Low Serum Alkaline Phosphatase Levels Research Articles

Prevalence of high and low serum alkaline phosphatase levels and the associated factors in patients with rheumatoid arthritis: results from the IORRA cohort study.

Prevalence of high and low serum alkaline phosphatase levels and the associated factors in patients with rheumatoid arthritis: results from the IORRA cohort study.

THU457 Variable Presentations Of Hypophosphatasia In Two Patients In The Outpatient Setting

Abstract Disclosure: A. Elmaaz: None. S. Batool: None. P. Dandona: None. Introduction: Hypophosphatasia is a rare disorder characterized by defective mineralization of bone and teeth which is caused by an autosomal inherited mutation in the tissue nonspecific alkaline phosphatase (ALP) encoding genes. Here we present two cases of multiple dental and bony defects secondary to low ALP enzyme activity due to hypophosphatasia. Case 1: A 27-year-old female with history of mitochondrial disease, gastroparesis, malabsorption syndrome, and autonomic dysfunction was referred to Endocrinology clinic because of persistently low serum ALP levels associated with recurrent muscle, joint, and bone pain since the age of 13. She had history of multiple tooth extractions because of dental developmental abnormalities and fractures. She also reported history of fractures of three of her fingers in both hands during her childhood and teenage years. The patient was adopted and was unaware of any biological family history. Physical examination was remarkable for short-statured female, 4'8". Notably, the middle phalanges in little fingers bilaterally were shorter than the other fingers. Workup showed vitamin D level of 21 (30-80) ng/ml, despite being on 50,000 IU twice a week for 6 months with normal PTH and ionized calcium levels. The repeated serum level of ALP was 24 (31-125) U/L with bone and liver isoenzymes levels of 42% and 58 % respectively. Vitamin B6 level was 13.2 (2.1-21.7) ng/ml. Bone mineral density was unremarkable. Case 2: A 53-year-old female with history of congenital left hip dysplasia, hypertension, and dyslipidemia was seen by Endocrinology service for evaluation of decreased ALP levels. She denied any history of falls or fractures. However, she reported chronic bone pain, especially in bilateral hip joints with history of multiple surgeries in her left hip joint. She had required teeth braces and multiple dental surgeries during her childhood due to dental maldevelopment. Her height was 4'8". Laboratory workup was remarkable for low serum ALP level of 30 U/L with bone isoenzyme of 24 %. Vitamin B6 level was 206.7 (2.1-21.7) ng/ml. She had elevated serum phosphorus levels with normal calcium, PTH, and vitamin D levels. Pyridoxal-5- Phosphate level was high. Bone mineral density revealed osteopenia. Conclusion: Hypophosphatasia is a rare disease, hence it could be easily missed due to high variability in clinical presentations and severity of symptoms. Low serum levels of ALP with history of bone pain, recurrent fractures, premature loss of deciduous teeth, or loss of adult dentition should raise the suspicion of hypophosphatasia. Resistance to vitamin D supplementation is another clue to the diagnosis. A multidisciplinary approach is required for appropriate management. Presentation: Thursday, June 15, 2023

Association between serum alkaline phosphatase levels in late pregnancy and the incidence of venous thromboembolism postpartum: a retrospective cohort study

