- Email: [email protected]
“Tertiary” hyperparathyroidism induced by osteomalacia resulting from phosphorus depletion
“Tertiary”
Hyperparathyroidism
Osteomalacia
Induced by
Resulting from
Phosphorus Depletion* GEORGE D. LUDWIG, M.D., G. CLAYTON KYLE, M.D. and M. DE BLANCO, M.D.? Philadelphia, Pennsylvania In the patient described clinical and chemical signs of osteomalacia developed as a result of phosphorus depletion caused by ingestion of excessive amounts of aluminum hydroxide. Symptoms disappeared and serum calcium and phosphorus levels were restored to normal by discontinuing these medications. Four years later hyperparathyroidism due to an autonomously functioning adenoma (“tertiary” hyperparathyroidism) developed. It is postulated that osteomalacia, with low serum calcium and phosphate concentrations, served as the stimulus for the development of secondary parathyroid hyperplasia and, in turn, to an autonomously functioning parathyroid adenoma. TN
1956 Davies, Dent and Willcox [ 11described
1 a patient with secondary hyperparathyroidism accompanying osteomalacia resulting from steatorrhea, in whom two discrete parathyroid adenomas subsequently developed. More recently the development of primary hyperparathyroidism due to autonomously functioning adenoma formation in parathyroid glands that have previously become hyperplastic secondary to chronic renal insufficiency has been demonstrated in additional patients [2-d). The term “tertiary” hyperparathyroidism has been suggested to apply to this sequence of events [2]. Described herein is a patient who had “tertiary” hyperparathyroidism superimposed upon a background of osteomalacia induced by severe phosphorus depletion resulting from excessive use of a combination of aluminum hydroxide gel and cathartics. The syndrome of osteomalacia and debility resulting from phosphorus depletion caused by ingestion of an excess of aluminum hydroxide gel has been defined recently [5]. CASE REPORT
A seventy-four year old white woman (G.S., HUP No. 10-31-14) was admitted to the Hospital of
the University of Pennsylvania in January 1961 because of weakness, stiffness and pain on movement of hips and knees. A diagnosis of primary pernicious anemia with posterolateral sclerosis had been made in 1953. The anemia had been corrected and neurologic symptoms had subsided during the intervening years as a result of parenteral vitamin B12 therapy. Achalasia and dilatation of the esophagus were found in 1957 and treated by means of bouginage on a number of occasions. For more than eighteen months the patient had been taking large amounts of magnesium-aluminum hydroxide (Maaloxa) daily to relieve symptoms related to achalasia of the esophagus. The exact amounts were not known, but were reputed to be as much as 200 to 240 ml. per day on some occasions. She had also taken liberal amounts of cathartics to relieve constipation. The patient showed lack of attention and loss of memory for recent events. There was a marked scoliosis of the spine to the right. The liver was palpable 1 cm. below the right costal margin and there was l+ pretibial edema. The right Achilles reflex was unobtainable, vibratory sense was absent and position sense was somewhat impaired in the lower extremities. Roentgenograms showed dilatation of the esophagus with narrowing at the esophagogastric junction.
* From the Department of Medicine, Hospital of the University of Pennsylvania, and School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. This work was supported in part by Clinical Research Center Grant 3MOl FR-40, Division of Research Facilities and Resources, National Institutes of Health. Manuscript received July 27,1966. t Kellogg Fellow in Endocrinology and Metabolism, University of Pennsylvania (1964-1966). 136
AMERICAN
JOURNAL
OF
MEDICINE
“Tertiary”
Hyperparathyroidism-Ludwig Hyperparathyroidism: I_
137
et al. 1965
PRCDNlSONC 2DMGm.V P”
w ?A 10 20 Feb. JM.
5 15 25
-
-
i9961-
Pzb.
5 MW
1962-
NOV.
1963
Juty
Sept.
k-4------” 1965
act.
NW
DRC
Tab 1966
Fm. 1. Sequential changes in serum concentrations of calcium and phosphate and in activity of alkaline phosphatase during five years. The stippled areas indicate normal levels. The decrease in the normal level for serum calcium by 0.5 mg. per 100 ml., indicated by the change in the stippled bar (top) between 1962 and 1963, is attributable to adoption of an EDTA method for measuring serum calcium, with its associated lower values.
There was generalized
demineralization in the hips, spine and extremities, with irregularity and sclerotic changes in the symphysis pubis. Marked hypertrophic changes were present in the lumbar vertebral bodies. No significant osseous abnormalities were noted in either knee or hip joints. There was diffuse demineralization of all bones examined, but no pseudofractures were evident. A Schilling test showed 1 per cent excretion of orally administered radioactive vitamin Br2 in twentyfour hours, confirming the previous diagnosis of primary pernicious anemia. The hemoglobin concentration varied between 13.4 and 14.1 mg. per 100 ml. The serum calcium concentration varied from 8.7 to 9.1 mg. per 100 ml.; serum phosphate was 2.0 mg. per 100 ml., serum alkaline phosphatase 23 Shinowara-Jones-Rinehart (SIR) units (normal 2 to 9), serum albumin 3.1 and globulin 2.1 gm. per 100 ml., serum sodium 139 to 141 mEq. per L., serum potassium 4.4 mEq. per L., serum chloride 107 to 111 mEq. per L. and serum carbon dioxide 26 to 31 mM per L. Random urine specimens were alkaline, the specific gravity varied between 1.016 and 1.032; sugar, protein and abnormal cellular elements were not present. An ammonium chloride loading test disclosed adequate ability to excrete acid and VOL.
