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NDT Advance Access originally published online on September 12, 2006
Nephrology Dialysis Transplantation 2006 21(11):3320-3323; doi:10.1093/ndt/gfl389
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
(Section Editor: A. Meyrier)

Perplexing hyperkalaemia

Chih-Jen Cheng1, Chin-Sheng Lin2, Li-Way Chang3 and Shih-Hua Lin1

1Division of Nephrology, 2Division of Cardiology, Department of Medicine and 3Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

Correspondence and offprint requests to: Shih-Hua Lin, MD, Division of Nephrology, Department of Medicine, Tri-Service General Hospital, Number 325, Section 2, Cheng-Kung Road, Neihu 114, Taipei, Taiwan. Email: shihhualin{at}yahoo.com

Keywords: cardiac glycoside; digoxin-like intoxication; electrocardiogram; hyperkalaemia; toad venom



   Introduction
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 Introduction
Case
 Discussion
 Teaching points
 References
 
Potassium (K+) homoeostasis is regulated by both renal and extrarenal mechanisms. Malfunction of these mechanisms resulting in hyperkalaemia may lead to neuromuscular dysfunction, arrhythmias and even death [1]. In general, hyperkalaemia in patients with reduced renal K+ excretion is chronic. In contrast, hyperkalaemia in patients with normal renal K+ excretion is almost always acute, resulting from disturbed extrarenal mechanisms and carries a much higher risk of complications [2]. Prompt diagnosis and treatment of hyperkalaemia is essential to prevent such catastrophes. In this article, we describe a healthy young girl who developed acute hyperkalaemia with elevated urine K+ excretion after eating a toad. The absence of characteristic hyperkalaemic patterns on electrocardiogram (ECG), and the presence of detectable digoxin in serum pointed to cardiac glycoside intoxication. Ingestion of toad venom and the use of toad venom extracts containing cardiac glycosides are less-appreciated causes of acute hyperkalaemia by nephrologists.



   Case
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 Introduction
 Case
Discussion
 Teaching points
 References
 
A 19-year-old girl and her father both suffered from persistent nausea, vomiting and chest tightness after eating toad (Bufo bufo gargarizans, Figure 1) along with the eggs as part of their dinner and were sent to the emergency department (ED). Her father was dead upon arrival. The girl presented with the aforementioned vomiting, along with muscular fatigue and paresthesia over her oral mucosa. She was previously healthy and took no medications; her family history was non-contributory.


Figure 1
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  		Fig. 1. A photo of toad (Bufo bufo gargarizans).

 
On physical examination, she was alert and oriented. Her body weight was 48 kg with body mass index 18.3 kg/m2. Her supine blood pressure was 140/60 mmHg, irregular heart rate at 94 beats/min (bpm), respiratory rate 18/min and body temperature 35.8°C. Her abdomen was non-tender. Her cranial nerves and muscular strength were intact. The rest of her examination was unremarkable.

Her complete blood count showed white cell count 13 200/µl, haemoglobin 156 g/l, and platelets 342 000/µl. Serum biochemical studies revealed severe hyperkalaemia (K+ 7.1 mmol/l), Na+ 133 mmol/l, Cl– 95 mmol/l, total calcium 2.4 mmol/l, magnesium 0.8 mmol/l, glucose 4.4 mmol/l, urea nitrogen 3.2 mmol/l, uric acid 0.3 mmol/l, creatinine 26.5 µmol/l, lactate dehydrogenase (LDH) 116 U/l, creatinine kinase (CK) 86 U/l, albumin 42 g/l and osmolality 289 mOsm/kg.H2O. Arterial blood gas analysis showed pH 7.37, PCO2 52 mmHg, PO2 82 mmHg and Formula 29 mmol/l. Urine biochemistries showed Na+ 66 mmol/l, K+ 146.5 mmol/l, Cl– 82 mmol/l, creatinine 9.2 mmol/l and osmolality 570 mOsm/kg.H2O. Transtubular potassium gradient (TTKG) was 10.5 and urine K+/creatinine ratio was 15.9. Her ECG revealed 1st-degree atrioventricular (AV) block with ventricular rate 80 bpm (Figure 2A). Six units of regular insulin in 40 ml of 50% dextrose and 34 mmol sodium bicarbonate were administered immediately to treat her hyperkalaemia.


