- Email: [email protected]
Chronic inorganic mercury poisoning due to laxative abuse
Chronic Inorganic Mercury Poisoning Due to Laxative Abuse A Clinical and Ultrastructural
JACK R. WANDS,
M.D.*
SHARON WHELAN WEISS, M.D JOHN H. YARDLEY, WILLIS C. MADDREY.
M.D. M.D.
Baltimore, Maryland
From the Departments of Medicine and Pathology, The Johns Hopkins Hospital and School of Medicine, Baltimore, Maryland 21205. This study was presented in part at the International Academy of Pathology (February 1973) [l] and the American Gastroenterological Association (May 1973) [2]. Requests for reprints should be addressed to Dr. Jack R. Wands. Manuscript accepted November 13, 1973. Present address: Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts 02 114. l
92
July 1974
The American
Study
Chronic mercury poisoning developed in two patients following long-term daily ingestion of a laxative preparation containing mercurous chloride (calomel). There were major clinical manifestations attributable to toxic effects of mercury on the kidneys, gastrointestinal tract and central nervous system. Chronic renal failure developed in both patients and was manifested by elevated serum urea nitrogen and creatinine levels, with proteinuria but no abnormalities in the urinary sediment. Both patients showed evidence of renal tubular defects. Both patients had colitis with intractable watery diarrhea. In one, the colitis was so severe as to require a diverting colostomy. Dementia was present in both patients, with tremor a prominent feature in one. Tissue mercury levels were highest in the colon (526 pg/g; normal 0.10 pug/g) and kidney (421 pg/g; normal 2.75 pg/g); levels were also significantly elevated in the liver, brain, heart, pancreas, hair, skin, blood and urine. At autopsy both patients showed melanosis coli and blackening of the renal cortex. By electron microscopy the pseudomelanin granules in the colon were atypical in that they were intimately associated with ultra dense crystals identified by electron diffraction as beta mercuric sulfide. Crystals of beta mercuric sulfide were also associated with lipofuscin deposits in renal tubular epithelium and were present free and within macrophages of the renal cortical interstitium and hepatic portal triads. Chronic mercury poisoning due to mercurous chloride-containing laxative preparations should be suspected in patients with a history of laxative abuse who present with unexplained renal failure, colitis, dementia or tremor. Toxicity from mercury may be caused by both organic and inorganic compounds. Organic mercury poisoning may result from exposure to methyl and ethyl mercury compounds utilized in industrial processes and pesticides [3-51. Inorganic mercury poisoning has been detected in cinnabar mind workers, hatters, thermometer makers and infants ingesting calomel-containing teething powders [S-lo]. The symptoms in these two types of mercury poisoning differ. Organic mercury intoxication usually presents with a rapidly
Journal of Medicine
Volume
57
MERCURY POISONING DUE TO LAXATIVE ABUSE-WANDS
progressive
neurologic
illness characterized
by men-
TABLE
Summary
I
Cases
tal deterioration, paresthesia.% ataxia, spasticity, deafness and coma [ 1 I]. In contrast, inorganic mercury poisoning most often presents insidiously, developing after years of exposure, and is characterized by renal failure, gastroenteritis, dermatitis, dementia and tremor [ 121. Chronic inorganic mercury poisoning may also result from medicinal sources such as mercurous chloride-containing laxative preparations. We describe two patients in whom chronic mercury poisoning developed after ingestion of a mercurous chloride-containing laxative for many years. The clinical
manifestations,
fication
of a mercury
fraction
are described.
CASE Case
findings
form
and identi-
by electron
dif-
REPORTS 1.
This 63 year old woman
12) was admitted development been
pathologic storage
of stupor over
generally
constipation,
(D.G.,
JHH No. 36-08-
to the hospital following the progressive good.
1 week.
Because
Her past health had
of long-standing
she had taken a mercurous
chronic
chloride-contain-
ing laxative (Calotabs@‘) every night for 25 years. On admission, the patient was in coma responding to pain stimuli. The blood pressure pulse rate
108/min
the cornea
and respirations
and sclera
stomatitis
150180
was
slow and deep.
present.
Both
Neither
On cardiovascular
the heart was of normal size with a ventricu-
tar gallop. The lungs were clear, and neither spleen was palpable. Neurologic examination tact cranial
only
mm Hg,
had a bluish discoloration.
nor gingivitis
examination
was
nerves,
symmetrical
reflexes,
the liver nor revealed in-
flaccid
extremi-
ties and no Babinski reflex. Initial laboratory mg/lOO
studies
ml and a serum
ml. Urinalysis
showed
revealed
a creatinine
urea nitrogen
no acetone;
of 16.0
of 167.0
2-t
mg/ 100
glucose
and
protein (Combistix@) with a pH of 7.0. The remainder initial laboratory genogram
1-I
of the
studies are given in Table I. A chest roent-
and an electrocardiogram
blood gas studies,
were normal.
using a 28 per cent Venturi
Arterial
mask,
re-
vealed an oxygen tension (~02) of 148 mm Hg, a carbon dioxide tension (pCOp) of 8 mm Hg and a pH of 7.07. Six liters of 0.9 per cent saline solution and 240 meq sodium bicarbonate
were required to correct
deficit and acidosis
during the first day of hospitalization.
There
was progressive
improvement
tal status, and she was completely
in the patient’s
movement. gait was
was observed She became noted.
which worsened ambulatory,
On lumbar
men-
alert by the 2nd hospi-
tal day. At this time a striking static tremor extremity
the initial fluid
puncture
of the upper
during voluntary
and a broad-based cerebrospinal
fluid
Laboratory
~~~____._~
Values in
_ Case 2 .~ __ __ -.
Case 1 1972
Laboratory Values Hematocrit (%) White blood count (per mm3) Sodium (meq/liter) Potassium (meq/liter) Serum urea nitrogen (mg/lOO ml) Bicarbonate (meq/liter) Chloride (meq/liter) Glucose (mg/lOO ml) Creatinine (mg/lOO ml) Calcium (mg/lOO ml) Phosphorous (mg/lOO ml) Magnesium (meq/liter) Urine specific gravity Protein Glucose
1960
1964
31.0 20,000 132.0 4.1
-23.0 5,800 135.0 4.3
18.0 8,700 129.0 4.5
167.0 3.0 99.0 181.0 16.0 5.7 9.8 1.5 1.010
30.0 22.0 100.0 110.0 1.8 9.5 4.2
150.0 9.0 108.0 90.0 16.0 8.0 5.4
. ..
.
1.012 2+
1.013 7+
1+ 2+ 7.0 0.8 5.0 31.0
1+ 2-k 6.5 7 0 PH 1.1 0 .9 Bilirubin (mg/lOO ml) . . SGOT (MIU) . . . . Alkaline phosphatase (MIU) ~. ~___ ._ ~~_~ ~.._ ~~~~-__ ~-------.NOTE: Normal values: bilirubin total 0.1 to 1.1 mg/lOO ml; serum glutamic oxaloacetic acid (SGOT) 0 to 19.0 milliInternational Units(MIU); alkaline phosphatase 10 to 32 MIU. slit lamp examination Audiometry revealed sorineural became
of the cornea and lens were normal. a 50 dB high frequency bilateral sen-
hearing loss.
Watery
diarrhea,
which had been present
profuse and amounted
sigmoidoscopy
the mucosa
with an easily removed, and cultures negative
on admission.
to 2.5 to 3.5 liters/day.
was purple,
for amoebae
and
On
firm and covered
white pseudomembrane.
of stool and a rectal
Smears
biopsy specimen
pathogenic
bacteria.
were At this
point mercury intoxication was clinically suspected because of the neurologic findings, severe colitis, renal failure and the additional
history of prolonged
laxative containing mercurous chloride. The patient’s renal function improved hospital
day, the serum
creatinine
mg/lOO
ml and the
mg/lOO
ml. On intravenous
measured phase
normal.
and phosphate excretion
clearance
the
urea
lateral diffuse slowing, consistent with a diffuse cerebral disturbance. The brain scan was normal. Visual fields and
carbonate
system
level
to 29.0
the kidheys each on the nephrogram
clearance
was
The
17 ml/min
24 hour protein
mg, with urinary sodium 84 meq/liter
presence
with a simultaneous
of a
and by the 23rd
nitrogen
3 ml/min.
54 meq/liter.
urine consistently
ingestion
level had fallen to 3.0
pyelogram,
Creatinine
was 305
and potassium vealed
serum
10 cm; the calyceal
was
pressure, glucose and protein were normal; no cells or organisms were present. Electroencephalogram showed bi-
* Each tablet of Calotabs contains 120 mg mercurous chloride combined with aloes, orizaba. extract bitter apples, oils of cloves and peppermint.
of Initial
1 and 2
ET AL.
of
Urine amino acid analysis cystine
had 2-F to 3-t
and
homocystine.
glucose
reThe
(Dextro-stix@),
blood sugar level of 90 to 140 mg/lOO
ml. The urine pH remained
above
6.5 despite
level of 12 to 18 meq/liter
a serum bi-
and a blood pH of
7.30 to 7.36. Renal tubular acidosis and diarrhea were considered the major factors causing the initial marked metabolic acidosis. On the 31st hospital day a diverting transverse colostomy was performed because of unremitting diarrhea, peri-
July 1974
The American
Journal
of Medicine
Volume
57
93
MERCURY POISONING DUE TO LAXATIVE ABUSE-WANDS
TABLE II
Tissue
Mercury
ET AL.
Levels MercuryLevel&g/g)
Case1
Tissue Colon Mucosa Muscularis Serosa Kidney Cortex Medulla 24 hour urine Ileum Mucosa Muscularis Serosa Rectum Cornea Heart Liver Stomach Pancreas Gallbladder Hair Skin Artery Brain Frontal cortex Cerebellum Feces Serum Bile Thyroid Adrenal Lung
Case 2
526.0 442.6 106.2 0 421.5,424.0* 506.8 103.1 i,OOO.O 200.0 111.6 58.9 0 104.0 29.9 26.3 24.3 22.5 16.9 9.9 9.7,13.5 7.7 6.8
16.0
“Normal” Values 0.10
.. ... ... 2.75
25.0 ...
