Normal Serum Alkaline Phosphatase Levels Research Articles

A rare case of adult hypophosphatasia masked with primary hyperparathyroidism

Abstract Introduction Hypophosphatasia (HPP) is a rare inherited disorder of bone and mineral metabolism due to mutations in the Alkaline Phosphatase-Liver (ALPL) gene encoding the tissue nonspecific alkaline phosphatase (TNSALP). Clinical features of HPP in adults include early loss of teeth, muscle weakness, musculoskeletal pain, osteoporosis and fragility fractures with delayed healing. The most typical biochemical manifestation of the disease is persistently low level of alkaline phosphatase (ALP). Primary hyperparathyroidism (PHPT) is a relatively common endocrine disorder leading to increase in bone turnover markers including ALP. Coexistence of HPP and PHPT is a very rare condition. Herein we present an adult HPP patient who presented with primary hyperparathyroidism and normal serum ALP levels, which decreased significantly after parathyroidectomy. Clinical Case A 33-year-old female with a past medical history of Hashimoto's thyroiditis and acne rosacea admitted to our outpatient clinic because of gradually increasing bone pain, fatigue and weakness. She had early teeth loss and dental problems, but she denied history of fractures and kidney stones. Her family history was remarkable for nephrolithiasis in both parents. On physical examination the patient had facial rash and telangiectasia. She also had teeth loss and many dental cavities. Her vital signs were within normal limits. In biochemical investigations creatinine was 0.45 mg/dL (0.7–1.4), ALP 81 U/L (35–105), PTH 531 pg/mL (15–65), calcium 10.84 mg/dL (8.5–10.5), albumin 4.9 g/dL (3.2–5.5), phosphorus 2.25 mg/dL (2.7–4.5), Vitamin D 5 ng/mL and urine calcium excretion 613 mg/day. Laboratory results were compatible with normocalcemic hyperparathyroidism and severe vitamin D deficiency. Bone mineral density of the lumbar spine and the femoral neck revealed osteopenia and 1/3 distal radius revealed osteoporosis. There was no evidence of nephrolithiasis and nephrocalcinosis on abdominal ultrasound. Neck ultrasound and CT scan and Tc-99m MIBI scanning of the patient revealed a parathyroid adenoma in the posteroinferior of thyroid gland's left lobe. A successful parathyroidectomy was performed. During follow-up the patient's serum ALP levels decreased significantly to 29 U/L with a repeat being 26 U/L. Bone-specific ALP was 4.2 μg/L (3–14 μg/L). Urine phosphoethanolamine was elevated to 68.6 μmol/g.Cr (0–48), which supported the diagnosis of HPP. Genetic analysis was performed and heterozygous p.N190del (c.568_570delAAC/c.566_568delACA) mutation was detected. This mutation was previously reported as pathogenic and has been associated with adult hypophosphatasia. Conclusion Although persistently low level of ALP is characteristic of HPP, disorders that increase bone turnover may result in an increase in serum ALP levels, which may mask underlying HPP. Acknowledgements We are thankful to Alexion Pharmaceuticals, Inc for providing fund for ALP substrates and genetic analysis of the patient.

Positive antimitochondrial antibody but normal serum alkaline phosphatase levels: Could it be primary biliary cholangitis?

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease, typically diagnosed by elevated cholestatic liver enzymes and a positive antimitochondrial antibody (AMA) test. The clinical significance of AMA positivity in patients with normal cholestatic liver enzymes is uncertain. Charts of patients with normal cholestatic liver enzymes and AMA positivity who underwent liver biopsy between 2012 and 2015 were retrospectively analyzed. Six AMA-positive patients with normal cholestatic liver enzymes who underwent a liver biopsy were identified. Four (67%) showed florid bile duct lesion compatible with early-stage PBC, whereas the other two showed mild and non-specific histological findings. The patients with histological findings compatible with PBC had higher enzyme-linked immunosorbent assay-determined AMA titers and significantly elevated immunoglobulin M (IgM) level. Patients with non-specific histological findings (33%) had low-titer AMA and a borderline elevated IgM level. Antimitochondrial antibody-positive patients with normal cholestatic liver enzymes should be meticulously evaluated for PBC including a liver biopsy, mainly in patients with high-titer seropositivity for AMA and a significantly elevated IgM level. More studies are required to clarify the role of liver biopsy in these patients and further follow-up may elucidate the relationship of these patients to those with more classical forms of PBC.

