Saturnine gout: A review of 42 patients

Seminars in Arthritis and Rheumatism VOL. XI, NO. 3

Saturnine

FEBRUARY

1982

Gout: A Review of 42 Patients By James T. Halla and Gene V. Ball

T

HE CONCEPT of lead poisoning acquired through negligence or malfeasance is as old as alchemy, from which the term saturnine, as in saturnine gout, is derived. In this review, we relate our long-term observation of patients with saturnine gout, a consequence of drinking leadcontaminated moonshine. The accidental contamination of alcoholic beverages with lead has been recognized for centuries. Lead has been added intentionally to wines to improve their flavor or prevent spoiling, attested by Imperial ordinances interdicting this practice as early as 1437, and as late as 1837, wines of France were examined by tasters trained to detect lead. Gout as a complication of chronic lead intoxication was described as “saturnine gout” by Musgrave in 1703, and considered at length by Garrod who noted that onefourth of all his gouty patients were painters or other artisans with occupational lead poisoning.‘,* Garrod’s attention was thus drawn to the role of lead poisoning in the pathogenesis of gout by the obvious occupational exposure of these patients, and by other recognizable features of plumbism, anemia being one. He did not consider alcohol as the source of saturnine gout in any of his patients, even though he was intrigued by the observation that gout was far more common among the bibulous English than among their equally bibulous Russian, Scottish, Polish, Swedish, and Danish counterparts, and he attributed this to a unique property of the port and other fortified wines favored by the English. Garrod analyzed various constituents of fortified wines in search of a gout-inducing property. He did not analyze the lead content of these wines, as was done a few years ago, and in which Seminars in Arthritis and Rheumatism, Vol. 1 1, No. 3 (February). 1982

we found as little as 320 pgrams of lead per liter in a 1800-1820 Malaga, and as much as 1900 pgrams of lead per liter in a 177&18 10 Canary wine. Lead levels of modern wines, determined as controls, were 100-200 mcg Pb/liter.3 This buttressed our supposition that lead poisoning might have contributed to the 18th and 19th century “epidemic” of gout in England. While this evidence which links wine and lead poisoning and 19th century gout is not irrefutable, moonshine is linked firmly to lead poisoning and saturnine gout. Moonshine, the “aqua-vitae” of Southern fable, began as contraband whiskey hurried ashore in Britain on nights illuminated by moonshine. Saturnine gout as a complication of long indulgence in moonshine has been recognized for many years and has been studied in areas of the South such as Durham, North Carolina, and central Alabama.4,5 This review examines our more recent experience with chronic lead intoxication and gout and the course of patients with saturnine gout. During the years 1970-1976, 462 patients at the Birmingham VA Hospital were assigned a code (ICDA) designating a history of exposure to lead with or without an increased body burden of lead: 79 of these 462 were given a primary diagnosis of plumbism, and of these 79, 42 had gout. The 42 patients comprised 36% of the total From the University of Alabama in Birmingham, Department of Medicine. Division of Clinical Immunology and Rheumatology. Birmingham, Alabama. Address reprint requests to Gene V. Ball, M.D., Department of Medicine, Division of Clinical Immunology and Rheumatology, University Station, Birmingham, Alabama 35294. 0 1982 by Grune & Stratton, Inc. 0049-0172/82/I 103-0001 $OI.OO/O

307

HALLA

number, 118, of gout patients seen during these years. Plumbism was suspected clinically and indicated an increased body burden of lead whether symptomatic or not. Plumbism was established by the following laboratory criteria? an unstimulated urinary lead value more than 0.08 mg per 24 hr, or urinary lead levels more than 0.6 mg per 24 hr following the intravenous infusion of 1 g of edetate disodium calcium (EDTA), or a serum delta aminolevulinic acid dehydratase (ALA-D) of less than 80 U. This enzyme, which catalyzes the conversion of delta aminolevulinic acid to porphobilinogen, is exquisitely sensitive to the effects of lead, low values having been found in inhabitants of inner cities whose exposure was presumed to be gasoline fumes.’ All but the most remote exposure to lead will generally depress enzyme activity that otherwise appears to be affected only by acute alcohol intoxication or blood transfusions.’ Determinations of the enzyme ALA-D were performed by the method of Burch and Seigel’ and lead levels using an atomic absorption spectrophotometer (Perkin-Elmer Model 303).” The statistical significance of the differences was assessed by Student’s t test and chi-square method. RESULTS