Two previous studies found alkaline phosphatase (ALP) levels were related with the development of venous thromboembolism (VTE) in hospitalised patients. VTE is a leading cause of death during pregnancy and postpartum. No prior study has investigated the associations of ALP levels and VTE postpartum, and the related mechanisms remain unclear. This study aimed to investigate the associations between ALP levels and VTE postpartum, and to reveal the potential mechanisms. In this retrospective cohort study, we included pregnant women who planned to deliver at the Department of Obstetrics and Gynecology in the three designated hospitals in a multicentre cohort of pregnant women in Wuhan, China, during two recruitment periods of January 1, 2018 to December 31, 2019, and May 14, 2020 to March 25, 2022. A total of 10,044 participants with serum ALP and whole blood hemoglobin measurements in late pregnancy (median, 37 (35, 39) weeks) were enrolled. The participants' incidences of VTE (deep venous thrombosis and/or pulmonary embolism) postpartum were confirmed from the medical records. Pregnant women with new-onset VTE postpartum (within 6 weeks after delivery) were confirmed as VTE cases. Approximately 0.8% (79/10,044) of the pregnant women were diagnosed with VTE postpartum. In the unadjusted model, pregnant women with the lowest quintile of serum ALP levels (≤116 U/L) in late pregnancy had higher risk of VTE postpartum compared with those with the highest quintile (≥199 U/L) (OR, 2.83 [1.32, 6.05]). After adjusting for covariates of demographic, life style, birth outcomes, and other liver enzymes, pregnant women with the lowest quintile of serum ALP levels (≤116 U/L) in late pregnancy had increased risk of VTE postpartum compared with those with the highest quintile (≥199 U/L) (OR, 2.48 [1.14, 5.40]). A one standard deviation decrease of ln-transformed ALP levels were associated with elevated risk of VTE postpartum (OR, 1.29 [1.02, 1.62]). Significant negative associations of ALP with VTE were found in the unadjusted and adjusted models. The negative associations between ALP and VTE remained consistent in sensitivity analyses among participants with non-GDM, single pregnancy, non-preeclampsia, non-postpartum hemorrhage, non-extremely/very preterm and cesarean delivery. Decreased serum ALP levels significantly (P<0.05) related to decreased hemoglobin, which was significantly (P<0.05) related to increased risk of VTE postpartum. Decreased hemoglobin significantly (P<0.05) mediated 7.59% of ALP-associated VTE postpartum. This study suggested that low serum ALP levels in late pregnancy were associated with increased risk of VTE postpartum, and the ALP-associated VTE risk may be partially mediated by hemoglobin, suggesting that serum ALP in late pregnancy could be a promising biomarker for the prediction of VTE postpartum. The National Natural Science Foundation of China, and the Program for HUST Academic Frontier Youth Team.

Romosozumab-aqqg in the Treatment of Osteoporosis in a Patient With Hypophosphatasia

Hypophosphatasia is a rare, inherited condition that causes osteomalacia and recurrent fractures. Therapeutic options for osteoporosis in patients with hypophosphatasia are limited because of concerns for a greater likelihood of atypical femoral fractures with antiresorptive agents. We report here the case of a patient with hypophosphatasia and osteoporosis who was treated with romosozumab-aqqg (Romo). An 81-year-old woman presented for management of osteoporosis with multiple fractures. She experienced a decline in bone mineral density over 20 years despite sequential osteoporosis treatment with oral bisphosphonates, hormone replacement therapy, teriparatide, and denosumab. Hypophosphatasia was suspected because of low serum alkaline phosphatase levels and was confirmed by genetic testing. After diagnosing hypophosphatasia, bone mineral density continued to decline and a trial of Romo was begun. After 1 year of Romo therapy, bone mineral density improved by 21%, and 10% at the lumbar spine and total hip, respectively. These changes were substantially greater than what she had experienced with prior teriparatide therapy. Blood alkaline phosphatase remained low on Romo. To our knowledge, this is the first report of a patient with hypophosphatasia and osteoporosis treated with Romo. In our patient, Romo did not significantly impact serum alkaline phosphatase, but improved bone mineral density significantly. In conclusion, Romo is a potential treatment option for osteoporosis in patients with hypophosphatasia for whom limited alternatives exist.

A Japanese single-center experience of the efficacy and safety of asfotase alfa in pediatric-onset hypophosphatasia