Bisphosphonate-associated atypical fracture of the femur: Spontaneous healing with drug holiday and re-appearance after resumed drug therapy with bilateral simultaneous displaced fractures — a case report

Our patient is a 64-year-old Chinese woman with a history of asthma with previous prednisolone usage, diabetes mellitus, and breast cancer—for which left simple mastectomy and axillary clearance was performed. Her menopause had been at 54 years and she had been on alendronate for 1 year for osteopenia, diagnosed by bone mineral density scan. She was referred to our department 1 month after her mastectomy for bilateral thigh pain that had lasted 2 weeks, to exclude metastases before commencing chemotherapy. The thighs were tender bilaterally. Plain radiographs of her femurs showed lateral cortex thickening bilaterally with a stress fracture of her right femoral shaft (Figure 1). She had increased uptake at the lower one-third of her right femur and the proximal one-third of her left femur on Tc-99m bone scan. Figure 1. Right (A) and left (C) femur showing lateral cortex thickening. Right femur also showing an undisplaced fracture (B; arrow). In view of the above findings, she was advised to stop alendronate and was wheelchair-mobilized for 6 weeks. The option of intramedullary nailing for the right femur stress fracture and prophylactic nailing of the left femur was discussed with the patient, but on follow-up, there was radiographic evidence of fracture healing (Figure 2). Figure 2. Right femur at 3-month follow-up showing a healing fracture (arrow). Bone mineral density scan at 3 years since stopping alendronate was normal. Repeat Tc-99m bone scan showed reduced uptake of tracer at the right femur compared to the previous bone scan, consistent with a healing fracture. Apart from occasional bilateral thigh pain, our patient was otherwise well. She was converted to letrazole with ibandronic acid by her oncologist at the 5-year follow-up. Once again, she complained of bilateral aching thigh pain on walking and standing, with difficulty climbing stairs. Plain radiographs of her femurs did not reveal any new fractures. She was still ambulating until 7 months after starting ibandronate, when she fell in the toilet after a sudden onset of severe bilateral thigh pain; she was brought to the emergency department with bilateral thigh pain and deformity. Plain radiographs of both her femurs showed bilateral shaft fractures (Figure 3). Blood biochemistry showed a normal serum alkaline phosphatase level, 41 U/L (32–103), and normal total serum calcium, 2.11 mmol/L (2.10–2.60). Her serum Ca 15-3 level, a tumor marker for breast carcinoma, was not elevated either. Figure 3. Fractures of the left and right femurs. Plate fixation of both femoral shafts was performed in a single operation instead of intramedullary nailing with a risk of fat embolism, in view of her history of asthma with baseline hypoxemia (Figure 4). She was wheelchair-mobilized again after surgery and histology from both fracture sites showed fracture hematoma with no evidence of malignancy. The fractures healed uneventfully. Figure 4. After plate fixation.

Symptomatic and Scintigraphic Improvement after Intravenous Pamidronate Treatment of Paget’s Disease of Bone in Patients with Normal Serum Alkaline Phosphatase Levels

To describe three patients with symptomatic Paget's disease of bone who presented with normal levels of serum alkaline phosphatase. We present three cases of Paget's disease of bone and chronicle the laboratory, scintigraphic, and clinical findings relative to treatment with intravenously administered pamidronate. Although measurement of serum total alkaline phosphatase usually provides a general indication of bone turnover in Paget's disease, about 15% of patients present with normal serum alkaline phosphatase levels. Nonetheless, these patients may have active Paget's disease when assessed with bone scintigraphy or urinary markers of bone resorption. All three study patients had xray findings characteristic of Paget's disease of bone, increased uptake of radiotracer material on bone scans, and elevated levels of urinary markers of bone resorption but normal alkaline phosphatase levels. They were treated with intravenously administered pamidronate, 60 mg once weekly for 2 to 3 consecutive weeks. After treatment, the serum alkaline phosphatase level decreased by 19 to 36%, markers of bone resorption normalized, bone scans showed improvement, and bone pain resolved. Pagetic activity in bone and related clinical manifestations may be present in the setting of a normal serum alkaline phosphatase level. Appropriate therapy should not be withheld because of the normal alkaline phosphatase.

