Jeetesh V. Patel1 and Paramjit Gill2 1 Dartmouth Medical Centre, West Bromwich, UK 2 University of Warwick, Coventry, UK Primary care is the cornerstone of most national healthcare systems, providing “front door” access for the greater majority of a country’s population. At its heart is general practice – doctors working as a general practitioner (GP) or family physician. GPs provide a broad‐based and holistic approach for patients seeking improved health and wellbeing. They are required to diagnose illness and to “filter” serious pathologies or conditions needing specialist hospital intervention and those who can be treated safely within the community setting under their care. Undertaking a full history and examination remains the cornerstone of managing a patient with abnormal s. Abnormal LFTs can be a challenge and create uncertainty for GPs in primary care. They are responsible for the regular interpretation of these tests for hundreds of patients each week. The reasons for this apprehension and uncertainty is multifactorial and relates in part to: (i) the high burden of mortality and morbidity associated with liver disease; (ii) wide variability in the relationship between LFTs and hepatocellular damage; and (iii) the incidental nature with which LFTs are requested. Liver disease is a key issue for the health of the population in England [1]. In 2020, cirrhosis and other diseases of the liver were the second highest cause of death in those aged 35–49 years, and among the top five causes among adults of other age groups [2]. Tragically, many of these deaths are preventable, where causes are related to lifestyle and unhealthy environments such as alcohol excess, obesity and some medications. As an investigation, LFTs represent a simple investigation for GPs synonymous with a “routine” assessment of general health. Unfortunately, LFTs do not appear to be reliable; they can be normal in the presence of serious liver disease and, conversely, abnormal in other pathologies. Of the liver enzymes common to LFTs, alanine amino transferase (ALT), aspartate amino transferase (AST), alkaline phosphatase (ALP), and gamma‐glutamyl transferase (GGT) are released by organs other than the liver. The degree of liver damage is difficult to interpret by absolute circulating levels of these enzymes alone [3]. These LFTs give us more of an appreciation of the possible pattern of a patient’s liver disorder, whether hepatocyte damage (AST, ALT), cholestasis (bilirubin, GGT, ALP) or both. In a UK study of 95 977 primary care patients free of liver disease, abnormal LFTs were seen in some 20% and, on 3.7 year follow‐up, 1.15% developed liver disease [4]. There is typically a “reactive” approach when it comes to the management of incidental abnormal LFTs in otherwise healthy patients. We lack a “proactive” approach to screen for liver disease itself. With much of the focus for the GP not to “miss” insidious disease, LFTs are frequently included as a first‐line investigation for patients with constitutional symptoms of loss of appetite, malaise and other vague symptoms, such as fatigue, itching, abdominal pain and distension. Signs such as jaundice, dark urine and pale stools appear more specific to the liver. Broadly speaking, the GP will commonly encounter liver disease in the form of neonatal jaundice, congenital and inherited disorders, immune and autoimmune disorders, fatty infiltration, toxicological and pharmacological damage, cholestatic syndromes, chronic infections and cancer. The aim of this chapter is to help primary care professionals to deal with incidental findings of abnormal LFTs, to appreciate when further investigation is warranted, what investigations to arrange in primary care and when to refer to a specialist. It is common place in primary care for an isolated AST or ALT to be seen in an otherwise healthy individual having a “routine” set of bloods taken. A repeat of the LFTs is likely to be the response, but what if it is sustained? What if there is a history of past bloods with similar trends? The likelihood is that the AST or ALT is raised in response to fatty infiltration because this is by far the most common liver disorder encountered in primary care. Non‐alcoholic fatty liver disease (NAFLD) covers a spectrum of diseases from non‐alcoholic fatty liver to non‐alcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is a common disorder, with an estimated worldwide prevalence of 25%, associated with type 2 diabetes, obesity, dyslipidemia and the metabolic syndrome [5]. This is typically recognized as a benign condition, although estimates suggest that up to 40% of patients with fatty liver progress to advanced stages of fibrosis [6]. The pathogenesis of NAFLD is complex, involving the interplay of lifestyle factors, microbiota, dyslipidemic metabolism, insulin resistance, and hepatocyte injury and inflammation. The most important factor in the adverse progression of the patient with fatty liver is the presence of fibrosis. While the progression of fibrosis is slow, it is accelerated in states such as NASH. It is important to note that cardiovascular disease remains the main cause of death in patients with NAFLD. Nonetheless, NAFLD is a considerable healthcare challenge in primary care. Given its link with obesity, it is, troublingly, increasingly more common in childhood. In the Avon Longitudinal Study of Parents and Children (ALSPAC), 1 in 5 young people was found to have steatosis and 1 in 40 had fibrosis around the age of 24 years [6]. The diagnosis of NAFLD can be made using ultrasound where steatosis is present in more than 5% of the parenchyma, alcohol intake is within normal limits (< 20 g or 2.5 units/day for women and < 30 g or 3.75 units/day in men), and in the absence of other secondary causes. It is important to note that NAFLD can be present in the absence of abnormal LFTs. Risk factors associated with the metabolic syndrome should raise a suspicion of NAFLD [7]. If NAFLD is present, it is important to use non‐invasive scoring systems to interpret the stage of disease (e.g. the enhanced liver fibrosis test, NAFLD Fibrosis Score, Fibrosis (FIB)‐4 score) [8]. Depending on these scores, a decision can be made as to whether to refer the patient who is at high risk of liver fibrosis to secondary care or to continue monitoring in the community. Long‐term heavy alcohol intake is globally recognized as a key cause for chronic liver disease, and in the UK around 7700 people die each year due to alcohol‐related liver disease, mostly between the ages of 40 and 65 years [9]. Heavy alcohol intake damages the liver in the form of alcoholic steatosis, alcoholic hepatitis, cirrhosis and hepatocellular carcinoma [10]. Prolonged abstinence from alcohol represents is the only real option to slow this progression. Interestingly, alcoholic liver disease is not confined to just those with alcohol dependency. The pathophysiology is complex, involving environmental and genetic factors that modulate the toxic effects of alcohol and its metabolites on the liver [8]. The challenge for primary care is to identify patients early and implement lifestyle changes. Many of these patients will be asymptomatic and are unlikely to present with concerns over their drinking habits. Clues to a diagnosis may come from other areas such as the presence of macrocytosis, gout, reduced albumin levels. GGT levels may be useful to decipher a history of heavy alcohol intake. Unfortunately, most patients with cirrhosis are undiagnosed and it is often the later complications of cirrhosis (e.g. ascites) that lead to the presentation of the patient [11]. In summary, patients with persistently elevated AST or ALT are likely to have NAFLD. A repeat set of bloods including GGT, a full blood count (and tests to investigate secondary causes as appropriate) are needed (Box 2.1). Ultrasound can be used to confirm the diagnosis and patients should be stratified with respect to alcohol intake and risk of fibrosis. A referral to secondary care is needed for those with a high risk of fibrosis.
2
Primary Care
Introduction
Liver Disease in the UK
Isolated Raised Liver Transaminase in a Healthy Individuals
Non‐alcoholic Fatty Liver Disease
Alcohol and Liver Disease
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