COMBINED PRIMARY AND SECONDARY HYPERPARATHYROIDISM: TWO CASE REPORTS AND A REVIEW

15 Pages·1960·3.261 MB·English

by  EMANUEL GOLDBERG, M.D., RICHARD M. TORACK, M.D

COMBINED PRIMARY AND SECONDARY HYPER
PARATHYROIDISM: TWO CASE REPORTS
AND A REVIEW *
By EMANUEL GOLDBERG, M.D., Brooklyn, N. Y., and
RICHARD M. TORACK, M.D., Bronx, N. Y.
ALTHOUGH the literature on hyperparathyroidism is extensive, there are
few case reports of functioning parathyroid adenoma occurring simultane
ously with secondary hyperplasia of the parathyroid gland.2'8' *»5'6 Albright
and Reifenstein discussed only one such case when they wrote their classic
monograph1 on metabolic bone disease. Most of the reported cases have
not been carefully studied ante mortem, and this is true of the two reported
below. Secondary hyperplasia following the removal of a functioning ade
noma where there has been irreversible damage to the kidneys has often
been reported27> 50'57'77> 78>79 and is not hard to understand. When the two
lesions occur simultaneously, the phenomenon is somewhat of a paradox
and more difficult to explain.
The two cases reported here were found in a survey of postmortem
examinations over a 10 year period at Montefiore Hospital.
CASE REPORTS
Case 1. A 59 year old white married female with four Montefiore Hospital
admissions between 1953 and 1955 was first told of hypertension in 1947. In early
1953 she noted anorexia, weakness, fatigue, loss of weight, dyspnea, orthopnea and
urinary frequency. She was admitted to Montefiore Hospital on July 3, 1953, for
progression of these complaints. Physical examination showed hypertension (215/
160 mm. of Hg) and evidence of severe right- and left-sided heart failure. Eye-
grounds showed retinal arterial changes of grade II, and the heart was enlarged to
the anterior axillary line.
Laboratory Findings: An electrocardiogram was consistent with left ventricular
hypertrophy. Chest x-ray showed a large heart. A hemogram was normal. Urine:
specific gravity, 1.010; albumin, 1 plus; some epithelial cells, and occasional clumps
of white blood cells. Fasting blood sugar, 95 mg.%; blood urea nitrogen, 58 mg.%.
The patient responded to treatment with a low salt diet, digitalis and mercurial
diuretics and was discharged on August 3, 1953. She was followed in the outpatient
department, where paroxysmal atrial fibrillation and a questionable nodule in the
right upper lobe of the thyroid were noted.
The patient was re-admitted for diagnostic study in October, 1953. An I131
uptake was 39% in 24 hours, and she was considered to be euthyroid. The thoracic
cage was mildly demineralized on x-ray. Skull films and esophagram were normal.
On a Fishberg concentration test the overnight collection had a specific gravity of
•Received for publication April 17, 1959.
From the Departments of Pathology and Medicine, Montefiore Hospital, Bronx, N. Y.
Requests for reprints should be addressed to Emanuel Goldberg, M.D., Department of
Medicine, State University of New York, Downstate Medical Center, 450 Clarkson Avenue,
Brooklyn 3, N. Y.
87
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88 EMANUEL GOLDBERG AND RICHARD M. TORACK January 1960
1.002, and the maximal concentration of any specimen was 1.006. All urine speci
mens had 3 plus to 4 plus albumin, and the standard and maximal clearances of urea
were 10% and 9% of average normal function, respectively. Treatment with Rau-
dixin and Apresoline was started.
Nausea and vomiting precipitated the third Montefiore Hospital admission, in
September, 1954. At that time the blood urea nitrogen was 70.6 mg.%; creatinine,
7.1 mg.%; sodium, 132 mEq./L.; potassium, 3.5 mEq./L.; carbon dioxide content,
22.6 mEq./L.; chlorides, 96 mEq./L.; calcium, 10.5 mg.%; inorganic phosphate,
6.1 mg.%. Hemoglobin, 11.5 gm. Regitine test, negative.
The patient responded to symptomatic treatment and was discharged on Sep
tember 24, 1954. Progressive weakness, loss of appetite and severe epistaxis prompted
her final admission, on October 22, 1955. Blood pressure was 180/100 mm. of Hg;
pulse, 72 and irregular; temperature, normal; respiration, 24. Fundi were un
changed. There was some periorbital edema. The lungs were clear. The heart
was enlarged to the anterior axillary line; A was greater than P ; there was a soft,
2 2
grade II apical systolic murmur. One plus pitting ankle edema was present. The
neurologic examination was negative.
