Renal and other organ failure caused by germanium intoxication

Birgitta Elisabeth Lück1, Helmut Mann2, Heinrich Melzer2, Lothar Dunemann3 and Jutta Begerow3

1 Medizinische Klinik II, Rheinisch-Westfälische-Technische Hochschule, Aachen, 2 Dialysezentrum, Aachen and 3 Medizinisches Institut für Umwelthygiene, Düsseldorf, Germany

Correspondence and offprint requests to: Prof. Dr med. Helmut Mann, Schurzelter Straße 564, 52074 Aachen, Germany.

Keywords: diabetes mellitus; germanium; polyneuropathy; renal failure; SDS–PAGE; SF-ICP-MS



   Introduction
 Top
 Introduction
 Case
 Discussion
 References
 
Germanium (Ge) is one of the ultratrace elements. Its natural occurrence in very low concentrations in food largely meets the requirements of humans [1,2]. Some Ge compounds have shown promise as antineoplastic or immunostimulatory agents [37] and are perceived as natural remedies. However, acute and chronic toxic effects of germanium dioxide (GeO2) and alkylgermanium compounds have been demonstrated [818]. Ge is a group IVB element situated between silicium (Si) and tin (Sn) in the periodic table. The chemical properties of Ge are to some extent comparable to that of Si and Sn. Potential health hazards exist when Ge is not consumed in ultra-low, i.e. `normal', quantities.

Previously, intake of Ge compounds was reported to cause renal failure, gastrointestinal disturbances, liver dysfunction, anaemia, neuropathy and even death [811,1322]. Most of the cases, however, were associated with other diseases and/or the intake of additional drugs, making it difficult to determine whether the effects were caused by Ge only. This is the first report on the toxic effects of Ge-lactate-citrate, taken by a healthy patient. The Ge concentrations in whole blood (EDTA bottle), serum, and urine were monitored in detail over a period of 5 months after the Ge intake was discontinued.



   Case
 Top
 Introduction
 Case
 Discussion
 References
 
A 58-year-old man sought medical help for nausea, vomiting, anorexia, and weight lost. He complained of having lost about 10 kg during the last 6 months. His body weight was 64 kg and his height was 180 cm. There was no history of previous renal, cardiac, metabolic, infectious, or other diseases and he had never been in hospital before. The patient was a manager of a small metal processing company and had never been abroad. His medication history revealed an intake of germanium-lactate-citrate (Ge content 18 weight %), illegally purchased in a pharmacy. A non-scientific brochure [23,24] described Ge compounds as antioxidants and as anti-cancer and immunostimulatory natural remedies, and stated that organic Ge compounds such as spirogermanium, carboxyethyl-germanium-sesquioxid (Ge-132) and germanium-lactate-citrate were harmless in contrast to inorganic Ge compounds. Without consulting a doctor the patient took a total dose of 426 g germanium-lactate-citrate orally over 6 months.

On examination, the patient was nearly cachectic, his skin was yellowish and he had an uraemic fetor. The patient was afebrile, the pulse was 120 beats/min, and the blood pressure was 130/80 mmHg. On auscultation, there were soft heart sounds and no murmurs, but a pericardial rub. The remainder of examination was normal. Laboratory studies revealed a raised sedimentation rate, normal leukocyte count, reduced erythrocyte count, and reduced thrombocyte count. The electrolytes were in the lower normal range. Other laboratory abnormalities and their follow-up are shown in Table 1Go.


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Table 1 Biochemical values in a patient with renal and other organ failure associated with Ge intoxication
 
The patient was admitted to hospital for renal failure. Further laboratory monitoring revealed normal values for C3 and C4 complement and circulating immunocomplexes. The autoantibodies ANA, ENA, dsDNA, ANCA, C3-nephritis factor, anti-GBM, and anti-tubular-BM, were all negative. The serology for hepatitis B, hepatitis C and Hanta-virus was also negative. Abnormalities for antistreptolysin, antistreptococcus-DNAase, serum IgA, and other immunoglobulins were not found. TSH was raised (22.9 mU/l), but free T3 and free T4 were normal. The fasting glucose (10.7 mmol/l), the glycosylated haemoglobin (HbA1c 11.1%) and the C-peptide (8.06 ng/ml) were increased. Urinalysis showed a few erythrocytes, which were normal in shape. The 24-h collection of urine revealed a proteinuria of 200 mg in 2840 ml. Sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS–PAGE) of the urinary protein indicated tubular damage. The creatinine clearance was 11 ml/min. The Ge concentrations were measured weekly in a specimen of the 24-h urine collection, serum and whole blood (EDTA-bottle) by sector field inductively coupled plasma mass spectrometry (SF-ICP-MS) [Dunemann et al., In preparation]. These data are given in Figure 1Go.



