Cardiac beriberi: morphological findings in two fatal cases
© Bello et al; licensee BioMed Central Ltd. 2011
Received: 24 October 2010
Accepted: 19 January 2011
Published: 19 January 2011
Cardiovascular beriberi is categorized into two main groups, according to its cause: alcoholic and non-alcoholic (dietary). Cardiovascular beriberi can also be divided into a fulminant form (Shoshin beriberi) and a chronic form. Shoshin beriberi is characterized by hypotension, tachycardia, and lactic acidosis and is mainly encountered in non-alcoholic patients in Asian countries, although it has also been seen in alcoholics in Western countries. Due to the complex clinical presentation and to the lack of diagnostic tests, thiamine deficiency is still being missed, especially among non-alcoholics patients. We present two fatal cases of non - alcohol associated cardiac beriberi. An acute myocardial infarction was observed in one case; extensive colliquative myocytolisis (grade 2) was described in the second case respectively. Morphologically, myocardial necrosis and colliquative myocytolysis are the histologic hallmarks of this acute, rare clinical entity. An increase in apoptotic myocytes was demonstrated probably sustaining the cardiogenic shock.
Thiamine deficiency (beriberi) has two major manifestations: dry beriberi (peripheral neuropathy) and wet beriberi (cardiovascular disease), which include Wernicke-Korsakoff syndrome and lactic acidosis . Deficiency of this vitamin may be nutritional or secondary to alcohol intoxication. Thiamine (vitamin B1) is a cofactor of key metabolic enzymes and thiamine deficiency (TD) may cause alterations in heart metabolism. However, very little is known about the effects of TD on the myocardium. Thiamine is considered a clinically important factor in heart function, and its deficiency has been reported to cause heart failure [2–4]. Due to the complex clinical presentation and to the lack of diagnostic tests, thiamine deficiency is still being missed, especially among non-alcoholics patients .
We present two fatal cases of non - alcohol associated cardiac beriberi. Clinical and cardiac morphologic findings are described and discussed.
Case 1: the ongoing arterial blood gas results are shown
14th day progressive arterial blood gas results
A 43 year - old man, admitted to an hospital due to a severe ulcerative rectocolitis, submitted to total parenteral nutrition (TPN) for 5 days. He underwent abdominal surgery and remained on TPN which was administered without a multivitamin solution. After 3 weeks of receiving TPN he presented hypotension and tachycardia, confusional state and agitation. He complained fever, abdominal pain, nausea, and vomiting; abdominal local tenderness was present. The clinical course quickly worsening; on the fourth week of TNP the man suddenly experienced cardiac arrest and unexplained lactic acidosis: pH7.140; pCO2 31.1 mmHg; lactate 19 mmol/L; HCO3 11.1 mmol; SBE -18.7 mmol. He was immediately administered vasoactive drugs and bicarbonate. One hour later he died. The dosing of the thiamine resulted equal to 60 nmol/L (n.v. 66 - 200 nmol/L).
Pathologic features were estimated using histologic sections stained by haematoxylin-eosin (H&E) and thrichrome stain. In addition, immunohistochemical investigation of samples was performed utilizing antibodies anti-CD 45, anti-CD15, anti-CD68 (DAKO, Copenhagen, Denmark) and TUNEL assay (Chemicon, Temecula, CA, USA). We used 4 mm thick paraffin sections mounted on slides covered with 3, amminopropyl-triethoxysilane (Fluka, Buchs, Switzerland). A pre-treatment was necessary to facilitate antigen retrieval and to increase membrane permeability to antibodies. The primary antibody was applied in a 1:600 ratio CD 45, in a 1:50 ratio CD15, in 1:200 ratio for CD68 and incubated for 120 min at 20°C. For TUNEL assay (Apotag Plus Peroxidase In Situ Apoptosis Detection Kit, Chemicon, Tamecula, CA, USA) sections were pre-treated with Proteinase K (Sigma-Aldrich, Buchs, Switzerland) (20 μg/ml) for 15 min, at 20°C; covered and incubated with the TdT enzyme, diluted in a ratio of 30% in reaction buffer for 60 min, at 38°C; put in a coupling jar containing working strength stop/wash buffer, agitated for 15 seconds, and incubated for 10 minutes at 20°C; covered and incubated with anti- digoxigenin conjugate for 30 minutes, at 20°C. The positive reaction was visualized by 3,3- diaminobenzidine peroxidation according to standard methods. The sections were counterstained with Mayer's haematoxylin, dehydrated, cover slipped and observed in a Leica DM4000B optical microscope (Leica, Cambridge, UK).
