Poster Presentation 29th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting 2019

An unusual case of transient alkaline hyperphosphatasemia in an adult: a diagnostic dilemma and a commentary on the utility of alkaline phosphatase isoenzyme assays (#98)

Difei Deng 1 , Helen Crowther 1 2 3 , Sue Lynn Lau 1 2 3 4
  1. Westmead Hospital, Sydney, NSW, Australia
  2. Blacktown Hospital, Sydney, NSW, Australia
  3. School of Medicine, Western Sydney University, Sydney, NSW, Australia
  4. School of Medicine, University of Sydney, Sydney, NSW, Australia

Case summary:

 

Mrs XJ, a 30-year-old lady of Chinese origin, attended routine haematology review for monitoring of aplastic anaemia, diagnosed 3 years prior. Blood tests revealed an elevated serum alkaline phosphatase (ALP) level of 793 IU/L (20-110 IU/L); other liver function tests (LFTs), including bilirubin, transaminases and gamma-glutamyltransferase were within normal range. Six days later, retesting at a different laboratory showed persisting isolated ALP elevation at 1096 IU/L. Previous ALP levels had been normal over the last 3 years, including a level of 54 IU/L four months earlier.

 

Aplastic anaemia had been diagnosed on bone marrow biopsy, following the incidental finding of pancytopaenia during her first pregnancy. Pancytopaenia resolved postpartum and cell counts remained stable subsequently.

 

Mrs XJ was asymptomatic, with no complaints of bone or abdominal pain. She had no recent travel history or infectious contacts. She had been on Chinese iron and chlorophyll supplements for many years and had recently commenced Elevit in preparation for a second pregnancy. She denied other drug use. Physical examination did not reveal any evidence of liver disease, lymphadenopathy or bony swelling or tenderness.

 

Haemoglobin and platelet counts were within normal range, with mild reduction of total white cell (3.8x109/L) and neutrophil count (1.6x109/L). Lactate dehydrogenase was slightly elevated at 252 units/L (120-250 U/L). Corrected serum calcium concentration was 2.23 mmol/L (2.15-2.55 mmol/L) with an appropriate parathyroid hormone concentration of 4.9 pmol/L (1.6-7.5 pmol/L) and 25-hydroxy vitamin D of 75 nmol/L. Procollagen Type 1 N-Terminal Propeptide (34 u/L) and C-Terminal Collage Type 1 Telopeptide (168 ng/L) were unremarkable. Hepatitis B and C serology, autoimmune liver panel and beta-HCG were negative.

 

Repeat LFTs a week later showed an increasing ALP level of 1694 IU/L, now 15 times the upper limit of normal. ALP isoenzyme analysis demonstrated approximately equal bone and liver isoenzymes. Simultaneous serum Ostase (Automated Chemiluminescence Enzyme Immunoassay, IDS-iSYS) measured 527.0 ug/L (range: 5.5-24.6), twenty-one times the upper limit of normal.

 

Abdominal ultrasound revealed no evidence of liver disease and Tc-99m radionucleotide whole body bone scan with SPECT/CT demonstrated mild diffuse osteoblastic uptake in the vertebrae and sternum without evidence of other focal osteoblastic abnormalities. A bone marrow biopsy demonstrated normal marrow cellularity and adequate trilineage haemopoiesis.

 

The ALP subsequently declined spontaneously, measuring 891 IU/L, 91 IU/L and 47 IU/L at 4 weeks, 8 weeks and 14 weeks respectively (Figure 1). The patient remains well.

 

Discussion:

 

Causes for ALP elevations:

Patients with isolated ALP elevation may pose diagnostic challenges for endocrinologists. Despite common usage as a biomarker in a wide range of conditions, the exact physiological role of ALP in humans is not well understood. Human ALP isoenzymes are the product of four gene loci consisting of: a tissue non-specific isoenzymes found in liver, bone and kidneys; placental isoenzyme; intestinal isoenzyme; and placental-like germ cell isoenzyme [1]. In healthy adults, bone and liver isoenzymes of ALP contribute equally to total serum ALP.

 

The most common causes for ALP elevation in adults involve disorders of the hepatobiliary system. A range of metabolic bone conditions elevate total serum ALP levels due to increased bone isoforms. Bone-specific alkaline phosphatase (BSAP) is expressed by osteoblasts and is involved in skeletal mineralisation [2]. BSAP reflects osteoblastic activity and can be significantly elevated in conditions such as Paget’s Disease, osteomalacia/rickets, and primary/secondary bone malignancies such as osteogenic sarcoma and osteoblastic bony metastases [3]. Moderate ALP elevation can occur with hyperparathyroidism, renal osteodystrophy, hyperthyroidism, fracture healing and acromegaly [4].

 

The diagnostic approach to a patient with elevated ALP therefore requires comprehensive and targeted history, examination and investigations to address the above differentials.

 

“Benign” transient hyperphosphatasaemia:

 Benign transient hyperphosphatasaemia (BTH) of infancy and early childhood has peak prevalence at 6-24 months of age. Incidence of 2.8% was reported in one prospective study [5]. It presents with significantly elevated ALP levels and equal elevations in liver and bone ALP isoenzymes on electrophoretic analysis [6]. This occurs in the absence of detectable bone or liver conditions and typically resolves spontaneously within 4 months.

 

A limited number of adult cases of BTH have been reported, with the same ALP isoenzyme analysis findings and a similar time-course to spontaneous resolution [7-11]. Case reports detail varying individual comorbidities, but no consistent features to suggest aetiology. Various mechanisms have been proposed. The clearance of bone and liver ALP is usually rapid, with a half-life of 7-8 days [12,13]. Modifications of the ALP molecule via sialylation could potentially prolong its serum half-life [14,15]. In children, a history of preceding viral infection was found in two thirds of cases [5] and some studies report seasonal clustering of BTH diagnoses in autumn/winter [6,14,16]. More recent studies demonstrated no evidence for seasonal clustering [5,13]. The predilection for childhood presentation is unexplained, and no large adult case series or mechanistic studies exist.

 

ALP isoenzyme assays:

Standard quantification of total ALP uses indirect spectrophotometry. Liver and bone isoenzymes are products of the same tissue non-specific gene but differ due to post-translational glycation and have different physico-chemical and electrophoretic properties [17]. ALP isoenzyme analysis uses electrophoretic techniques to separate isoenzymes of ALP and quantify them using densitometry. Additional techniques such as heat and amino-acid treatment can be employed [7].

 

Specific measurement of serum BSAP levels can be performed more rapidly using the Ostase immunoassay, however, there is some cross-reactivity with liver and other isoforms of ALP and results should be interpreted in tandem with electrophoretic ALP isoenzyme analysis [18].

 

Take-home messages:

  • Isolated ALP elevation occurs in a wide range of conditions including metabolic bone disorders and bone malignancies.
  • Comprehensive history and examination with targeted investigations is recommended to address these causes.
  • ALP isoenzyme analysis and the Ostase immunoassay are useful adjuncts, best interpreted in tandem.
  • “Benign” transient phosphatasaemia, whilst generally observed in infants, has been rarely reported in adults and is characterised by high serum ALP with approximately equal liver and bone isoenzymes and spontaneous resolution within 4 months. Suspicion and recognition of this condition may avoid unnecessary investigation in the well patient.

 

Figure 1: Mrs XJ’s ALP levels (IU/L) over time

5d1dc59eef4df-ALP+Graph.png

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