43,
JULY
1967
ammonia. There was no excess aminoaciduria or glycosuria. The quantitative urinary protein excretion was 49 mg. per twenty-four hours. Hypercalciuria was present exceeding 200 mg. per twenty-four hours. The serum carotene was 35 and 40 pg. per 100 ml., serum iron 94 pg. per 100 ml. and total iron-binding capacity 267 pg. per 100 ml. (36 per cent saturation). In a xylose tolerance test 3.9 gm. of xylose (normal 4.5 gm.) were excreted in five hours following an oral dose of 25 gm. Fecal fat excretion was within normal limits (less than 5 gm. per twenty-four hours). Blood urea nitrogen was 14 mg. per 100 ml. It was concluded that the osteomalacia resulted from phosphorus depletion caused by regular ingestion of large amounts of aluminum hydroxide coupled with excessive use of cathartics. It was decided to withhold vitamin D, calcium and phosphorus as specific therapy to determine whether the chemical indications of osteomalacia and the bone pain would disappear following the elimination of aluminum hydroxide gel and cathartics. These medications were discontinued; the serum calcium and phosphate concentration and serum alkaline phosphatase levels returned to normal during the next few weeks, and the patient’s symptoms disappeared (Fig. 1). She was readmitted to the hospital in February 1962
138
“Tertiary”
Hyperparathyroidism-Ludwig
because of malaise and jaundice which had first appeared several days earlier. Serum calcium was 10.3 and serum phosphate 2.3 mg. per 100 ml. An intravenous cholangiogram showed a markedly dilated common bile duct, with narrowing of its distal portion. Cholecystostomy and choledocholithotomy were performed. There was a rise in the alkaline phosphatase level which (Fig. 1, February 1962) was attributable to extrahepatic biliary obstruction, rather than to osseous involvement, as indicated by its decline to normal following choledocholithotomy. On three other occasions (May 1962, February 1963 and January 1964) the patient was admitted for treatment of achalasia of the esophagus. Values for serum calcium, phosphate and alkaline phosphatase were normal. (Fig. 1). In July 1965 an attack of weakness, with dyspnea, confusion and inability to walk, prompted another admission to the hospital. The findings on physical examination were little changed. There were a few rales at the base of the right lung, a grade 2 apical systolic murmur was heard and the liver ,edge was felt 2 cm. below the right costal margin. A glucose tolerance test yielded a normal curve; xylose excretion was 11 gm. in five hours. Serum was 10 and 10.4 mg. calcium concentration per 100 ml. Serum phosphate had decreased to 2.5 mg. per 100 ml. and serum alkaline phosphatase, which had been normal during the intervening years, was increased to 19 SJR units. The hemoglobin concentration was 14.3 gm. per 100 ml. The blood urea nitrogen was 14 mg. per 100 ml. and the serum electrolytes were within normal limits. Urinalysis did not reveal any abnormalities. Fecal fat was not increased. Roentgenograms of the chest showed some emphysematous changes. There was a radiolucent lesion in the left frontal bone, measuring approximately 1 cm. in its greatest diameter. A neurologic consultant believed that the patient had incipient senile dementia, with evidence of a past cerebral occlusion involving the right parietal lobe. Multiple myeloma and metastatic malignancy were also considered, but diagnostic studies offered no confirmation and the patient was discharged. The patient was readmitted in August 1965 because of her refusal to eat and drink and increasing confusion. These symptoms and signs had progressed over a three week period, and anorexia had become striking. Examination disclosed mental confusion progressing to somnolence and semicoma. The patient was disoriented in regard to time, place and persons. The liver was palpable. There was no peripheral edema. The remainder of the findings were unchanged. The hemoglobin, leukocyte and differential counts were within normal limits as were the serum electrolytes except for a moderately low potassium level. Blood urea nitrogen was 17 mg. per 100 ml. The serum calcium concentration was greatly increased;
et al.
