thiamine deficiency which is often listed among the causes of RS, may cause metabolic,
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neurologic and cardiovascular symptoms, similar to RS [12]. As frequently observed in
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children with leukemia receiving chemotherapy, our two patients before manifesting acute
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thiamine deficiency, presented severe and protracted gastrointestinal signs with poor food
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intake. In addition, one was treated with high doses of methotrexate, a drug which competes
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with cell thiamine transport systems [13], and the second erroneously received
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unsupplemented TPN. Thiamine deficiency was confirmed by serum thiamine measurement
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in one patient and by the finding of characteristic metabolic changes in both children (i.e.
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lactic acidosis combined with a specific urine organic acids profile). Besides these changes,
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both patients showed an electrolyte pattern in blood very similar to what observed in RS
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[10,11]. During refeeding, carbohydrate intake stimulates insulin secretion and reverts
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catabolism to anabolism, creating a sudden demand of inorganic phosphate for ATP synthesis,
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of potassium for intracellular glucose transport, of magnesium for synthesis reactions and of
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thiamine for carbohydrate and aminoacids oxidation [9]. Interestingly, similar electrolyte
192
disturbances can be observed in patients with poorly controlled diabetes mellitus, a condition
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with low insulin levels [14], suggesting that alternative mechanisms can be responsible for
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these electrolyte imbalances. In our patients we had clear evidence of severe renal tubular
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dysfunction, causing urinary losses of phosphate, potassium and magnesium. Hypokalemia
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[1,10] and hypophosphatemia [1] have been reported in patients with lactic acidosis due to
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thiamine deficiency however, tubular function has not been investigated in these cases [1]. In
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thiamine deficiency, the cytosolic conversion of pyruvate into lactate by anaerobic
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ACCEPTED MANUSCRIPT metabolism causes lactic acidosis. The presence of hypophosphatemia, hypokalemia and
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hypomagnesemia in our patients can be therefore interpreted as the consequence of an energy
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deprivation affecting renal tubular cells.
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Thiamine is not stored in appreciable amounts in cells, has a short half-life and cell stores are
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usually depleted within 20 days of malnutrition [12]. Abrupt increase of carbohydrate
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oxidation may precipitate acute deficiency since accelerates the consumption of residual
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thiamine stores [4]. Remarkably, our patients developed acute thiamine deficiency
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approximately 20 days after starting TPN. In one patient vitamin supplementation was found
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not being included in his TPN solution whereas in the other patient receiving high dose
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metotrexate, the TPN contained a standard thiamine dose, which is approximately 100 times
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lower than the amount required in case of thiamine deficiency [12].
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Thiamine is the cofactor of pyruvate dehydrogenase, branched-chain α-ketoacids
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dehydrogenase, transketolase and α-ketoglutarate dehydrogenase. These enzymes are
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involved in acetyl-CoA formation, in branched-chain aminoacids catabolism, in connecting
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the pentose phosphate pathway to glycolysis, and in Krebs cycle, respectively. When
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thiamine is deficient, a combined enzymatic defect occurs, as reflected by the
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characteristic organic acid pattern [1], causing Krebs cycle and ATP synthesis impairment
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[12]. In this view, thiamine deficiency may cause disruption of renal tubular function,
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resulting in decreased reabsorption of electrolytes as a consequence of impaired tubular ATP-
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dependent transport systems [15,16]. The dramatic response to a single thiamine dose
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supports this concept. Since through transketolase activity thiamine plays a pivotal role in
220
protecting against oxidative stress[17,18], in thiamine deficiency the insufficient ATP
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generation combined with toxic effects of reactive oxygen species can lead to acute tubular
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necrosis (ATN) through an ischaemia-reperfusion injury [19]. It can be therefore concluded
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that the urinary electrolyte losses in our patients is the result of an early phase of tubular
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ACCEPTED MANUSCRIPT impairment caused by thiamine deficiency. Not surprisingly, the most frequent renal finding
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in disorders of mitochondrial oxidative phosphorylation is a proximal tubular defect [20,21].
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Interestingly, the development of ATN has been described as part of a RS, in one patient [22].
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Our report indicates that, despite sharing many laboratory similarities, RS and acute thiamine
228
deficiency should be viewed as separate entities. It is possible that electrolyte abnormalities
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reported in cases of RS with thiamine deficiency and refractory lactic acidosis may be due to
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a renal tubular losses instead of a shifting from extracellular to intracellular compartment. In
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this view, hypophosphatemia, hypokalemia and hypomagnesemia in RS without lactic
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acidosis are most likely caused by an imbalance between intra- and extra-cellular
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compartments, whereas in presence of lactic acidosis these changes are more likely secondary
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to renal tubular losses caused by thiamine deficiency (Figure 3). Many reports concerning
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thiamine deficiency and development of refractory lactic acidosis along with neurological,
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cardiovascular and intestinal manifestations are described (Supplementary Table 2).
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Therefore, when such conditions are associated to severe lactic acidosis, a thiamine deficiency
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should be suspected.
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Conclusions
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Oncologic and malnourished patients should be carefully monitored in order to avoid severe
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electrolyte abnormalities related to thiamine deficiency, a life threatening condition that, if
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promptly recognized, dramatically responds to thiamine administration. However, further
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studies with a higher number of patients are necessary to support our findings.
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Acknowledgements
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AM conceptualized and designed the study, carried out data collection and analyses, drafted
248
the initial manuscript, reviewed and approved the final manuscript as submitted. GV carried
10
ACCEPTED MANUSCRIPT out the initial analyses, drafted the initial manuscript, and approved the final manuscript as
250
submitted. VC performed the data collection, participated in its design and coordination and
251
helped to draft the manuscript. ML performed the data collection, participated in its design
252
and coordination and approved the final manuscript as submitted. CR carried out the
253
instrumental data analyses, participated to the interpretation of data and participated in its
254
design. and coordination and helped to draft the manuscript. FE participated in its design and
255
coordination and critically reviewed the manuscript and approved the final manuscript as
256
submitted. CDV conceptualized and designed the study, designed the data collection
257
instruments, coordinated and supervised data collection, critically reviewed the manuscript
258
and approved the final manuscript as submitted. All authors read and approved the final
259
manuscript. The authors declare that they have no competing interests.
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ACCEPTED MANUSCRIPT References
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1. Svahn J, Schiaffino MC, Caruso U, Calvillo M, Minniti G, Dufour C: Severe lactic acidosis
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due to thiamine deficiency in a patient with B-cell leukemia/lymphoma on total parenteral
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nutrition during high-dose methotrexate therapy. J Pediatr Hematol Oncol 2003, 25:965-968.
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2. Thauvin-Robinet C, Faivre L, Barbier ML, Chevret L, Bourgeois J, Netter JC et al: Severe
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lactic acidosis and acute thiamine deficiency: a report of 11 neonates with unsupplemented
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total parenteral nutrition. J Inherit Metab Dis 2004, 27:700-704.
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3. Fattal-Valevski A, Kesler A, Sela BA, Nitzan-Kaluski D, Rotstein M, Mesterman R et al:
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Outbreak of life-threatening thiamine deficiency in infants in Israel caused by a defective soy-
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based formula. Pediatrics 2005, 115: e233-238. doi:10.1542/peds.2004-1255.
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4. Stanga Z, Brunner A, Leuenberger M, Grimble RF, Shenkin A, Allison SP et al: Nutrition
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in clinical practice-the refeeding syndrome: illustrative cases and guidelines for prevention
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5. Boateng AA, Sriram K, Meguid MM, Crook M: Refeeding syndrome: Treatment
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considerations based on collective analysis of literature case reports. Nutrition 2010,
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6. Burger GCE, Drummond JC, Sandstead HR: Malnutrition and Starvation in Western
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Netherlands, September 1944- July 1945. General State Printing Office: The Hague, 1948.
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7. Panteli JV, Crook MA. Refeeding syndrome still needs to be recognized and
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managed appropriately. Nutrition 2009, 25:130-131.
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8. Mehanna HM, Moledina J, Travis J: Refeeding syndrome: what it is, and how to prevent
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and treat it. BMJ 2008, 336:1495-1498.
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9. Crook MA, Hally V, Panteli JV: The importance of the refeeding syndrome. Nutrition
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2001, 17:632-637.
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ACCEPTED MANUSCRIPT 10. Centers for Disease Control and Prevention (CDC): Lactic acidosis traced to thiamine
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deficiency related to nationwide shortage of multivitamins for total parenteral nutrition --
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United States, 1997. MMWR Morb Mortal Wkly Rep 1997, 46:523-528.
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11. Oriot D, Wood C, Gottesman R, Huault G: Severe lactic acidosis related to acute thiamine
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deficiency. J Parenter Enteral Nutr 1991, 15:105-109.