. . ... ... ... ... ... . . ..
.. 5.3*,5.3f 3.9*,4.5t 3.2 1.f3,1.4,1.3t 0 0 0 0
... ... ... ... ... ... . . ... . . . ... .. ... ... . . ...
0.05
0.15 0.30 0.05
0.10
_____
NOTE: Values determined by Mr. Edward Dalton, USDA Laboratories, Beltsville, Maryland, unless otherwise indicated. * Mercury levels determined by Dr. L. Magos, MRC Toxicology Unit, Carshalton, Surrey, England. t Mercury levels determined by Mr. August Curley and Mr. Edward Girling, CDC, Atlanta, Georgia. neal
necrosis
erative
and fear of colonic
course
was complicated
perforation. by failure
The postopof wound
heal-
ing and fecal peritonitis. Bacteroides septicemia developed and the patient died on the 7ist hospital day. At autopsy (JHH 38440) an organizing peritonitis and pelvic abscess were found. Case 2. A 56 year old woman (A.B., JHH No. 42-12-56) took cascara daily for 15 years and two mercurous chloride-containing tablets (Calotabs) for 6 years prior to death. Her past health had been good, with no history of hypertension, diabetes or urinary tract infections. She had received multiple transfusions for a chronic anemia. She was first admitted (1960) to the hospital because of an elevated serum urea nitrogen level of 30 mg/lOO ml and a serum creatinine level of 1.8 mg/iOO ml. At that time she appeared as a thin, chronically ill woman who seemed unduly shy and totally disinterested in her sur-
94
July 1974
The American Journal of Medicine
Volume 57
roundings. Her general physical and neurologic examinations were within normal limits. Results of initial laboratory studies are listed in Table I. A Fishberg urinary concentration test revealed a maximum specific gravity of 1.013. Phenolsulfonphthalein excretion was less than 5 per cent at 15 minutes, 7 per cent at 1 hour and had a total value of 15 per cent at 2 hours. An x-ray series of the upper gastrointestinal tract and a barium enema were within normal limits. The patient was discharged with the diagnosis of chronic glomerulonephritis. She was hospitalized for the second t/me 3 years later (1963) for further evaluation of progressive renal failure. At this time the serum urea nitrogen was 45 mg/ 100 ml, serum creatinine 6.0 mg/ 100 ml and creatinine clearance 5.1 cc/min. Twenty-four hour urine protein excretion was 833 mg. A retrograde pyelogram showed a normal collecting system and renal contour. The oral glucose tolerance test had a peak 2 hour serum value of 103 mg/lOO ml with 3+ glucose (Dextrostix@) present in a simultaneous urine collection. The patient was followed in the outpatient department; her chief complaint was intermittent diarrhea and constipation, and she was readmitted 1 year later (1964). On this admission, the blood pressure was 120180 mm Hg, pulse rate 1 lO/min and temperature 98’F. The findings on physical examination were unremarkable. The stool was markedly guaiac positive. An intravenous pyelogram showed poorly visualized kidneys with a normal calyceal system. Lupus erythematosus cell preparations were negative. Twenty-four hour urine electrolyte levels were sodium 87 meq/liter and potassium 60 meq/liter. Diarrhea became profuse on the 2nd hospital day. Sigmoidoscopy demonstrated an irregular, edematous, purplish mucosa covered by a gray-white pseudomembrane. An x-ray series of the upper gastrointestinal tract was normal, and a barium enema revealed diffuse loss of haustral markings. Renal failure diminished on fluid replacement and by the 10th hospital day the serum urea nitrogen was 45 mg/lOO ml and serum creatinine 3.6 mg/lOO ml. However, a Klebsiella pneumonia developed and the patient died on the 21st hospital day. At autopsy (JHH 33415) diffuse bronchopneumonia and unilateral pyelonephritis were present. MATERIALS
AND METHODS
Mercury Levels. In Case 1 tissue samples, blood, urine, bile and cerebrospinal fluid were collected unfixed and stored in plastic containers at -7O“F; tissue mercury levels were measured by flameless atomic absorption [ 13,141. In Case 2 postmortem tissue mercury levels were measured by a calorimetric technic [ 151. Mercury analysis of these specimens was performed at the USDA Toxicology Laboratory in Beltsville, Maryland (Mr. Edward Dalton), Communicable Disease Center Toxicology Lab, Atlanta, Georgia (Mr. Edward Girling), and MRC Toxicology Laboratory, Carshalton, Surrey, England (Dr. L. Magos). Mercury analyses were performed separately on the cortex and medulla of the kidney and on the serosa, muscularis and mucosa of the gastrointestinal tract. Pathologic Studies. Sections for light microscopy were fixed in 10 per cent neutral formalin and stained with
MERCURY POISONING DUE TO LAXATIVE
ABUSE-WANDS
ET AL
Figure 7. Case 1. A, postmortem specimen of kidney shows granular cortical surface with pronounced black discoloration. B, specimen of renal cortex shows lipofuscin (short arrow) within renal tubular cells. A few black deposits (long arrow) are present in the cortical interstitium and correspond to free deposits of beta mercuric sulfide. Periodic acid-Schiff stain: original magnification X 9,000, reduced by 5 per cent.
and eosin, periodic acid-Schiff, Lilly stain for melanin, and Sudan black. Fresh biopsy or necropsy material was fixed for electron microscopy in chilled 3 per cent phosphate-buffered glutaraldehyde for 12 hours and postfixed in 1 per cent osmium tetroxide solution for an additional hour. Araldite@ was used for final embedding. Areas to be trimmed for thin sectioning were selected from thick sections (0.5 to 1.5 p) and stained with toluidine blue (1 per cent). Ultra thin sections were stained with 1 per cent uranyl acetate for 5 minutes and lead citrate for 4 minutes, and were examined with an AEI EM 801 electron microscope. Tissue for electron diffraction was prepared as described, with thin sections cut at 300 to 600 Angstroms, mounted on bare copper grids and examined in an unstained state, using the limited area technic described by Meek [ 161. Diffraction patterns obtained from crystalline structures within tissue sections were compared with known samples of mercurous chloride, mercurous sulfate, alpha or red mercuric sulfide, beta or black mercuric sulfide, mercuric sulfate, mercuric chloride, mercuric oxide and mercuric iodide. hematoxylin
l
RESULTS
Mercury Analysis. Results of the mercury analysis are shown in Table II. Three laboratories found almost identical mercury levels in the same tissue specimens (Table II). Levels were highest in the gastrointestinal tract, kidneys, heart and liver. In the kidMercurous sulfide, which decomposes at O”C, was not tested because of its instability.
ney, mercury levels were higher in the cortex than in the medulla. The gastrointestinal tract showed two patterns of mercury deposition. Mercury levels were increased in the stomach, even higher in the ileum and highest in the colon. Furthermore, in both the ileum and Colon the mucosa contained the most mercury, the muscularis less and the serosa none. Pathologic Findings. Kidneys: The kidneys in both patients were reduced in size; each weighed 80 g. The thinned, granular cortices had a striking black discoloration (Figure 1A). On light microscopy glomeruli in both cases were essentially normal. In both patients, however, there was a moderate amount of tubular atrophy at all levels of the nephron; in Case 1 it was most severe in the proximal tubule. In both cases ongoing renal damage was evident as spotty areas of regenerating tubular epithelium. Almost all tubular cells in the cortex contained delicate, light brown pigment having the tinctorial properties of lipofuscin (periodic acid-Schiff, Sudan ‘black and Lilly melanin positive) (Figure IB). The cortical interstitium in both kidneys was striking in that dense black deposits were present free and within macrophages (Figure 1B). These black deposits, unlike those in tubules, did not stain with the usual stains for lipofuscin, pseudomelanin or melanin (periodic acid-Schiff, Sudan black and Lilly melanin negative). Electron microscopy was performed on postmortem kidney in Case 1. The lipofuscin pigment present
July 1974
The American Journal of Medicine
Volume 57
95
MERCURY POISONING DUE TO LAXATIVE
ABUSE-WANDS
ET AL
Figure 2. Case 1. A, high magnification of standard thickness section (600 to 1,000 A) of pseudomelanin pigment (P) shows granular and membranous structures associated with ultra dense deposits. Uranyl acetate, lead citrate stain, original magnification X 6 1,800. 6, higher magnification of thin section (300 to 600 A) shows ultra ‘dense deposits associated with the pseudomelanin granules. Ultra dense deposits have been resolved into lamellated arrays of fine crystals that were identified by electron diffraction as beta mercuric sulfide. Unstained, original magnification X 126,000. C, lipofuscin pigment within renal tubular cell shows randomly arranged membrane structures. Lipofuscin is associated with ultra dense deposits (arrows) also identified as beta mercuric sulfide. Uranyl acetate, lead citrate stain, briginal hagnifica tion X 32,000.
typical complex memin tubular cells comprised brane-bounded folded structures (Figure 2C). In some areas the folded membranes appeared laminated. The electron microscopic appearance of this lipofustin was unusual, however, in that extremely electron dense deposits were associated with the membranes. With high magnification study of very thin sections (about 300 A), these ultra dense deposits could be resolved into fine crystalline aggregates having either a round or laminated profile (Figure 2B). The black deposits seen interstitially by light microscopy were resolved by electron microscopy into similar crystalline ultra dense inclusions. Ultra dense deposits in both locations were identified by electron diffraction as beta mercuric sulfide. Colon: Colonic biopsy specimens, obtained during sigmoidoscopy in both patients, revealed pigmentladened macrophages indicative of melanosis coli and nonspecific acute and chronic inflammation. In Case 1 the inflammation was accompanied by focal ulcerations and pseudomembrane formation. At autopsy, the entire length of colon in both cases showed melanosis coli (Figure 3) that began abruptly at the ileocecal valve. Occasional focal ulcerations were present in Case 1. There was marked reduction of acute inflammation in both cases as compared to biopsy specimens obtained 8 weeks (Case 1) and 3 weeks (Case 2) before death. The melanosis coli showed brown-black (periodic acid-Schiff and Sudan black positive) pseudomelanin granules in macrophages in the’lamina propria and superficial muscle layers (Figure 4).