Osteosarcoma arising in Paget's disease of the mandible

Although osteosarcoma is a well-known complication of Paget's disease of bone, it uncommonly develops in the jaw bones. We present an osteosarcoma arising in Paget's disease of the mandible with unique features of a normal serum alkaline phosphatase level, and histologic features of telangiectatic change in the osteosarcoma and association with cemento-osseous dysplasia. Sixteen reported cases of osteosarcoma arising in Paget's disease of the jaw bones (OPJ) are also reviewed and compared to osteosarcoma arising in Paget's disease occurring in the entire skeleton (OPS) and osteosarcoma arising de novo in the jaw bones (OJ). Females are more commonly involved in OPJ in contrast to a male predominance in OPS and OJ. OPJ also has a distinctively higher percentage involving blacks compared to OPS. The prognosis of OPJ is poor, with 69% of patients dying within two years after diagnosis. Early recognition, early and aggressive treatment are important to improve the prognosis and are hence emphasized.

Variable disease severity associated with a Paget's disease predisposition gene.

We have recently identified a region on the long arm of chromosome 18 that carries a predisposition gene for Paget's disease using linkage analysis. This region was explored because of earlier studies demonstrating the presence of a gene for another bone disorder, familial expansile osteolysis (FEO) within this region. FEO has many similarities to Paget's disease including osteoclast abnormalities and viral-like nuclear inclusions. Therefore, it was proposed that FEO and Paget's disease are disorders resulting from mutations at the same locus. For our linkage study, we utilized a large kindred with a high incidence of Paget's disease. The propositus in this family had polyostotic disease symptoms beginning at age 31. During the process of characterizing this family, four other family members were diagnosed with Paget's disease. One of the proband's siblings was asymptomatic but had high normal serum alkaline phosphatase levels; Paget's disease was identified only after bone scanning (at age 50). This implies that the predisposition gene does not consistently cause severe disease and raises a question concerning the mechanism of predisposition: Does the predisposition gene affect the age of onset and/or the severity of disease? To further explore this question, two individuals from this kindred, under age 30 and carrying the affected haplotype, were evaluated for early onset Paget's disease. No evidence of disease was observed after thorough evaluation. This implies that the age of onset is highly variable for this locus, indicating variable expression of disease in individuals carrying the same mutation.

SCLEROSING CHOLANGITIS IN CHILDHOOD: AN 18-YEAR EXPERIENCE

160 Sclerosing cholangitis (SC) in childhood is a heterogeneous condition. To define the relative incidence and prognosis of the different forms of SC, we have reviewed the features and outcome of 58 children diagnosed in our Unit between 1978-96. 37 (68%) [median age: 11 (2-16) yrs] had SC with serological features of autoimmunity [autoimmune SC (ASC)]; 5 (9%) [median age: 0.25(0.25-4) yrs] had neonatal SC (NSC); 6 (10%) [median age: 5 (3-14) yrs] had SC with other disorders [ulcerative colitis (UC) in 3, thyroiditis in 1, Langerhan cell histiocytosis (LCH) in 2]; 5 (9%) [median age: 7 (4-15) yrs] had SC associated with immunodeficiency (ID); 5 (9%) [median age: 5 (2-8) yrs] had no detectable association [primary SC (PSC)]. 29 (50%) were boys. Cholangiography showed abnormalities of intrahepatic ducts in 26 (45%), intra- and extrahepatic ducts in 32 (55%). At diagnosis, 30 (55%) were jaundiced (23 ASC, 5 NSC, 2 SC with LCH), 32 (55%) (16 ASC, 5 SC with ID, 5 SC with other disorders, 3 PSC, 3 NSC) had hepatosplenomegaly, 22 (38%) had normal serum alkaline phosphatase levels (18 ASC, 1 SC with ID, 2 SC with other disorders, 1 PSC), 14 (10 ASC, 2 SC with other disorders, 1 SC with ID, 1 PSC) had normalγ glutamyl transpeptidase. ANCA were positive in 29 (50%). On initial liver biopsy, biliary cirrhosis was noted in 13 (22%) (6 ASC, 1 SC with other disorders, 2 SC with ID, 2 PSC, 2 NSC). 35 (33 ASC, 2 SC with UC) were treated with immunosuppression, 31 (12 ASC, 5 SC with ID, 5 SC with other disorders, 4 PSC, 5 NSC) with ursodeoxycholic acid. Median follow up is 4 (1-18) yrs. 43(74%) are alive, 5 lost to follow up, 10 (17%) (3 ASC, 2 SC with ID, 2 SC with LCH, 1 PSC, 2 NSC) have died and/or had liver transplant from 1 to 9 (median: 2) years after diagnosis. Our results show that the most common form of SC in childhood is ASC. PSC, ie, SC without recognisable association, is rare.