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12. Sriram K, Manzanares W, Joseph K: Thiamine in nutrition therapy. Nutr Clin Pract 2012,
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27:41-50.
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13. Zhao R, Gao F, Wang Y, Diaz G, Gelb B, Goldman I: Impact of the reduced folate carrier
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on the accumulation of active thiamine metabolites in murine leukemia cells. J Biol Chem
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2001, 276:1114-1118.
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14. Matz R: Parallels between treated uncontrolled diabetes and the refeeding syndrome with
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emphasis on fluid and electrolyte abnormalities. Diabetes Care 1994, 17:1209-1213.
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15. Skou JC, Norby JG: Na+-K+-ATPase structure and kinetics. New York Academie Press
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Inc. New York, 1979, 549 pp.
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16. Green M, Ruiz OS, Kear F, Arruda JA: Dual effect of cyclic GMP on renal brush border
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Na-H antiporter. Proc Soc Exp Biol Med 1991, 198:846-851.
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17. Beltramo E, Berrone E, Tarallo S, Porta M: Effects of thiamine and benfotiamine on
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intracellular glucose metabolism and relevance in the prevention of diabetic complications.
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Acta Diabetol 2008, 45:131-141.
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18. Thornalley PJ: The potential role of thiamine (vitaminB1) in diabetic complications. Curr
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Diabetes Rev 2005, 1:287-298.
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19. Klooster A, Leuvenink HG, Gans RO, Bakker SJ: Tissue thiamine deficiency as potential
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cause of delayed graft function after kidney transplantation: thiamine supplementation of
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kidney donors may improve transplantation outcome. Med Hypotheses 2007, 69:873-878.
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20. Rotig A: Renal disease and mitochondrial genetics. J Nephrol 2003, 16:286-292.
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21. Emma F, Montini G, Salviati L, Dionisi-Vici C: Renal mitochondrial cytopathies. Int J
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Nephrol 2011, 609213.doi: 10.4061/2011/609213.
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22. Marinella MA: The refeeding syndrome and hypophosphatemia. Nutr Rev 2003, 61:320-
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323.
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Legends
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Table 1. Results of blood and urinary laboratory tests before and after thiamine
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administration.
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AG: anion gap (normal value 10-14) calculated by the formula Na – (HCO3- + Cl) (not
353
corrected for abumin levels); Nas: serum sodium level (normal value 136-145); FeNa:
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urinary fractional sodium excretion (normal value 1%); Mgs: serum magnesium level (normal
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value 1.7-2.3); FeMg: urinary fractional magnesium excretion (normal value 85%); Ks: serum potassium level (normal value 3.5-5.1); TTKG: trans-tubular
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potassium gradient (normal value 6-11); HCO3- 5 mEq/L n.v. 19-27; Glycemia normal value
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60-110 mg/dl. Lactate normal value 0.4-2.2 mMol/L.
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ACCEPTED MANUSCRIPT Figure 1. Urinary organic acids profile in thiamine deficiency. Thiamine is cofactor of
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piruvate dehydrogenase complex, 2-ketoglutatrate dehydrogenase complex and branched-
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chain α-ketoacid dehydrogenase complex. These enzymatic complexes catalyze the hydrolysis
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of the α-ketoacids which enter the Krebs cycle for their complete oxidation and ATP
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generation. Thiamine deficiency provokes accumulation of urinary α-ketoacids along with
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lactate, pyruvate, 2-hydroxybutyrate and 2-hydroxyisovalerate.
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1. Lactic acid; 2. 2-OH-butyric acid; 3. Pyruvic acid; 4. 2-OH-isovaleric acid; 5. 2-keto-
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butyric acid; 6. 2-keto-isovaleric acid; 7. 2-keto-3-methyl-valeric acid; 8. 2-keto-isocaproic
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acid; 9. 2-keto-glutaric acid; 10. 2-keto-adipic acid; IS1 (Internal standard1) 2-phenylbutyric
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acid; IS2 (Internal standard2) tricarballylic acid.
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Figure 2. Early effect of thiamine administration on metabolic acidosis. Plasma pH and
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bicarbonates returned to normal within three hours from thiamine administration.
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Figure 3. Speculative mechanisms of intracellular plasma electrolytes depletion. In
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continuous lines, electrolytes imbalance is explained as intracellular shift of electrolytes
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caused by the action of insulin, acutely released after carbohydrates administration. In dotted
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lines, thiamine deficiency provokes Krebs cycle impairment in tubular cells with metabolic
390
acidosis and urinary losses of electrolytes.
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PDH: piruvate dehydrogenase; α-KGDH: α- ketoglutarate dehydrogenase; BKDH: branched
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chain α-ketoacids dehydrogenase; TK: transketolase.
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Supplementary materials
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Table 2. Thiamine deficiency and lactic acidosis. M: male; F: female: TPN: total parenteral
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nutrition; BMT: bone marrow transplantation; 5-FU: 5-flurouracil; LLA: acute lymphoblastic
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leukemia; LMA: acute myeloblastic leukemia; Shoshin: acute pernicious or fulminating
402
beriberi heart disease.
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ACCEPTED MANUSCRIPT Table 1. Results of blood and urinary laboratory tests before and after thiamine administration. Case 1 AG (mEq/L) 21 ↑ 35 ↑
Lactate (mMol/L) 13.3 14.4
Glycemia (mg/dl) 158 ↑ 137 ↑
Nas (mEq/L) 132 ↓ 135 ↓
FeNa (%) 5↑ 11 ↑
FeMg Mgs (mEq/L) (%) 1.4 ↓ 4.8 ↑ 1.2 ↓ 8.6 ↑
1.6
115 90
137 142
1
2 1.7
3
15.5 14.9
270 ↑ 160 ↑
134 ↓ 134 ↓
10 ↑ 8↑
1.2↓ 1.1↓
5.2 ↑ 6.7 ↑
2.2
99 90
136 142
1
15
35 ↑ 31 ↑ 14
1.6 1.7
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3↓ 5↓ thiamine 37 ↑
AC C
Day 19 Day 20 Day 21 3hrs later Day 23 Day 29
3
TRP (%) 59 ↓ 40 ↓
TTKG Ks (mEq/L) 2.3 ↓ 12.5 ↑ 2.8 ↓ 20 ↑
3.5 4
95
3.9 4
7.5
1.2 ↓ 1.6 ↓
65↓ 60 ↓
2.5 ↓ 2.4 ↓
20 ↑ 25 ↑
3.3 4
95
3.6 4
7.5
SC
Case 2
Ps (mg/dl) 1.2 ↓ 0.9 ↓
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Day 19 Day 20 Day 21 3hrs later Day 23 Day 29
HCO3(mEq/L) 5↓ 11 ↓ thiamine 32 ↑
ACCEPTED MANUSCRIPT PDH sub E3 8
1.9e+07
1
1.8e+07 1.7e+07 1.6e+07
2
3
10 IS1
4
9
IS2
6
1.5e+07
RI PT
1.4e+07 1.3e+07 1.2e+07
7
1.1e+07 1e+07
5
9000000
SC
8000000 7000000 6000000
4000000 3000000 2000000 1000000 10.00
15.00
20.00
Time-->
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Figure 1
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5000000
25.00
30.00
35.00
M AN U
SC
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ACCEPTED MANUSCRIPT
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Figure 2