96
July 1974
The American Journal of Medicine
Volume 57
By electron microscopy, the pigment granules were found only in macrophages (Figure 5A). They varied in density and texture with juxtaposition of low to moderately high electron dense material in the same granule (Figure 5B). Much of the light to moderately electron dense material was amorphous and granular, whereas some denser clumps had a randomly oriented membrane pattern. All granules were bounded by a single membrane (although in places the membrane looked double where the contents had layered out in a parallel fashion). These features were entirely consistent with those noted previously in melanosis coli [ 17-201. An atypical feature of the pigment granules in this case, however, was the additional presence of ultra dense, rounded, deposits made up of crystals [Figure 2A] that were identical to those noted in the kidney. These ultra dense deposits, too, were identified as beta mercuric sulfide by electron diffraction. Liver: In Case 1 the liver was enlarged (2,050 g), and lipofuscin pigment was present within most hepatocytes. The Kupffer cells had small black deposits which did not stain with periodic acid-Schiff, Sudan black and Lilly melanin stain. In the portal areas there was a mild chronic inflammation, occasional bile plugs within bile ducts, and macrophages containing black deposits similar to those seen in the Kupffer cells and in other organs (Figure 6). In Case 2 the liver was grossly congested. Microscopically the hepatocytes had a heavy deposition of hemosiderin consistent with a history of multiple transfusions. However, lipofuscin was not present to any significant de-
MERCURY POISONING DUE TO LAXATIVE
Figure 3.
Case 1. Pronounced
melanosis
coli and focal ulceration
(arrow)
ABUSE-WANDS
ET AL.
is shown in a segment of colon.
Figure 4. Case 1. Melanosis coli corresponds microscopically to brown-black pigmented the lamina propria of the colon. Periodic acid-Schiff stain, original magnification X 575.
macrophages
(arrow)
in
Ionic crypt (C). Uranyl acetate, lead citrate stain; original magnification X 2,200, reduced by 5 per cent. 6, higher magnification of pseudomelanin granules reveals typical contents consisting of granular and membranous materials of varying densities (P). The ultrastructure of the pseudomelanin, however, is unusual in that ultra dense deposits (arrow) are associated with the membrane aggregates. Uranyl acetate, lead citrate stain; original magnification X 19,000. reduced by 5 per cent.
July 1974
The American
Journal
of Medicine
Volume
57
97
MERCURY POISONING DUE TO LAXATIVE
ABUSE-WANDS
ET AL.
contain black deposits like those identified as mercuric sulfide in the kidneys and liver. Brain: Except for a mild hydrocephalus ex vacua in Case 1, the brain was grossly normal in both cases. Microscopically the only abnormality was mild reduction of the granular cell layer in the cerebellum in both cases. Electron Diffraction Studies. Electron diffraction was carried out in Case 1 on the ultra dense crystalline deposits associated with pseudomelanin granules in the colon, those associated and unassociated with lipofuscin in the kidney, and those in the portal and submucosal macrophages in the liver and stomach, respectively. Diffraction was carried out in the colon in Case 2. At all sites the diffraction patterns were identical to those of beta or black mercuric sulfide and different from the other mercury salts tested (Figure 7). COMMENTS In most types
Figure 6. Case 1. Portal triad of liver shows mild chronic inflammation and macrophages containing black deposits (arrow) identified as beta mercuric sulfide. Hematoxylin and eosin stain, original magnification X 625.
gree. The portal areas were unremarkable and no black deposits were identified. By electron microscopy in Case 1 the black deposits in Kupffer cells and portal macrophages were resolved into ultra dense crystalline structures similar to those seen in the kidney and colon. The crystals were unassociated with lipofuscin pigment in these locations. Electron diffraction also identified the crystals in the liver as beta mercuric sulfide. The lipofustin present in hepatocytes was not associated with ultra dense deposits like those in the renal tubular cells. Stomach and small intestine: In Case 1 black deposits (periodic acid-Schiff, Sudan black and Lilly melanin negative) were found in macrophages, in the musculature of the stomach and in the submucosa throughout the small intestine. The deposits were smaller and less numerous than those in the kidney and colon, but they also were identified as beta mercuric sulfide. They were not associated with lipofustin. No black deposits were identified in Case 2. Spleen and lymph nodes: In both cases the spleen and lymph nodes were grossly normal. By light microscopy, splenic reticulum cells contained lipofuscin in Case 1 and hemosiderin consistent with transfusion in Case 2, but in neither case did the spleen
98
July 1974
The American Journal of Medicine
Volume 57
of inorganic
mercury
poisoning
there
is
general agreement that toxicity results from absorption of the mercuric ion. The situation is, however, less clearly defined with respect to mercurous chloride-containing laxatives. In early reports it was suggested that small amounts of insoluble mercurous chloride was converted to the mercuric ion in the bowel lumen [21] and that the laxative effect of calomel depended on absorption of small amounts of mercuric ion. Toxicity could result if sufficient amounts of mercuric ion were absorbed. However, data concerning the exact mode of this presumed intraluminal transformation of the monovalent to the divalent ion are scant. Alternatively, it is possible that the mercurous ion is absorbed directly and then transformed in vivo to the mercuric ion since there is ample evidence that some cells (e.g., red blood cells) possess the ability to accomplish the oxidation of elemental mercury to mercuric ion [22,23]. Either mechanism-absorption of small amounts of mercuric ion or slow absorption of mercurous ion with subsequent oxidation-could explain the slow progression of clinical symptoms. Cellular toxicity would then result from the high affinity binding of the mercuric ion to sulfhydryl groups, as has been suggested in other forms of inorganic mercury poisoning [ 241. The present electron diffraction studies have shown that large amounts of a mercuric form of mercury, beta mercuric sulfide, were stored in certain tissues after long-term use of a mercurous chloridecontaining laxative. Whether mercuric sulfide contributed to clinical toxicity or merely represented an inert end product cannot, however, be established by this study. Other unidentified mercury compounds more directly related to toxic effects could have been pres-
MERCURY POISONING DUE TO LAXATIVE
PATIENT
6
- HgS
PATIENT
ABUSE-WANDS
ET AL.
4 - HgS
Figure 7. Case 1. A, electron diffraction pattern of crystals found in patient’s tissues compared to alpha or red mercuric sulfide. The diffraction patterns are similar but not identical. B. electron diffraction oattern of crvstals found in oatient’s tissues compared to beta or black mercuric sulfide. The- diffraction patterns are identical.
ent in the tissue without being recognized by electron diffraction because they were not crystalline, or because they were not found in the sharply localized, high concentrations needed for the technic. Two types of renal mercury poisoning are described: (1) A dose-related toxicity giving rise to tubular damage as suggested by experimental studies using mercuric chloride [25,26]; and (2) a nondoserelated or idiosyncratic reaction giving rise to the nephrotic syndrome [27,28]. Both of our patients manifested tubular abnormalities consistent with dose-related toxicity. In Case 1 the diagnosis of adult Fanconi syndrome was suggested by a low renal threshold for glucose, aminoaciduria, elevated phosphate clearance and persistent urine alkalinity in the presence of systemic acidosis. In Case 2 a renal tubular defect was demonstrated by a decreased phenolsulfonphthalein excretion, impaired urinary concentrating ability and a low renal threshold for glucose. This patient also had moderate proteinuria. Although renal damage from ingestion of mercurous chloride is well recognized ]7,8,29], in most reports only the nephrotic syndrome has been described in association with chronic exposure to the compound. Tubular abnormalities are less common, and only one previous case of adult Fanconi syndrome secondary to mercurous chloride ingestion is documented [30]. The clinical findings of tubular defects in both patients were substantiated by the pathologic abnormalities showing tubular damage. The high mercury levels noted in the cortex correlate well with the sites of greatest histologic alteration and support the hy-
pothesis that the kidney is a prime target organ in mercury poisoning from mercurous chloride laxatives, as in other forms of inorganic mercury poisoning [ 12,31-331. Renal cortical predilection of mercury was reported in experimental toxicity studies [32], and it was suggested that renal accumulation may be related to a specific binding protein present in renal tubular cells (34-361. Although the finding of increased lipofuscin pigment in renal tubular cells was nonspecific, its close association with the mercury deposits suggests that it may have represented remnants of phagolysosomes involved in the disposal of mercury in a manner similar to that proposed for copper [ 371. Further support for the importance of lysosomes in the disposal of mercury is provided by previous ultracentrifugation [ 381 and ultrastructural studies [ 301. Gastroenteritis with nonspecific intestinal ulceration is a well recognized feature of inorganic mercury poisoning [ 121. Intractable watery diarrhea and colonic mucosal ulceration were noted in both of our patients. The gastroenteritis represented a major therapeutic problem in one (Case I), and she eventually required a diverting colostomy when perforation seemed imminent. The salient proctoscopic features in both patients included an edematous mucosa with a purple hue and a gray-white pseudomembrane. It is presumed that mercury deposited in the mucosa of the gastrointestinal tract caused or contributed to the mucosal necrosis and focal ulceration with resultant watery diarrhea. The stool contained large amounts of mercury (Table II) even after cessation of laxative
July 1974
The American
Journal
of Medicine
Volume
57
99
MERCURY POISONING DUE TO LAXATIVE
ABUSE-WANDS
ET AL.
intake. There are at least three possible reasons for the high colonic levels: (1) Relatively more of the mercury-containing laxative may become available in the colon due to incomplete dissolution of the laxative preparation in the more proximal intestinal tract. (2) Bacteria in the colon might enhance conversion of mercurous to mercuric ions, thereby facilitating mercury absorption. (3) There may be a high affinity of the colonic epithelium for mercury uptake [39] similar to that observed in the cortex of the kidney. Pathologically, the colitis, although nonspecific in appearance, was quite severe and correlated well with the high mercury levels present in the colon. Most of the mercury in the colon was found by analysis in the mucosa, and the heavy concentration of mercury noted in the macrophages in the lamina propria fitted well with this distribution. Mercury levels in the small bowel and stomach were considerably lower and were paralleled by the finding of smaller and less numerous black deposits of presumed beta mercuric sulfide. The coincidence of melanosis coli in both cases was quite striking. Melanosis coli was noted in earlier cases of mercury poisoning from mercurous chloride [ 401 as well as in lead poisoning [ 411. The intimate association of the pseudomelanin and beta mercuric sulfide crystals further supports the possibility of a causative relationship between melanosis coli and mercury poisoning in these two cases, perhaps on a basis similar to that proposed to explain association of beta mercuric sulfide and lipofuscin in the kidney. However, melanosis coli has been reported in a variety of patients [42] including cascara users, of which Case 2 is an example. Thus, a fortuitous occurrence of melanosis coli in these two cases cannot be excluded. Macrophage granules showing pseudomelanin associated with other unrelated materials were described earlier [ 431. Neurologic disturbances were evident in both patients. One (Case 1) had prominent dementia, ataxia and tremor. The other (Case 2) exhibited only progressive dementia over a period of several years, emphasizing the insidious progression of mental changes in chronic inorganic mercury poison.
