3 Saturnine gout

3 Saturnine gout GYULA POOR MILA MITUSZOVA

Saturnine gout is the form of gout in which the causative role of lead can clearly be proven. Saturn was the Roman god of agriculture and civilization to whom heaviness was attributed in astrology. The Roman Festival of Saturn held in December was observed as a time of general unrestrained merrymaking. Presumably large quantities of wine would be drunk during the Festival from lead goblets, thus causing lead toxicity and gouty arthritis.

HISTORY Mankind has used lead for 8000 years; thus lead poisoning is almost as old as human civilization. The opulence of preclassical Greece derived from the lead and silver mines of Attica. In Roman times, lead and lead-coated vessels were common in every household, meals being cooked and drinks served in them, since a special flavouring effect was attributed to lead. Lead syrup was added to wine to improve its quality, especially colour and flavour, and prevent fermentation. This is the reason why heavy wine consumption was thought to be the major cause of lead intoxication at that time (Mertz, 1983). According to Nriagu's estimation (Nriagu, 1983) the daily lead intake of some Roman aristocrats was as much as 250 lag, many times greater than the average consumption today. It was Nicander in the second century Bc who first recognized the symptoms of white lead intoxication (Major, 1959). Two thousand years ago, in the Roman medical literature, radial nerve palsy and other paralyses associated with abdominal colic and constipation were clearly described as symptoms and signs of lead intoxication. Leadinduced gout was a favourite subject of Martialis' and Juvenalis' satirical writings. Some authors consider that the mental deterioration of Claudius, Caligula, Nero and other Roman dignitaries and the decline of the Roman Empire were related to chronic lead poisoning (Nriagu, 1983). The first detailed description of industrial lead intoxication was given by Samuel Stockhausen in 1656 who gave a report on lead colic in German miners in Hiittenkatze. Bailli~re's ClinicalRheumatology--Vol. 3, No. 1, April 1989

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O. PO6R AND M. MITUSZOVA

The term 'saturnine gout', originally used in alchemy, was introduced by Musgrave in his book on the relationship between chronic lead intoxication and gout, published in 1723. Lead contaminating alcohol in drinks caused epidemics of lead intoxication in the eighteenth century. The Devonshire colic in 1767, caused by cider processed in lead presses, was correctly reported by George Baker (Major, 1959). Alfred Baring Garrod, in his famous book Tile Nature and Treaonent of Gout and Rheumatic Gout published in 1859, considered that lead intoxication from alcoholic drinks and paints accounted for one in four of his cases of gout. In the 1960s in Queensland, Australia, Emmerson (1968) studied 35 adult patients suffering from gout and renal injury who had been intoxicated in their childhood by absorbing lead-containing paints. In recent European publications, accidents and occupational exposure are considered to be the major causes of poisoning and lead-induced gout (Batuman et al, 1981). At highest risk are workers who manufacture and repair storage batteries, cut and weld lead panels, work with lead-containing paints, and lead metallurgists and potters (Choie and Richter, 1980). In the 1960s, in the United States, saturnine gout was frequently reported in consumers of homemade 'moonshine' ~vhiskywhich had been contaminated by lead in the illicit stills (Wright et al, 1984; Peitzman et al, 1985). In the United States and elsewhere, despite advanced technology and industrial hygiene, we still have to contend with chronic occupational intoxication (Wedeen et al, 1975). The most common source of urban pollution with tetraethyl lead is gasoline or petrol. Not only does this cause pollution of the air but also drinking water and vegetation (National Academy of Sciences , 1980; Frieberg and Vahter, 1983). EPIDEMIOLOGY To date, no epidemiological study of the prevalence of saturnine gout has been reported. It has been estimated that saturnine gout accounts for less than 5% of all causes of gout (Rapado, 1969; Halla and Ball, 1982). The prevalence of gout in both Eastern (Mituszova, 1987) and Western European countries (Currie, 1979) and in the United States (Hall et al, 1967) is of the order of 0.2 and 1.5%. Thus, it can be appreciated that saturnine gout is relatively uncommon. Po6r and Mituszova (1988) found four of 105 (3.8%) battery storage workers in Hungary, who were chronically exposed to lead, to have saturnine gout. This is a much higher percentage than that of primary gout observed in the male Hungarian population (0.25%). In addition, Po6r and Mituszova (1988) found 28 workers with asymptomatic hyperuricaemia (26.6%), a number which was significantly higher than that in a matched control group. Although industrial exposure to lead is still a current problem, the incidence of saturnine gout appears to be falling, at least judged by the number of publications. Emmerson (1968) observed a higher percentage of premenopausal females with saturnine gout compared to primary gout.