values of 15.0 to 15.1 mg. per 100 ml. being obtained in repeated measurements. The initial serum phosphate concentration was 3.2, but subsequent values were in the range of 2.0 to 2.5 mg. per 100 ml. The serum alkaline phosphatase was 5 and 7 SJR units. The serum protein-bound iodine was 5.0 pg. per 100 ml. Endogenous creatinine clearance was 58 ml. per minute, phosphate clearance was increased (17 to 20 ml. per minute) and tubular reabsorption of phosphate was low (60 to 71 per cent). Serum cortisol concentration was 23 pg. per 100 ml. Roentgenograms of the bones showed extensive demineralization. The radiolucent defect in the left frontal bone appeared to be somewhat larger than in films taken two months previously. Roentgen@ grams of the chest did not reveal any abnormalities. A series of roentgenograms of the upper gastrointestinal tract showed dilatation of the esophagus and a large duodenal cap, but no other abnormalities. Sternal bone marrow examination disclosed no plasma cells, tumor cells or other abnormalities. An intravenous urogram showed normal excretion bilaterally. The urinary calcium excretion was 73 mg. per twenty-four hours on a regular diet. The results of protein electrophoresis were within normal limits. A selenium’s_methionine scan showed an area of uptake near the left lower pole of the thyroid, suggesting a parathyroid adenoma. The oral administration of prednisone, 20 mg. daily, evoked dramatic improvement in the patient’s mental status. She became much more alert and better oriented. However, after two weeks of therapy, the serum calcium level fell only to the 13 to 14 mg. per 100 ml. range, a result interpreted as a negative “steroid suppression test,” compatible with hyperparathyroidism. It was surmised, prior to operation, that an autonomously functioning parathyroid adenoma had developed in the presence of previously existing secondary hyperparathyroidism which had been induced by a syndrome of calcium and phosphate depletion (osteomalacia) resulting from excessive use of aluminum hydroxide and cathartics. Exploration of the neck was performed on October 14, 1965, and a parathyroid adenoma, measuring 1.5 by 1.0 by 1.0 cm. and weighing 1.05 gm. was removed from behind the left lower pole of the thyroid gland. Another parathyroid gland was visible, but did not appear to be grossly enlarged. Because of the patient’s age and precarious condition, further exploration was considered unwarranted, and no biopsy specimens were taken from other parathyroid glands. The adenoma consisted mainly of chief cells arranged in cords (Fig. 2). A rim of normal parathyroid tissue was visible at the margin of the adenoma. Postoperatively, the serum calcium level fell to normal within thirty-six hours, and the serum phosphate level rose to normal within one week (Fig. I). The patient’s mental status improved greatly. Four AMERICAN
JOURNAL
OF
MEDICINE
“Tertiary”
Hyperparathyroidism-Ludwig
et al.
139
days after operation
clinical signs of hypocalcemia appeared. She was given 1 ampule of calcium gluconate intravenously. From then until her discharge on November 8, 1965, she was given calcium gluconate (4 gm. orally) and dihydrotachysterol (1 mg. parenterally) daily. Serum calcium and phosphate concentrations and alkaline phosphatase have remained within normal limits (Fig. 1). COMMENTS
The patient described herein clearly displayed chemical and clinical signs of osteomalacia in 1961. The calcium X phosphate ion product was low, ranging from 17 to 19 mg. per 100 ml., with serum calcium varying between 8.7 and 9.1 and serum phosphate between 2.0 and 2.1 mg. per 100 ml. The serum alkaline phosphatase was increased to 23 SJR units (N = 2 to 9 units). .4ssociated symptoms were debility, weakness and pain in bones and joints. Roentgenograms showed marked generalized demineralization, although without pseudofractures and without the subperiosteal bone erosion or osteitis fibrosa cystica which is characteristic of hyperparathyroidism. Renal function was good at the time. Specific types of malabsorption and steatorrhea were excluded. A &hilling test result was compatible with the diagnosis of primary pernicious anemia which had been made many years earlier. Pernicious anemia had been controlled adequately with parenteral vitamin B,z therapy and was considered to be unrelated to the patient’s current metabolic problem. Osteomalacia was attributed to phosphorus depletion inducedbythe chronic excessive ingestion of Maalox, because of its known capacity to bind phosphorus in the gut. At the time this patient was studied only one clinical case of osteomalacia resulting from phosphorus depletion due to aluminum products [6] had been recorded. The syndrome displayed by this patient has only recently been defined clearly by Lotz, Ney and Bartter [5]. They observed this syndrome in two patients and reproduced it in normal healthy subjects by giving them large amounts of aluminum hydroxide preparations. In our patient the excessive use of laxatives may have contributed to the development of hypocalcemia; however, in both their patients and experimental subjects Lotz and co-workers showed that a striking negative calcium balance resulted when excessive amounts of aluminum hydroxide gel were ingested for long periods of time. Discontinuing the intake of laxatives and Maalox was attended by disappearance of “or_.