ACCEPTED MANUSCRIPT
REFEEDING SYNDROME
ACUTE THIAMINE DEFICIENCY
Fasting/malnutrition Lipid/protein catabolism/insulin suppression
GLUCOSE
RI PT
Thiamine poor intake/ increased consumption/ impaired transport
Blockade of PDH, α-KGDH, BKDH, TK
Increased insulin secretion
SC
Energy deprivation
Intracellular shift of PO43-, K+, Mg2+ Hypophosphatemia Hypokalemia Hypomagnesemia
Urinary losses of PO43-, K+, Mg2+ Hypophosphatemia Hypokalemia Hypomagnesemia
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Figure 3
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Proximal tubular dysfunction
Lactic acidosis
ACCEPTED MANUSCRIPT Table 2. Thiamine deficiency and lactic acidosis Underlying condition
Precipitating cause
Clinical signs
Reference
30 years F
Severe obesity
Gastric bypass, vomiting
Stanga Z, Em J Clin Nutr, 20084
28 years F
Gastric carcinoma
9 infants 2,5-12 months
Healthy
Esophageal stenosis with disphagia, TPN, chemotherapy CDDP (5FU) Defective soybased infant formula
Lactic acidosis, pulmonary oedema, cardiomegaly, hypophosphatemia, hypokalemia Metabolic acidosis, deafness, ataxia, confusion, hypotension
Fattal-Valevski A, Pediatrics, 20053
1 patient M
Thiamine deficient diet
Severe dyspnea
1 patient M
Pancreatic cancer
Surgery, TPN
Lactic acidosis, vomiting, diarrhea, abdominal distension, lethargy, irritability, ophtalmoplegia, developmental delay, nystagmus, respiratory symptoms, failure to thrive Metabolic acidosis, heart failure Lactic acidosis
11 newborns
Vascular enteropathy, bowel angiomatosis, enterocolitis, bowel intolerance
TPN
Pre-term newborn
Hirschprung's disease
Biliar vomiting, feeding problems, surgery, TPN TPN
1 patient 6 patients 11 years M
11 months F
Malnutrition, severe dehydration, Thiamine deficient diet
AC C
1 month
Digestive disease Leukemia
3 years F
B cell leukemia/lymphoma, Propionic acidemia
1 newborn 2 months
Propionic acidemia Propionic acidemia
19 years M
Glucose infusion Weakness, lower limb oedema TPN Herpetic esophagitis, gastritis, vomiting, TPN Chemotherapy, stomatitis ,TPN Recurrent vomiting, TPN Paralitic ileus Recurrent vomiting, TPN TPN
Kondo K, Jpn J Clin Oncol, 199623
SC
M AN U
TE D
EP
2 years M
RI PT
Patients (age and sex)
Severe lactic acidosis, hypotension, vomting, agitation, hypotonia, lethargy, tachipnoea, tachycardia Severe metabolic acidosis, sepsi, hypoglycemia Severe metabolic acidosis, ileus Severe lactic acidosis Lactic acidosis Severe metabolic acidosis Severe lactic acidosis, hypotension, Wernicke Severe metabolic acidosis Severe lactic acidosis
Severe lactic acidosis Severe lactic acidosis Severe lactic acidosis
Ozawa H, Nutrition, 200124 Cho YP, Hepatogastroenterology, 200425 Thauvin-Robinet C, JIMD, 20042
Oguz SS, J Ped Endocrinol Metab, 201126 Roll C, Monatsschr Kinderheilkd, 19927 Teysser G, Presse Med, 198628 Klein M, J Emerg Med, 200429 Nakasaki H, Nutrition 199730 Mansour AH, Eur J Radiol Extra, 200531
Shvan J, Clin Lab Observ, 20031 Mayatepek E, JIMD, 199932 Matern D, J Ped, 199633 Matern D, J Ped, 199633 Romanski SA, Mayo Clin Proc, 199934
ACCEPTED MANUSCRIPT RCU
Colectomia, TPN
11 years F
Vomiting, TPN
19 years M
chronic idiopathic intestinal pseudoobstruction syndrome Chronic colecystitis
72 years M
Thiamine deficient diet
67 years M
Chronic alcoholism
38 years F 35 years F 63 years M 66 years M 1 child
Alcoholism
Caustic ingestion
TPN
1 child
Leukemia
TPN
3 patients
Brain tumor
Chemotherapy, irradiation, (TPN)
6 patients
Alcoholism
3 patients
Wernicke
65 years F 60 years 2 years M
Gastric cancer, surgery
Poor feeding, TPN
2 years F
Blind-loop syndrome of proximal jejunum Nephroblastoma
8 years M
Lymphoma
3 years M 1 child
LLA LMA
Surgery, chilous ascites, TPN Chemotherapy, irradiation, surgery, malnutrition, TPN Chemotherapy, irradiation, surgery, malnutrition, TPN TPN BMT
Lactic acidosis, Wernicke Lactic acidosis, paralitic ileus Lactic acidosis, neurological, cardiovascular, digestive symptoms Lactic acidosis, neurological, cardiovascular, digestive symptoms Lactic acidosis Lactic acidosis
37 years 44 years 1 patient
Abdominal surgery
TPN
Lactic acidosis
Vomiting, TPN
Metabolic acidosis, shoshin Lactic acidosis, hyponatraemia, shoshin Lactic acidosis, heart failure Lactic acidosis, shoshin Lactic acidosis, shoshin Lactic acidosis, convulsions, hyponatraemia, rhabdomyolysis Lactic acidoiìsis, convulsions,
12 years F
Intestinal obstruction Heavy drink beer
1 patient
Alcoholism
1 patient
Alcoholism
1 patient
Alcoholism
1 patient
Alcoholism
CDC, MMWR, Morb Mort Wkly Rep, 199710 CDC, MMWR, Morb Mort Wkly Rep, 199710
Lactic acidosis, hyperammonemia Lactic acidosis
Pela I, Clin Nephrol, 200038
SC
Lactic acidosis, consciousness impairment Lactic acidosis, shoshin 1 with lactic acidosis
M AN U
Congestive heart failure
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AC C
1 patient
Surgery, TPN
Severe metabolic acidosis Metabolic acidosis, hypotension, Wernicke Lactic acidosis, Wernicke Lactic acidosis, Wernicke Lactic acidosis, heart failure, shoshin Lactic acidosis, Wernicke
TPN
CDC, MMWR, Morb Mort Wkly Rep, 199710 Essa E, J Cardiovasc Magn Reson, 201135 Reinhardt D, Praxis (Bern 1994), 201136 Donnino MW, Ann Emerg Med, 200737
RI PT
32 years M
Remond C, Ann FrAnesth Reanim, 199939 Kuba H, J Neurosurg, 199840
ter Maaten JC, Neth J Med, 199541 Heye N, Intensive Care Med, 199442 Kitamura K, Tokoku J Exp Med, 1993 43 Lange R, Em J Ped Surg, 199244 Rouzet P, Arch Fr Pediatr, 199145
Rouzet P, Arch Fr Pediatr, 199145 Oriot D, JPEN, 199111 Rovelli A, Haematologia, 199046 Klein G, Dtsch Med Wochenschr, 199047 Naidoo DP, S Afr Med, 198948 Delorme N, Presse Med, 198649 La Selve P, JPEN, 198650 Seedat YK, S Afr Med J, 198551 Thomas L, Presse Med, 198552 Thomas L, Presse Med, 198552
Thomas L, Presse Med, 198552
ACCEPTED MANUSCRIPT Vomiting, TPN
19 years M
Nasopharyngeal carcinoma
Chemotherapy (5FU), TPN
30 years M
Alcoholism
15 patients
Cerebral malaria
6 patients
Sepsis
X patients
Burn
7 patients
Lymphoma and chronic lymphocytic leukemia
Lactic acidosis Hyperlactatemia Lactic acidosis
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Thiamine deficient diet Thiamine deficiency Thiamine deficiency Thiamine deficiency
Kosarkoff Metabolic acidosis, shoshin Lactic acidosis, encephalopathy, vegetative instability, neuropathy Metabolic acidosis, hyponatraemia, shoshin Lactic acidosis
Attas M, Circulation, 197853 Rosen A, Case Rep Oncol, 201154
Engbers JG, Br Heart J, 198455 Krishna S, Lancet , 199956
RI PT
Alcoholism
SC
36 years M
Donnino MW, J Crit Care, 201057 Falder S, Burns, 201058 Friedenberg AS, Medicine (Baltimore), 200759
ACCEPTED MANUSCRIPT Supplementary references
2
23. Kondo K, Fujiwara M, Murase M, Kodera Y, Akiyama S, Ito K et al: Severe acute metabolic
3
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24. Ozawa H, Homma Y, Arisawa H, Fukuuchi F, Handa S: Severe metabolic acidosis and heart
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28. Teyssier G, Rayet I, Martin O, Damon G, Frappaz D: Carbohydrate infusion inducing lactic
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30. Nakasaki H, Ohta M, Soeda J, Makuuchi H, Tsuda M, Tajima T et al: Clinical and biochemical
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aspects of thiamine treatment for metabolic acidosis during total parenteralnutrition.
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encefalopathy in a child with leukemia. Eur J Radiol Extra 2005, 54: 43-45.
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32. Mayatepek E, Schulze A: Metabolic decompensation and lactic acidosis in propionic acidaemia
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complicated by thiamine deficiency. J Inherit Metab Dis 1999,22:189-90.
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33. Matern D, Seydewitz HH, Lehnert W, Niederhoff H, Leititis JU, Brandis M: Primary treatment
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ACCEPTED MANUSCRIPT 34. Romanski SA, McMahon MM: Metabolic acidosis and thiamine deficiency. Mayo Clin
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Wernicke's encephalopathy. Ann Emerg Med 2007,50:722-5.
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38. Pela I, Seracini D, Lavoratti GC, Sarti A: Efficacy of hemodiafiltration in a child with severe
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lactic acidosis due to thiamine deficiency. Clin Nephrol 2000,53:400-3.
