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A 55-year-old Asian man was referred to a gastroenterology clinic by his general practitioner following an incidental finding of raised alkaline phosphatase (ALP) on routine blood testing. His ALP was found to be 198 (NR 35–129) with otherwise normal liver function tests. His past medical history consists of essential hypertension, type 2 diabetes and ischaemic heart disease. He was asymptomatic except for an intermittent ache over his left clavicle, which he had put down to angina. His gamma glutamyltransferase (GGT) was normal at 33 (NR 11–50) making bone the most likely source of his raised ALP. Imaging, including x-ray, CT and bone scan, showed an area of abnormality in the left clavicle. The appearances were consistent with fibrous dysplasia.
We discuss the interpretation and investigation of deranged ‘liver’ function tests and suggest a rational and cost-effective diagnostic path to follow.
Deranged liver function tests are a commonly encountered problem in many fields of medicine, surgery and general practice. This case highlights the importance of correctly interpreting abnormalities in liver function tests and planning appropriate further investigation. It aims to raise awareness of the difference in cost between the options for further investigation and, therefore, encourage efficient use of resources. It also raises the question of how far a general practitioner (GP) should investigate these abnormal results before referring to a specialist. Would further investigation in primary care result in more appropriate referral or just delay the referral process?
A 55-year-old man was referred to the gastroenterology clinic for review after his GP noted an isolated raised ALP on routine blood testing. He was originally from Pakistan but had been living in the UK for over 20 y. His past medical history includes essential hypertension, type 2 diabetes and ischaemic heart disease. He had previously undergone primary percutaneous coronary intervention (PCI) for unstable angina in Pakistan in 2006 and now gets occasional angina on exertion. He remains a smoker but abstains from alcohol.
On review in clinic, he was asymptomatic except for a minor complaint of intermittent ache over his left shoulder, which he had put down to angina. He denied any history of jaundice, abdominal pain or other abdominal symptoms. On examination he had no stigmata of chronic liver disease and an entirely normal cardiovascular, respiratory and abdominal examination. Pain overlying the left clavicle could not be re-produced by palpation and no abnormality could be felt. Range of movement at the left shoulder was full and pain free.
To further investigate the cause of the isolated raised ALP a measurement of GGT was made, which was within normal limits at 33 (NR 11–50). Therefore, it was decided that a hepatic cause for the raised ALP was unlikely and no further liver investigations were warranted. Instead, a bony source was investigated, initially with radiographs of the left clavicle where the patient had complained of pain. This showed an expansile lesion at the medial end of the clavicle. A CT and bone scan were arranged for further characterisation and together these suggested a benign process such as abnormal remodelling of the bone after trauma to the sternoclavicular joint or fibrous dysplasia. As there was no history of trauma, fibrous dysplasia was thought to be the most appropriate diagnosis.
The differential diagnosis of ALP elevation can be broadly grouped into liver or bone causes. Biliary obstruction due to stones, strictures or tumours could all account for this finding. Other hepatic causes to be considered in this case would included autoimmune diseases (primary biliary cirrhosis and sclerosing cholangitis), although in a patient with diabetes and raised cholesterol (as in this case) fatty liver or non-alcoholic steatohepatitis (NASH) are perhaps more likely. An concurrent elevation of the GGT level would be expected in these causes.
In terms of bone pathology, the most common causes include Pagets disease, hyperparathyroidism, metastatic bone disease and recent fracture. However, the imaging results in this case were suggestive of fibrous dysplasia.
Fibrous dysplasia is a developmental anomaly of bone-forming mesenchyme that manifests as a defect in osteoblastic differentiation and maturation. It is not hereditary and the cause and incidence are unknown. Any bone can be affected but most commonly rib, femur, tibia or craniofacial bones. Facial fibrous dysplasia bone is said to produce the characteristic ‘chubby-cheeked’ appearance of cherubs. Presentation is usually with pain or pathological fracture and the only significant laboratory abnormality is an isolated elevated ALP. Although associated with endocrinopathies, the lesions rarely (<1%) undergo malignant change.
Surgical treatment is sometimes necessary, especially when long weight-bearing bones are involved. Studies have also shown that bone pain is reduced after treatment with bisphosphonates although there is no specific medical treatment for fibrous dysplasia.1
Follow-up with an orthopaedic surgeon is necessary if there is deformity or involvement of long bones. Endocrine tests should be undertaken and were normal in this case. Any abnormalities should prompt endocrine referral. In asymptomatic cases, long-term follow-up is not usually needed as radiological and biochemical findings tend to stabilise once bone maturity is reached.
Interpreting and investigating abnormal liver function tests appropriately means better use of resources and can lead to more timely diagnosis and/or referral. For example, in a NHS biochemistry laboratory, measurement of GGT costs approximately 70 pence whereas testing ALP isoenzymes (intrahepatic ALP-1 vs bone ALP-2) costs over £16. Isolating the source of raised ALP will obviously guide further investigations and, therefore, reduce the number of unnecessary investigations (eg, liver ultrasonography). However, despite its cost-effective advantage, it should also be taken into account that previous studies have cast doubt over the sensitivity and specificity of GGT measurements in determining the source of raised ALP.2
Analysis of how abnormal liver function tests are dealt with in primary care has previously shown that an important minority of patients with persistently abnormal results are not investigated sufficiently and are not referred. It was also shown that investigation of these patients yields important diagnoses, including communicable, potentially life-threatening, diseases.3
Competing interests: None.
Patient consent: Patient/guardian consent was obtained for publication.