43,
JULY
1967
FIG. 2. Histologic pattern of parathyroid adenoma excised from left lower pole. Note mainly chief cells arranged in cords. 4 rim of normal parathyroid tissue (not shown) was visible at the margin of the adenoma. Original magnification X 240.
skeletal pain and weakness, and by a gradual return of the serum calcium, serum phosphate and serum alkaline phosphatase levels to normal. During the course of the ensuing four years values for serum calcium, phosphate and alkaline phosphatase were normal on a number of occasions. It is noteworthy that serum phosphate levels remained in the low normal range. Although the serum calcium level was not elevated during the first admission in July 1965, mental symptoms, anorexia, weakness and bone lesions compatible with hyperparathyroidism were present; the serum phosphorus level was again low and the alkaline phosphatase level high. Marked hypercalcemia was present at the time of the second admission (August to September 1965) when numerous diagnostic procedures supported a diagnosis of hyperparathyroidism. Subsequently, an adenoma was excised surgically, and the serum calcium, phosphate and alkaline phosphatase returned to normal. It is assumed that phosphorus depletion and subsequent negative calcium balance, which resulted in low calcium and phosphate concentrations in the serum (chemical osteomalacia), led to secondary hyperparathyroidism; this, in turn, afforded the stimulus for the eventual development of an autonomously functioning adenoma. The lack of symptoms, and the finding of normal serum calcium, serum phosphate and serum alkaline phosphatase values on many occasions during the four year interval between the time that the intake of Maalox and cathartics was dis-
140
“Tertiary”
Hyperparathyroidism-Ludwig
continued and the symptoms, signs and biochemical changes characteristic of primary hyperparathyroidism appeared, provide convincing evidence that the autonomously functioning adenoma was of recent origin. Four years earlier the chemical and clinical signs and symptoms were clearly those of osteomalacia rather than hyperparathyroidism. It has been well documented that the development of autonomous parathyroid hyperfunction due to adenoma formation subsequent to secondary hyperparathyroidism, an occurrence for which the term “tertiary” hyperparathyroidism has been suggested [Z], is secondary to chronic renal insufficiency in a number of instances [Z41. Hyperparathyroidism persisting for many months following renal homotransplantation has been described recently [7]. However, in these cases, parathyroid autonomy has been ascribed to hyperplasia rather than to adenoma formation. Other than the patient described by Davies et al. [I], this is, to our knowledge, the first patient hyperparathyroidism ocin whom “tertiary” curred secondary to some cause other than chronic renal failure. Plough and Kyle [8] described a patient with acute pancreatitis in whom hyperparathyroidism was found eight years later and was cured by removal of an adenoma ; they suggested that in this case osteomalacia caused by chronic pancreatic insufficiency had resulted in secondary parathyroid hyperplasia and eventual adenoma formation. However, the prior existence of primary hyperparathyroidism was not excluded in their patient. As discussed fully elsewhere [9-l 71, there is evidence to indicate that pancreatitis occurred secondary to hyperparathyroidism in most of the cases recorded in
et al.
which the two conditions were associated, rather than the reverse. However, it is reasonable to expect that “tertiary” hyperparathyroidism may develop in some patients as a result of chronic pancreatitis and steatorrhea as suggested by Plough and Kyle [B].
REFERENCES 1. DAVIES, D. R., DENT, C. E. and WILLCOX, A. Hyperparathyroidism and steatorrhea. Brit. M. J., 2: 1133,1956. 2. Case Records of the Massachusetts General Hospital. Case 29, 1963. New England J. Med., 268: 943, 1963. 3. MCPHAUL, J. J., JR., MCINTOSH, D. A., HAMMOND, W. S. and PARK, 0. K. Autonomous secondary (renal) parathyroid hyperplasia. New England J. Med., 271: 1342,1964. 4. GOLDEN, A., CANARY, J. and KERWIN, D. M. Concurrence of hyperplasia and neoplasia of the parathyroid glands. Am. J. Med., 38: 562, 1965. 5. LOTZ, M., NEY, R. and BARTTER, F. C. Osteomalacia and debility resulting from phosphorus depletion. Tr. A. Am. Physicians, 77: 281, 1964. 6. BLOOM,W. L. and FLINCHUM,D. Osteomalacia with pseudofractures caused by the ingestion of aluminum hvdroxide. J.A.M.A.. 174: 1347.1960. 7. MCINTOSH,‘D. A. and MCPHAUL, J. J., Jk. Hyperparathyroidism complicating renal homotransplantation. Clin. Res., 14: 384,1966. 8. PLOUGH, I. C. and KYLE, L. H. Pancreatic insufficiency and hyperparathyroidism. Ann. Znt. Med., 47: 590,1957. 9. COPE, O., CULVER, P. J., MIXTER, C. G. and NARDI, G. L. Pancreatitis, diagnostic clue to hyperparathyroidism. Ann. Surg., 145: 857, 1957. 10. MIXTER, C. G., JR., KEYNES, W. M. and COPE, 0. Further experience with pancreatitis as a diagnostic clue to hyperparathyroidism. New England J. Med., 266: 265, 1962. 11. LUDWIG, G. D. and CHAYKIN, L. Pancreatitis associated with primary hyperparathyroidism. M. Clin. North America, 50: 1403, 1966.