For semi-quantitative analysis, slides were scored in a blinded manner by two observers (MN, IR). Intensity of immunopositive expression was assessed semiquantitatively in the scale 0-4 as follows: 0 = no immunoreactivity, 1 = mild immunopositivity in scattered cells, 2 = immunopositivity in up to one third of cells, 3 = immunopositivity in up to half cells and 4 = strong immunopositivity in the majority or all cells. In cases of divergent scoring, a third observer (VF) decided the final category. The samples were also examined under a confocal microscope, and a three-dimensional reconstruction was performed (True Confocal Scanner, Leica TCS SPE).
In both cases, myocytes nuclei labelled by TUNEL assay showed an intense, wide, positive reaction. In order to obtain the determination of the fraction of myocytes nuclei labelled by TUNEL, the number of myocytes nuclei per unit area of tissue was determined by counting an average of 10 fields, 1.4 mm2 each, at a magnification of x10 in each area of myocardium sampled. The percentage of apoptotic myocytes nuclei was determined. In case 1, the immunohistochemical study revealed an intensive positive result to TUNEL assay: approximately 38 ± 18% apoptotic cells were observed. CD15 and CD45 positive reactions interesting the anterior left ventricular samples, were observed too.
In case 2, the immunohistochemical study revealed an intensive positive result to TUNEL assay: approximately 54 ± 16% apoptotic cells were observed. CD68 positive reaction was observed around the foci of myocardial necrosis.
In both cases the careful post-mortem examination led to acute cardiac failure due to beriberi as cause of death.
The presented fatal cases are paradigmatic about cardiac manifestation due to TD. The present report demonstrated the presence of cardiac pathological changes in both cases. Acute myocardial infarction was observed in one case; extensive colliquative myocytolisis (grade 2) was described in the second case respectively. We use the term colliquative myocytolysis to define a progressive loss of myofibrils paralleled by intramyocellular edema . This process starts around apparently normal nuclei with myofibrillar disappearance producing an increasing vacuolization of myocardial cells until a histologic pattern of empty sarcolemmal tubes without any cellular reaction or signs of healing results. This lesion is generally present in the subendocardial half of the cardiac wall. The disappearance of myofibrils especially in the early phases of colliquative myocytolysis is difficult to quantify. Thus, a semi-quantitative evaluation of the extent of this lesion was adopted only when there was total, or almost total, loss of myofibrils. We distinguished the following grades of change: 0-no loss of myofibrils; 1-occasional or small groups of "empty" myocells were seen; 2-less than and 3-more than 50% of myocells in the subendocardial half of the cardiac wall presented this pattern .