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Fig. 1. Time course of Ge concentrations in whole blood, serum and urine determined by SF-ICP-MS.

 
The abdominal ultrasound scan showed normal kidneys in size and texture. Cardiac ultrasound revealed pericardial effusion (150 ml). The ECG showed a sinus tachycardia and the thoracic radiographs were normal. The patient was examined by a neurologist for muscular weakness, muscular pain and numbness. Clinically typical neurological signs were not found. The nerve-conduction studies and electromyography revealed pathological spontaneous muscular activity and myotonic discharge. The neural conduction velocity was normal for the median nerve and delayed for the peroneal nerve. Dialysis and renal, muscle, and liver biopsies were not performed because of the patient's refusal.

The patient received intravenous nutrition, insulin, and electrolytes. A daily recommendation of 1 g frusemide orally was taken irregularly due to the patient's non-compliance. Anti-emetic treatment was given with metoclopramide and dimenhydrinate. After stabilization of his nutritional condition he was discharged. At that time the insulin regime consisted of a mixture of short- and medium-acting insulin in the morning and short-acting insulin around meals.

Six months after the first consultation his insulin requirement lowered to one injection of short-acting insulin daily. The TSH and the liver function returned to normal, but he still complained of nausea and occasional vomiting. The pericardial effusion regressed, but the sinus tachycardia continued. The renal dysfunction (creatinine clearance 25 ml/min) as well as the polyneuropathy persisted.



   Discussion
 Top
 Introduction
 Case
 Discussion
 References
 
Germanium-lactate-citrate and other organic Ge compounds, such as spirogermanium and carboxyethyl-germanium-sesquioxid (Ge-132), are widely promoted as natural remedies. The fact that these substances are `organic' is interpreted by scientifically less educated persons to indicate that they are harmless.

Our patient took Ge-lactate-citrate to cure general malaise and prevent cancer. Over 6 months he ingested 426 g of the compound, which equals 76 g of elemental Ge. He developed renal failure, gastrointestinal symptoms and pericarditis. Laboratory studies and clinical course also revealed liver and thyroid dysfunction, polyneuropathy, and diabetes mellitus. The chronic intake of Ge-lactate-citrate along with the simultaneous onset of multi-organ dysfunction and the exclusion of other systemic diseases led to the conclusion that the patient suffered from Ge intoxication. The determination of Ge using SF-ICP-MS was started 1 week after cessation of the chronic intake of the compound and continued for 5 months. The results for the Ge concentrations in the whole blood, serum and urine are summarized in Figure 1Go. The initial values of 4.3 mg Ge/l in whole blood, 3.7 mg Ge/l in serum, and 13.4 mg Ge/l in urine indicate strong intoxication compared to values found in unexposed humans, i.e. less than 0.01 mg/l in whole blood and less than 0.002 mg/l in serum and urine. The Ge concentration in whole blood and serum rapidly decreased during the first 4 weeks and then more slowly. Even 5 months after cessation of the Ge intake, the concentration was still elevated to 0.040 mg/l in whole blood and 0.058 mg/l in serum. The Ge concentrations in whole blood and serum are almost similar. This fact indicates that, in contrast to Pb, Ge is distributed uniformly in erythrocytes and serum.

The urine measurements are less clear. The constant decrease of the Ge concentration was interrupted by a massive increase after 24 and 31 days. The further course of Ge concentration in urine is similar to the results for the blood. Even 5 months after the cessation of the Ge intake, the concentration was still elevated to 0.060 mg/l, which is 30 times the value found for unexposed persons. An explanation for the urine values after 24 and 31 days could be that the patient took Ge-lactate-citrate again despite his assurance of having stopped the intake. If we consider that most of the Ge compound is rapidly excreted through urine and only a small part of it is stored in the body, the amount in the urine should increase during intake. The blood and serum values, however, should not change significantly. This is supported by the results of another study. Rapid excretion of most of the Ge within 3 h was found in an investigation with healthy persons who took a single dose of 100 mg of Ge-132 orally [17,25].