AMERICAN
JOURNAL
OF
MEDICINE
Hyperparathyroidism
Osteomalacia
Induced by
Resulting from
Phosphorus Depletion* GEORGE D. LUDWIG, M.D., G. CLAYTON KYLE, M.D. and M. DE BLANCO, M.D.? Philadelphia, Pennsylvania In the patient described clinical and chemical signs of osteomalacia developed as a result of phosphorus depletion caused by ingestion of excessive amounts of aluminum hydroxide. Symptoms disappeared and serum calcium and phosphorus levels were restored to normal by discontinuing these medications. Four years later hyperparathyroidism due to an autonomously functioning adenoma (“tertiary” hyperparathyroidism) developed. It is postulated that osteomalacia, with low serum calcium and phosphate concentrations, served as the stimulus for the development of secondary parathyroid hyperplasia and, in turn, to an autonomously functioning parathyroid adenoma. TN
1956 Davies, Dent and Willcox [ 11described
1 a patient with secondary hyperparathyroidism accompanying osteomalacia resulting from steatorrhea, in whom two discrete parathyroid adenomas subsequently developed. More recently the development of primary hyperparathyroidism due to autonomously functioning adenoma formation in parathyroid glands that have previously become hyperplastic secondary to chronic renal insufficiency has been demonstrated in additional patients [2-d). The term “tertiary” hyperparathyroidism has been suggested to apply to this sequence of events [2]. Described herein is a patient who had “tertiary” hyperparathyroidism superimposed upon a background of osteomalacia induced by severe phosphorus depletion resulting from excessive use of a combination of aluminum hydroxide gel and cathartics. The syndrome of osteomalacia and debility resulting from phosphorus depletion caused by ingestion of an excess of aluminum hydroxide gel has been defined recently [5]. CASE REPORT
A seventy-four year old white woman (G.S., HUP No. 10-31-14) was admitted to the Hospital of
the University of Pennsylvania in January 1961 because of weakness, stiffness and pain on movement of hips and knees. A diagnosis of primary pernicious anemia with posterolateral sclerosis had been made in 1953. The anemia had been corrected and neurologic symptoms had subsided during the intervening years as a result of parenteral vitamin B12 therapy. Achalasia and dilatation of the esophagus were found in 1957 and treated by means of bouginage on a number of occasions. For more than eighteen months the patient had been taking large amounts of magnesium-aluminum hydroxide (Maaloxa) daily to relieve symptoms related to achalasia of the esophagus. The exact amounts were not known, but were reputed to be as much as 200 to 240 ml. per day on some occasions. She had also taken liberal amounts of cathartics to relieve constipation. The patient showed lack of attention and loss of memory for recent events. There was a marked scoliosis of the spine to the right. The liver was palpable 1 cm. below the right costal margin and there was l+ pretibial edema. The right Achilles reflex was unobtainable, vibratory sense was absent and position sense was somewhat impaired in the lower extremities. Roentgenograms showed dilatation of the esophagus with narrowing at the esophagogastric junction.
* From the Department of Medicine, Hospital of the University of Pennsylvania, and School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. This work was supported in part by Clinical Research Center Grant 3MOl FR-40, Division of Research Facilities and Resources, National Institutes of Health. Manuscript received July 27,1966. t Kellogg Fellow in Endocrinology and Metabolism, University of Pennsylvania (1964-1966). 136
AMERICAN
JOURNAL
OF
MEDICINE
“Tertiary”
Hyperparathyroidism-Ludwig Hyperparathyroidism: I_
137
et al. 1965
PRCDNlSONC 2DMGm.V P”
w ?A 10 20 Feb. JM.
5 15 25
-
-
i9961-
Pzb.
5 MW
1962-
NOV.
1963
Juty
Sept.
k-4------” 1965
act.
NW
DRC
Tab 1966
Fm. 1. Sequential changes in serum concentrations of calcium and phosphate and in activity of alkaline phosphatase during five years. The stippled areas indicate normal levels. The decrease in the normal level for serum calcium by 0.5 mg. per 100 ml., indicated by the change in the stippled bar (top) between 1962 and 1963, is attributable to adoption of an EDTA method for measuring serum calcium, with its associated lower values.
There was generalized
demineralization in the hips, spine and extremities, with irregularity and sclerotic changes in the symphysis pubis. Marked hypertrophic changes were present in the lumbar vertebral bodies. No significant osseous abnormalities were noted in either knee or hip joints. There was diffuse demineralization of all bones examined, but no pseudofractures were evident. A Schilling test showed 1 per cent excretion of orally administered radioactive vitamin Br2 in twentyfour hours, confirming the previous diagnosis of primary pernicious anemia. The hemoglobin concentration varied between 13.4 and 14.1 mg. per 100 ml. The serum calcium concentration varied from 8.7 to 9.1 mg. per 100 ml.; serum phosphate was 2.0 mg. per 100 ml., serum alkaline phosphatase 23 Shinowara-Jones-Rinehart (SIR) units (normal 2 to 9), serum albumin 3.1 and globulin 2.1 gm. per 100 ml., serum sodium 139 to 141 mEq. per L., serum potassium 4.4 mEq. per L., serum chloride 107 to 111 mEq. per L. and serum carbon dioxide 26 to 31 mM per L. Random urine specimens were alkaline, the specific gravity varied between 1.016 and 1.032; sugar, protein and abnormal cellular elements were not present. An ammonium chloride loading test disclosed adequate ability to excrete acid and VOL.