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39. Rémond C, Viard L, Paut O, Giraud P, Camboulives J: Severe lactic acidosis and thiamine
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deficiency during parenteral nutrition in a child. Ann Fr Anesth Reanim 1999,18:445-50.
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40. Kuba H, Inamura T, Ikezaki K, Kawashima M, Fukui M: Thiamine-deficient lactic acidosis
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with brain tumor treatment. Report of three cases. J Neurosurg 1998,89:1025-8.
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41. ter Maaten JC, Hoorntje SJ, Hillen HF: Acute pernicious or fulminating beriberi heart disease.
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42. Heye N, Terstegge K, Sirtl C, McMonagle U, Schreiber K, Meyer-Gessner M: Wernicke's
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43. Kitamura K, Takahashi T, Tanaka H, Shimotsuma M, Hagiwara A, Yamaguchi T et al: Two
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cases of thiamine deficiency-induced lactic acidosis during total parenteral nutrition. Tohoku J Exp
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Med 1993,171:129-33.
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44. Lange R, Erhard J, Eigler FW, Roll C: Lactic acidosis from thiamine deficiency during
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parenteral nutrition in a two-year-old boy. Eur J Pediatr Surg 1992,2:241-4.
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45. Rouzet P, Rubie H, Robert A, Dutour A, Olives JP, Scipioni C et al: Severe hyperlactacidemia in
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2 children treated for malignant tumors. Role of vitamin B1. Arch Fr Pediatr 1991,48:423-6.
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ACCEPTED MANUSCRIPT 46. Rovelli A, Bonomi M, Murano A, Locasciulli A, Uderzo C: Severe lactic acidosis due to
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thiamine deficiency after bone marrow transplantation in a child with acute monocytic leukemia.
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Haematologica 1990,75:579-81.
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47. Klein G, Behne M, Probst S, Dudziak R, Förster H, Asskali F: Life-threatening lactic acidosis
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during total parenteral nutrition. Successful therapy with thiamine. Dtsch Med
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Wochenschr 1990,115:254-6.
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48. Naidoo DP, Singh B, Haffejee A, Aitcheson J, Barker EM: Acute pernicious beriberi in a
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patient receiving parenteral nutrition. A case report. S Afr Med J 1989,75:546-548.
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49. Delorme N, Cornette A, Maurin P, Polu JM, Sadoul P: Shoshin beriberi with hyponatremia in a
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beer drinker. Presse Med 1986,15:2005-9.
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50. La Selve P, Demolin P, Holzapfel L, Blanc PL, Teyssier G, Robert D: Shoshin beriberi: an
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unusual complication of prolonged parenteral nutrition. JPEN J Parenter Enteral Nutr 1986,10:102-
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3.
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51. Seedat YK, Cassim B, Dyer R: Acute pernicious or fulminating beriberi with severe lactic
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acidosis. A case report. S Afr Med J 1985,68:817-8.
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52. Thomas L, Fay D, Moraillon X, Delubac G, Berthet P, Demingeon G: Lactic acidosis treated
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with thiamine. 3 cases. Presse Med 1985,14:1871-5.
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53. Attas M, Hanley HG, Stultz D, Jones MR, McAllister RG: Fulminant beriberi heart disease with
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lactic acidosis: presentation of a case with evaluation of left ventricular function and review of
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pathophysiologic mechanisms. Circulation 1978,58:566-72.
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54. Rosen A, van Kuilenburg A, Assmann B, Kuhlen M, Borkhardt A: Severe encephalopathy,
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lactic acidosis, vegetative instability and neuropathy with 5-Fluorouracil treatment - pyrimidine
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degradation defect or beriberi? Case Rep Oncol 2011,4:371-6.
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55. Engbers JG, Molhoek GP, Arntzenius AC: Shoshin beriberi: a rare diagnostic problem. Br Heart
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J 1984,51:581-2.
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ACCEPTED MANUSCRIPT 56. Krishna S, Taylor AM, Supanaranond W, Pukrittayakamee S, ter Kuile F, Tawfiq KM et al:
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Thiamine deficiency and malaria in adults from southeast Asia.
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Lancet 1999,353:546-9.
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57. Donnino MW, Carney E, Cocchi MN, Barbash I, Chase M, Joyce N et al: Thiamine deficiency
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in critically ill patients with sepsis. J Crit Care 2010,25:576-81.
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58. Falder S, Silla R, Phillips M, Rea S, Gurfinkel R, Baur E et al: Thiamine supplementation
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increases serum thiamine and reduces pyruvate and lactate levels in burn patients.
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Burns 2010,36:261-9.
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85
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59. Friedenberg AS, Brandoff DE, Schiffman FJ: Type B lactic acidosis as a severe metabolic complication in lymphoma and leukemia: a case series from a single institution and literature
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review. Medicine (Baltimore) 2007,86:225-32.
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S0899-9007(14)00124-5
DOI:
10.1016/j.nut.2014.02.019
Reference:
NUT 9237
To appear in:
Nutrition
Received Date: 26 December 2013 Revised Date:
18 February 2014
Accepted Date: 19 February 2014
Please cite this article as: Maiorana A, Vergine G, Coletti V, Luciani, M, Rizzo C, Emma F, DionisiVici, C, Acute thiamine deficiency and refeeding syndrome: similar findings but different pathogenesis, Nutrition (2014), doi: 10.1016/j.nut.2014.02.019. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. 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.
ACCEPTED MANUSCRIPT 1
Acute thiamine deficiency and refeeding syndrome: similar findings but different
2
pathogenesis.
3
Arianna Maiorana1, MD, PhD, Gianluca Vergine2, MD, Valentina Coletti3, MD, Matteo
4
Luciani3,MD, Cristiano Rizzo1, MD, Francesco Emma2, MD, Carlo Dionisi-Vici1,MD.
8 9 10
Department of Pediatric Medicine, Division of Metabolism and Research Unit of Metabolic
Biochemistry; 2
Department of Nephrology & Urology, Division of Nephrology and Dialysis;
3
Department of Hematology and Oncology, Division of Hematology, Bambino Gesù
Children’s Hospital and Research Institute, Rome, Italy.
11 12
Running head: Proximal tubular dysfunction in thiamine deficiency.
13
Authors' contribution
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AM conceptualized and designed the study, carried out data collection and analyses, drafted
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the initial manuscript, reviewed and approved the final manuscript as submitted. GV carried
17
out the initial analyses, drafted the initial manuscript, and approved the final manuscript as
18
submitted. VC performed the data collection, participated in its design and coordination and
19
helped to draft the manuscript. ML performed the data collection, participated in its design
20
and coordination and approved the final manuscript as submitted. CR carried out the
21
instrumental data analyses, participated to the interpretation of data and participated in its
22
design. and coordination and helped to draft the manuscript. FE participated in its design and
23
coordination and critically reviewed the manuscript and approved the final manuscript as
24
submitted. CDV designed the data collection instruments, coordinated and supervised data
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ACCEPTED MANUSCRIPT 25 26
collection, critically reviewed the manuscript and approved the final manuscript as submitted. All authors read and approved the final manuscript.
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Word count 2545
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Figures 3
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Tables 1
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Address correspondence to: Arianna Maiorana, Department of Pediatric Medicine, Division
33
of Metabolism, Bambino Gesù Children’s Hospital, piazza S. Onofrio 4, 00165, Rome, Italy,
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phone number +390668592275, fax number +390668592791, email
35
[email protected]
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Abstract Objective: Refeeding syndrome can occur in several contexts of relative malnutrition in which an overaggressive nutritional support is started. The consequences are life-threatening
53
with multiorgan impairment, and severe electrolyte imbalances. During refeeding, glucose-
54
involved insulin secretion causes abrupt reverse of lipolysis and a switch from catabolism to
55
anabolism. This creates a sudden cellular demand of electrolytes (phosphate, potassium and
56
magnesium) necessary for ATP synthesis, glucose transport and other synthesis reactions,
57
resulting in decreased serum levels. Laboratory findings and multiorgan impairment similar to
58
refeeding syndrome are also observed in acute thiamine deficiency.
59
Methods: We describe two patients with leukemia who developed acute thiamine deficiency
60
with an electrolyte pattern suggestive of refeeding syndrome, severe lactic acidosis and
61
evidence of proximal renal tubular dysfunction.
62
Results: A single thiamine administration led to rapid resolution of the tubular dysfunction
63
and normalization of acidosis and electrolytes imbalance. This demonstrated that thiamine
64
deficiency was responsible for the electrolyte imbalance, caused by tubular electrolytes losses.