Three major drugs are available for treatment of mercury poisoning: British anti-Lewisite (BAL), calcium ethylene diamine tetra-acetate (CaEDTA), and N-acetyl-D,L-penicillamine (NAP). BAL gave variable clinical results [44,45] and CaEDTA gave poor results in increasing urinary mercury excretion and in ameliorating symptoms of acrodynia [46]. NAP, a compound containing sulfhydryl groups, was specifically designed for the treatment of mercury poisoning. Clinical improvement with a severalfold increase in urinary mercury excretion has followed the oral administration of NAP and indicates the need for further trials with the drug [47,48]. Our patients received no specific treatment for mercury poisoning. NAP could not be obtained soon enough after making the diagnosis in Case 1, and in Case 2 the diagnosis was made postmortem. Chronic poisoning from laxatives containing mercurous chloride, with melanosis coli and dark kidneys, was first reported in 1867 [40]. However, inorganic mercury poisoning due to mercurous chloridecontaining laxatives represents a source of toxicity of unknown epidemiologic significance. The disease could go undetected in many patients with inorganic mercury intoxication from laxatives because of the insidious onset of poisoning, the prolonged presymptomatic phase and the failure to elicit the appropriate drug history. As illustrated in this report, chronic inorganic mercury poisoning should be suspected in any patient with a history of laxative abuse who presents with renal failure, gastroenteritis, dementia or tremor. Furthermore, the finding of unusual gross darkening of the mucous membrane of the colon indicative of melanosis coli, black deposits associated with typical pseudomelanin pigment, and black discoloration of the renal cortex should suggest the diagnosis at the time of endoscopy, biopsy or autopsy.
ACKNOWLEDGMENT We gratefully acknowledge the photographic assistance of Mr. Phillip Rutledge and Mr. Raymond Lung and the technical assistance of Mr. Gerald Horne and Miss Nancy Warner.
REFERENCES 1.
2.
3.
100
Weiss SW, Wands JR, Yardley JH: Demonstration by electron diffraction of black mercuric sulfide (&HgS) in a case of “melanosis coli and black kidneys” caused by chronic inorganic mercury poisoning. Lab Invest 28: 401, 1973. Wands JR, Weiss SW, Schnitzer TR, Yardley JH. Maddrey WC: Chronic inorganic mercury poisoning due to laxative abuse: a clinical and pathological study. Gastroenterology 64: 816. 1973. Felton JS, Kahn E, Salick B, VanNatta FC, Whitehouse MW: Heavy metal poisoning: mercury and lead. Ann Intern Med 76: 779, 1972.
July 1974
The American Journal of Medicine
Volume 57
4.
5. 6. 7. 8. 9.
Joselow MM, Louria DB, Browder AA: Mercurialism: environmental and occupational aspects. Ann Intern Med 76: 119, 1972. Curley A: Organic mercury identified as cause of poisoning in humans and hogs. Science 172: 65, 1971. Hunter D: The Diseases of Occupation, 3rd ed, Boston, Little, Brown & Co., 1962. Wilson VK, Thompson ML, Holyel A: Mercury poisoning in young children. Br Med J 1: 358, 1952. Farquhar HG: Mercurial poisoning in early childhood. Lancet 2: 1186, 1953. Hamilton A: Industrial diseases of fur cutters and hatters. J
MERCURY POISONING DUE TO LAXATIVE ABUSE-WANDS
10. 11.
12. 13.
14.
15.
16.
17. 18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
Ind Hyg 4: 219, 1922. Wright W: A clinical study of fur cutters and felt hat workers. J Ind Hyg 4: 296, 1922. Cowers WR: Mercurial poisoning, Manual of Diseases of the Nervous System, vol 2, 2nd ed, London, J. & A. Churchill, Ltd., 1893, p 268. Bidstrup PL: Toxicity of Mercury and Its Compounds. Amsterdam, Elsevier Press, Inc., 1964. Willis JB: Determination of lead and other heavy metals in urine by atomic absorption spectroscopy. Anal Chem 34: 614. 1962. Hatch WR, Ott WL: Determination of sub-microgram quantities of mercury by atomic absorption spectrophotometry. Anal Chem 40: 2085, 1966. Stolman A, Stewart CP: Metallic poisons, Toxicology Mechanisms and Analytical Methods, vol 2 (Stewart CP, Stolman A, eds), New York, Academic Press, Inc.. 1960. Meek GA: Basic operational procedures, chap 10, Practical Electron Microscopy for Biologists, London, Wiley Interscience, 1971. Schrodt J. Randolph G: Melanosis coli: a study with the electron microscope. Dis Colon Rectum 6: 277, 1963. Ghadially FN, Parry EW: An electron microscope and histochemical study of melanosis coli. J Pathol 92: 313. 1966. Won KH. Ramchand S: Melanosis of ileum. Case report and electron microscopic study. Am J Dig Dis 15: 57. 1970. Kermarec J. Duplay H, Daniel R: Histochemical and electron microscope study of pigments in colonic melanosis and Dubin-Johnson syndrome. Ann Biol Clin (Paris) 30: 567, 1972. Finge E: Cathartics and laxatives, chap 49, The Pharmacological Basis of Therapeutics (Goodman LS, Gilman A, eds), London, The MacMillan Co.. 1970. MAC Committee. Maximum allowable concentrations of mercury compounds. Arch Environ Health 19: 891, 1969. Clarkson TW, Gatzy J, Dalton C: Studies on the equilibration of mercury vapor with blood. AEC Report No 582, 1961. Hughes WL: A physiochemical rationale for the biological activity of mercury and its compounds. Ann NY Acad Sci 65: 454, 1957. Bank N. Mutz BF. Aynedjian HS: The role of “leakage” of tubular fluid in anuria due to mercury poisoning. J Clin Invest 46: 695, 1967. Rodin AE, Crowson CN: Mercury nephrotoxicity in the rat. I. Factors influencing the localization of tubular lesions. Am J Pathol 41: 287, 1962. Becker CG, Becker EL, Maher JF. Schreiner GF: Nephrotoxic syndrome after contact with mercury. Arch Intern Med 1 IO: 178, 1962. Heptinstall RH: The nephrotic syndrome, chap 13, The Kidney, Boston, Little, Brown & Co., 1966.
29.
30. 31. 32. 33. 34.
35
36.
37
38
39
40. 41. 42.
43
44
45. 46.
47.
48.
July 1974
ET AL
Kazantzis G, Schiller KFR. Asscher AW. Drew RG: Albuminuria and the nephrotic syndrome following exposure to mercury and its compounds. 0 J Med 3 1: 403, 1962. Lee DBN, Drinkard JP, Rosen VJ, Gonick HC: The adult Fanconi syndrome. Medicine 51: 107. 1972. Clarkson TW: The pharmacology of mercury compounds. Annu Rev Pharmacol 12: 375, 1972. Cafrung EJ: The site and mechanism of action of mercurial diuretics. Pharmacol Rev 20: 89, 1968. Passow H, Rothstein A, Clarkson TW: General pharmacology of the heavy metals. Pharmacol Rev 13: 185, 196 1. Pulido P, Kagi JRH, Vallee BL: Isolation and some properties of human metallothionein. Biochemistry 5: 1768, 1966. Wisniewska JM, Trojanowska B, Piotrowski J, Jakubowski M: Binding of mercury in the rat kidney by metallothionein. Toxicol Appl Pharmacol 16: 754, 1970. Jakubowski M, Piotrowski J, Trojanowska 8: Binding of mercury in the rat: studies using 203HgC12and gel filtration. Toxicol Appl Pharmacol 16: 743, 1970. Gedigk P: Pigmentation caused by inorganic materials, chap 1, Pigments in Pathology (Wolman M, ed), New York, Academic Press, Inc., 1969. Norseth T. Bendeford M: Intracellular distribution of inorganic and organic mercury in rat livers after exposure to methylmercury salts. Biochem Pharmacol 20: 110 1, 1971. Norseth T, Clarkson TW: Intestinal transport of *03Hg labeled methyl mercury chloride. Arch Environ Health 22: 568, 1971. Williams CT: Black deposit in the large intestine from the presence of mercury. Tr Path Sot Lond 18: 111, 1867. Pitt GN: Colon pigmented black throughout with lead. Tr Path Sot London 42: 109, 1891. Wittoesh JH, Jackman RJ. McDonald JR: Melanosis coli: general review and study of 887 cases. Dis Colon Rectum 1: 172. 1958. Gonzalez-Licea A, Yardley JH: Whipple’s disease in the rectum. Light and electron microscopic findings. Am J Pathol 52: 1191, 1968. Longcope WT, Luetscher JA: The uses of BAL (British AntiLewisite) in the treatment of the injurious effects of arsenic, mercury, and other metallic poisoning. Ann intern Med 31: 545, 1949. Bivings L: Acrodynia: summary of BAL therapy reports and case report of calomel disease. J Pediatr 34: 322, 1949. McCoy JE, Carrb IJ, Freeman M: A controlled trial of endathamil calcium disodium in acrodynia. Pediatrics 25: 304, 1960. Kark PAR, Poskanzer DC, Bulloch JD. Boylen G: Mercury poisoning and its treatment with N-acetyl-D.L-penicillamine. N Engl J Med 285: 10. 1971. Smith ADM, Miller TW: Treatment of inorganic mercury poisoning with N-acetyl-D,L-penicillamine. Lancet 1: 640. 1961.