BackgroundHypophosphatasia (HPP) is a rare inherited metabolic disorder caused by mutations in the ALPL gene, which encodes tissue nonspecific alkaline phosphatase. The severity of HPP is widely diverse from the perinatal form to the adult mild form. The former represents the most severe form and was earlier associated with high mortality due to pneumonia which was caused by severe hypomineralization of the bones—such as chest deformity and fractured ribs—and muscle weakness. Enzyme replacement therapy using asfotase alfa (AA) was approved in 2015 in Japan for treating patients with HPP and has improved their pulmonary function and life prognosis. There are several practical and ethical challenges related to using orphan drugs for a rare disorder in a publicly funded healthcare system. Sharing experiences about their application is essential towards formulating guidelines to assist clinicians with decisions about their initiation and withdrawal. We report the details of AA experience in ten cases of pediatric-onset HPP in nine families from January 2015 to November 2019 (median [interquartile range] age 11.0 [7.6–12.5] years; 60% male). This is a study of a single-center cohort describing the clinical course of patients with HPP, mainly consisting of the mild childhood form of HPP, treated with AA in Japan.ResultsOne case of perinatal form of HPP, two cases of benign prenatal form, and seven cases of childhood form were observed. The most common symptom at onset was pain. All patients had low serum alkaline phosphatase levels as compared to the age-matched reference range before the commencement of AA. All HPP patients seem to have responded to AA treatment, as evidenced by pain alleviation, increased height standard deviation, improvement in respiratory condition and 6-min walk test result improvement, disappearance of kidney calcification, alleviation of fatigue, and/or increases in bone mineralization. There were no serious adverse events, but all patients had an injection site reaction and skin changes at the injection sites. Genetic analysis showed that eight out of ten patients had compound heterozygosity.ConclusionsAA may be effective in patients with mild to severe pediatric-onset forms of HPP.

O14 An atypical femoral fracture without a history of bisphosphonate use

Case report - IntroductionA 60-year-old female presented with an insufficiency fracture of the midshaft of the left femur and a persistently low serum alkaline phosphatase. A diagnosis of adult hypophosphatasia was made. We present this case alongside a series of other cases that we have identified locally and discuss the importance of identifying this condition in clinical practice.Case report - Case descriptionA 60-year-old female presented with left thigh pain and an 8-year history of polyarthralgia involving the medium-large sized joints. She had a traumatic fracture of the humerus 4 years previously. She had no history or examination findings suggestive of an inflammatory arthritis, connective tissue disease or systemic illness.An X-ray of left femur revealed a cortical-based lucency at the lateral cortex of midshaft. An MRI identified a focal area of cortical thickening but no evidence of bone marrow oedema suggestive of an osteoid osteoma. Finally, a CT scan confirmed the diagnosis of a healed stress fracture. The patient had never received any form of bisphosphonate treatment, no previous history of a non-traumatic fracture and no history of dental problems.Laboratory evaluation revealed persistently low levels of serum alkaline phosphatase (∼23 IU/L) with a normal vitamin D and PTH level. Bone density scan showed a T-score of -1.1 at the femoral neck and -2.6 at the lumbar spine. Serum pyridoxal phosphate level was elevated at 457 nmol/L (35-100). A diagnosis of adult hypophosphatasia was suspected and genetic study for ALPL gene confirmed the diagnosis.The following table summarises a number of other cases of adult hypophosphatasia, which we have identified locally. CaseAge / GenderPresentationAlkaline phospha tase (IU/L)Pyridoxal phosphate (nmol/L)Notes1 (Index case)62 / FWidespread pain, Atypical femoral fracture23457Genetic study confirmed278 / FWidespread pain, Osteomalacia22201Genetic study confirmed356 / MSon of Case 2, Osteoporosis, Diabetes mellitus22 – 29awaited Bisphosphonate stoppedGenetic study awaited 440 / FRecurrent metatarsal fractures, Low BMD24NormalBisphosphonate stopped548 / FPremature loss of teeth, fatigue, Widespread pain, Diabetes mellitus, hyperlipidaemia13-23327Genetic study confirmed675 / FSeronegative polyarthritis21-26120Genetic study awaitedCase report - DiscussionHypophosphatasia (HPP) is a rare inherited metabolic disease caused by mutations in the alkaline phosphatase liver type (ALPL) gene, localized on the chromosome region 1p36.1–34, encoding the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). The disease is related to a decrease in both level and activity of alkaline phosphatase enzyme (ALP). The clinical expression is highly variable, ranging from lethal forms to mild forms diagnosed in adults. Fractures, chondrocalcinosis, calcific periarthritis, and chronic muscle and bone pain are key features for the diagnosis of HPP in adults. Teriparatide has been used for treatment in some case reports with inconsistent results. Antiresorptive drugs are contraindicated as they can worsen underlying osteomalacia.Case report - Key learning pointsCheck for persistent low serum alkaline phosphatase levels in adults presenting with fragility fractures, crystal-related arthropathies and nonspecific generalised aches.Avoid bisphosphonates in patients with low alkaline phosphatase.