The 42 saturnine gout patients had either elevation of urinary lead or decrease in ALA-D or both. In 33, stimulated urinary lead levels were increased, and in 24, the ALA-D activity was decreased (Table 1). The majority of these 42 men were black, and by history all had consumed regular and excessive quantities of moonshine for a minimum of 3 yr. Table 1. Criteria for Diagnosis of Plumbism in 42 Patients With Saturnine

Gout The features of gout in these 42 patients were examined in more detail. All had serum urate levels greater than 7.0 mg/dl (range: 7-19; mean: 10.7). The diagnosis of gout was made by identifying joint fluid intracellular urate crystals in 33, or by noting a rapid disappearance of typical arthritis in response to anti-inflammatory agents in nine (colchicine, five; indomethacin, four) without evidence of other rheumatic diseases. Tophi were noted in four (9.5%) and radiographic changes compatible with gout were seen in nine of 37 (24%) patients: (metatarsophalangeal joints, eight; wrist, one). The pattern of joint involvement at the time of active synovitis was defined as polyarticular (more than 3 joints) in 15 (36%). As given in Table 2, a total of 154 joints was involved, most often in the lower extremity (99/164 = 60%); individual joint involvement was knee, metatarsophalangeal, ankle, and wrist in decreasing frequency. The relationship between onset of gouty arthritis and diagnosis of plumbism was determined for each patient. In 26 (62%) patients, gout and plumbism were diagnosed simultaTable 2. Distribution

Criteria

17

Elevated stimulatad urinary lead and depressed ALA-Dt

of Involvement

of Individual Joints in

Patients With Saturnine

Elevated stimulated 24-hr urinary lead*

16

Elevated unstimulated urinary lead and

Gout

Joint

Knee

35 (83%)

MTP

25 (60%)

Ankle

23 (55%)

Wrist

20 (48%)

6

Tarsal

12 (30%)

Depressed ALA-D

2

Shoulder

10 (24%)

Elevated unstimulatad urinary lead

1

Hand*

9 (22%)

Hipt Sternoclaviculart

4 (9.5%)

depressed ALA-D$

l24-hr

urinary lead value greater than 0.6

mg following

edetate disodium calcium (EDTA). tDelta aminolevulinic acid dehydratase (ALA-D) level lass than 80 U. $24-hr urinary lead value greater than 0.08 mg/24 hr.

BALL

Neurologic and gastrointestinal problems related either to lead intoxication or ethanol intake in the 42 patients with gout were compared to those 37 patients with plumbism not having gout. The frequency of liver disease in the form of alcoholic hepatitis or cirrhosis, peripheral neuropathy or seizures did not differ in the two groups, whereas pancreatic disease occurred with a higher frequency in the gouty group (p = 0.015).

Gout Patients

AND

*Proximal

1 (2%)

interphalangaal and metacarpaphalangeal

considered as one. tNo crystals or radiographic changes noted.

joints

neously; in 11 (26%), the diagnosis of plumbism preceded the diagnosis of gout by a mean of 4.5 years (range: l-11); and in five (12%), the diagnosis of gout preceded the diagnosis of plumbism by a mean of 4.2 yr (range: 2-8). Two of these five had indications of possible plumbism, including mild azotemia and anemia, at the time gout first appeared. Plumbism was considered in the diagnostic evaluation whenever a history of chronic moonshine ingestion was obtained in a patient with mild azotemia and anemia. Information pertaining to the course of gout was available for 35 patients (Table 3). Two or more attacks of gout occurred in 24 patients and there was no recurrence in 11. These two groups were evaluated with respect to renal status and EDTA therapy. In the group having recurrent gout, the mean follow-up was longer than those not having recurrent gouty attacks (p = 0.03) and renal function was stable in about 50% of the patients in each group. Adequate deleading for a single course of EDTA was defined as a 24-hr urinary lead value less than 0.6 mg after administration of 1 g of EDTA intravenously following a 3-5-day treatment course (a course consisted of 1 g of EDTA administered intravenously for 3-5 days).5,6 In the group with recurrent gout, 10 patients received 20 courses of EDTA. Available data concerning adequacy of deleading indicated that only one patient achieved a urinary lead value less than 0.6 mg per 24 hr. In the remaining 14, no EDTA therapy was given. In the group without recurrent