SATURNINE GOUT

53

LEAD TOXICITY Lead is classified as an aphysiological toxic trace element of living organisms (Zumkley and Bertram, 1982). The daily intake of lead in humans derived from food and drinking water is between 100 and 500~tg. Of this 10% is absorbed. Depending on atmospheric pollution and whether the individual is a smoker, some 1-120 ~tg of lead are inhaled daily and, of this, some 40% is absorbed. The average daily lead absorption has thus been estimated as 35 f.tg (range 10-100 I-tg) (Kehoe, 1964). In the case of occupational exposure, the average daily intake is much higher. According to the WHO standards (WHO Task Group on Environmental Health Criteria for Lead, 1977), 45 ~tgof lead is the allowable maximum daily intake. In the blood, lead is primarily bound to red cells. The lead content of these cells is in dynamic equilibrium with the amount absorbed and that excreted by the kidneys, and the lead content of the tissues (Rabinowitz et al, 1976). Lead is mainly excreted by glomerular filtration in the kidneys, with smaller amounts by the gastrointestinal tract and in sweat. The excreted amount, however, is generally less than that ingested, thus resulting in accumulation of 5-7 ~tg of lead per day. As a result, the lead content of the body gradually increases, and during the lifespan of an individual as much as 120 mg (range 50-200mg) may accumulate (Schroeder et al, 1968). A small amount of absorbed lead is deposited in soft tissues from where it is excreted in a few days or weeks. The largest amount of absorbed lead, however, accumulates in the bones and becomes tightly bound to hydroxyapatite. Because of the slow turnover, lead in bone is excreted slowly over years---on average 10 4 days (Rabinowitz et al, 1976). In addition to the skeleton, considerable lead accumulation occurs in the nails, hair and aorta, while smaller amounts are deposited in the liver, kidneys, spleen and lungs. The toxicity of lead is primarily due to its interaction with the sulphhydryl groups of different enzymes and cell membrane proteins. As a result, lead is capable of blocking, in a dose-dependent manner, the activities of these enzymes and special transport processes of membranes (Choie and Richter, 1980). The toxic effects of lead can be considered in three stages: 1. 2. 3.

Absorption without causing damage. Preintoxication with demonstrable biochemical changes but without organ damage. Intoxication resulting in reversible or irreversible changes in one or more organs.

The relationship between lead toxicity and saturnine gout, and especially the mechanism whereby the latter is produced, has been the subject of a number of publications. Some workers opine that lead has little effect on purine metabolism and on the development of gout and consider other factors, such as heredity, obesity, alcohol consumption and hypertension, to be important (Reynolds et al, 1983). Ludwig (1957) suggested that lead accelerated nucleoprotein turnover and that this was the mechanism of saturnine gout. Garrod's original contention that lead inhibited renal

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G. PO6R AND M. MITUSZOVA

Table 1. Average values of urate metabolism and urinary N-acctyl-~-D-glucosaminidase (NAG) enzyme excretion in a group of Hungarian storage battery workers exposed to lead. Lead-exposed group

Control group

n = 105

n = 105

P

423.8_+68.4 0.23 + 0.05 4.9_+0.9 9.6+2.5

331.9_56.1 0.29_+ 0.07 7.0+ 1.2 3.4-+ 1.0

<0.01 < 0.01 <0.01 <0.001

Serum urate (pmol-litre)* Urinary uric acid/urinary creatinine Fractional urate excretion (%) Urinary NAG (units/mmol creatinine)

* Mean _+ SD. To convert values for serum urat¢ to mg/100 ml, divide by 59.48. From Po6r and Mituszova (1988).

0.27

0.24

0.21 E +J

g (J

0.18

0.15 o L_ 3

0.12

0.09

0.06

+

/

l

450

~

I

i

500 550 600 Serum urate (umol/litre)

.