Laboratory Findings: Hemoglobin, 8 gm.%; blood urea nitrogen, 97 mg.%;
creatinine, 7.2 mg.%; sodium, 132 mEq./L.; potassium, 3.9 mEq./L.; carbon dioxide
content, 14.9 mEq./L.; chloride, 94 mEq./L.; calcium, 11.0 mg.%; inorganic phos
phorus, 8.3 mg.%; alkaline phosphatase, 18.2 Bodansky units. X-rays of the skull
showed cystic changes. The remainder of the bones were generally demineralized,
and there were areas of subperiosteal resorption of the bone. The lamina dura was
not seen in x-rays of the mandible. An increase in density of the right renal shadow
suggested nephrocalcinosis.
Hospital Course: Deterioration was progressive despite treatment with parenteral
fluids and packed red cells. Vomiting and abdominal distention were a persistent
feature. The patient died on November 13, 1955. The clinical impression was
chronic pyelonephritis with secondary hypertensive cardiovascular disease, hyper
parathyroidism and uremia.
Necropsy revealed a well developed, well nourished white female. The kidneys
weighed 65 and 75 gm. respectively. There was gross scarring of the renal paren
chyma, with some loss of distinction of cortical striations and the cortical medullary
junction. There was marked accentuation of the arcuate arteries. The pelves and
calyces were not remarkable. Four parathyroid glands were found, three of which
were moderately large, tan and somewhat lobulated. The fourth gland was much
larger than the rest, measuring 1.0 by 1.5 cm. in greatest diameter, but it was also
tan in color. The heart weighed 575 gm., and the left ventricle was hypertrophied.
On microscopic examination there was marked renal arterial and arteriolar sclerosis,
with extensive fibrous scars throughout the renal parenchyma. The majority of the
glomeruli were partially or completely fibrotic, and the tubules showed degeneration,
atrophy, regeneration and marked dilatation. There was also a diffuse lymphocytic
infiltration. No calcium deposits were seen. The largest parathyroid contained no
significant fat. The cells were regular in size and shape, and were largely chief
cells, but there were islands of wasserhelle cells and oxyphil cells (figure 1). The
remaining glands contained a decreased amount of fat, and the cells were normal-
appearing chief cells (figure 2). There was evidence of bone resorption, with many
trabeculae containing cystic spaces. In addition, other trabeculae showed evidence
of osteoid formation with calcification. Pathologic diagnosis was: renal arterial and
arteriolar sclerosis, left ventricular hypertrophy, parathyroid chief cell adenoma,
secondary parathyroid hyperplasia, osteitis fibrosa cystica.
Case 2. A 58 year old white male was admitted to Montefiore Hospital on
December 27, 1952, because of mental confusion, restlessness, occipital headaches and
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Vol. 52, No. 1 HYPERPARATHYROIDISM 89
weakness of the left leg of several weeks' duration. Two months prior to admission
a triple phosphate calculus had been removed from the left kidney at another hospital.
The pain in the left flank had disappeared promptly at that time, but symptoms of
"Parkinsonism" were noted for the first time postoperatively. Poor appetite and
generalized weakness persisted from the time of operation until the onset of the com
plaints and findings noted above. One day prior to admission a neurologist had
FIG. 1. Case 1. Parathyroid adenoma with well developed acinar structure in some foci.
Most cells represent chief cells, some of which have clear cytoplasm. X 240
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90 EMANUEL GOLDBERG AND RICHARD M. TORACK January 1960
FIG. 2. Case 1. Secondary parathyroid hyperplasia, showing decreased amount of fat.
The cells are largely active chief cells. X 240
examined the patient and found a left hemi paresis. Past history was not remarkable
except for a fracture of the left arm in 1950.
Physical examination on admission showed: temperature 98° F.; pulse 92; respi
ration, 20; blood pressure, 180/98 mm. of Hg. The patient appeared to be chroni
cally ill and slightly confused. There was bilateral nasal blurring of the optic discs
but no definite papilledema. A systolic murmur was heard over the precordium.
No masses were palpable in the neck. Neurologic examination: Positive findings
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Vol. 52, No. 1 HYPERPARATHYROIDISM 91
included mental confusion, left hemiparesis, increased muscle tone in all extremities,
and active reflexes except for absent superficial abdominals bilaterally. Bilateral
Babinski's responses were present, and there was a questionable sensory defect in the
left hand.