attacks, nine received 14 courses of EDTA, and seven were deleaded adequately once. In the absence of valid information concerning continued alcohol use, these apparent differences will not be emphasized. Renal In the group of 37 patients with plumbism but without gout, 24 (75%) had variable renal insufficiency (serum creatinine > 1.2 mg/lOO ml) at some time during their follow-up, and 24 were hypertensive (>140/90). In the saturnine gout group, 24 (57%) were hypertensive. The mean of 166 serum creatinines determined for the 42 patients with saturnine gout was 1.9 mg/dl (range: 0.8-9.5). At the time of diagnosis of gout, 13 (3 1%) had a normal serum creatinine concentration (Table 4). Eight of these 13 were followed an average of 5.8 yr (range: 3-8) and continued with a normal creatinine. In the other five, follow-up was longer (average: 11.4 yr; range: 9-17 yr) and the serum creatinines increased (mean: 1.9; range: 1.5-2.6). Recurrent gouty attacks occurred but seemed to be less severe and less frequent in these 13 patients compared to those patients whose serum creatinines were elevated at the time of diagnosis of gout. Twenty-nine (69%) of the saturnine gout Table 4.

Follow-Up Information

Normal Renal Function Number of patients

Table 3. Follow-Up Information

on the Course of Gout in

35 Patients With Saturnine

Gout

for 35 Patients Based on

Renal Function at the Time of Initial Diagnosis of Plumbism

13

Abnormal Renal Functwn 22

Creatinine (Mean)

1 .O mgjdl

1.9 mg/dl

Duration of follow-w

7.5 yr

5.5 yr

(2-17)

(1-l

1)

Renal status Number of patients Mean duration of follow-up

24 6.4+

3.7yP

11 4.1 r 1.9yr

EDTA Tharapyt

8

5

14

11

14

3.5

0

Stable renal function

6

5

10

9

Worsening renal function

5

9

7

12

Adequate

1

7

Inadequate

9

2

EDTA therapy Adequate* Inadequate

Renal Statust Stable

14

6

Worsened

10

5

*Mean k standard deviation (in years). tAdequate deleading defined as a 24-hr urinary lead value less than 0.6 mg after 1 g edetate disodium calcium (EDTA). tAbnormal renal function defined as serum creatinine greater than 1.2 mg/dl.

6

Recurrent gout

Average number of recurrences/year

Stable Worsening

3t 49

4t 87

*Adequate deleading defined as a 24-hr urinary lead value less than 0.6 mg after 1 g edatate disodium calcium (EDTA) following a 3-5-day

treatment course.

tAll patients had stable renal function. SAli patients had worsening renal function. SAlI patients had stable renal function. %aven patients had worsening renal function.