Case of Juvenile Onset Hypophosphatasia Diagnosed in an Adult Patient

Background: Hypophosphatasia is a rare multisystem disease caused by mutations in genes encoding tissue nonspecific alkaline phosphatase, a key player in promoting bone mineralization1. Here we present a case of hypophosphatasia in a patient with history of recurrent fractures and dental caries since childhood. Case Report: Patient is a 52-year-old woman with history of multiple fractures who initially presented for follow up of osteoporosis following an atraumatic ankle fracture. Further questioning revealed a history of 16 atraumatic fractures since the age of 4, involving ankles, toes, and fingers. Several adult teeth had never developed requiring braces to fill in gaps at age 13, dental caries and tooth fractures involving the majority of her adult teeth. DEXA scan in 2019 revealed T score of -2.4 in the left femoral neck. Suspicion for hypophosphatasia in February 2019 following an ankle fracture and patient’s prior history prompted further workup, revealing low serum alkaline phosphatase levels of 29 and 32 (bone fraction 62 percent, liver fraction 38 percent), and Vitamin B6 levels elevated to 66.2. Remainder of workup, with Vitamin D, PTH, Magnesium, and Calcium was normal. A childhood history of multiple atraumatic fractures, various dental issues, with elevated Vitamin B6 and low serum alkaline phosphatase suggested Hypophosphatasia. As bisphosphonates are contraindicated in these patients due to their potential to reduce ALP, teriparatide was initiated. Discussion: Hypophosphatasia involves mutations in tissue nonspecific alkaline phosphatase, a key player in bone mineralization. In normal individuals, this enzyme dephosphorylates inorganic pyrophosphate (PPi), which otherwise inhibits bone mineralization. The mutated TNSALP leads to accumulation of PPi, and thereby unmineralized osteoid.1 Although individual presentations can vary, developmental abnormalities, such as delayed growth, early loss of primary or secondary teeth, or history of multiple fractures are characteristic. Due to the rarity of the disease, and its potential to be confused for more common bone and rheumatologic diseases, diagnosis is often delayed1. Patients in whom suspicion for hypophosphatasia is present, should undergo further testing with bone specific Alkaline phosphatase and Vitamin B6 which would be low and elevated, respectively and may be candidates for enzyme replacement therapy with bone-targeting recombinant alkaline phosphatase1. Traditional treatments such as bisphosphonates potentially decrease ALP and worsen disease, making accurate diagnosis all the more crucial. References1 Bishop N. Clinical management of hypophosphatasia. Clin Cases Miner Bone Metab. 2015;12(2):170–173.

Active search of adult patients with persistently low serum alkaline phosphatase levels for the diagnosis of hypophosphatasia.

Alkaline phosphatase (ALP) is the main laboratory marker of hypophosphatasia (HPP), a rare disease unknown to most physicians. The prevalence of HPP has been widely discussed in the literature due to the diverse phenotypes of HPP. The purpose of this study was to search for patients with hypophosphatasemia based on previous biochemistry tests and reevaluate them to confirm the diagnosis of HPP. A total of 289,247 biochemical tests for ALP in adults were performed from 2015 to 2019 in two tertiary hospitals in Rio de Janeiro were reviewed (Clementino Fraga Filho University Hospital - HUCFF - and Bonsucesso Federal Hospital - BFH). A total of 1,049 patients were identified with ALP levels below 40 U/L, and 410 patients had hypophosphatasemia confirmed by at least two exams. After the active search of medical reports and/or interviews based on structured questionnaires, 398 subjects were excluded due to secondary causes of reduced ALP. The remaining 12 patients were invited to attend the medical consultation at HUCFF, accompanied by at least one first-degree relative. None of the patients or their relatives had a history or clinical manifestations consistent with HPP. Serum ALP was within reference values in all relatives, but persistently low in further laboratory evaluation in all the 12 patients, in whom secondary causes were ruled out. Thus, we cannot exclude the possibility that they might carry the mutations associated with HPP. Further image evaluations and genetic testing would be appropriate to confirm this asymptomatic adult form of HPP.