65
Conclusions: Our report indicates that, despite sharing many laboratory similarities, refeeding
66
syndrome and acute thiamine deficiency should be viewed as separate entities in which the
67
electrolyte abnormalities reported in cases of refeeding syndrome with thiamine deficiency
68
and refractory lactic acidosis may be due to a renal tubular losses instead of a shifting from
69
extracellular to intracellular compartment. In oncologic and malnourished patients, categories
70
at particular risk of developing refeeding syndrome, in presence of these biochemical
71
abnormalities, acute thiamine deficiency should be suspected and treated, because it promptly
72
responds to thiamine administration.
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ACCEPTED MANUSCRIPT 74
Key words: lactic acidosis, thiamine, methotrexate, renal tubular dysfunction,
75
hypophosphatemia, refeeding syndrome.
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Introduction Thiamine deficiency can occur in anorexia nervosa, in leukemia/cancer [1], in patients
101
receiving unsupplemented total parenteral nutrition (TPN) [2], in children fed with defective
102
soy-based infant formulas [3], or in chronic alcohol abuse [4]. Clinical features of thiamine
103
deficiency include neurological, cardiovascular and metabolic manifestations [2].
104
Furthermore, acute thiamine deficiency has been considered a component of the refeeding
105
syndrome (RS), a potentially lethal condition characterized by severe electrolyte and fluid
106
imbalance [5]. RS was originally described in grossly malnourished prisoners released from
107
concentration camps during the Second World War who presented heart failure, neurological
108
complications with convulsions and coma following refeeding [5,6]. RS characteristically
109
occurs when malnourished and starved subjects receive high carbohydrate feeding causing a
110
sudden change of the energy sources, from fat to carbohydrates, which causes a sustained
111
increase in insulin secretion. The insulin action induces a sudden shift of salt from
112
extracellular to intracellular compartment. The laboratory hallmark of RS is
113
hypophosphatemia; additional features include reduced plasma potassium and magnesium
114
levels, hyperglycemia, metabolic acidosis, along with sodium and water retention causing
115
fluid overload [4,7,8]. The consequences of these severe changes can be life-threatening.
116
Conditions at high risk include recent weight loss, secondary to poor caloric intake or nutrient
117
losses [8]. Patients with malignancy are at particular risk of developing RS because they
118
frequently develop malnutrition and are depleted of micronutrients and electrolytes as a
119
consequence of their treatment. An excessive parenteral carbohydrate supply may act as a
120
trigger for RS, especially if glucose supply is not adequately supplemented with vitamins and
121
oligoelements [4,9]. Interestingly, laboratory findings similar to RS are also observed in
122
acute thiamine deficiency [1]. We report on two children with leukemia who developed acute
123
thiamine deficiency and showed an electrolyte pattern of RS, whose pathogenetic mechanism
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ACCEPTED MANUSCRIPT 124
was due to a severe proximal renal tubular dysfunction which promptly responded to thiamine
125
administration.
126
Case reports
128
Case 1
129
This female patient presented at 5 months of age with intestinal bleeding, severe anemia, and
130
thrombocytopenia leading to the diagnosis of B-cell leukemia. She was enrolled in the
131
International Collaborative Treatment Protocol for Children under one year of age
132
(INTERFANT 2006). During consolidation phase, few days after the first administration of
133
i.v. high dose Methotrexate 5000 mg/m2, the child presented with diarrhea and vomiting
134
treated by parenteral hydration with 5% glucose saline solution for a week. A complete
135
parenteral nutrition support (TPN) with glucose concentration of 33% was started on the
136
following day (day 0), when a second dose of i.v. Methotrexate 5000 mg/m2 was
137
administered. Feeding difficulties persisted and TPN was continued. On day 19th, clinical
138
conditions further deteriorated with appearance of tachypnoea and lethargy. Blood gas
139
analysis revealed severe metabolic acidosis (pH 6.9, normal value 7.32-7.48; BE –25
140
mEq/L, nv -2/+3; HCO3- 5 mEq/L), high anion gap (21mEq/L), hyperlactatemia (13.3
141
mMol/L, nv 0.4-2.2, 120 mg/dl, nv 4-20 ), and moderate hyperglycemia (158 mg/dl). Further
142
laboratory findings showed severe hypophosphatemia (0.9 mg/dl), hypokalemia (2.5 mEq/L)
143
and hypomagnesemia (1.4 mg/dl). As shown in Table 1, mineral and electrolyte imbalance
144
was consistent with a proximal tubular dysfunction with renal loss of phosphate, magnesium
145
and potassium. Despite intravenous administration of large dose bicarbonate, up to 10
146
mEq/kg, and electrolyte supplementation, clinical conditions and severe metabolic acidosis
147
and electrolyte imbalance further deteriorated. Continuous veno-venous hemofiltration
148
(CVVH) was started on day 20th but caused only slight improvement. On day 21st,
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ACCEPTED MANUSCRIPT examination of urinary organic acids showed a characteristic pattern as seen in thiamine
150
deficiency [1] (Figure 1). Soon after 300 mg thiamine administration, we observed an almost
151
immediate improvement of clinical conditions with complete normalization of metabolic
152
acidosis within 3 hours (Figure 2). In the following 24-48 hours, blood electrolyte
153
abnormalities fully recovered with normalization of blood lactate and of urine organic acid
154
profile. Proximal tubular dysfunction completely resolved in the following days (Table 1).
155
Case 2
156
Acute myeloid leukemia was diagnosed at the age of 9 years in this male patient who was
157
enrolled in the Italian Protocol AIEOP LAM 2002. During the first chemotherapy course, he
158
developed persistent vomiting requiring TPN with a 33% glucose concentration (day 0). On
159
day 19th, he suddenly developed mental status changes, hypothermia, hypotension and
160
tachypnoea. Cerebral magnetic resonance imaging (MRI) showed bilateral high-intensity
161
signals of basal ganglia. Blood gas analysis revealed severe metabolic acidosis (pH 6.8, BE
162
–29 mEq/L, HCO3- 3 mEq/L, anion gap 35 mEq/L), hyperlactatemia (15.5 mMol/L, 140
163
mg/dl), and hyperglycemia (270 mg/dl). Further laboratory findings showed
164
hypophosphatemia (1.2 mg/dl), hypokalemia (2.4 mEq/L) and hypomagnesemia (1.2 mg/dl).
165
Similarly to patient 1, urinary investigation showed evidence of proximal renal tubular
166
dysfunction (Table 1). Attempts to correct metabolic acidosis with iv sodium bicarbonate
167
were ineffective. Reviewing of TPN prescription showed that vitamin supplementation was
168
missed. Thiamine deficiency was confirmed by analysis of plasma levels (30 nmol/L, normal
169
66.5-200) and by analysis of urinary organic acids which showed a characteristic profile.
170
Three hours after administration of 300 mg thiamine, metabolic acidosis disappeared;
171
electrolyte abnormalities and renal tubular dysfunction fully recovered within 5 days (Table
172
1).
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173
7
ACCEPTED MANUSCRIPT Discussion
175
Malnourished patients presenting with acute illnesses receiving parenteral hydration with
176
high concentration glucose solutions or treated with enteral or parenteral nutrition without
177
adequate vitamin supplementation, are at high risk for developing the RS [1,5,7,10,11].
178
Thiamine deficiency which is often listed among the causes of RS, may cause metabolic,
179
neurologic and cardiovascular symptoms, similar to RS [12]. As frequently observed in
180
children with leukemia receiving chemotherapy, our two patients before manifesting acute
181
thiamine deficiency, presented severe and protracted gastrointestinal signs with poor food
182
intake. In addition, one was treated with high doses of methotrexate, a drug which competes
183
with cell thiamine transport systems [13], and the second erroneously received
184
unsupplemented TPN. Thiamine deficiency was confirmed by serum thiamine measurement
185
in one patient and by the finding of characteristic metabolic changes in both children (i.e.
186
lactic acidosis combined with a specific urine organic acids profile). Besides these changes,
187
both patients showed an electrolyte pattern in blood very similar to what observed in RS
188
[10,11]. During refeeding, carbohydrate intake stimulates insulin secretion and reverts
189
catabolism to anabolism, creating a sudden demand of inorganic phosphate for ATP synthesis,
190
of potassium for intracellular glucose transport, of magnesium for synthesis reactions and of
191
thiamine for carbohydrate and aminoacids oxidation [9]. Interestingly, similar electrolyte
192
disturbances can be observed in patients with poorly controlled diabetes mellitus, a condition
193
with low insulin levels [14], suggesting that alternative mechanisms can be responsible for
194
these electrolyte imbalances. In our patients we had clear evidence of severe renal tubular
195
dysfunction, causing urinary losses of phosphate, potassium and magnesium. Hypokalemia
196
[1,10] and hypophosphatemia [1] have been reported in patients with lactic acidosis due to
197
thiamine deficiency however, tubular function has not been investigated in these cases [1]. In
198
thiamine deficiency, the cytosolic conversion of pyruvate into lactate by anaerobic
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8
ACCEPTED MANUSCRIPT metabolism causes lactic acidosis. The presence of hypophosphatemia, hypokalemia and
200
hypomagnesemia in our patients can be therefore interpreted as the consequence of an energy
201
deprivation affecting renal tubular cells.