Laboratory Data: Hemoglobin, 13 gm.; white blood count, 8,100 per milliliter;
red blood count, 4,390,000 per milliliter. Urine: specific gravity 1.008; albumin,
negative; glucose, negative; microscopic: many white blood cells. Spinal tap: crystal
FIG. 3. Case 2. Secondary parathyroid hyperplasia with increased cellularity and
decreased fat. Most of the cells are chief cells. X 240
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92 EMANUEL GOLDBERG AND RICHARD M. TORACK January 1960
FIG. 4. Case 2. Parathyroid adenoma with poorly formed acinar structure
and prominent fibrous stroma. X 240
clear fluid under normal pressure. Sugar, 71 mg.%; total protein, 40 mg.%. Sero
logic reaction and culture, negative. Chest x-ray was within normal limits. Skull
films showed some demineralization of the sella. X-rays of the lumbar spine showed
some demineralization.
Hospital Course: The patient remained afebrile, but his condition gradually
declined, his mental state degenerating into complete disorientation and stupor. A
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Vol. 52, No. 1 HYPERPARATHYROIDISM 93
few moments before death he became cyanotic, his blood pressure fell, and the pupils
dilated and became fixed. No papilledema was noted at that time. The patient died
quietly on January 6, 1953. The clinical impressions were: (1) right frontoparietal
tumor with extension to the left side; (2) bilateral brain stem metastases from an
unknown primary neoplasm, or (3) a midbrain vascular lesion. Parkinsonism was
a subsidiary diagnosis.
Necropsy revealed a well developed, poorly nourished white male. Four mod
erately enlarged parathyroid glands were identified. Adjoining one of the glands
was a large, yellow-tan nodule measuring 2.5 cm. in greatest diameter. The kidneys
weighed 170 and 180 gm. The surfaces of the kidneys were smooth except for one
small scar. The cortices and medullae were intact and not remarkable. The pelves
and calyces were also grossly not remarkable. No bone changes were noted. The
heart weighed 410 gm. and the left ventricle was hypertrophied. The lungs were
congested. The brain was grossly normal. On microscopic examination, the para
thyroid glands showed cellular hyperplasia and diminished fat. Most of the cellular
elements were normal-appearing chief cells (figure 3). The large nodule contained
no significant fat and was composed of closely packed sheets of normal-appearing
chief cells (figure 4). The kidneys showed widespread calcification, most promi
nently in the glomeruli and tubules. There were also small subcapsular fibrous
scars. There was mild generalized osteoporosis, with small foci of myelofibrosis.
Foci of bone resorption with osteoclasts were present, but there were no areas of
cyst formation. The brain showed necrobiosis of cells in the substantia nigra and
the globus pallidus. Pathologic diagnosis: parathyroid chief cell adenoma, secondary
parathyroid hyperplasia, nephrocalcinosis, left ventricular hypertrophy, necrobiosis
of the substantia nigra and the globus pallidus.
DISCUSSION
Each of these two cases represents one of the two ways that simul
taneous primary and secondary hyperparathyroidism may occur. In the
first case, secondary parathyroid hyperplasia and hyperparathyroidism are
seen as the outcome of renal disease with uremia.9' "•54'59 The adenoma was
either an incidental occurrence or, as some suggest,1'4'7 a neoplastic response
to the nonspecific stimulation to hyperplasia. The high serum calcium levels
in the presence of hyperphosphatemia and acidosis, and the presence and pre
dominance of chief cells in the adenoma,5'8'32 favor the presumption that the
adenoma was secreting actively. In the second case, the absence of primary
renal disease argues strongly for the sequence of a primary hyperfunctioning
parathyroid adenoma producing nephrocalcinosis and renal insufficiency,
with secondary hyperplasia and hyperfunction of the remainder of the para
thyroid glands.
Cases reported in the literature are of these two general types.
In 1937 Kalbfleisch2 reported a case of multiple endocrine adenomata
including a chromophobe tumor of the pituitary, five islet cell tumors of the
pancreas, and a chief cell adenoma of one parathyroid gland with enlarge
ment ("pea sized"), hyperplasia, and loss of fatty stroma in the remaining
three glands. A left renal calculus was present, but the kidneys were other
wise normal. No blood calcium determinations were reported.