43,
JULY
1967
ammonia. There was no excess aminoaciduria or glycosuria. The quantitative urinary protein excretion was 49 mg. per twenty-four hours. Hypercalciuria was present exceeding 200 mg. per twenty-four hours. The serum carotene was 35 and 40 pg. per 100 ml., serum iron 94 pg. per 100 ml. and total iron-binding capacity 267 pg. per 100 ml. (36 per cent saturation). In a xylose tolerance test 3.9 gm. of xylose (normal 4.5 gm.) were excreted in five hours following an oral dose of 25 gm. Fecal fat excretion was within normal limits (less than 5 gm. per twenty-four hours). Blood urea nitrogen was 14 mg. per 100 ml. It was concluded that the osteomalacia resulted from phosphorus depletion caused by regular ingestion of large amounts of aluminum hydroxide coupled with excessive use of cathartics. It was decided to withhold vitamin D, calcium and phosphorus as specific therapy to determine whether the chemical indications of osteomalacia and the bone pain would disappear following the elimination of aluminum hydroxide gel and cathartics. These medications were discontinued; the serum calcium and phosphate concentration and serum alkaline phosphatase levels returned to normal during the next few weeks, and the patient’s symptoms disappeared (Fig. 1). She was readmitted to the hospital in February 1962
138
“Tertiary”
Hyperparathyroidism-Ludwig
because of malaise and jaundice which had first appeared several days earlier. Serum calcium was 10.3 and serum phosphate 2.3 mg. per 100 ml. An intravenous cholangiogram showed a markedly dilated common bile duct, with narrowing of its distal portion. Cholecystostomy and choledocholithotomy were performed. There was a rise in the alkaline phosphatase level which (Fig. 1, February 1962) was attributable to extrahepatic biliary obstruction, rather than to osseous involvement, as indicated by its decline to normal following choledocholithotomy. On three other occasions (May 1962, February 1963 and January 1964) the patient was admitted for treatment of achalasia of the esophagus. Values for serum calcium, phosphate and alkaline phosphatase were normal. (Fig. 1). In July 1965 an attack of weakness, with dyspnea, confusion and inability to walk, prompted another admission to the hospital. The findings on physical examination were little changed. There were a few rales at the base of the right lung, a grade 2 apical systolic murmur was heard and the liver ,edge was felt 2 cm. below the right costal margin. A glucose tolerance test yielded a normal curve; xylose excretion was 11 gm. in five hours. Serum was 10 and 10.4 mg. calcium concentration per 100 ml. Serum phosphate had decreased to 2.5 mg. per 100 ml. and serum alkaline phosphatase, which had been normal during the intervening years, was increased to 19 SJR units. The hemoglobin concentration was 14.3 gm. per 100 ml. The blood urea nitrogen was 14 mg. per 100 ml. and the serum electrolytes were within normal limits. Urinalysis did not reveal any abnormalities. Fecal fat was not increased. Roentgenograms of the chest showed some emphysematous changes. There was a radiolucent lesion in the left frontal bone, measuring approximately 1 cm. in its greatest diameter. A neurologic consultant believed that the patient had incipient senile dementia, with evidence of a past cerebral occlusion involving the right parietal lobe. Multiple myeloma and metastatic malignancy were also considered, but diagnostic studies offered no confirmation and the patient was discharged. The patient was readmitted in August 1965 because of her refusal to eat and drink and increasing confusion. These symptoms and signs had progressed over a three week period, and anorexia had become striking. Examination disclosed mental confusion progressing to somnolence and semicoma. The patient was disoriented in regard to time, place and persons. The liver was palpable. There was no peripheral edema. The remainder of the findings were unchanged. The hemoglobin, leukocyte and differential counts were within normal limits as were the serum electrolytes except for a moderately low potassium level. Blood urea nitrogen was 17 mg. per 100 ml. The serum calcium concentration was greatly increased;
et al.