The American
Journal
of Medicine
Volume
57
101
JACK R. WANDS,
M.D.*
SHARON WHELAN WEISS, M.D JOHN H. YARDLEY, WILLIS C. MADDREY.
M.D. M.D.
Baltimore, Maryland
From the Departments of Medicine and Pathology, The Johns Hopkins Hospital and School of Medicine, Baltimore, Maryland 21205. This study was presented in part at the International Academy of Pathology (February 1973) [l] and the American Gastroenterological Association (May 1973) [2]. Requests for reprints should be addressed to Dr. Jack R. Wands. Manuscript accepted November 13, 1973. Present address: Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts 02 114. l
92
July 1974
The American
Study
Chronic mercury poisoning developed in two patients following long-term daily ingestion of a laxative preparation containing mercurous chloride (calomel). There were major clinical manifestations attributable to toxic effects of mercury on the kidneys, gastrointestinal tract and central nervous system. Chronic renal failure developed in both patients and was manifested by elevated serum urea nitrogen and creatinine levels, with proteinuria but no abnormalities in the urinary sediment. Both patients showed evidence of renal tubular defects. Both patients had colitis with intractable watery diarrhea. In one, the colitis was so severe as to require a diverting colostomy. Dementia was present in both patients, with tremor a prominent feature in one. Tissue mercury levels were highest in the colon (526 pg/g; normal 0.10 pug/g) and kidney (421 pg/g; normal 2.75 pg/g); levels were also significantly elevated in the liver, brain, heart, pancreas, hair, skin, blood and urine. At autopsy both patients showed melanosis coli and blackening of the renal cortex. By electron microscopy the pseudomelanin granules in the colon were atypical in that they were intimately associated with ultra dense crystals identified by electron diffraction as beta mercuric sulfide. Crystals of beta mercuric sulfide were also associated with lipofuscin deposits in renal tubular epithelium and were present free and within macrophages of the renal cortical interstitium and hepatic portal triads. Chronic mercury poisoning due to mercurous chloride-containing laxative preparations should be suspected in patients with a history of laxative abuse who present with unexplained renal failure, colitis, dementia or tremor. Toxicity from mercury may be caused by both organic and inorganic compounds. Organic mercury poisoning may result from exposure to methyl and ethyl mercury compounds utilized in industrial processes and pesticides [3-51. Inorganic mercury poisoning has been detected in cinnabar mind workers, hatters, thermometer makers and infants ingesting calomel-containing teething powders [S-lo]. The symptoms in these two types of mercury poisoning differ. Organic mercury intoxication usually presents with a rapidly
Journal of Medicine
Volume
57
MERCURY POISONING DUE TO LAXATIVE ABUSE-WANDS
progressive
neurologic
illness characterized
by men-
TABLE
Summary
I
Cases
tal deterioration, paresthesia.% ataxia, spasticity, deafness and coma [ 1 I]. In contrast, inorganic mercury poisoning most often presents insidiously, developing after years of exposure, and is characterized by renal failure, gastroenteritis, dermatitis, dementia and tremor [ 121. Chronic inorganic mercury poisoning may also result from medicinal sources such as mercurous chloride-containing laxative preparations. We describe two patients in whom chronic mercury poisoning developed after ingestion of a mercurous chloride-containing laxative for many years. The clinical
manifestations,
fication
of a mercury
fraction
are described.
CASE Case
findings
form
and identi-
by electron
dif-
REPORTS 1.
This 63 year old woman
12) was admitted development been
pathologic storage
of stupor over
generally
constipation,
(D.G.,
JHH No. 36-08-
to the hospital following the progressive good.
1 week.
Because
Her past health had
of long-standing
she had taken a mercurous
chronic
chloride-contain-
ing laxative (Calotabs@‘) every night for 25 years. On admission, the patient was in coma responding to pain stimuli. The blood pressure pulse rate
108/min
the cornea
and respirations
and sclera
stomatitis
150180
was
slow and deep.
present.
Both
Neither
On cardiovascular
the heart was of normal size with a ventricu-
tar gallop. The lungs were clear, and neither spleen was palpable. Neurologic examination tact cranial
only
mm Hg,
had a bluish discoloration.
nor gingivitis
examination
was
nerves,
symmetrical
reflexes,
the liver nor revealed in-
flaccid
extremi-
ties and no Babinski reflex. Initial laboratory mg/lOO
studies
ml and a serum
ml. Urinalysis
showed
revealed
a creatinine
urea nitrogen
no acetone;
of 16.0
of 167.0
2-t
mg/ 100
glucose
and
protein (Combistix@) with a pH of 7.0. The remainder initial laboratory genogram
1-I
of the
studies are given in Table I. A chest roent-
and an electrocardiogram
blood gas studies,
were normal.
using a 28 per cent Venturi
Arterial
mask,
re-
vealed an oxygen tension (~02) of 148 mm Hg, a carbon dioxide tension (pCOp) of 8 mm Hg and a pH of 7.07. Six liters of 0.9 per cent saline solution and 240 meq sodium bicarbonate
were required to correct
deficit and acidosis
during the first day of hospitalization.
There
was progressive
improvement
tal status, and she was completely
in the patient’s
movement. gait was
was observed She became noted.
which worsened ambulatory,
On lumbar
men-
alert by the 2nd hospi-
tal day. At this time a striking static tremor extremity
the initial fluid
puncture
of the upper
during voluntary
and a broad-based cerebrospinal
fluid
Laboratory
~~~____._~
Values in
_ Case 2 .~ __ __ -.
Case 1 1972
Laboratory Values Hematocrit (%) White blood count (per mm3) Sodium (meq/liter) Potassium (meq/liter) Serum urea nitrogen (mg/lOO ml) Bicarbonate (meq/liter) Chloride (meq/liter) Glucose (mg/lOO ml) Creatinine (mg/lOO ml) Calcium (mg/lOO ml) Phosphorous (mg/lOO ml) Magnesium (meq/liter) Urine specific gravity Protein Glucose
1960
1964
31.0 20,000 132.0 4.1
-23.0 5,800 135.0 4.3
18.0 8,700 129.0 4.5
167.0 3.0 99.0 181.0 16.0 5.7 9.8 1.5 1.010
30.0 22.0 100.0 110.0 1.8 9.5 4.2
150.0 9.0 108.0 90.0 16.0 8.0 5.4
. ..
.
1.012 2+
1.013 7+
1+ 2+ 7.0 0.8 5.0 31.0
1+ 2-k 6.5 7 0 PH 1.1 0 .9 Bilirubin (mg/lOO ml) . . SGOT (MIU) . . . . Alkaline phosphatase (MIU) ~. ~___ ._ ~~_~ ~.._ ~~~~-__ ~-------.NOTE: Normal values: bilirubin total 0.1 to 1.1 mg/lOO ml; serum glutamic oxaloacetic acid (SGOT) 0 to 19.0 milliInternational Units(MIU); alkaline phosphatase 10 to 32 MIU. slit lamp examination Audiometry revealed sorineural became
of the cornea and lens were normal. a 50 dB high frequency bilateral sen-
hearing loss.
Watery
diarrhea,
which had been present
profuse and amounted
sigmoidoscopy
the mucosa
with an easily removed, and cultures negative
on admission.
to 2.5 to 3.5 liters/day.
was purple,
for amoebae
and
On
firm and covered
white pseudomembrane.
of stool and a rectal
Smears
biopsy specimen
pathogenic
bacteria.
were At this
point mercury intoxication was clinically suspected because of the neurologic findings, severe colitis, renal failure and the additional
history of prolonged
laxative containing mercurous chloride. The patient’s renal function improved hospital
day, the serum
creatinine
mg/lOO
ml and the
mg/lOO
ml. On intravenous
measured phase
normal.
and phosphate excretion
clearance
the
urea
lateral diffuse slowing, consistent with a diffuse cerebral disturbance. The brain scan was normal. Visual fields and
carbonate
system
level
to 29.0
the kidheys each on the nephrogram
clearance
was
The
17 ml/min
24 hour protein
mg, with urinary sodium 84 meq/liter
presence
with a simultaneous
of a
and by the 23rd
nitrogen
3 ml/min.
54 meq/liter.
urine consistently
ingestion
level had fallen to 3.0
pyelogram,
Creatinine
was 305
and potassium vealed
serum
10 cm; the calyceal
was
pressure, glucose and protein were normal; no cells or organisms were present. Electroencephalogram showed bi-
* Each tablet of Calotabs contains 120 mg mercurous chloride combined with aloes, orizaba. extract bitter apples, oils of cloves and peppermint.
of Initial
1 and 2
ET AL.
of
Urine amino acid analysis cystine
had 2-F to 3-t
and
homocystine.
glucose
reThe
(Dextro-stix@),
blood sugar level of 90 to 140 mg/lOO
ml. The urine pH remained
above
6.5 despite
level of 12 to 18 meq/liter
a serum bi-
and a blood pH of
7.30 to 7.36. Renal tubular acidosis and diarrhea were considered the major factors causing the initial marked metabolic acidosis. On the 31st hospital day a diverting transverse colostomy was performed because of unremitting diarrhea, peri-
July 1974
The American
Journal
of Medicine
Volume
57
93
MERCURY POISONING DUE TO LAXATIVE ABUSE-WANDS
TABLE II
Tissue
Mercury
ET AL.
Levels MercuryLevel&g/g)
Case1
Tissue Colon Mucosa Muscularis Serosa Kidney Cortex Medulla 24 hour urine Ileum Mucosa Muscularis Serosa Rectum Cornea Heart Liver Stomach Pancreas Gallbladder Hair Skin Artery Brain Frontal cortex Cerebellum Feces Serum Bile Thyroid Adrenal Lung
Case 2
526.0 442.6 106.2 0 421.5,424.0* 506.8 103.1 i,OOO.O 200.0 111.6 58.9 0 104.0 29.9 26.3 24.3 22.5 16.9 9.9 9.7,13.5 7.7 6.8
16.0
“Normal” Values 0.10
.. ... ... 2.75
25.0 ...
. . ... ... ... ... ... . . ..