HALLA AND BALL

310

patients had serum creatinines greater than 1.2 mg/dl at the time of diagnosis. Follow-up data was sufficient for 22, with a mean follow-up of 5.5 yr; 14 had increasing azotemia and eight, stable serum creatinine concentrations. In the group with increasing azotemia, mean initial serum creatinine was 1.6 mg/dl and during a 7-yr follow-up, gout was recurrent in nine of the 14. In those eight with stable but initially abnormal renal function, the first creatinine was 1.7 mg/dl, the average follow-up short (3 yr), and gout recurrent in five. In the azotemic group as a whole, gout tended to be more polyarticular as evidenced by the fact that of the 15 patients with polyarticular gout, 13 were azotemic; otherwise, the clinical features of gouty arthritis were similar in patients regardless of initial renal function. Results of treatment with EDTA are recorded in Table 4. Among the group of 13 patients having normal renal function at first determination, 26 courses of EDTA were given to seven. In the eight patients whose renal function remained stable, data was insufficient for evaluation of deleading in five, and three were adequately deleaded as evidenced by 24-hr urinary lead levels less than 0.6 mg. None of these was retreated in the follow-up period of this study. Of those five remaining patients who became azotemic, four received EDTA but continued to have urinary lead values greater than 1 mg in 24 hr. Twelve of the 22 whose serum creatinines were elevated at first determination received 35 courses of EDTA. Those patients with urinary lead levels greater than 0.6 mg per 24 hr postEDTA (inadequate deleading) experienced progressive renal failure. Renal biopsy was obtained in four to determine the etiology of chronic renal insufficiency. All four had evidence of chronic interstitial nephritis characterized by interstitial fibrosis, tubular degeneration, periadvential fibrosis of small vessels and paucity of inflammatory cells. Hematologic At the time of diagnosis of gout, 36 of 42 (86%) patients had a hematocrit less than 39% with a mean of 33 (range: 24-42). Basophilic stippling was looked for in 30 patients and was found in 18. Hemoglobin electrophoresis or

sickle cell preparation was performed in 26 patients; AS hemoglobin was found in only two patients. The others had AA hemoglobin or a negative sickle cell preparation. Three of 25 patients had less than 10% saturation of total iron binding capacity. DISCUSSION

Poisoning acquired from lead contaminated paint, earthenware, or alcoholic beverages has dogged mankind from the beginning of recorded history. Homemade alcohol has been the usual source of lead in the southeastern United States, alleged to be the moonshine belt. A study of moonshine made in Alabama in the early 1960s showed quantities of lead presumed to be toxic in 40% of specimens.” Since this alcohol is produced illegally and profit is a powerful incentive for moonshining, distilleries are made of easily available and inexpensive materials. Thus, an automobile radiator with its many leadsoldered connections often serves as a condenser. Reminiscent of the spoiled wines of France and their treatment with “litharge,” lead plates may even be added to the mixture by the distiller to “improve” the taste. In the late 1960s the production of illegal alcohol was estimated at greater than 55 million gallons per year; however, moonshining seems to have declined gradually in the United States since 1955. One measure of this decreased production can be found in the number of stills seized by federal and state authorities.‘2*‘3 The total number of stills seized between 1950-l 955 remained fairly stable at 18,000-20,000 per year; however, this number was 5000-6000 in 1970 and in the hundreds in the early 1970s. In the late 1970s this number dropped even further and law enforcement is now handled almost entirely at state and local levels. The decline in moonshine production is attributed to active law enforcement at all levels, rising costs of production, and a widespread public information campaign warning of moonshine poisoning. This may in part be responsible for the observed decrease in cases of saturnine gout in the Birmingham VA Hospital during the period represented in this study. At present, few cases of saturnine gout are being seen and they now represent less than 5% of all gout in this hospital.

311

Clinical lead poisoning gives rise to recognized but nonspecific syndromes. Many organ systems are vulnerable to the effects of lead and our paper emphasizes three: (1) musculoskeletal (gout); (2) renal (interstitial nephritis); and (3) hematopoietic (anemia). Almost all patients reported with saturnine gout due to inveterate consumption of moonshine have been black males lacking a family history for gout.4,5*‘4The features of gout in our patients were not unlike those of gout due to any cause. As in primary gout, the lower extremities were involved most commonly, the foot less than the knee. The frequency of polyarticular involvement may have been higher, at least in males, than that generally reported in primary gout,15 whereas tophi occurred less commonly and gouty attacks in our patients responded in the usual fashion to standard therapy. These findings are not unlike those noted by Emmerson16 in his follow-up of gouty patients who had a past history of childhood lead poisoning. However, he did note a large number of females in his gouty patients, as well as milder disease. In addition, sequelae of acute lead encephalopathy and a family history of hypertension were common in these patients. These differences probably reflect the different etiologies of lead toxicity in the two groups. The effect of lead on the kidney may be acute or chronic. Acute renal effects are seen, usually in children, after exposure to high levels of lead and are reversible by chelation therapy.‘* Nonspecific degenerative changes typically in the proximal tubule are the usual pathological findings.” A more recently described effect of lead of unknown clinical significance involves the distal tubule and is manifested by a decreased activity of the renin-aldosterone system.” The chronic effects of lead are the consequence of prolonged lead exposure; a slowly progressive lead nephropathy results and has been described as an aftermath of childhood lead poisoning,6,” long-term industrial exposure to lead,22923and long-term drinking of lead-contaminated alcohol.24 Attempts to confirm the relationship between childhood lead intoxication and chronic nephropathy have not been successful in at least two studies in the United States.25*26 Patients acquiring lead poisoning from alcohol