I

650

Figure 1. Relation between serum urate and urinary uric acid values in hyperuricaemic cases in a group of 28 workers exposed to lead. r = -0.823; y = 0 . 7 2 6 - 0 . 0 0 1 2 x; P<0.0001.

SATURNINE GOUT

55

tubular urate excretion (Garrod, 1859) was confirmed by Emmerson (1965) and Ball and Sorensen (1969) by labelled glycine incorporation and labelled urate turnover studies. The fact that saturnine gout is frequently associated with renal failure supports a renal mechanism (Wedeen et al, 1979; Batuman et al, 1981; Wright et al, 1984). The role played by subclinical lead exposure in causing gout was studied by Campbell et al (1978) in Glasgow, Scotland. In 105 storage battery workers in Hungary chronically exposed to lead there was a decreased value of fractional urate excretion (urate clearance/ creatinine clearance × 100) and of the urinary uric acid/creatinine ratio (Table 1) (Po6r and Mituszova, 1988). In 28 workers with hyperuricaemia the serum urate concentrations and urinary uric acid/creatinine ratios showed an inverse correlation (Figure 1). These results indicate that the enzymes involved in the renal tubular transport of uric acid are very sensitive to lead toxicity. The finding of an increase in N-acetyI-fl-D-glucosaminidase excretion by Po6r et al (1987) in these workers (Table 1) also supports the view that the renal tubules are very sensitive to lead, as has also been reported by others (Meyer et al, 1984). It is worth noting that parenchymal renal damage was not observed in any of the workers studied by Po6r and Mituszova (1988). Tak et al (1981) made the intriguing observation of lead-urate complexes in the serum of patients with saturnine gout. These complexes promoted urate nucleation and crystallization, which may explain the mechanism of acute gouty arthritis occurring in saturnine gout. Farkas et al (1978) noted that lead predisposed to the formation of guanine crystals, but the role of these in causing acute gouty arthritis in saturnine gout remains to be established. CLINICAL FEATURES In both acute and chronic lead intoxication the onset of gout is usually preceded by symptoms of lead toxicity, such as colic and constipation, radial and peroneal nerve palsies, etc (Crutcher, 1963). Due to disturbance in porphyrin synthesis and increased fragility of red blood cells, anaemia and basophil stippling may develop (Albahary, 1972). Prognosis of lead poisoning depends largely on the extent of renal damage (Wedeen et al, 1975). Renal damage is often accompanied by hypertension (Batuman et al, 1983). Gout is usually the consequence of renal failure but might develop without clinical evidence of renal failure (Campbell et al, 1978; Po6r and Mituszova, 1988). Primary gout is traditionally considered in three stages: asymptomatic hyperuricaemia, acute gouty arthritis, and later chronic gout. However, in saturnine gout, acute gouty arthritis may not occur. The serum urate concentrations are usually higher in saturnine gout than in primary gout, but the urinary uric acid excretion and urate clearance are significantly lower (Emmerson, 1965; Po6r and Mituszova, 1988). In acute gouty arthritis due to lead intoxication, uric acid crystals are