.. 5.3*,5.3f 3.9*,4.5t 3.2 1.f3,1.4,1.3t 0 0 0 0
... ... ... ... ... ... . . ... . . . ... .. ... ... . . ...
0.05
0.15 0.30 0.05
0.10
_____
NOTE: Values determined by Mr. Edward Dalton, USDA Laboratories, Beltsville, Maryland, unless otherwise indicated. * Mercury levels determined by Dr. L. Magos, MRC Toxicology Unit, Carshalton, Surrey, England. t Mercury levels determined by Mr. August Curley and Mr. Edward Girling, CDC, Atlanta, Georgia. neal
necrosis
erative
and fear of colonic
course
was complicated
perforation. by failure
The postopof wound
heal-
ing and fecal peritonitis. Bacteroides septicemia developed and the patient died on the 7ist hospital day. At autopsy (JHH 38440) an organizing peritonitis and pelvic abscess were found. Case 2. A 56 year old woman (A.B., JHH No. 42-12-56) took cascara daily for 15 years and two mercurous chloride-containing tablets (Calotabs) for 6 years prior to death. Her past health had been good, with no history of hypertension, diabetes or urinary tract infections. She had received multiple transfusions for a chronic anemia. She was first admitted (1960) to the hospital because of an elevated serum urea nitrogen level of 30 mg/lOO ml and a serum creatinine level of 1.8 mg/iOO ml. At that time she appeared as a thin, chronically ill woman who seemed unduly shy and totally disinterested in her sur-
94
July 1974
The American Journal of Medicine
Volume 57
roundings. Her general physical and neurologic examinations were within normal limits. Results of initial laboratory studies are listed in Table I. A Fishberg urinary concentration test revealed a maximum specific gravity of 1.013. Phenolsulfonphthalein excretion was less than 5 per cent at 15 minutes, 7 per cent at 1 hour and had a total value of 15 per cent at 2 hours. An x-ray series of the upper gastrointestinal tract and a barium enema were within normal limits. The patient was discharged with the diagnosis of chronic glomerulonephritis. She was hospitalized for the second t/me 3 years later (1963) for further evaluation of progressive renal failure. At this time the serum urea nitrogen was 45 mg/ 100 ml, serum creatinine 6.0 mg/ 100 ml and creatinine clearance 5.1 cc/min. Twenty-four hour urine protein excretion was 833 mg. A retrograde pyelogram showed a normal collecting system and renal contour. The oral glucose tolerance test had a peak 2 hour serum value of 103 mg/lOO ml with 3+ glucose (Dextrostix@) present in a simultaneous urine collection. The patient was followed in the outpatient department; her chief complaint was intermittent diarrhea and constipation, and she was readmitted 1 year later (1964). On this admission, the blood pressure was 120180 mm Hg, pulse rate 1 lO/min and temperature 98’F. The findings on physical examination were unremarkable. The stool was markedly guaiac positive. An intravenous pyelogram showed poorly visualized kidneys with a normal calyceal system. Lupus erythematosus cell preparations were negative. Twenty-four hour urine electrolyte levels were sodium 87 meq/liter and potassium 60 meq/liter. Diarrhea became profuse on the 2nd hospital day. Sigmoidoscopy demonstrated an irregular, edematous, purplish mucosa covered by a gray-white pseudomembrane. An x-ray series of the upper gastrointestinal tract was normal, and a barium enema revealed diffuse loss of haustral markings. Renal failure diminished on fluid replacement and by the 10th hospital day the serum urea nitrogen was 45 mg/lOO ml and serum creatinine 3.6 mg/lOO ml. However, a Klebsiella pneumonia developed and the patient died on the 21st hospital day. At autopsy (JHH 33415) diffuse bronchopneumonia and unilateral pyelonephritis were present. MATERIALS
AND METHODS
Mercury Levels. In Case 1 tissue samples, blood, urine, bile and cerebrospinal fluid were collected unfixed and stored in plastic containers at -7O“F; tissue mercury levels were measured by flameless atomic absorption [ 13,141. In Case 2 postmortem tissue mercury levels were measured by a calorimetric technic [ 151. Mercury analysis of these specimens was performed at the USDA Toxicology Laboratory in Beltsville, Maryland (Mr. Edward Dalton), Communicable Disease Center Toxicology Lab, Atlanta, Georgia (Mr. Edward Girling), and MRC Toxicology Laboratory, Carshalton, Surrey, England (Dr. L. Magos). Mercury analyses were performed separately on the cortex and medulla of the kidney and on the serosa, muscularis and mucosa of the gastrointestinal tract. Pathologic Studies. Sections for light microscopy were fixed in 10 per cent neutral formalin and stained with
MERCURY POISONING DUE TO LAXATIVE
ABUSE-WANDS
ET AL
Figure 7. Case 1. A, postmortem specimen of kidney shows granular cortical surface with pronounced black discoloration. B, specimen of renal cortex shows lipofuscin (short arrow) within renal tubular cells. A few black deposits (long arrow) are present in the cortical interstitium and correspond to free deposits of beta mercuric sulfide. Periodic acid-Schiff stain: original magnification X 9,000, reduced by 5 per cent.
and eosin, periodic acid-Schiff, Lilly stain for melanin, and Sudan black. Fresh biopsy or necropsy material was fixed for electron microscopy in chilled 3 per cent phosphate-buffered glutaraldehyde for 12 hours and postfixed in 1 per cent osmium tetroxide solution for an additional hour. Araldite@ was used for final embedding. Areas to be trimmed for thin sectioning were selected from thick sections (0.5 to 1.5 p) and stained with toluidine blue (1 per cent). Ultra thin sections were stained with 1 per cent uranyl acetate for 5 minutes and lead citrate for 4 minutes, and were examined with an AEI EM 801 electron microscope. Tissue for electron diffraction was prepared as described, with thin sections cut at 300 to 600 Angstroms, mounted on bare copper grids and examined in an unstained state, using the limited area technic described by Meek [ 161. Diffraction patterns obtained from crystalline structures within tissue sections were compared with known samples of mercurous chloride, mercurous sulfate, alpha or red mercuric sulfide, beta or black mercuric sulfide, mercuric sulfate, mercuric chloride, mercuric oxide and mercuric iodide. hematoxylin
l
RESULTS
Mercury Analysis. Results of the mercury analysis are shown in Table II. Three laboratories found almost identical mercury levels in the same tissue specimens (Table II). Levels were highest in the gastrointestinal tract, kidneys, heart and liver. In the kidMercurous sulfide, which decomposes at O”C, was not tested because of its instability.
ney, mercury levels were higher in the cortex than in the medulla. The gastrointestinal tract showed two patterns of mercury deposition. Mercury levels were increased in the stomach, even higher in the ileum and highest in the colon. Furthermore, in both the ileum and Colon the mucosa contained the most mercury, the muscularis less and the serosa none. Pathologic Findings. Kidneys: The kidneys in both patients were reduced in size; each weighed 80 g. The thinned, granular cortices had a striking black discoloration (Figure 1A). On light microscopy glomeruli in both cases were essentially normal. In both patients, however, there was a moderate amount of tubular atrophy at all levels of the nephron; in Case 1 it was most severe in the proximal tubule. In both cases ongoing renal damage was evident as spotty areas of regenerating tubular epithelium. Almost all tubular cells in the cortex contained delicate, light brown pigment having the tinctorial properties of lipofuscin (periodic acid-Schiff, Sudan ‘black and Lilly melanin positive) (Figure IB). The cortical interstitium in both kidneys was striking in that dense black deposits were present free and within macrophages (Figure 1B). These black deposits, unlike those in tubules, did not stain with the usual stains for lipofuscin, pseudomelanin or melanin (periodic acid-Schiff, Sudan black and Lilly melanin negative). Electron microscopy was performed on postmortem kidney in Case 1. The lipofuscin pigment present
July 1974
The American Journal of Medicine
Volume 57
95
MERCURY POISONING DUE TO LAXATIVE
ABUSE-WANDS
ET AL
Figure 2. Case 1. A, high magnification of standard thickness section (600 to 1,000 A) of pseudomelanin pigment (P) shows granular and membranous structures associated with ultra dense deposits. Uranyl acetate, lead citrate stain, original magnification X 6 1,800. 6, higher magnification of thin section (300 to 600 A) shows ultra ‘dense deposits associated with the pseudomelanin granules. Ultra dense deposits have been resolved into lamellated arrays of fine crystals that were identified by electron diffraction as beta mercuric sulfide. Unstained, original magnification X 126,000. C, lipofuscin pigment within renal tubular cell shows randomly arranged membrane structures. Lipofuscin is associated with ultra dense deposits (arrows) also identified as beta mercuric sulfide. Uranyl acetate, lead citrate stain, briginal hagnifica tion X 32,000.
typical complex memin tubular cells comprised brane-bounded folded structures (Figure 2C). In some areas the folded membranes appeared laminated. The electron microscopic appearance of this lipofustin was unusual, however, in that extremely electron dense deposits were associated with the membranes. With high magnification study of very thin sections (about 300 A), these ultra dense deposits could be resolved into fine crystalline aggregates having either a round or laminated profile (Figure 2B). The black deposits seen interstitially by light microscopy were resolved by electron microscopy into similar crystalline ultra dense inclusions. Ultra dense deposits in both locations were identified by electron diffraction as beta mercuric sulfide. Colon: Colonic biopsy specimens, obtained during sigmoidoscopy in both patients, revealed pigmentladened macrophages indicative of melanosis coli and nonspecific acute and chronic inflammation. In Case 1 the inflammation was accompanied by focal ulcerations and pseudomembrane formation. At autopsy, the entire length of colon in both cases showed melanosis coli (Figure 3) that began abruptly at the ileocecal valve. Occasional focal ulcerations were present in Case 1. There was marked reduction of acute inflammation in both cases as compared to biopsy specimens obtained 8 weeks (Case 1) and 3 weeks (Case 2) before death. The melanosis coli showed brown-black (periodic acid-Schiff and Sudan black positive) pseudomelanin granules in macrophages in the’lamina propria and superficial muscle layers (Figure 4).