Primary sclerosing cholangitis in 32 children: Clinical, laboratory, and radiographic features, with survival analysis

The clinical presentation and outcome of 32 children with primary sclerosing cholangitis (PSC) are reviewed, the largest North American series. The majority of patients were diagnosed in their second decade (median age: 13 years). Four children presented before the age of 2 years, but none in the neonatal period. Seventeen patients had inflammatory bowel disease (IBD), all with colitis, 14 ulcerative colitis, and 3 Crohn's disease. Eight patients presented with chronic liver disease before clinical onset of IBD. Only 8 of 32 patients were jaundiced at presentation. Fifteen of 32 had a normal serum alkaline phosphatase (ALP) level at presentation. Nine children presented with features similar to those of autoimmune hepatitis. Cholangiography was performed in all cases and classified by a scoring system specifically developed for pediatric patients. Intrahepatic disease predominated; in only three cases a common bile duct stricture was identified requiring stenting. Findings on the initial liver biopsy were classified according to Ludwig's criteria for staging PSC: there were 15 biopsies in stages 1 to 2 and 17 biopsies stages 3 to 4. HLA class I and II antigens were determined in 27 patients. An increased incidence of HLA B8 and DR2(15) but not DRw52a (DRB3∗0101) was found. Anti-neutrophil cytoplasmic antibody (ANCA) was positive in 10 of 24 patients tested. Survival analysis indicated that a later age at presentation, splenomegaly, and prolonged prothrombin time (PT) at presentation were significant contributors to the prediction of poor outcome (i.e., death or listing for transplantation). Liver transplantation was successfully performed in seven children. Physicians must maintain a high index of suspicion of PSC in any child or young adult presenting with chronic liver disease, especially in the presence of IBD, even with a normal serum alkaline phosphatase level.

Primary sclerosing cholangitis in 32 children: Clinical, laboratory, and radiographic features, with survival analysis

The clinical presentation and outcome of 32 children with primary sclerosing cholangitis (PSC) are reviewed, the largest North American series. The majority of patients were diagnosed in their second decade (median age: 13 years). Four children presented before the age of 2 years, but none in the neonatal period. Seventeen patients had inflammatory bowel disease (IBD), all with colitis, 14 ulcerative colitis, and 3 Crohn's disease. Eight patients presented with chronic liver disease before clinical onset of IBD. Only 8 of 32 patients were jaundiced at presentation. Fifteen of 32 had a normal serum alkaline phosphatase (ALP) level at presentation. Nine children presented with features similar to those of autoimmune hepatitis. Cholangiography was performed in all cases and classified by a scoring system specifically developed for pediatric patients. Intrahepatic disease predominated; in only three cases a common bile duct stricture was identified requiring stenting. Findings on the initial liver biopsy were classified according to Ludwig's criteria for staging PSC: there were 15 biopsies in stages 1 to 2 and 17 biopsies stages 3 to 4. HLA class I and II antigens were determined in 27 patients. An increased incidence of HLA B8 and DR2(15) but not DRw52a (DRB3*0101) was found. Anti-neutrophil cytoplasmic antibody (ANCA) was positive in 10 of 24 patients tested. Survival analysis indicated that a later age at presentation, splenomegaly, and prolonged prothrombin time (PT) at presentation were significant contributors to the prediction of poor outcome (i.e., death or listing for transplantation). Liver transplantation was successfully performed in seven children. Physicians must maintain a high index of suspicion of PSC in any child or young adult presenting with chronic liver disease, especially in the presence of IBD, even with a normal serum alkaline phosphatase level.