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6. PO6R AND M. MITUSZOVA

found, as in primary gout, and are the cause of the inflammatory reaction (Malawista et al, 1985). Whether lead-urate crystals form as well in acute saturnine gout is not known. Acute saturnine gout tends to affect the knee joint more commonly than the first metatarsophalangeal joint, in contrast to primary gout (Halla and Ball, 1982). Polyarticular acute saturnine gout is not uncommon and appears to be more common than in the primary form of gout. The frequency and duration of acute saturnine gouty arthritis are similar to those in primary gout but may be milder (Emmerson, 1968). As in primary gout, recurrent acute attacks occur in saturnine gout. Acute gouty attacks become less severe in saturnine gout once the chronic tophaceous stage is reached (Halla and Ball, 1982). The tophi in saturnine gout have the same histological features as in primary gout. Although uric acid nephrolithiasis is common in primary gout (Klinenberg et al, 1975), renal calculi are rare in saturnine gout because of the diminished uric acid excretion (Emmerson, 1965). An important clinical finding differentiating primary gout from saturnine gout is that, in the former, renal failure is a late occurrence, whereas, in the latter, it frequently precedes the onset of articular manifestations. Pyelonephritis has been reported to be rare in saturnine gout (Morgan et al, 1966). In primary gout, ischaemic heart disease and cerebrovascular disease are major causes of death (Yii and Talbott, 1980). However, there are no reliable data on the risk of these complications in lead-induced hyperuricaemia and gout. DIAGNOSIS The diagnosis of saturnine gout rests on the triad of: (1) verification of the diagnosis of gout; (2) confirmation of lead exposure prior to the onset of gout; and (3) exclusion of other causes of gout. The diagnosis of gout in no way differs from that of primary gout (Wallace et al, 1977). Verification of lead exposure is somewhat more difficult. The earliest biochemical abnormality indicating lead toxicity is decrease in ~5aminolaevulinic acid dehydratase in red blood cells. The function of this enzyme is to catalyse transformation of iS-aminolaevulinic acid to porphobilinogen. Both the levels of this enzyme and that of lead in serum and urine quickly return to normal when exposure to lead ceases (Morgan and Burch, 1972). Increase of urinary b-aminolaevulinic acid and coproporphyrin III persist for a longer period after exposure to lead. Previous lead exposure occurring some years before can only be confirmed by a calcium disodium edetate, CaNaz-EDTA, test which mobilizes lead from the bones by chelation (Emmerson, 1963) or by X-ray fluorescence analysis (Ahlgren et al, 1976). Morgan and Burch (1972) have suggested the following laboratory parameters for confirming lead exposure. 1.

iS-Aminolaevulinic acid dehydratase concentration in blood lower than 80U.

SATURNINE GOUT

57

2.

Lead content of blood in excess of 80ttg/100ml (1 tlg/100ml lead = 0.048 itmol/litre). 3. Baseline lead excretion in urine in excess of 80rig/24 hours. 4. Urinary6-aminolaevulinic acid concentration higher than 600 ttg/100 ml. 5. Lead excretion in excess of 650 ttg/24 hours after calcium disodium edetate, administered as l g intravenously or two intramuscular injections totalling 1 g. The diagnosis of saturnine gout essentially rests on the exclusion of other causes of gouty arthritis, especially alcohol-induced gout (Boss and Seegmiller, 1979). Unlike primary gout, a history of gout in family members does not occur in saturnine gout. TREATMENT Treatment of saturnine gout consists of elimination of lead from the body and the treatment of gout. The latter is treated in more or less the same way as primary gout. Acute gouty arthritis should be controlled with nonsteroidal anti-inflammatory analgesics or, if persistent, with corticosteroids, as in other forms of gout (Wallace, 1977). Colchicine is best avoided in view of its toxicity. Allopurinol is the drug of choice to normalize the hyperuricaemia and is given in the same dosage as in primary gout (Yi, 1974), provided renal function is normal. Uricosuric agents, such as probenecid and sulphinpyrazone, should only be prescribed in case of intolerance to allopurinol. Intercurrent urinary tract infections should be treated promptly and hypertension, if present, controlled. It is useful to keep the urine pH at an optimum of 6.4-6.8, and 1.5-21itres of fluid should be drunk daily. Excessive alcoholic consumption should be prohibited to avoid renal urate retention from lactic acidosis (Lieber et al, 1962). In saturnine gout, renal failure is frequently present and it is therefore important to reduce the dose of allopurinol because of the prolonged half-life of the active metabolite, oxypurinol. Serious toxic effects of allopurinol, including the syndrome of fever, skin rash, progressive renal failure, eosinophilia and hepatitis (the so-called allopurinol hypersensitivity syndrome), occur in patients with renal failure. The mortality from this complication is high, emphasizing the need to adjust the dose of allopurinol if renal failure exists. The toxic effects of allopurinol are enhanced by thiazide diuretics. Uricosuric agents increase the excretion of oxipurinol but the half-life of probenecid is prolonged by about 50% by allopurinol. The first step in the treatment of lead toxicity is to remove the patient from the source of lead poisoning at his work place or from what he is ingesting. Removal of lead from the body can be achieved by calcium disodium edetate which acts by forming highly stable chelates with lead which are excreted by the kidneys in large quantities (Chisholm, 1970). The successful use of calcium disodium edetate in plumbism is due to a large extent to the greater affinity of the drug for lead than for calcium, so allowing the former to replace the latter in the complex. Treatment should begin as soon as the diagnosis is made and continued until all the lead has been excreted.