The case of Downs and Scott (1941)3 was cited by Albright and Reifen-
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94 EMANUEL GOLDBERG AND RICHARD M. TORACK January 1960
stein x as a convincing example of primary parathyroid adenoma with gen
eralized bony demineralization, nephrocalcinosis, renal failure and secondary
hyperplasia of the three remaining nonadenomatous parathyroid glands.
Serum calciums were 7.5 and 7.6 mg.%, and the serum inorganic phos
phorus was 4.1 and 5.8 mg.%, respectively. At the postmortem examina
tion there was much cystic change in the adenoma, which may explain both
the low serum calcium and the secondary hyperplasia; i.e., if the cystic
TABLE 1
Case Ref. PPaaraththoylorgoyid Kidneys Bones mBUg.N% vColO. *% mCg.a % mgP. %
1. Kalbfleisch,* 1937 Chief cell adenoma, Renal calculi Decalcif.
hyperplasia with
loss of interstitial
fat
2. Downs and Scott,» Chief cell adenoma, Nephro Decalcif. Up 7.5 4.1
1941 secondary hyper calcinosis 7.6 5.8
plasia
3. Soffer and Cohen/ 1/30/38—4 enl. Renal func 29 50.5 14.0 3.3
1943 glands at surg.; tion poor;
2 removed. Chief bladder
cell adenoma in calculi
one, some hyper
plasia of oxyphilic
and clear cells in
the other. 10/36
—1 and J glands
removed; hyper 13 13.1 3.1
plasia of all ele
ments
4. Lee et al.,5 1955 (case 6) Chief cell adenoma Nephro Osteitis 10.5 7.2
3 cm. X 2.5 cm. calcinosis fibrosa 11.1 11.2
3 enl. glands, 11.3 9.4
1.5 X 0.5 cm. 165 9.2 16.9
with secondary
hyperplasia
5. Bogdonoff et al.,6 (case 17) Adenoma and Nephro 224 10.8 8.8
1956 secondary calcinosis 10.5
hyperplasia
6. Case 1 Adenoma and Intrinsic Osteitis 70.6 10.5 6.1
secondary renal dis. fibrosa 49 11.1 4.8
hyperplasia (chr. pyelo 97.4 11.0 8.3
nephritis) 93.6 10.6 6.3
7. Case 2 Adenoma and Nephro Moderate
secondary calcinosis, demin-
hyperplasia renaljCal- eral.
culi
degeneration took place after the development of nephrocalcinosis with
uremia, there would not be enough circulating parathormone to maintain
the blood calcium in the face of acidosis and a rising serum phosphorus.
The resulting low calcium would then, according to traditional theory,
result in secondary parathyroid hyperplasia.
Soffer and Cohen's case 4 was that of a 42 year old white male with an
epulis of the lower jaw, generalized bony demineralization and cystic changes
in the bones, and bladder calculi. The blood calcium was 14.0 mg.%; in
organic phosphorus, 3.3 mg.%; blood urea nitrogen, 29 mg.%. At opera
tion, all four parathyroid glands were enlarged. Two were removed, and
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Vol. 32, No. 1 HYPERPARATHYROIDISM 95
a chief cell adenoma was found in one gland, with some hyperplasia of the
oxyphil and clear cells in the other. Fifteen months later the blood calcium
was 13.1 mg.%, inorganic phosphorus, 3.1 mg.%. The specific gravity
of the urine was fixed at 1.012, the urea clearance was 43% of normal, and
the phenolsulfonphthalein test showed 15% excretion of dye in four hours.
The remainder of one gland and one-half of a second gland were removed.
Microscopic examination of these specimens revealed diffuse hyperplasia of
all cell types. The authors believe the sequence of events to be a function
ing parathyroid adenoma producing a bladder stone which, in turn, caused
a chronic nephritis and secondary parathyroid hyperplasia. This case is
unusual in that secondary parathyroid hyperplasia was found in the absence
of hypocalcemia, hyperphosphatemia, marked azotemia or acidosis (CO2
was 50.5 vol.%).
A well documented case, similar to the one reported by Downs and Scott,8
is described by Lee et al.5 They note that since, in the phosphorus retention
of severe renal disease leading to secondary hyperparathyroidism, the serum
calcium usually falls, the elevated serum calcium (11 mg.%) in this case
supports the conclusion that the functioning adenoma preceded the renal dis
ease. They do not feel that the two other cases reported by them of hyper
plasia and adenoma are bona fide examples of combined primary and secon
dary hyperparathyroidism.28
A third case of a functioning parathyroid adenoma leading to nephro-
calcinosis, renal failure and secondary parathyroid hyperplasia was reported
by Bogdonoff et al.6 Here, also, the serum calcium level was higher than
that usually seen in simple secondary hyperplasia.