202
Thiamine is not stored in appreciable amounts in cells, has a short half-life and cell stores are
203
usually depleted within 20 days of malnutrition [12]. Abrupt increase of carbohydrate
204
oxidation may precipitate acute deficiency since accelerates the consumption of residual
205
thiamine stores [4]. Remarkably, our patients developed acute thiamine deficiency
206
approximately 20 days after starting TPN. In one patient vitamin supplementation was found
207
not being included in his TPN solution whereas in the other patient receiving high dose
208
metotrexate, the TPN contained a standard thiamine dose, which is approximately 100 times
209
lower than the amount required in case of thiamine deficiency [12].
210
Thiamine is the cofactor of pyruvate dehydrogenase, branched-chain α-ketoacids
211
dehydrogenase, transketolase and α-ketoglutarate dehydrogenase. These enzymes are
212
involved in acetyl-CoA formation, in branched-chain aminoacids catabolism, in connecting
213
the pentose phosphate pathway to glycolysis, and in Krebs cycle, respectively. When
214
thiamine is deficient, a combined enzymatic defect occurs, as reflected by the
215
characteristic organic acid pattern [1], causing Krebs cycle and ATP synthesis impairment
216
[12]. In this view, thiamine deficiency may cause disruption of renal tubular function,
217
resulting in decreased reabsorption of electrolytes as a consequence of impaired tubular ATP-
218
dependent transport systems [15,16]. The dramatic response to a single thiamine dose
219
supports this concept. Since through transketolase activity thiamine plays a pivotal role in
220
protecting against oxidative stress[17,18], in thiamine deficiency the insufficient ATP
221
generation combined with toxic effects of reactive oxygen species can lead to acute tubular
222
necrosis (ATN) through an ischaemia-reperfusion injury [19]. It can be therefore concluded
223
that the urinary electrolyte losses in our patients is the result of an early phase of tubular
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9
ACCEPTED MANUSCRIPT impairment caused by thiamine deficiency. Not surprisingly, the most frequent renal finding
225
in disorders of mitochondrial oxidative phosphorylation is a proximal tubular defect [20,21].
226
Interestingly, the development of ATN has been described as part of a RS, in one patient [22].
227
Our report indicates that, despite sharing many laboratory similarities, RS and acute thiamine
228
deficiency should be viewed as separate entities. It is possible that electrolyte abnormalities
229
reported in cases of RS with thiamine deficiency and refractory lactic acidosis may be due to
230
a renal tubular losses instead of a shifting from extracellular to intracellular compartment. In
231
this view, hypophosphatemia, hypokalemia and hypomagnesemia in RS without lactic
232
acidosis are most likely caused by an imbalance between intra- and extra-cellular
233
compartments, whereas in presence of lactic acidosis these changes are more likely secondary
234
to renal tubular losses caused by thiamine deficiency (Figure 3). Many reports concerning
235
thiamine deficiency and development of refractory lactic acidosis along with neurological,
236
cardiovascular and intestinal manifestations are described (Supplementary Table 2).
237
Therefore, when such conditions are associated to severe lactic acidosis, a thiamine deficiency
238
should be suspected.
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239
Conclusions
241
Oncologic and malnourished patients should be carefully monitored in order to avoid severe
242
electrolyte abnormalities related to thiamine deficiency, a life threatening condition that, if
243
promptly recognized, dramatically responds to thiamine administration. However, further
244
studies with a higher number of patients are necessary to support our findings.
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245 246
Acknowledgements
247
AM conceptualized and designed the study, carried out data collection and analyses, drafted
248
the initial manuscript, reviewed and approved the final manuscript as submitted. GV carried
10
ACCEPTED MANUSCRIPT out the initial analyses, drafted the initial manuscript, and approved the final manuscript as
250
submitted. VC performed the data collection, participated in its design and coordination and
251
helped to draft the manuscript. ML performed the data collection, participated in its design
252
and coordination and approved the final manuscript as submitted. CR carried out the
253
instrumental data analyses, participated to the interpretation of data and participated in its
254
design. and coordination and helped to draft the manuscript. FE participated in its design and
255
coordination and critically reviewed the manuscript and approved the final manuscript as
256
submitted. CDV conceptualized and designed the study, designed the data collection
257
instruments, coordinated and supervised data collection, critically reviewed the manuscript
258
and approved the final manuscript as submitted. All authors read and approved the final
259
manuscript. The authors declare that they have no competing interests.
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260 261
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266 267 268 269
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ACCEPTED MANUSCRIPT References
275
1. Svahn J, Schiaffino MC, Caruso U, Calvillo M, Minniti G, Dufour C: Severe lactic acidosis
276
due to thiamine deficiency in a patient with B-cell leukemia/lymphoma on total parenteral
277
nutrition during high-dose methotrexate therapy. J Pediatr Hematol Oncol 2003, 25:965-968.
278
2. Thauvin-Robinet C, Faivre L, Barbier ML, Chevret L, Bourgeois J, Netter JC et al: Severe
279
lactic acidosis and acute thiamine deficiency: a report of 11 neonates with unsupplemented
280
total parenteral nutrition. J Inherit Metab Dis 2004, 27:700-704.
281
3. Fattal-Valevski A, Kesler A, Sela BA, Nitzan-Kaluski D, Rotstein M, Mesterman R et al:
282
Outbreak of life-threatening thiamine deficiency in infants in Israel caused by a defective soy-
283
based formula. Pediatrics 2005, 115: e233-238. doi:10.1542/peds.2004-1255.
284
4. Stanga Z, Brunner A, Leuenberger M, Grimble RF, Shenkin A, Allison SP et al: Nutrition
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in clinical practice-the refeeding syndrome: illustrative cases and guidelines for prevention
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and treatment. Eur J Clin Nutr 2008, 62:687-694.
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5. Boateng AA, Sriram K, Meguid MM, Crook M: Refeeding syndrome: Treatment
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considerations based on collective analysis of literature case reports. Nutrition 2010,
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26:156-167.
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6. Burger GCE, Drummond JC, Sandstead HR: Malnutrition and Starvation in Western
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Netherlands, September 1944- July 1945. General State Printing Office: The Hague, 1948.
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7. Panteli JV, Crook MA. Refeeding syndrome still needs to be recognized and
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managed appropriately. Nutrition 2009, 25:130-131.
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8. Mehanna HM, Moledina J, Travis J: Refeeding syndrome: what it is, and how to prevent
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and treat it. BMJ 2008, 336:1495-1498.
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9. Crook MA, Hally V, Panteli JV: The importance of the refeeding syndrome. Nutrition
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2001, 17:632-637.
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ACCEPTED MANUSCRIPT 10. Centers for Disease Control and Prevention (CDC): Lactic acidosis traced to thiamine
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deficiency related to nationwide shortage of multivitamins for total parenteral nutrition --
300
United States, 1997. MMWR Morb Mortal Wkly Rep 1997, 46:523-528.
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11. Oriot D, Wood C, Gottesman R, Huault G: Severe lactic acidosis related to acute thiamine
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deficiency. J Parenter Enteral Nutr 1991, 15:105-109.
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12. Sriram K, Manzanares W, Joseph K: Thiamine in nutrition therapy. Nutr Clin Pract 2012,
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27:41-50.
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13. Zhao R, Gao F, Wang Y, Diaz G, Gelb B, Goldman I: Impact of the reduced folate carrier
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on the accumulation of active thiamine metabolites in murine leukemia cells. J Biol Chem
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2001, 276:1114-1118.
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14. Matz R: Parallels between treated uncontrolled diabetes and the refeeding syndrome with
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emphasis on fluid and electrolyte abnormalities. Diabetes Care 1994, 17:1209-1213.
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15. Skou JC, Norby JG: Na+-K+-ATPase structure and kinetics. New York Academie Press
311
Inc. New York, 1979, 549 pp.
312
16. Green M, Ruiz OS, Kear F, Arruda JA: Dual effect of cyclic GMP on renal brush border
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Na-H antiporter. Proc Soc Exp Biol Med 1991, 198:846-851.
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17. Beltramo E, Berrone E, Tarallo S, Porta M: Effects of thiamine and benfotiamine on
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intracellular glucose metabolism and relevance in the prevention of diabetic complications.
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Acta Diabetol 2008, 45:131-141.
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18. Thornalley PJ: The potential role of thiamine (vitaminB1) in diabetic complications. Curr
318
Diabetes Rev 2005, 1:287-298.