Polycystic Kidney Disease and Polycythemia Vera

Symptomatic erythrocytosis developed in a 59-year-old man with polycystic kidney disease (PKD) while he was receiving maintenance hemodialysis. Major clinical and laboratory data suggested a diagnosis of polycythemia vera (PV), despite a normal serum alkaline phosphatase level and leukocyte count. Secondary erythrocytosis, related to chronic hypoxemia and increased erythropoietin production, was excluded by appropriate laboratory studies. Despite previous documentation of secondary erythrocytosis in patients receiving hemodialysis, to my knowledge, PV has not been described in this population.

Cholestatic Jaundice With a Normal Serum Alkaline Phosphatase Level: Another Case of Hypophosphatasia in an Adult?

A patient with cholestatic jaundice and normal serum alkaline phosphatase was found to have low levels of the enzyme before and after this illness. It is suggested that this patient has hypophosphatasia because of the low serum alkaline phosphatase, a leukocyte alkaline phosphatase value of zero, and increased excretion of urinary phosphoethanolamine to 12 times normal. There were no bony abnormalities except for osteoporosis compatible with his age and some old rib fractures that followed trauma. His serum magnesium, B12, and thyroid function tests were normal.

The antiscorbutic action of l-ascorbic acid and d-isoascorbic acid (erythorbic acid) in the guinea pig

Female guinea pigs were fed a scorbutigenic diet supplemented with either L-ascorbic acid or D-isoascorbic acid or combinations of these. Their responses were judged by changes in body weight, serum alkaline phosphatase levels, wound healing, and tooth structure. Large additions (100 mg daily) of D-isoascorbic acid to the scorbutigenic diet resulted in normal growth over a 7-wk period and normal serum alkaline phosphatase levels, tooth structure development, and collagen formation after wounding. The addition of 0.5 or 5.0 mg of L-ascorbic acid to this high D-isoascorbic diet improved neither growth rate nor collagen deposition during wound healing. On the basis of changes in tooth structure, D-isoascorbic acid has 1/20 the potency of L-ascorbic acid. Its effect is additive to subminimal maintenance levels of L-ascorbic acid implying that there is no competitive inhibition in the utilization of the two compounds. The relatively weak activity of D-isoascorbic acid is probably due to poor transport to the tissues and ineffective binding to functional sites. This explains why the onset of scurvy is much more rapid after withdrawal of D-isoascorbic acid from the diet when it had been the sole antiscorbutic dietary constituent. It is concluded that D-isoascorbic acid is a "weakly" antiscorbutic agent on the basis that it is both poorly absorbed and retained by the tissue; that in fact it may, to the degree that it is taken up by the tissues and retained, be equal in antiscorbutic potency to L-ascorbic acid.

Monostotic Paget's disease of the mandible.

Abstract A review of the literature and a case report of monostotic Paget's disease affecting the mandible are presented. This rare case is of interest because no other bone lesions were detected and it was associated with a normal serum alkaline phosphatase level.