Figure 2
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  		Fig. 2. Serial electrocardiographic changes (lead II) of toad venom poisoning. (A) In ED, 1st-degree AV block with ventricular rate 80 bpm with occasional junctional escape (arrow) and dropped conduction (arrowhead), narrow QRS complex, depressed ST segment, shortened QT interval and flattened T wave at serum K+ level 7.1 mmol/l. (B) At 3 h, high-degree AV block with ventricular rate 48 beats per minute at serum K+ level 6.2 mmol/l. (C) At 12 h, first-degree AV block with ventricular rate 90 bpm at serum K+ level 4.0 mmol/l.

 
High-degree AV block with ventricular rate 48 bpm followed by hypotension to 100/50 mmHg was noted 3 h later at serum K+ level of 6.2 mmol/l (Figure 2B). Atropine (1 mg) and epinephrine (2–5 µg/min) were injected intravenously. Although she denied ingesting high K+ foods or medications, including digoxin or ß-blockers, she had a serum digoxin level of 0.54 nmol/l (detectable range >0.25 nmol/l). This finding, combined with her persistent gastrointestinal complaints and ECG features, raised the suspicion for digoxin-like intoxication from toad venom. Therefore, 80 mg of digoxin-specific antibody Fab fragments (Digibind) was administered. Her cardiac rhythm changed to 1st-degree AV block 12 h later at serum K+ level of 4.0 mmol/l (Figure 2C) and became normal sinus rhythm 24 h later. Serum K+ and digoxin level decreased to 3.7 mmol/l and 0.29 nmol/l, respectively. After 5 days of observation, she was discharged with a regular heart beat of 60 bpm.



   Discussion
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 Introduction
 Case
 Discussion
Teaching points
 References
 
The cause of acute hyperkalaemia in this patient with normal renal function and severe vomiting is perplexing. The elevated urine K+ excretion rate as seen by TTKG 10.5 and urine K+/creatinine ratio 15.9 indicated a non-renal mechanism [3]. Pseudohyperkalaemia and cell lysis were ruled out by the lack of supporting data, such as high CK, LDH, uric acid or haemolytic anaemia.

Derangements of transcellular K+ shift are another cause of hyperkalaemia. This may occur via several mechanisms. First, in a patient with hyperglycaemia and/or metabolic acidosis, impairment of Na+/H+ exchanger activity by diminished insulin action may lead to reduced K+ shift into cells. Second, patients with a family history of hyperkalaemic periodic paralysis, an autosomal dominant skeletal muscle disorder, caused by mutations in the SCN4A gene, encoding the skeletal muscle voltage-gated Na+ channel allowing persistent inflow of Na+ into cells and concomitant K+ leakage. Third, {alpha}-agonists, ß-blockers, digoxin, and fluoride intoxication can inhibit the Na+–K+ ATPase leading to accumulation of extracellular K+. The detectable serum digoxin concentration but no use of digoxin raised our suspicion for a toxic digitalis-like substance. The patient was proved to be poisoned by toad venom which contained natural-derived cardiac glycosides (Table 1) based on the history of ingesting toad venom in her dinner.


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  		Table 1. Common sources of naturally derived cardiac glycosides

 
In Southeast Asia, toads are a common folk remedy for strengthening the heart, eliminating toxins, reducing oedema and relieving pain. With regard to western countries, at least two cases of poisoning by toad and eggs have been reported in the United States [4,5]. Although toads have several geographic and generic variations, their venoms contain similar components. Bufadienolides, the major animal-derived cardiac glycoside in venom, account for these pharmacological effects. Venom is present in the entire body of the toad, with highest concentration in the skin, followed by the parotid gland, viscera and eggs in descending order. The bufadienolides have similar structure and biochemical activity to digitalis and cardenolides, the major plant-derived cardiac glycosides (Table 1) [6]. Elevation of serum digoxin level is universally presented in patients with toad venom poisoning because of structural cross-reactivity on assays. Once bufadienolides are ingested, around 50% is passively absorbed in the intestine and then extensively bound to the {alpha} subunit of the Na+–K+ ATPase in myocardium, skeletal muscle, kidney, as well as red blood cells [7]. Myocardium has the highest concentration of Na+–K+ ATPase (505–760 pmol/g), thus accounting for the conspicuous cardiotoxicity of bufadienolides [8].