have been described in American sources as male, usually black, aged 45-55, often azotemic and anemic, but otherwise asymptomatic except for gout.4.27 The occurrence of gouty arthritis offers a contrast with other types of renal failure in which hyperuricemia but not gout is common.28 Lead related changes include small-sized kidneys, interstitial and periadvential fibrosis, and slowly-progressive renal failure. For reasons that are unclear, occupational lead nephropathy due to long-term industrial lead exposure and childhood lead exposure in the United States apparently are uncommonly associated with gout and disturbances of urate metabolism; this is different from the experience of childhood lead poisoning in Australia and the nephropathy related to moonshine ingestion.‘9*25529,30Also, in contrast to findings in Europe and Australia, saturnine gout and adult lead nephropathy have rarely been recorded in the United States except in drinkers of moonshine whiskey in the southeastern states.3’ While hyperuricemia in plumbism may have several etiologies, a decreased urate clearance is the main cause,*’ the patients being under excretors and normo-producers of urate. Twenty-nine of our saturnine gout patients had elevated creatinine levels at the time gout was established, while 13 had normal levels. This observation is of interest in light of earlier studies reported from this institution in which it was determined that while impaired renal excretion was the sole cause of hyperuricemia in three patients with saturnine gout, there was a greater decrease in the renal clearance of uric acid than could be accounted for solely on the basis of decreased glomerular filtration.*’ This disparity between reduction of tubular urate secretion and creatinine clearance suggests a specific effect of lead on tubular function similar to the inhibition of tubular secretion of urate by weak organic acids.** Alcoholism, common in these patients, undoubtedly imposes additional barriers to the excretion of urate. Baraf et al.32 observed that plumbism was not an invariable finding in hypertensive patients who had drunk moonshine. Only 50% of their patients exposed to moonshine demonstrated excessive lead stores. They suggested that alcohol and other factors such as

312

hypertension may be significant in the production of hyperuricemia and gout. Morgan and Hartley33 also reported that alcohol and hypertension may be potentiating factors in the development of lead nephropathy. The third organ system to be considered is the hematopoietic system. The in vivo effects of lead on erythrocytes in humans are numerous: accumulation of lead, increased osmotic resistance, increased mechanical fragility, increased glucose consumption, decreased sodium-potassium dependent ATPase activity in membrane fragments, and elevation in the number of immature red blood cells.‘8”“36 Anemia of varying degree is a manifestation, often the earliest, of clinical lead intoxication. The mechanism of the anemia appears to be a combination of decreased erythrocyte production as a result of the interference of lead with hemoglobin synthesis and increased destruction as a result of direct damage by lead to the red cell itself. Leadinduced disturbances in heme synthesis are a manifestation of the inhibitory effect of lead on the activity of sulfhydryl-dependent enzymes in soft tissue. The anemia noted in almost 90% of our patients may have been due to factors other than lead; however, sickle cell disease was not one of them. Serum iron and iron binding capacity were determined in almost 50% of patients and found to be compatible with chronic illness. Furthermore, about 70% of these patients had some degree of renal failure. Limited data on serum folic acid and B12 levels and erythrocyte glucose-6-phosphate dehydrogenase levels suggested a minor role for these in the pathogenesis of the anemia. Thus, lead toxicity appeared to be of major importance in the pathogenesis of anemia in these patients. In order to consider the efficacy of chelation therapy with EDTA, a brief review of lead metabolism seems warranted. The dynamics partitioning absorbed lead among various body tissues are still poorly understood. Nevertheless, there appears to be agreement that the major site of storage of lead is bone; this constitutes the largest quantity of body lead with the slowest turnover. The slow removal may result from binding of lead to metabolically sluggish bone.18 The physiological significance of increased bone storage is not entirely clear, but it is clear that as

