Hypophosphatasia: from birth to adulthood

ABSTRACT Hypophosphatasia (HPP) is an inherited disease caused by a low activity of tissue-nonspecific alkaline phosphatase, a hydrolase that removes phosphate groups from many molecules. Decreased alkaline phosphatase activity leads to the accumulation of three main metabolites, i.e., pyridoxal 5'-phosphate (PLP), inorganic pyrophosphate (PPi), and phosphoethanolamine. Impairment in PLP dephosphorylation induces seizures, while PPi accumulation inhibits bone mineralization. Clinically, HPP has a wide spectrum of presentations, ranging from neonatal death to an apparent lack of symptoms. This disease is classified into six subtypes according to the age at onset of first signs or symptoms. The clinical manifestations of the disease include rickets-like bone changes, bone demineralization, fragility fractures, reduced muscular strength, chest deformity, pulmonary hypoplasia, nephrolithiasis, nephrocalcinosis, and chondrocalcinosis. Treatment of HPP consists of enzyme replacement therapy. Before this therapy was approved, treatment was palliative and associated with high morbidity and mortality. Asfotase alfa has changed the prognosis of the disease by reducing bone deformity and improving bone mineralization, lung function, and muscle weakness, among other benefits. In adults, teriparatide and anti-sclerostin antibody have been used off-label in selected cases, demonstrating benefit in accelerating fracture healing and in concomitant treatment of osteoporosis. This review summarizes the main aspects of HPP and identifies the particularities of the disease in adult patients.

Incidence, characteristics and long-term outcomes of patients with diabetic ketoacidosis: a prospective prognosis cohort study in an emergency department

ABSTRACT BACKGROUND: Diabetic ketoacidosis is the most frequent hyperglycemic complication in the evolution of diabetes mellitus. Common precipitating factors include newly diagnosed diabetes mellitus, noncompliance with therapy and infections. However, few studies have been conducted in Brazil and none were prospective in design. OBJECTIVE: To describe the incidence, clinical and laboratory characteristics and precipitating factors of diabetic ketoacidosis among emergency department patients in a tertiary-level teaching hospital in Brazil. We also aimed to identify immediate and long-term mortality within two years. DESIGN AND SETTING: Prospective prognosis cohort study conduct at a tertiary-level teaching hospital in São Paulo, Brazil. METHODS: All patients > 12 years old presenting diabetic ketoacidosis who were admitted to the emergency department from June 2015 to May 2016 were invited to participate. RESULTS: The incidence of diabetic ketoacidosis per 1,000 admissions was 8.7. Treatment noncompliance and infection were the most common causes of diabetic ketoacidosis. The immediate mortality rate was 5.8%, while the six-month, one-year and two-year mortality rates were 9.6%, 13.5% and 19.2%, respectively. Death occurring within two years was associated with age, type 2 diabetes, hypoalbuminemia, infection at presentation and higher sequential organ failure assessment (SOFA) score at admission. CONCLUSIONS: Diabetic ketoacidosis among patients presenting to the emergency department was relatively frequent in our hospital. Treatment noncompliance and infection were major precipitating factors and presence of diabetic ketoacidosis was associated with immediate and long-term risk of death.

A two-year follow-up of asfotase alfa replacement in a patient with hypophosphatasia: clinical, biochemical, and radiological evaluation

SUMMARY Hypophosphatasia (HPP) is a rare disease with a high mortality rate in its severe forms. It is caused by mutations within the gene encoding the tissue-nonspecific alkaline phosphatase (TNSALP), an enzyme responsible for bone mineralization. In 2015, the Food and Drug Administration approved the use of asfotase alfa, the first medication showing benefit in the treatment of HPP. We describe a case with a 2-year follow-up of the first Brazilian child treated with asfotase alfa. A 5-year-old boy, born to consanguineous parents, was diagnosed with HPP at the age of 20 months. During prenatal ultrasonography, polyhydramnios and shortening of long bones were detected. After birth, he presented delayed motor development, repeated respiratory infections, and bone deformities. At the age of 2 years and 8 months, he started walking and had already lost his primary teeth. He had reduced levels of alkaline phosphatase (ALP), elevated levels of pyridoxal 5'-phosphate (PLP), and a p.Ala33Val (c.98C>T) missense mutation in homozygosis in the TNSALP gene. His parents and sister also had reduced ALP levels, high PLP levels, and the same mutation in heterozygosis. His father and sister were healthy, and his mother was diagnosed with rickets in childhood, which resulted in short physical stature and lower limb deformities. The patient was started on asfotase alfa at the age of 2 years and 10 months. After 2 years of treatment, he improved his motor skills, had no further episodes of severe respiratory infection, and showed improved radiological findings of rickets, without any severe side effect.