Significance of hyperphosphatasemia in alcoholics with liver disease: An analysis of fifty-eight cases, with histologic diagnoses

Alcoholic cirrhosis is associated with normal serum alkaline phosphatase levels, but significant hyperphosphatasemia may accompany biliary tract obstruction, fatty metamorphosis of the liver, florid cirrhosis, neoplastic or granulomatous infiltrations of the liver, hepatic abscesses and drug hepatoxicity. To evaluate the frequency, as well as the clinical and laboratory features of the various hepatobiliary disorders that increases in alkaline phosphatase in alcoholics, fifty-eight consecutive patients with alkaline phosphatase levels of 12 S.J.R. units or more were studied. In each patient, a tissue diagnosis was made by liver biopsy, surgery or autopsy. Five clinicopathologic groups were distinguished. Thirty-two patients were found to have florid cirrhosis. Their clinical picture varied from that of acute toxicity to one of apparent good health. The serum alkaline phosphatase levels ranged from 12 to 20 S.J.R. units. The scrum cholesterol level was normal or low, thus distinguishing these cases from the fatty liver syndrome in which these levels are elevated. In many cases the alkaline phosphatase level remained elevated even after the jaundice had cleared. Histologically, florid cirrhosis shows an active inflammatory process with intense bile duct proliferation. There is evidence that the ductules help form liver parenchyma. Since the alkaline phosphatase concentration in the ductule cells is high, it is postulated that these elements account for the increased serum levels of this enzyme. Eleven patients had intrahepatic cholestasis from fatty metamorphosis of the liver. The laboratory findings were similar to those seen in extrahepatic obstruction, with hyperbilirubinemia, hypercholestremia and an elevated serum alkaline phosphatase. Liver biopsy shows the liver cells to be markedly distended with fat, and the presence of bile plugs in the ductules. Adequate nutrition and abstinence from alcohol produces a prompt improvement and distinguishes this condition from extrahepatic obstruction. Zieve's syndrome with hyperlipemia and hemolytic anemia is a variant. The mechanism of cholestasis and hyperphosphatasemia may result from structural and functional changes in the bile ductules and microvilli. Three patients had extrahepatic obstruction of the biliary tract. Initially, two of these were believed to have intrahepatic cholestasis from fatty metamorphosis of the liver because of the liver biopsy findings. Ultimately, pancreatic carcinoma was discovered. Lack of improvement in the obstructive pattern despite adequate nutrition serves to exclude the fatty liver syndrome. The third patient was thought to have silent pancreatitis and possibly superimposed chlorpromazine hepatoxicity. Despite the reportedly increased incidence of cholelithiasis in cirrhotic subjects, gallstones appear to be an uncommon cause of jaundice. Ten patients had primary carcinoma of the liver. There was nothing to differentiate this group from the others. The alkaline phosphatase levels ranged from 12 to 66 S.J.R. units. Three had minimal jaundice. Four patients, who had SGOT levels over 500 units, died after a brief hospital course. Two alcoholics had granulomatous infiltrations of the liver causing hyperphosphatasemia. This was believed to be due to tuberculosis in both. Few clinical and laboratory features were characteristic for a group. Hepatoma was found only in elderly patients, while the fatty liver syndrome occurred in the young alcoholic. Fever can result from active liver disease or concurrent infection. With persistent spiking temperatures, cholangitis, liver abscesses and granulomatous diseases must be excluded. Ascites was a common finding in all groups and usually had the characteristics of a transudate, but three patients with hepatoma had an exudate. Ascitic fluid from six patients with hepatoma was examined for tumor cells and found to be negative. Massive firm hepatomegaly suggests neoplasm. Increased serum alkaline phosphatase activity and bromsulfalein retention, without a corresponding increase in serum bilirubin, may occur with infiltrative disease, abscess, neoplasm, florid cirrhosis and some hepatotoxic drugs. In the presence of an elevated serum alkaline phosphatase level the concurrent increase in serum bilirubin and cholesterol indicates intraor extrahepatic obstruction. An increase in serum bilirubin in the absence of an increase in serum cholesterol suggests florid cirrhosis or infiltrative disease. Nonvisualization of the gallbladder on cholecystograms is common in the presence of impaired hepatic function. Liver biopsy is of indisputable value in these cases, but the histologic findings must be interpreted in the light of clinical and laboratory findings. While the cirrhotic process itself may produce substantial increases in serum alkaline phosphatase activity, to attribute all phosphatase elevations to “active cirrhosis” may lead to serious diagnostic errors. In this study 25 per cent of the patients had hepatobiliary disease other than alcoholic liver disease. Careful consideration of the clinical and laboratory findings is imperative in each case.