HALLA AND BALL

the intake of lead increases, the rate of absorption may exceed the rate at which lead can be excreted or stored in bone; when this occurs blood and soft tissue lead levels rise.5.‘43’8.‘9~37 Lead deposition occurring in the brain, kidney, and hematopoietic system is of considerable toxicologic significance. Blood lead is mainly (>90%) bound to erythrocytes. This pool is in direct equilibrium with ingested lead, body tissue lead, and urinary lead, 283384 although measurement of blood lead concentration may not correlate well with symptoms related to lead intoxication. Anemia is characteristic of lead intoxication and since blood lead is bound mainly to erythrocytes, serum lead concentration may be measured artifactually low unless one corrects for anemia.’ When lead exposure ceases, the remaining blood lead is fairly rapidly excreted. However, the kinetics of lead distribution indicate intercompartmental exchange among all compartments and residual soft tissue lead may be metabolically active. The adverse effects of lead are related to its concentration in the soft tissue. Chelation therapy mobilizes lead from bone and soft tissue. Since lead is stored in bone and bone renews itself slowly, there is a gradual reequilibration leading to sustained lead levels in blood and soft tissue even without additional lead exposure.5,7.‘4.‘9.4’43 Studies in human adult volunteers and in adult dogs have shown that it takes at least twice as long to excrete an excessive body burden of lead as it does to acquire it.44 Therefore, a rest period between treatments is indicated in treating the chronically leadexposed patient, allowing for redistribution of lead and increasing the amount of available lead in succeeding treatments. Chelation therapy has been reported to be successful in acute plumbism, in reversing hematologic changes and in improving neurologic complication due to lead.37*4U6 Chisolm has advanced the concept that successful chelation therapy requires the administration of a sufficient molar excess of the chelating agent over the lead, which apparently minimizes dissociation of metal chelates during mobilization and excretion. This implies that the highest dosage of chelating agent consistent with safety is required. Since the most pronounced effects of EDTA on urinary excretion of lead occur during

SATURNINE

313

GOUT

the initial phase of intoxication, early therapy is most effective.44*4S The toxicity of EDTA is, in general, relatively low. EDTA is freely filtered at the glomerulus and is rapidly excreted via the kidney; nephrotoxicity is the major adverse effect seen with EDTA therapy and is usually associated with very high doses (>8 g) of drug.47*4*The renal toxicity may depend on the amount of chelated metal delivered to the tubules, the blood EDTA level and the time of exposure of the proximal tubules to EDTA. Batuman and Wedeen49 have pointed out the considerable experience throughout the world that has accumulated regarding the use of EDTA as a diagnostic and therapeutic agenPO and it has proven safe and effective. There is meager information regarding therapy of chronic lead nephropathy although Morgan reported the results of treatment of 17 patients with lead nephropathy.23*s’ Modest reduction or stabilization of serum creatinine values following repeated short courses of intravenously administered EDTA were noted in five patients; however, 12 who either continued to ingest moonshine or were inadequately treated had progressive renal disease despite EDTA

therapy. Wedeen et al.’ studied the effects of chelation therapy on renal function in occupational lead nephropathy. Eight patients received long-term chelation therapy (1 g EDTA intramuscularly thrice weekly for 6-50 mo) and all were removed from lead exposure. In four patients, the glomerular filtration rate rose more than 20% during treatment while EDTA mobilized urinary lead levels fell to normal; in two, no significant changes in renal function occurred and in the remaining two patients, slight deterioration was seen. In our patients, those with worsening renal function, albeit followed the longest time, were for the most part inadequately deleaded and those with stable renal function were adequately deleaded. Similar results were found regarding recurrent gout in that patients adequately deleaded tended not to have recurrent attacks of gout. However, several factors obviate a rigid interpretation of the results of EDTA therapy in regard to chronic nephropathy and gout: the doubt regarding continued moonshine ingestion, the failure to repeat lead mobilization therapy in several of our patients and the naturally slow progression of lead-induced renal disease.

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