Low serum alkaline phosphatase levels in patients with chronic liver diseases: Possible contributions to disease pathogenesis

ObjectivesA low serum alkaline phosphatase (ALP) level is an uncommon finding in patients with chronic liver disease (CLD). The prevalence of this finding and whether low ALP expression influences CLD remain to be determined. The objectives of this study were: (1) to document the prevalence of low serum ALP levels in adult CLD patients and (2) compare features of CLD in patients with low versus normal or elevated serum ALP levels. MethodsAn adult, outpatient liver disease database was searched for patients with low serum ALP levels (<40 IU/L). Hepatic inflammation, function, fibrosis and disease severity were determined by serum aminotransferases, albumin, bilirubin and INR levels, Fib-4 calculations and MELD scores respectively. ResultsOf 19,037 patients entered into the database, 47 (0.25%) had consistently low serum ALP levels, 51 (0.27%) low levels on the majority and 469 (2.44%) on the minority of determinations. Patients with consistently low levels were matched (1:2) by age, gender and nature of the underlying liver disease to patients with normal or elevated serum ALP levels. Matched patients with consistently low ALP levels had significantly lower serum aminotransferase and bilirubin levels at their initial visit and throughout the follow-up period (p < 0.05 respectively) while Fib-4 levels and MELD scores were similar at the initial and last follow-up visit. ConclusionsThese results establish the prevalence of low serum ALP levels in adult CLD patients and describe a hitherto unreported association between low serum ALP levels and less biochemical evidence of active disease.

1247: Low Serum Alkaline Phosphatase Level and Acute Kidney Injury in Children With Severe Sepsis

1247: Low Serum Alkaline Phosphatase Level and Acute Kidney Injury in Children With Severe Sepsis

Biochemical and clinical findings distinguishing between the genetic and the acquired conditions in osteoporotic patients with low serum alkaline phosphatase levels

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Epidemiological, Clinical and Genetic Study of Hypophosphatasia in A Spanish Population: Identification of Two Novel Mutations in The Alpl Gene

Hypophosphatasia (HPP) is a genetic disease caused by one or several mutations in ALPL gene encoding the tissue-nonspecific alkaline phosphatase affecting the mineralization process. Due to its low prevalence and lack of recognition, this metabolic disorder is generally confused with other more frequent bone disorders. An assessment of serum total alkaline phosphatase (ALP) levels was performed in 78,590 subjects. Pyridoxal-5′-phosphate (PLP) concentrations were determined and ALPL gene was sequenced in patients potentially affected by HPP. Functional validation of the novel mutations found was performed using a cell-based assay. Our results showed persistently low serum ALP levels in 0.12% of subjects. Among the studied subjects, 40% presented with HPP-related symptoms. Nine of them (~28%) had a history of fractures, 5 (~16%) subjects showed chondrocalcinosis and 4 (~13%) subjects presented with dental abnormalities. Eleven subjects showed increased PLP concentrations. Seven of them showed ALPL gene mutations (2 of the mutations corresponded to novel genetic variants). In summary, we identified two novel ALPL gene mutations associated with adult HPP. Using this protocol, almost half of the studied patients were diagnosed with HPP. Based on these results, the estimated prevalence of mild HPP in Spain could be up to double than previously reported.