It is difficult to predict the time it will take for the Ge concentration to return to a normal level in our patient. Given that the Ge concentration in serum decreased by one-half over 3 months, one can predict that it will take at least one and a half years for the Ge concentration to reach a normal level.

Ge intoxication can cause multi-organ failure. The damaged organs in reported cases are summarized in Table 2Go. It is remarkable that the kidneys were impaired in all cases. In many reports, liver function, gastrointestinal tract, muscles, and nervous system were also affected by Ge intoxication. Interestingly, all the organs listed in Table 2Go were also damaged in our case.


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Table 2 Organ damage in previously reported cases of Ge intoxication
 
In our case, renal failure developed without major proteinuria or haematuria. The urine volume in 24 h ranged from 2500 to 3500 ml. The protein concentration in the urine varied from 0.022 to 0.194 g/l, which equals a daily amount of 80–600 mg. Although histological examination of the kidneys was not performed, tubular damage was confirmed by differentiation of the urine proteins using SDS–PAGE, which is illustrated in Figure 2Go. In addition to albumin, low-molecular-weight proteins were detected in the SDS–PAGE pattern. These findings coincide with histological examinations of the kidneys in cases of Ge intoxication [811,13,20,21]. In these cases, tubular degeneration was found along with minor glomerular abnormalities.



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Fig. 2. Laser densitogram of urine proteins separated by SDS–PAGE, which indicates tubular damage. The albumin peak (65 kDa), the peak for {alpha}1-microglobulin (31.5 kDa) and retinol binding protein (21 kDa) are marked.

 
Diabetes mellitus has never been described as consequence of Ge intoxication. Further laboratory studies for differential diagnosis of the diabetes showed a lack of autoantibodies and an elevated C-peptide, indicating that the diabetes was caused by a diminished effectiveness of endogenous insulin. The fact that the insulin requirement of our patient decreased over 6 months suggests that the diabetes mellitus was related to Ge intoxication.

Furthermore, a normocytic normochromic anaemia without reticulocytosis or haemolysis was diagnosed. Most probably the anaemia is a consequence of Ge intoxication. In the past Ge compounds have been shown to be toxic to bone marrow, directly causing anaemia. However, Ge can indirectly cause anaemia secondary to the renal failure and malnutrition [811,13,18]

The partial thyroid failure also seems related to the Ge intoxication. High concentrations of Ge in the tissue of the thyroid glands were found in patients who died after chronic intake of GeO2, [8,9] which underscores our assumption. Hashimoto thyroiditis is unlikely, due to the fact that the thyroid autoantibodies were negative and the TSH returned to normal.

Finally, we also attribute the gastrointestinal disturbances and the peripheral neuropathy to Ge intoxication. Routine gastrointestinal examination revealed no abnormalities. Six months after discontinuing the Ge intake, nausea, vomiting as well as the peripheral neuropathy persisted. Continuation of these symptoms 2–8 months after Ge use was stopped is described in previous reports [10,18]. Obara et al. [18] observed a delay in gastrointestinal transit time in a patient who vomited frequently despite strong anti-emetic treatment, indicating an impairment of gastrointestinal motor activity. This suggests that Ge adversely affects both, peripheral and autonomic nerves.

In summary, within the 6 months of observation, the thyroid gland and the liver recovered. The pericardial effusion disappeared and the insulin requirement decreased. There was only partial improvement of the renal failure and the polyneuropathy persists, requiring morphine treatment. Similar to other cases prognosis is not positive [911,18,21,22].