Cardiovascular beriberi is categorized into two main groups, according to its cause: alcoholic and non-alcoholic (dietary). Cardiovascular beriberi can also be divided into a fulminant form (Shoshin beriberi) and a chronic form. Shoshin beriberi is characterized by hypotension, tachycardia, and lactic acidosis and is mainly encountered in non-alcoholic patients in Asian countries, although it has also been seen in alcoholics in Western countries . Patients may be critically ill with hypotension, hypothermia, and obtundation. Lactic acidosis, oftentimes severe, may occur in thiamine-deficient states. Colliquative myocytolysis is the histological hallmark of congestive heart failure, including acute myocardial infarction in which colliquative myocytolysis expresses a secondary non-ischemic complication involving subendocardial myocardium preserved in infarct necrosis . Few experimental studies showed that thiamine deficiency (during 35 days) decreased the rate of contraction. On the other hand, thiamine deprivation has been reported to cause congestive heart failure . We may only speculate that a decreased contractile compliance by reducing the relaxation phase of the contraction cycle  is likely a prime metabolic disorder of the myocardial cell with reduced Ca++ removal from troponine-tropomyosine complex and consequent persistence or prevalence of a contracted state. This is supported by an excess of intramyocellular calcium ; strong dependence of systolic and end-diastolic velocity on both number of myocytes and density of myocardial beta- adrenergic receptors [8, 9]; increased length with normal length of the sarcomeres of normally sized myocardial cells sampled from failing hearts excised at transplantation and cultured in vitro . In particular, the latter finding suggests an abnormal sarcomerogenesis with a longitudinal apposition of sarcomeres unable to completely relax. An abortive hypertrophy without an increase in myocellular volume thus explain the paradox of an increased heart weight with normal thickness of cardiac walls and myocardial cells in failing hearts . Until it reaches a point of no return, colliquative myocytolysis is likely a reversible lesion, reparable by a re-synthesis of myofibrils . Keep in mind that congestive heart failure in which colliquative myocytolysis predominates, clinical signs (lactic acid formation, low pH, etc.) and symptoms of ischemia are generally present [11, 12].
Cardiac beriberi is usually difficult to diagnose because not all cases display the classical signs and there are no specific laboratory tests that can diagnose or rule out the syndrome. Also the measurements of blood thiamine concentration or of the red blood cell transketolase activity miss of specificity and are technically difficult. Thiamine is a cofactor for several essential enzymes in the Krebs cycle and the pentose phosphate pathway, including α-ketoglutarate dehydrogenase, pyruvate dehydrogenase, and transketolase. Thiamine is the precursor for the cofactor of both pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, enzymes that catalyze the oxidative decarboxylation of pyruvate to acetyl-CoA and the oxidative decarboxylation of α-ketoglutarate to succinyl-CoA, respectively. Pyruvate dehydrogenase and α-ketoglutarate dehydrogenase are both key enzymes of the Krebs cycle. A decrease in their activity may lead to increased buildup of toxic intermediates. Lactate accumulation occurs both in the brain and serum because pyruvate cannot enter the Krebs cycle. TD causes an increase in blood and cellular pyruvate concentration and could impair mitochondrial function. Acute heart failure accompanied by ST-segment elevation in patients with a history of alcohol abuse, malabsorption states, malnutrition or eating disorder should prompt the clinician to consider the presumptive diagnosis of cardiac beriberi .
Conclusively, there is still an high rate of incorrect ante-mortem diagnosis for wet beriberi, especially in non alcohol - dependent patients. Morphologically, myocardial necrosis and colliquative myocytolysis are the histologic hallmarks of this acute, rare clinical entity. During TD experimentally induced, greater proportion of apoptotic myocytes by TdT-mediated dUTP nick end labeling (TUNEL) and caspase-3 reactivity techniques have been recently described . These results indicate that during TD, reactive oxygen species (ROS) production may be enhanced as a consequence of the installed acidosis . The perturbation in the cardiac myocytes redox balance was responsible for the increase in apoptosis. In our two fatal cases an increase in apoptotic myocytes was demonstrated probably sustaining the cardiogenic shock .
Written informed consent was obtained from the Medical Examiner Department, Court of Justice, for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
List of abbreviations
- HRP- conjugated antibodies:
Horseradish Peroxidase-Conjugated Antibodies
magnetic resonance imaging
- TdT enzyme:
Terminal Deoxynucleotidyl Transferase Enzyme
total parenteral nutrition
terminal deoxynucleotidyl transferase dUTP nick end labeling.
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