Ectopic Ocular Surface Calcification in Patients With Hypophosphatasia Treated With Asfotase Alfa

To assess for ectopic ocular calcification in a series of patients with hypophosphatasia (HPP) treated with asfotase alfa, a recombinant tissue-nonspecific alkaline phosphatase. This is a retrospective analysis of subjects enrolled at Duke University Medical Center in ENB-009-10 (ClinicalTrials.gov: NCT01163149), a randomized controlled trial of asfotase alfa in adolescents and adults with HPP. Seven patients between the ages of 45 and 66 years diagnosed with HPP based on clinical features and low serum alkaline phosphatase levels were enrolled at our site. Subjects were randomized to receive either daily subcutaneous injections of asfotase alfa or no treatment. After 24 weeks, during the open-label extension phase, all subjects received treatment for at least 4 years. All subjects underwent comprehensive eye examinations at baseline and at 24-week intervals throughout the study to assess for development of ocular calcifications. By week 120, all 7 subjects developed asymptomatic white refractile deposits in the interpalpebral perilimbal conjunctiva. Biopsy of the conjunctival lesions in 2 subjects revealed elastosis with subepithelial calcification. The lesions were nonprogressive and in 5 subjects exhibited some degree of regression. Asfotase alfa was invariably associated with development of mild focal conjunctival calcification, likely through disinhibition of hydroxyapatite crystal propagation. The calcifications were not symptomatic or vision-threatening and should not preclude enzyme replacement therapy for patients with this rare and often debilitating disease.

Case series: Odontohypophosphatasia or missed diagnosis of childhood/adult-onset hypophosphatasia? – Call for a long-term follow-up of premature loss of primary teeth

IntroductionHypophosphatasia, a metabolic bone disease caused by a tissue-nonspecific alkaline phosphatase deficiency, leads to undermineralization of bone and/or teeth, impaired vitamin B6 metabolism, and a spectrum of disease presentation. At the mild end of the spectrum, it presents as pathologic fractures in later adulthood. Patients with isolated dental manifestations, typically presenting as premature loss of primary teeth, are classified as having odontohypophosphatasia (odontoHPP). A subset of patients diagnosed with odontoHPP in childhood can later develop extra-dental manifestations that constitute childhood- or adult-onset hypophosphatasia. Case reports: methods/resultsRetrospective data related to onset, detailed clinical course, and method of diagnosis were collected as part of a natural history of adult patients with hypophosphatasia.Of 9 initial patients, all had low serum alkaline phosphatase levels for their age and gender at adult presentation (Table 2). The majority (8/9) demonstrated childhood dental signs of hypophosphatasia as the initial clinical manifestation: premature loss of primary teeth (7/9), absent primary teeth (1/9), and delayed loss of primary teeth (1/9). Despite childhood dental presentation and/or other signs/symptoms, diagnosis of hypophosphatasia was delayed 20–54years (median=46) since the primary tooth problems and 8–45years (median=27) since the first fracture or onset of a major adult tooth problem. ConclusionPatients with primary tooth loss in childhood were often diagnosed with hypophosphatasia later in life. Pediatric patients classified as having odontoHPP under present practice can manifest significant disease burden later in life.

Autoimmune cholangitis within the spectrum of autoimmune liver disease.

Autoimmune cholangitis is an idiopathic disorder with mixed hepatocellular and cholestatic findings. Our goal was to characterize the disease prospectively by application of uniform diagnostic criteria. Twenty patients were identified and compared with 242 patients with conventional forms of autoimmune liver disease. Patients with autoimmune cholangitis were distinguished from type 1 autoimmune hepatitis (AIH) by lower serum levels of aspartate transaminase (AST), gamma-globulin, and immunoglobulin G; higher serum levels of alkaline phosphatase; and lower frequencies of autoantibodies. They were distinguished from primary biliary cirrhosis (PBC) by higher serum levels of AST and bilirubin, lower serum concentrations of immunoglobulin M, and greater occurrence of autoantibodies. Their female predominance, lower serum alkaline phosphatase levels, higher frequency of autoantibodies, and absence of inflammatory bowel disease differentiated them from primary sclerosing cholangitis (PSC). Laboratory findings ranged widely and did not characterize individual patients. HLA risk factors were similar to those of type 1 AIH and PBC, and different from those of PSC. Treatment responses to corticosteroids or ursodeoxycholic acid were poor. Composite histological patterns resembled mainly PBC or PSC. We conclude that autoimmune cholangitis diagnosed by prospective analysis cannot be assimilated into a single, conventional, diagnostic category. It may represent variant forms of diverse conditions, a transition stage, or a separate entity with varying manifestations.