   References
 Top
 Introduction
 Case
 Discussion
 References
 

  1. Anke M, Groppel B, Arnold W, Langer M, Krause U. Trace Elements in Clinical Medicine. Springer Verlag, Berlin, 1990; 361
  2. Gerber GB. Germanium. In: Seiler H, Sigel H, eds. Handbook on Toxicity of Inorganic Compounds. Dekker, New York 1988; 301–305
  3. Schein PS, Slavik M, Smythe T et al. Phase I clinical trial of spirogermanium. Cancer Treat Rep 1980; 64: 1051–1056[ISI][Medline]
  4. Kuebler JP, Tormey DC, Harper GR, Chang YC, Khandekar JD, Falkson G. Phase II study of spirogermanium in advanced breast cancer. Cancer Treat Rep 1984; 68: 1515–1516[ISI][Medline]
  5. Falkson G, Falkson HC. Phase II clinical trial of spirogermanium for treatment of advanced breast cancer. Cancer Treat Rep 1983; 67: 189–190[ISI][Medline]
  6. Mizushima Y, Shoji Y, Kaneko K. Restoration of impaired immunoresponse by germanium in mice. Int Archs Allergy Appl Immun 1980; 63: 338–339
  7. Suzuki F. Antitumor activity of Ge-132, a new organogermanium compound, in mice is expressed through the functions of macrophages and T lymphocytes. Gan-To Kagaku Ryoho 1985; 12: 1445–1452
  8. Nagata N, Yoneyama T, Yanagida K et al. Accumulation of germanium in the tissues of a long-term user of germanium preparation who died of acute renal failure. J Toxicol Sci 1985; 10: 333–341[Medline]
  9. Matsusaka T, Fujii M, Nakano T et al. Germanium-induced nephropathy: Report of two cases and review of the literature. Clin Nephrol 1988; 30: 341–345[ISI][Medline]
  10. Okuda S, Kiyama S, Oh Y et al. Persistent renal dysfunction induced by chronic intake of germanium-containing compounds. Curr Ther Res 1987; 41: 265–275[ISI]
  11. Sanai T, Okuda S, Onoyama K et al. Germanium-dioxide-induced nephropathy: A new type of renal disease. Nephron 1990; 54: 53–60[ISI][Medline]
  12. Cremer JE, Aldridge WN. Toxicological and biochemical studies on some trialkylgermanium compounds. Br J Ind Med 1964; 21: 214–217[ISI][Medline]
  13. Takeuchi A, Yoshizawa N, Oshima S et al. Nephrotoxicity of germanium compounds: Report of a case and review of the literature. Nephron 1992; 60: 436–442[ISI][Medline]
  14. Asaka T, Nitta E, Makifuchi T et al. Germanium intoxication with sensory ataxia. J Neurol Sci 1995; 130: 220–223[ISI][Medline]
  15. Schauss AG. Nephrotoxicity in humans by the ultratrace element germanium. Renal Fail 1991; 13: 1–4[ISI][Medline]
  16. Schauss AG. Nephrotoxicity and neurotoxicity in humans from organogermanium compounds and germanium dioxide. Biol Trace Element Res 1991; 29: 267–280[ISI][Medline]
  17. Tao SH, Bolger PM. Hazard assessment of germanium supplements. Regul Toxicol Pharmacol 1997; 25: 211–219[ISI][Medline]
  18. Obara K, Saito T, Sato H et al. Germanium poisoning: Clinical symptoms and renal damage caused by long-term intake of germanium. Jpn J Med 1991; 30: 67–72[Medline]
  19. van der Spoel JI, Stricker BH, Esseveld MR, Schipper ME. Dangers of dietary germanium supplements. Lancet 1990; 336: 111[ISI][Medline]
  20. Krapf R, Schaffner T, Iten PX. Abuse of germanium associated with fatal lactic acidosis. Nephron 1992; 62: 351–356[ISI][Medline]
  21. Raisin J, Hess B, Blatter M et al. Toxizität einer organischen Germanium-Verbindung: Deletäre Folgen eines `Naturheilmittels'. Schweiz Med Wochenschr 1992; 122: 11–13[ISI][Medline]
  22. Hess B, Krapf R, Zimmermann A et al. Toxizität organischer Germanium (Ge)- Verbindungen: Deletäre Folgen eines `Naturheilmittels'. Schweiz Med Wochenschr 1991; 121 [Suppl 38]: 8
  23. Goodman S. Germanium. Semmelweis Verlag Hoya, 1988
  24. Asai K. Miracle Cure: Organic Germanium. Japan Publications Inc., 1980
  25. Chen Y, Wang N, Shangguan G et al. Determination of germanium in urine and studies on pharmacokinetics of Ge-132 in body. Zhongguo Yiyuan Yaoxue Zazhi 1993; 13: 103–109
Received for publication: 27.10.98
Accepted in revised form: 7. 6.99





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