values of 15.0 to 15.1 mg. per 100 ml. being obtained in repeated measurements. The initial serum phosphate concentration was 3.2, but subsequent values were in the range of 2.0 to 2.5 mg. per 100 ml. The serum alkaline phosphatase was 5 and 7 SJR units. The serum protein-bound iodine was 5.0 pg. per 100 ml. Endogenous creatinine clearance was 58 ml. per minute, phosphate clearance was increased (17 to 20 ml. per minute) and tubular reabsorption of phosphate was low (60 to 71 per cent). Serum cortisol concentration was 23 pg. per 100 ml. Roentgenograms of the bones showed extensive demineralization. The radiolucent defect in the left frontal bone appeared to be somewhat larger than in films taken two months previously. Roentgen@ grams of the chest did not reveal any abnormalities. A series of roentgenograms of the upper gastrointestinal tract showed dilatation of the esophagus and a large duodenal cap, but no other abnormalities. Sternal bone marrow examination disclosed no plasma cells, tumor cells or other abnormalities. An intravenous urogram showed normal excretion bilaterally. The urinary calcium excretion was 73 mg. per twenty-four hours on a regular diet. The results of protein electrophoresis were within normal limits. A selenium’s_methionine scan showed an area of uptake near the left lower pole of the thyroid, suggesting a parathyroid adenoma. The oral administration of prednisone, 20 mg. daily, evoked dramatic improvement in the patient’s mental status. She became much more alert and better oriented. However, after two weeks of therapy, the serum calcium level fell only to the 13 to 14 mg. per 100 ml. range, a result interpreted as a negative “steroid suppression test,” compatible with hyperparathyroidism. It was surmised, prior to operation, that an autonomously functioning parathyroid adenoma had developed in the presence of previously existing secondary hyperparathyroidism which had been induced by a syndrome of calcium and phosphate depletion (osteomalacia) resulting from excessive use of aluminum hydroxide and cathartics. Exploration of the neck was performed on October 14, 1965, and a parathyroid adenoma, measuring 1.5 by 1.0 by 1.0 cm. and weighing 1.05 gm. was removed from behind the left lower pole of the thyroid gland. Another parathyroid gland was visible, but did not appear to be grossly enlarged. Because of the patient’s age and precarious condition, further exploration was considered unwarranted, and no biopsy specimens were taken from other parathyroid glands. The adenoma consisted mainly of chief cells arranged in cords (Fig. 2). A rim of normal parathyroid tissue was visible at the margin of the adenoma. Postoperatively, the serum calcium level fell to normal within thirty-six hours, and the serum phosphate level rose to normal within one week (Fig. I). The patient’s mental status improved greatly. Four AMERICAN
JOURNAL
OF
MEDICINE
“Tertiary”
Hyperparathyroidism-Ludwig
et al.
139
days after operation
clinical signs of hypocalcemia appeared. She was given 1 ampule of calcium gluconate intravenously. From then until her discharge on November 8, 1965, she was given calcium gluconate (4 gm. orally) and dihydrotachysterol (1 mg. parenterally) daily. Serum calcium and phosphate concentrations and alkaline phosphatase have remained within normal limits (Fig. 1). COMMENTS
The patient described herein clearly displayed chemical and clinical signs of osteomalacia in 1961. The calcium X phosphate ion product was low, ranging from 17 to 19 mg. per 100 ml., with serum calcium varying between 8.7 and 9.1 and serum phosphate between 2.0 and 2.1 mg. per 100 ml. The serum alkaline phosphatase was increased to 23 SJR units (N = 2 to 9 units). .4ssociated symptoms were debility, weakness and pain in bones and joints. Roentgenograms showed marked generalized demineralization, although without pseudofractures and without the subperiosteal bone erosion or osteitis fibrosa cystica which is characteristic of hyperparathyroidism. Renal function was good at the time. Specific types of malabsorption and steatorrhea were excluded. A &hilling test result was compatible with the diagnosis of primary pernicious anemia which had been made many years earlier. Pernicious anemia had been controlled adequately with parenteral vitamin B,z therapy and was considered to be unrelated to the patient’s current metabolic problem. Osteomalacia was attributed to phosphorus depletion inducedbythe chronic excessive ingestion of Maalox, because of its known capacity to bind phosphorus in the gut. At the time this patient was studied only one clinical case of osteomalacia resulting from phosphorus depletion due to aluminum products [6] had been recorded. The syndrome displayed by this patient has only recently been defined clearly by Lotz, Ney and Bartter [5]. They observed this syndrome in two patients and reproduced it in normal healthy subjects by giving them large amounts of aluminum hydroxide preparations. In our patient the excessive use of laxatives may have contributed to the development of hypocalcemia; however, in both their patients and experimental subjects Lotz and co-workers showed that a striking negative calcium balance resulted when excessive amounts of aluminum hydroxide gel were ingested for long periods of time. Discontinuing the intake of laxatives and Maalox was attended by disappearance of “or_.