Hypophosphatasia: diagnostic application of linked DNA markers in the dominantly inherited adult form

Hypophosphatasia is a rare disease characterized by low serum levels of tissue non-specific alkaline phosphatase (TNSALP) and a spectrum of skeletal disease varying from the severest form with death in utero to mild with no clinical abnormality in adults. Currently, the diagnosis of hypophosphatasia is made on the basis of clinical findings, radiography, low serum alkaline phosphatase levels and raised abnormal phosphorylated metabolites; there are elevations in serum pyridoxal 5'-phosphate, urinary phosphoethanolamine and inorganic pyrophosphate. In borderline cases the biochemical diagnosis remains uncertain. Prenatally, diagnosis is made using radiography and ultrasonography together with chorionic villus tissue biopsy, in which TNSALP levels are measured using an antibody-based assay. Since hypophosphatasia results from mutations in the TNSALP gene we have, for the first time in two U.K. families, undertaken restriction fragment length polymorphism (RFLP) analysis using three intragenic RFLPs for BclI and MspI at the ALPL locus. One family was informative, and a mutant-allele-specific haplotype with respect to three RFLPs was defined. In the other family the disease was shown to segregate with one allele of the BclI RFLP, but the MspI RFLPs were not informative. The disease segregated in the two families with different alleles of the BclI RFLP, suggesting that the mutations are likely to be different. We confirm that DNA analysis is likely to be the way ahead for diagnosing hypophosphatasia, and that standardized screening methods need to be developed for detecting mutations in these and other families.

Frequency and significance of the variant syndromes of autoimmune hepatitis

The variant syndromes of autoimmune hepatitis (AIH) have features of AIH and primary biliary cirrhosis (AIH/PBC), AIH and primary sclerosing cholangitis (AIH/PSC), and autoimmune cholangitis (AC). AIMS: To evaluate the frequency and nature of the variant syndromes of AIH and to determine their distinguishing characteristics and prognostic significance. METHODS: Two hundred twenty-six patients with the clinical diagnoses of AIH (162 patients), PBC (37 patients) and PSC (27 patients) were graded by the scoring system of the International Autoimmune Hepatitis Group for probable and definite diagnoses of AIH. Patients in the clinical category of AIH who were graded as probable or no AIH were scrutinized further for variant features. Patients who were graded as probable or definite AIH in the clinical categories of PBC and PSC were regarded as variant syndromes. RESULTS: Variant syndromes of AIH, including those with features of PBC (15 patients), PSC (15 patients) and AC (11 patients), were present in 41 of the 226 patients with autoimmune liver disease (18%). Patients with AC had fewer features of AIH than the other variants and the lowest autoimmune score compared to definite AIH (10.4 _+ 0.8 vs 18.5 _+ 0.2, p<0.0001). In contrast, patients with AIH/PBC had the most features in common with definite AIH, including similar serum aspartate aminotransferase (565 _+ 159 U/L vs 519 _+ 38 U/L), bilirubin, and alkaline phosphatase (433 _+ 68 U/L/vs 360_+ 26 U/L) levels. They differed mainly by having antimitochondrial antibodies (p<0.0001), higher IgM levels (p=0.0006), and a lower frequency of the A1-BS-DR3 phenotype (p=0.02). Patients with AIH/PSC were distinguished from definite AIH by their male predominance (67%), low occurrence of autoantibodies (p=0.004), increased alkaline phosphatase levels (p<0.0001), and low prevalence of HLA DR4 (p=0.01). Only patients with AC failed to respond to corticosteroids. Remission occurred less frequently in these patients than in those with definite AIH (0% vs 55%, p=0.003). Similarly, remission occurred less often in patients with AIH/PSC than in definite AIH (2% vs 55%, p=0.01) and they more commonly experienced an adverse outcome (70% vs 22%, p=0.003). In contrast, patients with AII-I/PBC responded as well to corticosteroids as those with definite AIH. The principal finding associated with corticosteroid responsiveness among all variants was a serum alkaline phosphatase level of less than twofold normal (p=0.0009). CONCLUSIONS: Variant syndromes of AIH are common. AIH/PBC is the variant that most closely resembles AIH and it frequently improves with corticosteroid therapy. AC is an outlier variant and it may be a separate disease. Steroid responsiveness is associated with low serum alkaline phosphatase levels.