96
July 1974
The American Journal of Medicine
Volume 57
By electron microscopy, the pigment granules were found only in macrophages (Figure 5A). They varied in density and texture with juxtaposition of low to moderately high electron dense material in the same granule (Figure 5B). Much of the light to moderately electron dense material was amorphous and granular, whereas some denser clumps had a randomly oriented membrane pattern. All granules were bounded by a single membrane (although in places the membrane looked double where the contents had layered out in a parallel fashion). These features were entirely consistent with those noted previously in melanosis coli [ 17-201. An atypical feature of the pigment granules in this case, however, was the additional presence of ultra dense, rounded, deposits made up of crystals [Figure 2A] that were identical to those noted in the kidney. These ultra dense deposits, too, were identified as beta mercuric sulfide by electron diffraction. Liver: In Case 1 the liver was enlarged (2,050 g), and lipofuscin pigment was present within most hepatocytes. The Kupffer cells had small black deposits which did not stain with periodic acid-Schiff, Sudan black and Lilly melanin stain. In the portal areas there was a mild chronic inflammation, occasional bile plugs within bile ducts, and macrophages containing black deposits similar to those seen in the Kupffer cells and in other organs (Figure 6). In Case 2 the liver was grossly congested. Microscopically the hepatocytes had a heavy deposition of hemosiderin consistent with a history of multiple transfusions. However, lipofuscin was not present to any significant de-
MERCURY POISONING DUE TO LAXATIVE
Figure 3.
Case 1. Pronounced
melanosis
coli and focal ulceration
(arrow)
ABUSE-WANDS
ET AL.
is shown in a segment of colon.
Figure 4. Case 1. Melanosis coli corresponds microscopically to brown-black pigmented the lamina propria of the colon. Periodic acid-Schiff stain, original magnification X 575.
macrophages
(arrow)
in
Ionic crypt (C). Uranyl acetate, lead citrate stain; original magnification X 2,200, reduced by 5 per cent. 6, higher magnification of pseudomelanin granules reveals typical contents consisting of granular and membranous materials of varying densities (P). The ultrastructure of the pseudomelanin, however, is unusual in that ultra dense deposits (arrow) are associated with the membrane aggregates. Uranyl acetate, lead citrate stain; original magnification X 19,000. reduced by 5 per cent.
July 1974
The American
Journal
of Medicine
Volume
57
97
MERCURY POISONING DUE TO LAXATIVE
ABUSE-WANDS
ET AL.
contain black deposits like those identified as mercuric sulfide in the kidneys and liver. Brain: Except for a mild hydrocephalus ex vacua in Case 1, the brain was grossly normal in both cases. Microscopically the only abnormality was mild reduction of the granular cell layer in the cerebellum in both cases. Electron Diffraction Studies. Electron diffraction was carried out in Case 1 on the ultra dense crystalline deposits associated with pseudomelanin granules in the colon, those associated and unassociated with lipofuscin in the kidney, and those in the portal and submucosal macrophages in the liver and stomach, respectively. Diffraction was carried out in the colon in Case 2. At all sites the diffraction patterns were identical to those of beta or black mercuric sulfide and different from the other mercury salts tested (Figure 7). COMMENTS In most types
Figure 6. Case 1. Portal triad of liver shows mild chronic inflammation and macrophages containing black deposits (arrow) identified as beta mercuric sulfide. Hematoxylin and eosin stain, original magnification X 625.
gree. The portal areas were unremarkable and no black deposits were identified. By electron microscopy in Case 1 the black deposits in Kupffer cells and portal macrophages were resolved into ultra dense crystalline structures similar to those seen in the kidney and colon. The crystals were unassociated with lipofuscin pigment in these locations. Electron diffraction also identified the crystals in the liver as beta mercuric sulfide. The lipofustin present in hepatocytes was not associated with ultra dense deposits like those in the renal tubular cells. Stomach and small intestine: In Case 1 black deposits (periodic acid-Schiff, Sudan black and Lilly melanin negative) were found in macrophages, in the musculature of the stomach and in the submucosa throughout the small intestine. The deposits were smaller and less numerous than those in the kidney and colon, but they also were identified as beta mercuric sulfide. They were not associated with lipofustin. No black deposits were identified in Case 2. Spleen and lymph nodes: In both cases the spleen and lymph nodes were grossly normal. By light microscopy, splenic reticulum cells contained lipofuscin in Case 1 and hemosiderin consistent with transfusion in Case 2, but in neither case did the spleen
98
July 1974
The American Journal of Medicine
Volume 57
of inorganic
mercury
poisoning
there
is
general agreement that toxicity results from absorption of the mercuric ion. The situation is, however, less clearly defined with respect to mercurous chloride-containing laxatives. In early reports it was suggested that small amounts of insoluble mercurous chloride was converted to the mercuric ion in the bowel lumen [21] and that the laxative effect of calomel depended on absorption of small amounts of mercuric ion. Toxicity could result if sufficient amounts of mercuric ion were absorbed. However, data concerning the exact mode of this presumed intraluminal transformation of the monovalent to the divalent ion are scant. Alternatively, it is possible that the mercurous ion is absorbed directly and then transformed in vivo to the mercuric ion since there is ample evidence that some cells (e.g., red blood cells) possess the ability to accomplish the oxidation of elemental mercury to mercuric ion [22,23]. Either mechanism-absorption of small amounts of mercuric ion or slow absorption of mercurous ion with subsequent oxidation-could explain the slow progression of clinical symptoms. Cellular toxicity would then result from the high affinity binding of the mercuric ion to sulfhydryl groups, as has been suggested in other forms of inorganic mercury poisoning [ 241. The present electron diffraction studies have shown that large amounts of a mercuric form of mercury, beta mercuric sulfide, were stored in certain tissues after long-term use of a mercurous chloridecontaining laxative. Whether mercuric sulfide contributed to clinical toxicity or merely represented an inert end product cannot, however, be established by this study. Other unidentified mercury compounds more directly related to toxic effects could have been pres-
MERCURY POISONING DUE TO LAXATIVE
PATIENT
6
- HgS
PATIENT
ABUSE-WANDS
ET AL.
4 - HgS
Figure 7. Case 1. A, electron diffraction pattern of crystals found in patient’s tissues compared to alpha or red mercuric sulfide. The diffraction patterns are similar but not identical. B. electron diffraction oattern of crvstals found in oatient’s tissues compared to beta or black mercuric sulfide. The- diffraction patterns are identical.
ent in the tissue without being recognized by electron diffraction because they were not crystalline, or because they were not found in the sharply localized, high concentrations needed for the technic. Two types of renal mercury poisoning are described: (1) A dose-related toxicity giving rise to tubular damage as suggested by experimental studies using mercuric chloride [25,26]; and (2) a nondoserelated or idiosyncratic reaction giving rise to the nephrotic syndrome [27,28]. Both of our patients manifested tubular abnormalities consistent with dose-related toxicity. In Case 1 the diagnosis of adult Fanconi syndrome was suggested by a low renal threshold for glucose, aminoaciduria, elevated phosphate clearance and persistent urine alkalinity in the presence of systemic acidosis. In Case 2 a renal tubular defect was demonstrated by a decreased phenolsulfonphthalein excretion, impaired urinary concentrating ability and a low renal threshold for glucose. This patient also had moderate proteinuria. Although renal damage from ingestion of mercurous chloride is well recognized ]7,8,29], in most reports only the nephrotic syndrome has been described in association with chronic exposure to the compound. Tubular abnormalities are less common, and only one previous case of adult Fanconi syndrome secondary to mercurous chloride ingestion is documented [30]. The clinical findings of tubular defects in both patients were substantiated by the pathologic abnormalities showing tubular damage. The high mercury levels noted in the cortex correlate well with the sites of greatest histologic alteration and support the hy-
pothesis that the kidney is a prime target organ in mercury poisoning from mercurous chloride laxatives, as in other forms of inorganic mercury poisoning [ 12,31-331. Renal cortical predilection of mercury was reported in experimental toxicity studies [32], and it was suggested that renal accumulation may be related to a specific binding protein present in renal tubular cells (34-361. Although the finding of increased lipofuscin pigment in renal tubular cells was nonspecific, its close association with the mercury deposits suggests that it may have represented remnants of phagolysosomes involved in the disposal of mercury in a manner similar to that proposed for copper [ 371. Further support for the importance of lysosomes in the disposal of mercury is provided by previous ultracentrifugation [ 381 and ultrastructural studies [ 301. Gastroenteritis with nonspecific intestinal ulceration is a well recognized feature of inorganic mercury poisoning [ 121. Intractable watery diarrhea and colonic mucosal ulceration were noted in both of our patients. The gastroenteritis represented a major therapeutic problem in one (Case I), and she eventually required a diverting colostomy when perforation seemed imminent. The salient proctoscopic features in both patients included an edematous mucosa with a purple hue and a gray-white pseudomembrane. It is presumed that mercury deposited in the mucosa of the gastrointestinal tract caused or contributed to the mucosal necrosis and focal ulceration with resultant watery diarrhea. The stool contained large amounts of mercury (Table II) even after cessation of laxative
July 1974
The American
Journal
of Medicine
Volume
57
99
MERCURY POISONING DUE TO LAXATIVE
ABUSE-WANDS
ET AL.
intake. There are at least three possible reasons for the high colonic levels: (1) Relatively more of the mercury-containing laxative may become available in the colon due to incomplete dissolution of the laxative preparation in the more proximal intestinal tract. (2) Bacteria in the colon might enhance conversion of mercurous to mercuric ions, thereby facilitating mercury absorption. (3) There may be a high affinity of the colonic epithelium for mercury uptake [39] similar to that observed in the cortex of the kidney. Pathologically, the colitis, although nonspecific in appearance, was quite severe and correlated well with the high mercury levels present in the colon. Most of the mercury in the colon was found by analysis in the mucosa, and the heavy concentration of mercury noted in the macrophages in the lamina propria fitted well with this distribution. Mercury levels in the small bowel and stomach were considerably lower and were paralleled by the finding of smaller and less numerous black deposits of presumed beta mercuric sulfide. The coincidence of melanosis coli in both cases was quite striking. Melanosis coli was noted in earlier cases of mercury poisoning from mercurous chloride [ 401 as well as in lead poisoning [ 411. The intimate association of the pseudomelanin and beta mercuric sulfide crystals further supports the possibility of a causative relationship between melanosis coli and mercury poisoning in these two cases, perhaps on a basis similar to that proposed to explain association of beta mercuric sulfide and lipofuscin in the kidney. However, melanosis coli has been reported in a variety of patients [42] including cascara users, of which Case 2 is an example. Thus, a fortuitous occurrence of melanosis coli in these two cases cannot be excluded. Macrophage granules showing pseudomelanin associated with other unrelated materials were described earlier [ 431. Neurologic disturbances were evident in both patients. One (Case 1) had prominent dementia, ataxia and tremor. The other (Case 2) exhibited only progressive dementia over a period of several years, emphasizing the insidious progression of mental changes in chronic inorganic mercury poison.