Bufadienolides cause hyperkalaemia via its binding to the {alpha} subunit of Na+–K+ ATPase thus inhibiting the reuptake of K+ from the extracellular space. Since skeletal muscle, with its sheer mass, contains the major pool of Na+–K+ ATPase in the body, the severity of hyperkalaemia is determined by the extent of K+ release from skeletal muscles [8,9]. The low weight of this girl might explain why a given amount of the animal derived cardiac glycoside was more toxic than in a person with a higher body mass. Theoretically, the severity of intoxication may be reflected by the serum K+ level in patients with cardiac glycoside poisoning [10,11]. The patient's father's death was likely due to arrhythmia precipitated by hyperkalaemia.

Besides acute hyperkalaemia, characteristic ECG features may also provide important clues to the diagnosis of cardiac glycoside toxicity in this patient. Typical ECG changes include flattened or inverted T waves, shortened QT intervals, depressed ST segments, increased U waves amplitude and rhythmic changes (delayed conduction with heart block and escape rhythm, and enhanced automaticity with ectopic beats). These cardiac glycoside changes may complicate or mask the typical ECG features of hyperkalaemia. Consistent with previous reports of cardiac glycoside intoxication with hyperkalaemia [6,12,13], we did not find typical ECG features of hyperkalaemia in this patient. Sustained AV block after the normalization of serum K+ from 7.1 to 4.0 mmol/l in this patient was indicative of a high tissue binding bufadienolides with a long half-life.

In addition to the toxic effect of direct toad venom ingestion, toad venom extracts are used in many traditional Chinese medicines. Chan Su, Kyushin and Lu-Shen Wan are prepared from the dried white secretions of the auricular and skin glands of Chinese toads. Their effects include stimulation of myocardial contraction, anti-inflammation and pain relief, and have also been used for the treatment of tonsillitis, sore throat, palpitation and heart failure [14]. Besides these therapeutic purposes, bufadienolides have also been used as aphrodisiacs (‘Stone’ or ‘Love Stone’) through their hallucinogenic effects [15]. Besides these human intoxications, some animals, like dogs, cats and snakes that may eat poisonous toads or come in contact with their venom will also suffer a lethal outcome [16,17]. Hence, it is necessary to be very careful while considering a toad meal or using its venom extract.

The benefit of calcium administration to antagonize the cardiac effects of hyperkalaemia remains controversial in patients with cardiac glycoside intoxication because it may enhance after depolarization and result in fatal arrhythmia. Because the total body K+ is normal to low in such patients, overzealous use of diuretics or K+-lowering resins may cause hypokalemia, which can further enhance the toxicity of cardiac glycosides. Insulin and ß-agonists to shift K+ into cells should be the first therapeutic choices. Dialysis is ineffective at removing cardiac glycosides due to their high protein-binding and large volume of distribution. High-dose administration of digoxin-specific antibody Fab fragments (Digibind 400 mg) has been reported to be life-saving in patients with fatal arrhythmia and hyperkalaemia, even though it binds to bufadienolides with less affinity than digoxin [18].



   Teaching points
Top
 Introduction
 Case
 Discussion
 Teaching points
References
 

  1. Acute hyperkalaemia in patients with normal renal function without cell lysis is caused by disturbed extra-renal K+ mechanism (transcellular K+ shift).
  2. Toad venom and extracts share chemical structure and action with digitalis and cardenolides and can lead to acute life-threatening hyperkalaemia.
  3. Cardiac glycosides cause hyperkalaemia by binding and inhibiting the ubiquitous Na+–K+ ATPase, preventing reuptake of K+ into cells, even in the presence of severe vomiting.
  4. Hyperkalaemia without typical ECG changes and the presence of elevated serum digoxin level and gastrointestinal symptoms suggest cardiac glycoside intoxication.
  5. Naturally derived cardiac glycoside intoxication should be kept in mind as a cause of acute hyperkalaemia, and digoxin-specific antibody Fab fragments may be a life-saving therapy in addition to conventional management.