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The principal toxic effect of calcium disodium edetate is on the kidney, the proximal tubules being especially vulnerable. This probably results from lead, either released from, or as part of the lead chelate, causing interference with susceptible intracellular enzyme systems in tubular cells. Since the renal toxicity of the drug is dose-dependent (Gilman et al, 1980), regular monitoring of renal function during treatment is mandatory. Other complications of calcium disodium edetate include a histamine-like reaction, with sneezing, nasal congestion and lacrimation, anaemia and glycosuria, prolongation of the prothrombin time, a dermatitis similar to that seen in vitamin B6 deficiency, transient mild hypotension and inversion of T waves on ECG. Calcium sodium edetate is poorly absorbed when given orally; for therapeutic use it must therefore be administered parenterally. One gram in 250-500ml of 5% glucose in water or 0.9% saline solution is administered slowly by intravenous infusion over a period of an hour. Thrombophlebitis may occur if the solution is too concentrated. A febrile reaction may occasionally occur following intravenous administration. Two courses can be administered daily for 3-5 days and then repeated after 2-14 days as indicated. It is recommended that the total dose should not exceed 500 mg/ kg if toxicity is to be avoided. Calcium disodium edetate can also be administered intramuscularly, 1 g being given one to three times a week. In the case of lead nephropathy, Wedeen et al (1979) recommend 1 g intramuscularly three times a week over a period of 6 to 50 months. This, he claims, not only normalizes lead excretion by the kidney but also significantly improves the glomerular filtration rate. Renal function has also been observed to improve following intravenous therapy (Morgan, 1975). Tetraethyl lead poisoning which occurs in the petroleum industry responds poorly to treatment with calcium disodium edetate. Dimercaprol is another chelating agent which is frequently used in the treatment of lead poisoning, often together with calcium disodium edetate. Dimercaprol is administered intramuscularly in a dose of 4 mg/kg every 4 hours for 48 hours, then every 6 hours for 48 hours, and finally every 6-12 hours for an additional week. The combination of calcium disodium edetate and dimercaprol is more effective than either alone. It is important that, if the two drugs are used in combination, the dose of calcium disodium edetate be given 4 hours after the administration of dimercaprol. o-penicillamine is well absorbed when given orally and may be used together with the two other chelating drugs in a dose of 250 mg four times daily for 5 days. With chronic administration the dose should not exceed 40 mg/kg per day. Lead poisoning in children often presents with severe encephalopathy and has a high mortality. Treatment requires to be begun as promptly as possible, with both calcium disodium edetate and dimercaprol in the followlng dosage: first dose, dimercaprol only, 4 mg/kg intramuscularly; every 4 hours thereafter, in addition to dimercaprol, calcium disodium edetate 12.5 mg/kg intramuscularly. This is continued for 5 days and has proven to date the most effective form of therapy.

SATURNINE GOUT

59

It is a platitude but, nevertheless, a truth that the prevention of lead toxicity, especially as an occupational hazard, is of p a r a m o u n t importance.

SUMMARY The history of saturnine gout is almost as old as civilization itself. Studies carried out in recent decades explain the development of hyperuricaemia and gout, with the inhibiting effect of lead on the tubular urate transport causing decreased urate excretion. In the case of lead intoxication these effects are often associated with renal failure but may occur without clinical features of lead toxicity and renal damage. The clinical features of saturnine gout are essentially similar to those of primary gout; however, acute attacks tend to occur in the knee m o r e frequently than the first metatarsophalangeal joint. Acute attacks in saturnine gout are frequently polyarticular and tophi rarely develop. The diagnosis of saturnine gout rests on the history of exposure to lead, clinical features of lead toxicity, biochemical confirmation of high serum lead levels and other biochemical abnormalities, and the exclusion of other forms of gout. T r e a t m e n t consists of excluding the patient from further exposure to lead, the use of chelating agents to remove lead, and control of acute gouty arthritis and hyperuricaemia.

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