319
19. Klooster A, Leuvenink HG, Gans RO, Bakker SJ: Tissue thiamine deficiency as potential
320
cause of delayed graft function after kidney transplantation: thiamine supplementation of
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kidney donors may improve transplantation outcome. Med Hypotheses 2007, 69:873-878.
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20. Rotig A: Renal disease and mitochondrial genetics. J Nephrol 2003, 16:286-292.
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21. Emma F, Montini G, Salviati L, Dionisi-Vici C: Renal mitochondrial cytopathies. Int J
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Nephrol 2011, 609213.doi: 10.4061/2011/609213.
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22. Marinella MA: The refeeding syndrome and hypophosphatemia. Nutr Rev 2003, 61:320-
326
323.
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332 333 334 335
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340 341 342 343
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344 345 346 347
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ACCEPTED MANUSCRIPT 348
Legends
349
Table 1. Results of blood and urinary laboratory tests before and after thiamine
351
administration.
352
AG: anion gap (normal value 10-14) calculated by the formula Na – (HCO3- + Cl) (not
353
corrected for abumin levels); Nas: serum sodium level (normal value 136-145); FeNa:
354
urinary fractional sodium excretion (normal value 1%); Mgs: serum magnesium level (normal
355
value 1.7-2.3); FeMg: urinary fractional magnesium excretion (normal value 85%); Ks: serum potassium level (normal value 3.5-5.1); TTKG: trans-tubular
358
potassium gradient (normal value 6-11); HCO3- 5 mEq/L n.v. 19-27; Glycemia normal value
359
60-110 mg/dl. Lactate normal value 0.4-2.2 mMol/L.
M AN U
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360
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361 362
365 366 367 368
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369 370 371
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ACCEPTED MANUSCRIPT Figure 1. Urinary organic acids profile in thiamine deficiency. Thiamine is cofactor of
373
piruvate dehydrogenase complex, 2-ketoglutatrate dehydrogenase complex and branched-
374
chain α-ketoacid dehydrogenase complex. These enzymatic complexes catalyze the hydrolysis
375
of the α-ketoacids which enter the Krebs cycle for their complete oxidation and ATP
376
generation. Thiamine deficiency provokes accumulation of urinary α-ketoacids along with
377
lactate, pyruvate, 2-hydroxybutyrate and 2-hydroxyisovalerate.
378
1. Lactic acid; 2. 2-OH-butyric acid; 3. Pyruvic acid; 4. 2-OH-isovaleric acid; 5. 2-keto-
379
butyric acid; 6. 2-keto-isovaleric acid; 7. 2-keto-3-methyl-valeric acid; 8. 2-keto-isocaproic
380
acid; 9. 2-keto-glutaric acid; 10. 2-keto-adipic acid; IS1 (Internal standard1) 2-phenylbutyric
381
acid; IS2 (Internal standard2) tricarballylic acid.
M AN U
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382 383
Figure 2. Early effect of thiamine administration on metabolic acidosis. Plasma pH and
384
bicarbonates returned to normal within three hours from thiamine administration.
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Figure 3. Speculative mechanisms of intracellular plasma electrolytes depletion. In
387
continuous lines, electrolytes imbalance is explained as intracellular shift of electrolytes
388
caused by the action of insulin, acutely released after carbohydrates administration. In dotted
389
lines, thiamine deficiency provokes Krebs cycle impairment in tubular cells with metabolic
390
acidosis and urinary losses of electrolytes.
391
PDH: piruvate dehydrogenase; α-KGDH: α- ketoglutarate dehydrogenase; BKDH: branched
392
chain α-ketoacids dehydrogenase; TK: transketolase.
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393 394 395 396
16
ACCEPTED MANUSCRIPT 397
Supplementary materials
398
Table 2. Thiamine deficiency and lactic acidosis. M: male; F: female: TPN: total parenteral
400
nutrition; BMT: bone marrow transplantation; 5-FU: 5-flurouracil; LLA: acute lymphoblastic
401
leukemia; LMA: acute myeloblastic leukemia; Shoshin: acute pernicious or fulminating
402
beriberi heart disease.
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403
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Supplementary references of Table 2
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17
ACCEPTED MANUSCRIPT Table 1. Results of blood and urinary laboratory tests before and after thiamine administration. Case 1 AG (mEq/L) 21 ↑ 35 ↑
Lactate (mMol/L) 13.3 14.4
Glycemia (mg/dl) 158 ↑ 137 ↑
Nas (mEq/L) 132 ↓ 135 ↓
FeNa (%) 5↑ 11 ↑
FeMg Mgs (mEq/L) (%) 1.4 ↓ 4.8 ↑ 1.2 ↓ 8.6 ↑
1.6
115 90
137 142
1
2 1.7
3
15.5 14.9
270 ↑ 160 ↑
134 ↓ 134 ↓
10 ↑ 8↑
1.2↓ 1.1↓
5.2 ↑ 6.7 ↑
2.2
99 90
136 142
1
15
35 ↑ 31 ↑ 14
1.6 1.7
M AN U
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3↓ 5↓ thiamine 37 ↑
AC C
Day 19 Day 20 Day 21 3hrs later Day 23 Day 29
3
TRP (%) 59 ↓ 40 ↓
TTKG Ks (mEq/L) 2.3 ↓ 12.5 ↑ 2.8 ↓ 20 ↑
3.5 4
95
3.9 4
7.5
1.2 ↓ 1.6 ↓
65↓ 60 ↓
2.5 ↓ 2.4 ↓
20 ↑ 25 ↑
3.3 4
95
3.6 4
7.5
SC
Case 2
Ps (mg/dl) 1.2 ↓ 0.9 ↓
RI PT
Day 19 Day 20 Day 21 3hrs later Day 23 Day 29
HCO3(mEq/L) 5↓ 11 ↓ thiamine 32 ↑
ACCEPTED MANUSCRIPT PDH sub E3 8
1.9e+07
1
1.8e+07 1.7e+07 1.6e+07
2
3
10 IS1
4
9
IS2
6
1.5e+07
RI PT
1.4e+07 1.3e+07 1.2e+07
7
1.1e+07 1e+07
5
9000000
SC
8000000 7000000 6000000
4000000 3000000 2000000 1000000 10.00
15.00
20.00
Time-->
AC C
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Figure 1
M AN U
5000000
25.00
30.00
35.00
M AN U
SC
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ACCEPTED MANUSCRIPT
AC C
EP
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Figure 2
ACCEPTED MANUSCRIPT
REFEEDING SYNDROME
ACUTE THIAMINE DEFICIENCY
Fasting/malnutrition Lipid/protein catabolism/insulin suppression
GLUCOSE
RI PT
Thiamine poor intake/ increased consumption/ impaired transport
Blockade of PDH, α-KGDH, BKDH, TK
Increased insulin secretion
SC
Energy deprivation
Intracellular shift of PO43-, K+, Mg2+ Hypophosphatemia Hypokalemia Hypomagnesemia
Urinary losses of PO43-, K+, Mg2+ Hypophosphatemia Hypokalemia Hypomagnesemia
AC C
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Figure 3
M AN U
Proximal tubular dysfunction
Lactic acidosis
ACCEPTED MANUSCRIPT Table 2. Thiamine deficiency and lactic acidosis Underlying condition
Precipitating cause
Clinical signs
Reference
30 years F
Severe obesity
Gastric bypass, vomiting
Stanga Z, Em J Clin Nutr, 20084
28 years F
Gastric carcinoma
9 infants 2,5-12 months
Healthy
Esophageal stenosis with disphagia, TPN, chemotherapy CDDP (5FU) Defective soybased infant formula
Lactic acidosis, pulmonary oedema, cardiomegaly, hypophosphatemia, hypokalemia Metabolic acidosis, deafness, ataxia, confusion, hypotension
Fattal-Valevski A, Pediatrics, 20053
1 patient M
Thiamine deficient diet
Severe dyspnea
1 patient M
Pancreatic cancer
Surgery, TPN
Lactic acidosis, vomiting, diarrhea, abdominal distension, lethargy, irritability, ophtalmoplegia, developmental delay, nystagmus, respiratory symptoms, failure to thrive Metabolic acidosis, heart failure Lactic acidosis