Bone structural and metabolic changes at the end of pregnancy and lactation in rats

OBJECTIVE: The objective of this study was to elucidate the net change of bone structure and metabolism in the lumbar trabecular bone of rats at the end of the pregnancy and lactation. STUDY DESIGN: Female virgin Sprague-Dawley rats aged 200 days were mated, and bone mineral density by dual-energy x-ray absorptiometry, bone histomorphometry, and serum bone metabolic markers were measured at the end of pregnancy (day 22 of pregnancy), after delivery (day 5 post partum), and at the end of lactation (day 21 post partum). RESULTS: At the end of pregnancy bone mineral density, bone volume, trabecular thickness, and serum calcium decreased; serum parathyroid hormone increased; and the histomorphometric parameters indicated that bone resorption were higher than those variables in nonpregnant rats; but bone formation was suppressed, as demonstrated by the low histomorphometric parameters and by the low serum alkaline phosphatase levels. After delivery the bone mineral density of nonlactating rats recovered rapidly, as in nonpregnant rats, but nonlactating rats showed more bone formation by histomorphometry than nonpregnant rats did. At the end of lactation, bone mineral density and serum calcium levels decreased considerably, and lactating rats showed substantial bone formation, bone resorption, and high serum alkaline phosphatase levels. The correlation between the number of pups ( x) of the lactating and nonlactating groups and the bone mineral density ( y, in grams per square centimeter) showed simple linear regression ( y = -0.0067 · x + 0.2517, r = 0.949, p < 0.0001). CONCLUSIONS: These results indicate that significant decreases occur in the trabecular bone of rats at the end of pregnancy and lactation and that lactational intensity is related to bone mineral density. (Am J Obstet Gynecol 1998;178:180-5.)

Prognostic indicators in Indian childhood cirrhosis.

Nineteen cases of Indian childhood cirrhosis (ICC) were studied for determining prognostic indicators. Lower serum bilirubin and high serum alkaline phosphatase were associated with good prognosis. Mere presence of hyaline did not influence the clinical and biochemical parameters, however excess hyaline formation was associated with rapidly deteriorating course. Extent of reticulin condensation had no specific significance, but extensive fibrosis was associated with low serum alkaline phosphatase level and shorter survival period. There were six survivors in the study with a follow up upto 26 months and repeat liver biopsies in most of them showed very little changes.

Serum enzyme changes due to trace amounts of some transition metal ions on the induction of experimental diabetes.

The intravenous injection of zinc chloride immediately before and 15 minutes after alloxan or dithizone prevented the usual hyperglycaemia observed 24 hours after induction of diabetes. The intravenous injection of manganese chloride prevented any marked rise of blood glucose, while chromium and cobalt chlorides lowered the blood glucose level to a certain extent. In alloxan diabetic rats, serum GOT and GPT levels were significantly higher than normal. The serum GOT levels were higher in animals injected with chromium than cobalt, zinc and manganese; while serum GPT levels were higher in cobalt than in chromium, zinc and manganese. In dithizone diabetes, serum GOT and GPT were increased in animals injected with cobalt than chromium, zinc and manganese. Alloxan diabetic rats showed lower serum alkaline phosphatase levels and higher in animals injected with cobalt than chromium, zinc and manganese. For dithizone, there are statistically significant differences in all cases. In alloxan diabetes, coeruloplasmin was higher than normal, while intravenous injection of dithizone was without effect on serum coeruloplasmin.