43,
JULY
1967
FIG. 2. Histologic pattern of parathyroid adenoma excised from left lower pole. Note mainly chief cells arranged in cords. 4 rim of normal parathyroid tissue (not shown) was visible at the margin of the adenoma. Original magnification X 240.
skeletal pain and weakness, and by a gradual return of the serum calcium, serum phosphate and serum alkaline phosphatase levels to normal. During the course of the ensuing four years values for serum calcium, phosphate and alkaline phosphatase were normal on a number of occasions. It is noteworthy that serum phosphate levels remained in the low normal range. Although the serum calcium level was not elevated during the first admission in July 1965, mental symptoms, anorexia, weakness and bone lesions compatible with hyperparathyroidism were present; the serum phosphorus level was again low and the alkaline phosphatase level high. Marked hypercalcemia was present at the time of the second admission (August to September 1965) when numerous diagnostic procedures supported a diagnosis of hyperparathyroidism. Subsequently, an adenoma was excised surgically, and the serum calcium, phosphate and alkaline phosphatase returned to normal. It is assumed that phosphorus depletion and subsequent negative calcium balance, which resulted in low calcium and phosphate concentrations in the serum (chemical osteomalacia), led to secondary hyperparathyroidism; this, in turn, afforded the stimulus for the eventual development of an autonomously functioning adenoma. The lack of symptoms, and the finding of normal serum calcium, serum phosphate and serum alkaline phosphatase values on many occasions during the four year interval between the time that the intake of Maalox and cathartics was dis-
140
“Tertiary”
Hyperparathyroidism-Ludwig
continued and the symptoms, signs and biochemical changes characteristic of primary hyperparathyroidism appeared, provide convincing evidence that the autonomously functioning adenoma was of recent origin. Four years earlier the chemical and clinical signs and symptoms were clearly those of osteomalacia rather than hyperparathyroidism. It has been well documented that the development of autonomous parathyroid hyperfunction due to adenoma formation subsequent to secondary hyperparathyroidism, an occurrence for which the term “tertiary” hyperparathyroidism has been suggested [Z], is secondary to chronic renal insufficiency in a number of instances [Z41. Hyperparathyroidism persisting for many months following renal homotransplantation has been described recently [7]. However, in these cases, parathyroid autonomy has been ascribed to hyperplasia rather than to adenoma formation. Other than the patient described by Davies et al. [I], this is, to our knowledge, the first patient hyperparathyroidism ocin whom “tertiary” curred secondary to some cause other than chronic renal failure. Plough and Kyle [8] described a patient with acute pancreatitis in whom hyperparathyroidism was found eight years later and was cured by removal of an adenoma ; they suggested that in this case osteomalacia caused by chronic pancreatic insufficiency had resulted in secondary parathyroid hyperplasia and eventual adenoma formation. However, the prior existence of primary hyperparathyroidism was not excluded in their patient. As discussed fully elsewhere [9-l 71, there is evidence to indicate that pancreatitis occurred secondary to hyperparathyroidism in most of the cases recorded in
et al.
which the two conditions were associated, rather than the reverse. However, it is reasonable to expect that “tertiary” hyperparathyroidism may develop in some patients as a result of chronic pancreatitis and steatorrhea as suggested by Plough and Kyle [B].
REFERENCES 1. DAVIES, D. R., DENT, C. E. and WILLCOX, A. Hyperparathyroidism and steatorrhea. Brit. M. J., 2: 1133,1956. 2. Case Records of the Massachusetts General Hospital. Case 29, 1963. New England J. Med., 268: 943, 1963. 3. MCPHAUL, J. J., JR., MCINTOSH, D. A., HAMMOND, W. S. and PARK, 0. K. Autonomous secondary (renal) parathyroid hyperplasia. New England J. Med., 271: 1342,1964. 4. GOLDEN, A., CANARY, J. and KERWIN, D. M. Concurrence of hyperplasia and neoplasia of the parathyroid glands. Am. J. Med., 38: 562, 1965. 5. LOTZ, M., NEY, R. and BARTTER, F. C. Osteomalacia and debility resulting from phosphorus depletion. Tr. A. Am. Physicians, 77: 281, 1964. 6. BLOOM,W. L. and FLINCHUM,D. Osteomalacia with pseudofractures caused by the ingestion of aluminum hvdroxide. J.A.M.A.. 174: 1347.1960. 7. MCINTOSH,‘D. A. and MCPHAUL, J. J., Jk. Hyperparathyroidism complicating renal homotransplantation. Clin. Res., 14: 384,1966. 8. PLOUGH, I. C. and KYLE, L. H. Pancreatic insufficiency and hyperparathyroidism. Ann. Znt. Med., 47: 590,1957. 9. COPE, O., CULVER, P. J., MIXTER, C. G. and NARDI, G. L. Pancreatitis, diagnostic clue to hyperparathyroidism. Ann. Surg., 145: 857, 1957. 10. MIXTER, C. G., JR., KEYNES, W. M. and COPE, 0. Further experience with pancreatitis as a diagnostic clue to hyperparathyroidism. New England J. Med., 266: 265, 1962. 11. LUDWIG, G. D. and CHAYKIN, L. Pancreatitis associated with primary hyperparathyroidism. M. Clin. North America, 50: 1403, 1966.
AMERICAN
JOURNAL
OF
MEDICINE