The occurrence of parathyroid adenoma and secondary hyperplasia is
probably more common than the scanty reports in the literature would in
dicate. One author, for example, notes in a personal communication that
he has seen three such cases in the presence of severe intrinsic renal disease.7
Castleman,8'9 Black82 and others 10'13 have outlined the criteria for diag
nosis and the problems confronting the pathologist when describing and
interpreting pathologic alterations of the parathyroid. In brief, all of the
various cell types of the parathyroid gland may be represented in a function
ing adenoma. However, adenomas consisting of eosinophilic cells alone do
not secrete excess parathormone. The intensity of function is independent
of cell type or size of the adenoma. Multiple functioning adenomas are rare,
but have a similarity to secondary hyperplasia with adenomatous change and
must be carefully distinguished.29 The diffuse wasserhelle hyperplasia, a
cause of primary hyperparathyroidism, is easily separated from the more
heterogeneous secondary variety. Also, adenomas have not been reported
in the presence of such primary hyperplasia,60 with one possible exception.79
Causes of secondary hyperplasia of the parathyroid gland are numerous lt
u.14,15,38,42,56,58 u although not always,12'14'47'58 correlated
and are usua y>
with a factor lowering the serum calcium. Bergstrand,54 MacCallum 55 and
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96 EMANUEL GOLDBERG AND RICHARD M. TORACK January 1960
Pappenheimer and Wilens1X related renal insufficiency to parathyroid hyper-
function and secondary hyperplasia. Bone changes in renal insufficiency
are those of failure of calcification of osteoid (as in rickets), as well as
osteitis fibrosa cystica.54 Snapper76 reviewed the evidence favoring acidosis
as a cause of the osseous pathologic changes of renal disease. Stanbury 63
supports parathyroid hyperfunction as a cause of the bony lesions of renal
disease. Much work has been done to implicate phosphorus retention as a
cause of increased parathyroid activity,12*13' 14'18'19'20' 21'22'47'51 but even to
the present, authorities are unconvinced, a decrease in the ionized blood cal
cium remaining the only proved stimulus to parathyroid hyperfunction.23'24'
25, si, es 1 ^^ Ham et al.64 fed vitamin D-deficient rats on a diet high in
calcium and phosphorus and obtained high serum levels of both calcium and
phosphorus, but no increase in the weight of the parathyroids. Parathyroid
hypertrophy was found when the diet was either high or low in phosphorus,
but uniformly low in calcium with corresponding changes in blood serum
levels. No such experiment has been done in the presence of uremia.
Since the initial investigations of Albright et al.1,8S into parathyroid
physiology many workers have offered evidence modifying the original
theory that one hormone and the effect upon one target organ were re
sponsible for the entire abnormal physiology of hyperparathyroidism, with
blood and bone changes dependent upon the consequences of decreased tubular
reabsorption of phosphorus on a fixed equilibrium product of calcium and
phosphate ions in the body fluids.14'26'47
A variety of parathyroid functions have been proposed, e.g., calcium
mobilization directly from bone,23'26 growth inhibition,36 promotion of
diuresis,15 elevation of blood pressure in the rat and in man,34'68 mobilization
of mucopolysaccharide,37'45'46 mobilization of citrate,39'40 regulation of lac
tation,47 regulation of magnesium metabolism,61 and, as mentioned above,
inhibition of phosphate resorption by the kidney tubule. Fractions of the
crude hormone have been isolated, with claims of varying validity that one
or another property is dominant in a particular fraction.15'41 Some suggest
that there are two principal hormones secreted by the gland, one stimu
lated by an elevated serum phosphorus, the other by a lowered serum cal
cium.14' 16'47
The cases reported here cannot be readily explained by the available data.
It is clear, however, that secondary hyperplasia of the parathyroids, a func
tioning parathyroid adenoma, and a normal or elevated serum calcium may
all be present in the same individual at the same time. It also seems reason
able to conclude that, in cases 2, 4, 5 and 7, where the adenoma was the
first event in the pathologic sequence, the secondary parathyroid hyperplasia
developed without there ever having been a significant lowering of the serum
calcium.
The following explanations are suggested: (1) that the serum calcium,
while not low, is below the threshold to which the gland has been "accli-
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