11 newborns
Vascular enteropathy, bowel angiomatosis, enterocolitis, bowel intolerance
TPN
Pre-term newborn
Hirschprung's disease
Biliar vomiting, feeding problems, surgery, TPN TPN
1 patient 6 patients 11 years M
11 months F
Malnutrition, severe dehydration, Thiamine deficient diet
AC C
1 month
Digestive disease Leukemia
3 years F
B cell leukemia/lymphoma, Propionic acidemia
1 newborn 2 months
Propionic acidemia Propionic acidemia
19 years M
Glucose infusion Weakness, lower limb oedema TPN Herpetic esophagitis, gastritis, vomiting, TPN Chemotherapy, stomatitis ,TPN Recurrent vomiting, TPN Paralitic ileus Recurrent vomiting, TPN TPN
Kondo K, Jpn J Clin Oncol, 199623
SC
M AN U
TE D
EP
2 years M
RI PT
Patients (age and sex)
Severe lactic acidosis, hypotension, vomting, agitation, hypotonia, lethargy, tachipnoea, tachycardia Severe metabolic acidosis, sepsi, hypoglycemia Severe metabolic acidosis, ileus Severe lactic acidosis Lactic acidosis Severe metabolic acidosis Severe lactic acidosis, hypotension, Wernicke Severe metabolic acidosis Severe lactic acidosis
Severe lactic acidosis Severe lactic acidosis Severe lactic acidosis
Ozawa H, Nutrition, 200124 Cho YP, Hepatogastroenterology, 200425 Thauvin-Robinet C, JIMD, 20042
Oguz SS, J Ped Endocrinol Metab, 201126 Roll C, Monatsschr Kinderheilkd, 19927 Teysser G, Presse Med, 198628 Klein M, J Emerg Med, 200429 Nakasaki H, Nutrition 199730 Mansour AH, Eur J Radiol Extra, 200531
Shvan J, Clin Lab Observ, 20031 Mayatepek E, JIMD, 199932 Matern D, J Ped, 199633 Matern D, J Ped, 199633 Romanski SA, Mayo Clin Proc, 199934
ACCEPTED MANUSCRIPT RCU
Colectomia, TPN
11 years F
Vomiting, TPN
19 years M
chronic idiopathic intestinal pseudoobstruction syndrome Chronic colecystitis
72 years M
Thiamine deficient diet
67 years M
Chronic alcoholism
38 years F 35 years F 63 years M 66 years M 1 child
Alcoholism
Caustic ingestion
TPN
1 child
Leukemia
TPN
3 patients
Brain tumor
Chemotherapy, irradiation, (TPN)
6 patients
Alcoholism
3 patients
Wernicke
65 years F 60 years 2 years M
Gastric cancer, surgery
Poor feeding, TPN
2 years F
Blind-loop syndrome of proximal jejunum Nephroblastoma
8 years M
Lymphoma
3 years M 1 child
LLA LMA
Surgery, chilous ascites, TPN Chemotherapy, irradiation, surgery, malnutrition, TPN Chemotherapy, irradiation, surgery, malnutrition, TPN TPN BMT
Lactic acidosis, Wernicke Lactic acidosis, paralitic ileus Lactic acidosis, neurological, cardiovascular, digestive symptoms Lactic acidosis, neurological, cardiovascular, digestive symptoms Lactic acidosis Lactic acidosis
37 years 44 years 1 patient
Abdominal surgery
TPN
Lactic acidosis
Vomiting, TPN
Metabolic acidosis, shoshin Lactic acidosis, hyponatraemia, shoshin Lactic acidosis, heart failure Lactic acidosis, shoshin Lactic acidosis, shoshin Lactic acidosis, convulsions, hyponatraemia, rhabdomyolysis Lactic acidoiìsis, convulsions,
12 years F
Intestinal obstruction Heavy drink beer
1 patient
Alcoholism
1 patient
Alcoholism
1 patient
Alcoholism
1 patient
Alcoholism
CDC, MMWR, Morb Mort Wkly Rep, 199710 CDC, MMWR, Morb Mort Wkly Rep, 199710
Lactic acidosis, hyperammonemia Lactic acidosis
Pela I, Clin Nephrol, 200038
SC
Lactic acidosis, consciousness impairment Lactic acidosis, shoshin 1 with lactic acidosis
M AN U
Congestive heart failure
TE D
EP
AC C
1 patient
Surgery, TPN
Severe metabolic acidosis Metabolic acidosis, hypotension, Wernicke Lactic acidosis, Wernicke Lactic acidosis, Wernicke Lactic acidosis, heart failure, shoshin Lactic acidosis, Wernicke
TPN
CDC, MMWR, Morb Mort Wkly Rep, 199710 Essa E, J Cardiovasc Magn Reson, 201135 Reinhardt D, Praxis (Bern 1994), 201136 Donnino MW, Ann Emerg Med, 200737
RI PT
32 years M
Remond C, Ann FrAnesth Reanim, 199939 Kuba H, J Neurosurg, 199840
ter Maaten JC, Neth J Med, 199541 Heye N, Intensive Care Med, 199442 Kitamura K, Tokoku J Exp Med, 1993 43 Lange R, Em J Ped Surg, 199244 Rouzet P, Arch Fr Pediatr, 199145
Rouzet P, Arch Fr Pediatr, 199145 Oriot D, JPEN, 199111 Rovelli A, Haematologia, 199046 Klein G, Dtsch Med Wochenschr, 199047 Naidoo DP, S Afr Med, 198948 Delorme N, Presse Med, 198649 La Selve P, JPEN, 198650 Seedat YK, S Afr Med J, 198551 Thomas L, Presse Med, 198552 Thomas L, Presse Med, 198552
Thomas L, Presse Med, 198552
ACCEPTED MANUSCRIPT Vomiting, TPN
19 years M
Nasopharyngeal carcinoma
Chemotherapy (5FU), TPN
30 years M
Alcoholism
15 patients
Cerebral malaria
6 patients
Sepsis
X patients
Burn
7 patients
Lymphoma and chronic lymphocytic leukemia
Lactic acidosis Hyperlactatemia Lactic acidosis
AC C
EP
TE D
M AN U
Thiamine deficient diet Thiamine deficiency Thiamine deficiency Thiamine deficiency
Kosarkoff Metabolic acidosis, shoshin Lactic acidosis, encephalopathy, vegetative instability, neuropathy Metabolic acidosis, hyponatraemia, shoshin Lactic acidosis
Attas M, Circulation, 197853 Rosen A, Case Rep Oncol, 201154
Engbers JG, Br Heart J, 198455 Krishna S, Lancet , 199956
RI PT
Alcoholism
SC
36 years M
Donnino MW, J Crit Care, 201057 Falder S, Burns, 201058 Friedenberg AS, Medicine (Baltimore), 200759
ACCEPTED MANUSCRIPT Supplementary references
2
23. Kondo K, Fujiwara M, Murase M, Kodera Y, Akiyama S, Ito K et al: Severe acute metabolic
3
acidosis and Wernicke's encephalopathy following chemotherapy with 5-fluorouracil and cisplatin:
4
case report and review of the literature. Jpn J Clin Oncol 1996, 26:234-236.
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24. Ozawa H, Homma Y, Arisawa H, Fukuuchi F, Handa S: Severe metabolic acidosis and heart
6
failure due to thiamine deficiency. Nutrition 2001,17:351-352.
7
25. Cho YP, Kim K, Han MS, Jang HJ, Kim JS, Kim YH et al: Severe lactic acidosis and thiamine
8
deficiency during total parenteral nutrition--case report. Hepatogastroenterology 2004,51:253-255.
9
26. Oguz SS, Ergenekon E, Tümer L, Koç E, Turan O, Onal E et al: A rare case of severe lactic
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1
acidosis in a preterm infant: lack of thiamine during total parenteral nutrition. J Pediatr Endocrinol
11
Metab 2011,24:843-845.
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27. Roll C, Lange R, Klüting N, Hanssler L: Vitamin B1 deficiency as cause of a severe lactic
13
acidosis and ileus symptoms. Monatsschr Kinderheilkd 1991,139:699-702.
14
28. Teyssier G, Rayet I, Martin O, Damon G, Frappaz D: Carbohydrate infusion inducing lactic
15
acidosis. Role of thiamine deficiency in an infant with malnutrition. Presse Med 1986, 15:120-121.
16
29. Klein M, Weksler N, Gurman GM: Fatal metabolic acidosis caused by thiamine deficiency. J
17
Emerg Med 2004,26:301-303.
18
30. Nakasaki H, Ohta M, Soeda J, Makuuchi H, Tsuda M, Tajima T et al: Clinical and biochemical
19
aspects of thiamine treatment for metabolic acidosis during total parenteralnutrition.
20
Nutrition 1997,13:110-7.
21
31. Mansour AH, Kamona A, Qandeel M, Jamil A, Sweidan M, Faqih N et al: Wernicke
22
encefalopathy in a child with leukemia. Eur J Radiol Extra 2005, 54: 43-45.
23
32. Mayatepek E, Schulze A: Metabolic decompensation and lactic acidosis in propionic acidaemia
24
complicated by thiamine deficiency. J Inherit Metab Dis 1999,22:189-90.
25
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