Three major drugs are available for treatment of mercury poisoning: British anti-Lewisite (BAL), calcium ethylene diamine tetra-acetate (CaEDTA), and N-acetyl-D,L-penicillamine (NAP). BAL gave variable clinical results [44,45] and CaEDTA gave poor results in increasing urinary mercury excretion and in ameliorating symptoms of acrodynia [46]. NAP, a compound containing sulfhydryl groups, was specifically designed for the treatment of mercury poisoning. Clinical improvement with a severalfold increase in urinary mercury excretion has followed the oral administration of NAP and indicates the need for further trials with the drug [47,48]. Our patients received no specific treatment for mercury poisoning. NAP could not be obtained soon enough after making the diagnosis in Case 1, and in Case 2 the diagnosis was made postmortem. Chronic poisoning from laxatives containing mercurous chloride, with melanosis coli and dark kidneys, was first reported in 1867 [40]. However, inorganic mercury poisoning due to mercurous chloridecontaining laxatives represents a source of toxicity of unknown epidemiologic significance. The disease could go undetected in many patients with inorganic mercury intoxication from laxatives because of the insidious onset of poisoning, the prolonged presymptomatic phase and the failure to elicit the appropriate drug history. As illustrated in this report, chronic inorganic mercury poisoning should be suspected in any patient with a history of laxative abuse who presents with renal failure, gastroenteritis, dementia or tremor. Furthermore, the finding of unusual gross darkening of the mucous membrane of the colon indicative of melanosis coli, black deposits associated with typical pseudomelanin pigment, and black discoloration of the renal cortex should suggest the diagnosis at the time of endoscopy, biopsy or autopsy.
ACKNOWLEDGMENT We gratefully acknowledge the photographic assistance of Mr. Phillip Rutledge and Mr. Raymond Lung and the technical assistance of Mr. Gerald Horne and Miss Nancy Warner.
REFERENCES 1.
2.
3.
100
Weiss SW, Wands JR, Yardley JH: Demonstration by electron diffraction of black mercuric sulfide (&HgS) in a case of “melanosis coli and black kidneys” caused by chronic inorganic mercury poisoning. Lab Invest 28: 401, 1973. Wands JR, Weiss SW, Schnitzer TR, Yardley JH. Maddrey WC: Chronic inorganic mercury poisoning due to laxative abuse: a clinical and pathological study. Gastroenterology 64: 816. 1973. Felton JS, Kahn E, Salick B, VanNatta FC, Whitehouse MW: Heavy metal poisoning: mercury and lead. Ann Intern Med 76: 779, 1972.
July 1974
The American Journal of Medicine
Volume 57
4.
5. 6. 7. 8. 9.
Joselow MM, Louria DB, Browder AA: Mercurialism: environmental and occupational aspects. Ann Intern Med 76: 119, 1972. Curley A: Organic mercury identified as cause of poisoning in humans and hogs. Science 172: 65, 1971. Hunter D: The Diseases of Occupation, 3rd ed, Boston, Little, Brown & Co., 1962. Wilson VK, Thompson ML, Holyel A: Mercury poisoning in young children. Br Med J 1: 358, 1952. Farquhar HG: Mercurial poisoning in early childhood. Lancet 2: 1186, 1953. Hamilton A: Industrial diseases of fur cutters and hatters. J
MERCURY POISONING DUE TO LAXATIVE ABUSE-WANDS
10. 11.
12. 13.
14.
15.
16.
17. 18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
Ind Hyg 4: 219, 1922. Wright W: A clinical study of fur cutters and felt hat workers. J Ind Hyg 4: 296, 1922. Cowers WR: Mercurial poisoning, Manual of Diseases of the Nervous System, vol 2, 2nd ed, London, J. & A. Churchill, Ltd., 1893, p 268. Bidstrup PL: Toxicity of Mercury and Its Compounds. Amsterdam, Elsevier Press, Inc., 1964. Willis JB: Determination of lead and other heavy metals in urine by atomic absorption spectroscopy. Anal Chem 34: 614. 1962. Hatch WR, Ott WL: Determination of sub-microgram quantities of mercury by atomic absorption spectrophotometry. Anal Chem 40: 2085, 1966. Stolman A, Stewart CP: Metallic poisons, Toxicology Mechanisms and Analytical Methods, vol 2 (Stewart CP, Stolman A, eds), New York, Academic Press, Inc.. 1960. Meek GA: Basic operational procedures, chap 10, Practical Electron Microscopy for Biologists, London, Wiley Interscience, 1971. Schrodt J. Randolph G: Melanosis coli: a study with the electron microscope. Dis Colon Rectum 6: 277, 1963. Ghadially FN, Parry EW: An electron microscope and histochemical study of melanosis coli. J Pathol 92: 313. 1966. Won KH. Ramchand S: Melanosis of ileum. Case report and electron microscopic study. Am J Dig Dis 15: 57. 1970. Kermarec J. Duplay H, Daniel R: Histochemical and electron microscope study of pigments in colonic melanosis and Dubin-Johnson syndrome. Ann Biol Clin (Paris) 30: 567, 1972. Finge E: Cathartics and laxatives, chap 49, The Pharmacological Basis of Therapeutics (Goodman LS, Gilman A, eds), London, The MacMillan Co.. 1970. MAC Committee. Maximum allowable concentrations of mercury compounds. Arch Environ Health 19: 891, 1969. Clarkson TW, Gatzy J, Dalton C: Studies on the equilibration of mercury vapor with blood. AEC Report No 582, 1961. Hughes WL: A physiochemical rationale for the biological activity of mercury and its compounds. Ann NY Acad Sci 65: 454, 1957. Bank N. Mutz BF. Aynedjian HS: The role of “leakage” of tubular fluid in anuria due to mercury poisoning. J Clin Invest 46: 695, 1967. Rodin AE, Crowson CN: Mercury nephrotoxicity in the rat. I. Factors influencing the localization of tubular lesions. Am J Pathol 41: 287, 1962. Becker CG, Becker EL, Maher JF. Schreiner GF: Nephrotoxic syndrome after contact with mercury. Arch Intern Med 1 IO: 178, 1962. Heptinstall RH: The nephrotic syndrome, chap 13, The Kidney, Boston, Little, Brown & Co., 1966.
29.
30. 31. 32. 33. 34.
35
36.
37
38
39
40. 41. 42.
43
44
45. 46.
47.
48.
July 1974
ET AL
Kazantzis G, Schiller KFR. Asscher AW. Drew RG: Albuminuria and the nephrotic syndrome following exposure to mercury and its compounds. 0 J Med 3 1: 403, 1962. Lee DBN, Drinkard JP, Rosen VJ, Gonick HC: The adult Fanconi syndrome. Medicine 51: 107. 1972. Clarkson TW: The pharmacology of mercury compounds. Annu Rev Pharmacol 12: 375, 1972. Cafrung EJ: The site and mechanism of action of mercurial diuretics. Pharmacol Rev 20: 89, 1968. Passow H, Rothstein A, Clarkson TW: General pharmacology of the heavy metals. Pharmacol Rev 13: 185, 196 1. Pulido P, Kagi JRH, Vallee BL: Isolation and some properties of human metallothionein. Biochemistry 5: 1768, 1966. Wisniewska JM, Trojanowska B, Piotrowski J, Jakubowski M: Binding of mercury in the rat kidney by metallothionein. Toxicol Appl Pharmacol 16: 754, 1970. Jakubowski M, Piotrowski J, Trojanowska 8: Binding of mercury in the rat: studies using 203HgC12and gel filtration. Toxicol Appl Pharmacol 16: 743, 1970. Gedigk P: Pigmentation caused by inorganic materials, chap 1, Pigments in Pathology (Wolman M, ed), New York, Academic Press, Inc., 1969. Norseth T. Bendeford M: Intracellular distribution of inorganic and organic mercury in rat livers after exposure to methylmercury salts. Biochem Pharmacol 20: 110 1, 1971. Norseth T, Clarkson TW: Intestinal transport of *03Hg labeled methyl mercury chloride. Arch Environ Health 22: 568, 1971. Williams CT: Black deposit in the large intestine from the presence of mercury. Tr Path Sot Lond 18: 111, 1867. Pitt GN: Colon pigmented black throughout with lead. Tr Path Sot London 42: 109, 1891. Wittoesh JH, Jackman RJ. McDonald JR: Melanosis coli: general review and study of 887 cases. Dis Colon Rectum 1: 172. 1958. Gonzalez-Licea A, Yardley JH: Whipple’s disease in the rectum. Light and electron microscopic findings. Am J Pathol 52: 1191, 1968. Longcope WT, Luetscher JA: The uses of BAL (British AntiLewisite) in the treatment of the injurious effects of arsenic, mercury, and other metallic poisoning. Ann intern Med 31: 545, 1949. Bivings L: Acrodynia: summary of BAL therapy reports and case report of calomel disease. J Pediatr 34: 322, 1949. McCoy JE, Carrb IJ, Freeman M: A controlled trial of endathamil calcium disodium in acrodynia. Pediatrics 25: 304, 1960. Kark PAR, Poskanzer DC, Bulloch JD. Boylen G: Mercury poisoning and its treatment with N-acetyl-D.L-penicillamine. N Engl J Med 285: 10. 1971. Smith ADM, Miller TW: Treatment of inorganic mercury poisoning with N-acetyl-D,L-penicillamine. Lancet 1: 640. 1961.
The American
Journal
of Medicine
Volume
57
101