Conflict of interest statement. None declared.



   References
Top
 Introduction
 Case
 Discussion
 Teaching points
 References
 

  1. Weiner ID and Wingo CS. (1998) Hyperkalemia: a potential silent killer. J Am Soc Nephrol 9:1535–1543.[Web of Science][Medline]
  2. Cheng CJ, Chiu JS, Huang WH, Lin SH. (2005) Acute hyperkalemic paralysis in a uremic patient. J Nephrol 18:630–633.[Web of Science][Medline]
  3. Halperin ML and Kamel KS. (1998) Potassium. Lancet 352:135–140.[Web of Science][Medline]
  4. Licht LE. (1967) Death following possible ingestion of toad eggs. Toxicon 5:141–142.[Medline]
  5. Hitt M and Ettinger DD. (1986) Toad toxicity. N Engl J Med 314:1517.[Web of Science][Medline]
  6. Newman LS, Feinberg MW, LeWine HE. (2004) Clinical problem-solving. A bitter tale. N Engl J Med 351:594–599.[Free Full Text]
  7. Chen KK and Kovarikova A. (1967) Pharmacology and toxicology of toad venom. J Pharm Sci 56:1535–1541.[Web of Science][Medline]
  8. Clausen T. (1998) Clinical and therapeutic significance of the Na+, K+ pump. Clin Sci 95:3–17.[CrossRef][Web of Science][Medline]
  9. Doherty JE, Perkins WH, Flanigan WJ. (1967) The distribution and concentration of tritiated digoxin in human tissues. Ann Intern Med 66:116–124.[Abstract/Free Full Text]
  10. Chi HT, Hung DZ, Hu WH, Yang DY. (1998) Prognostic implications of hyperkalemia in toad toxin intoxication. Hum Exp Toxicol 17:343–346.[Abstract/Free Full Text]
  11. Eddleston M, Ariaratnam CA, Sjostrom L, et al. (2000) Acute yellow oleander (Thevetia peruviana) poisoning: cardiac arrhythmias, electrolyte disturbances, and serum cardiac glycoside concentrations on presentation to hospital. Heart 83:301–306.[Abstract/Free Full Text]
  12. Carlebach M, Hasdan G, Shimoni T, Korzets Z. (2001) Vomiting, hyperkalaemia and cardiac rhythm disturbances. Nephrol Dial Transplant 16:169–170.[Free Full Text]
  13. Gowda RM, Cohen RA, Khan IA. (2003) Toad venom poisoning: resemblance to digoxin toxicity and therapeutic implications. Heart 89:e14.[Abstract/Free Full Text]
  14. Ko R, Greenwald M, Loscutoff S, et al. (1996) Lethal ingestion of Chinese tea containing Chan Su. West J Med 164:71–75.[Web of Science][Medline]
  15. Barry TL, Petzinger G, Zito SW. (1996) GC/MS comparison of the West Indian aphrodisiac "Love Stone" to the Chinese medication "Chan Su": Bufotenine and related bufadienolides. J Forensic Sci 41:1068–1073.[Web of Science][Medline]
  16. Bedford PG. (1974) Toad venom toxicity and its clinical occurrence in small animals in the United Kingdom. Vet Rec 94:613–614.[Web of Science][Medline]
  17. Phillips BL, Brown GP, Webb JK, Shine R. (2006) Invasion and the evolution of speed in toads. Nature 439:803.[CrossRef][Medline]
  18. Brubacher JR, Ravikumar PR, Bania T, Heller MB, Hoffman RS. (1996) Treatment of toad venom poisoning with digoxin-specific Fab fragments. Chest 110:1282–1288.[Web of Science][Medline]
Received for publication: 23. 5.06
Accepted in revised form: 1. 6.06


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