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Non-alcoholic fatty liver disease (NAFLD) is increasingly being encountered in primary care, often in obese patients with no overt signs of disease, but with raised alanine transaminase (ALT) levels. A framework is required in which to diagnose and evaluate these patients correctly. Non-alcoholic fatty liver disease encompasses a spectrum of liver diseases ranging from benign NAFLD to the more aggressive non-alcoholic steatohepatitis (NASH). Non-alcoholic fatty liver disease is characterised by excess fatty infiltration of the hepatocytes, whereas NASH is associated with changes of necro-inflammation with fibrosis, and has the potential to develop to cirrhosis1 and also hepatocellular carcinoma.2

Currently, 20–30% of the population is affected by NAFLD, with NASH being detected in 2% of the general population.1 At our local teaching hospital, Hope Hospital, Salford, the biochemistry department processes 169 isolated raised ALT tests per month (personal communication, Dr Tony Redmond, Dean of Hope Hospital).

The underlying pathophysiology of NAFLD is insulin resistance,1 with 80% of patients fulfilling the criteria for a diagnosis of metabolic syndrome.3,4 Current figures from the World Health Organization estimate that, globally, 400 million people are obese, and it predicts that this epidemic will increase to 700 million by 2015.5 As a result, the prevalence of metabolic syndrome is also likely to soar and, consequently, that of NAFLD, which is now also a recognised condition in children. Nearly 20% of patients with NASH will develop cirrhosis within 10 years. Once cirrhosis is present, 45% of patients will develop consequent complications such as variceal bleeding, ascites, and liver failure.1 Given the liver’s excellent capacity for regeneration, however, early detection combined with holistic lifestyle management and medication can improve ALT levels and liver histology.2

Diagnosis of NAFLD

Often asymptomatic, NAFLD is usually an incidental finding on liver biochemistry testing. In symptomatic patients, the history is often vague. Predominant features include:2,6

• fatigue
• chronic malaise
• disturbed sleep
• abdominal pain.

This group of symptoms is non-specific and, therefore, may not provoke suspicion of NAFLD specifically as the underlying cause. Box 1 lists signs found on clinical investigation that are indicative of NAFLD.

Liver biochemistry often shows raised levels of serum ALT and aspartate transaminase (AST), although in the early stages of NAFLD, frequently ALT alone is elevated.2 Some patients will have a raised level of gamma glutamyl transpeptidase and the clinician must exclude the possibility of excessive alcohol intake. In 60% of cases, patients will also have increased serum ferritin levels,1 a manifestation of liver injury rather than as a result of iron overload.

Ultrasonography demonstrates increased echogenicity, often described as a ‘bright’ liver, on imaging, which indicates steatosis. Studies have reported that hepatic ultrasonography detects NAFLD in 22% of the population, with 76% of these individuals being obese.7 Ultrasound has a sensitivity of 89% and is an excellent method for assessing the presence of fat accumulation.7 However, it is unable to detect fibrosis and, therefore, cannot distinguish between NAFLD and NASH.7

A liver biopsy is the gold standard investigation for detecting fibrosis. However, this is an invasive test that is expensive and has a small morbidity and mortality rate. Standard liver biopsy in patients with normal coagulation has a mortality rate of 1/10,000. There is a risk of puncturing other organs, of bleeding, and the side-effect of some pain to the patient.8

Box 2 lists the steps involved in reaching a diagnosis of NAFLD.

Box 1: Signs indicative of NAFLD

These are: raised liver enzymes ALT and AST exclusion of other aetiology for liver disease ultrasound evidence of fat accumulation central abdominal obesity raised triglycerides or fasting sugars, which, in combination with central abdominal obesity, are suggestive of the metabolic syndrome, and when linked to the raised ALT are indicative of NAFLD

NAFLD=non-alcoholic fatty liver disease; ALT=alanine transaminase; AST=aspartate transaminase

Box 2: Procedure for the diagnosis of NAFLD

1. Carry out tests for ALT/AST levels 2. If levels are raised, exclude alternative causes: alcoholic liver disease—history of excessive alcohol consumption, AST:ALT ratio >2, possible macrocytosis viral hepatitis—hepatitis serology autoimmune hepatitis—antinuclear, smooth muscle, and antimitochondrial antibodies haemochromatosis—high serum iron and ferritin with decreased total iron-binding capacity drug side-effects and toxicity 3. Look for indicators of NAFLD: increased serum transaminases increased BMI >25 kg/m2 features of metabolic syndrome: type 2 diabetes mellitus hypertension central obesity (waist circumference: men >102 cm, women >88 cm) increased triglycerides 4. Perform ultrasound scan to identify hepatic steatosis 5. If steatosis is present, confirm diagnosis of NAFLD and begin management 6. Look for the following features of NASH: age >45 years BMI >30 kg/m2 Type 2 diabetes mellitus AST>ALT 7. Refer patient to hepatology for biopsy to confirm diagnosis of NASH

NAFLD=non-alcoholic fatty liver disease; ALT=alanine transaminase; AST=aspartate transaminase; BMI=body mass index; NASH=non-alcoholic steatohepatitis

Differential diagnosis

Following abnormal findings on liver biochemistry, the primary care clinician must exclude other common possibilities before making a diagnosis of NAFLD (see Box 2).

Alcoholic liver disease

Alcoholic liver disease (ALD) induces the same fatty changes within the liver as NAFLD, and is histologically indistinguishable from NASH. For a diagnosis of NAFLD to be reached, NICE has stipulated that the maximum alcohol intake should be 14 units/week in men and 7 units/week in women.7 However, an accurate history of alcohol intake can be difficult to obtain when many psychosocial factors are involved. Recent studies have investigated the efficacy of exclusion criteria in distinguishing ALD from NAFLD.9 Good predictors of ALD are a combination of macrocytosis, a normal or reduced body mass index, and an AST:ALT ratio of greater than 2 (see Box 2). Aspartate transaminase is preferentially raised in ALD compared to NAFLD.9

Viral hepatitis

The presence of viral hepatitis can be ruled out in the absence of any factors that would increase a patient’s risk of this disease. These include:

• history of travel to countries where the virus is prevalent
• sexual history—multiple partners, homosexual/bisexual relationships
• partners who have travelled to countries where hepatitis is endemic
• presence of tattoos
• previous use of blood products or blood transfusion
• intravenous drug abuse.

Investigation for viral hepatitis involves hepatitis serology. This looks for:8

• hepatitis A IgM antibodies
• hepatitis B surface antigen
• hepatitis C antibodies.

Autoimmune liver disease

Autoimmune hepatitis is more common in women, occurring in both young adults as well as in patients in their 50s. The presence of high titres of antinuclear antibody or smooth muscle antibody are diagnostic. Primary biliary cirrhosis will reveal a cholestatic picture on investigation and can be confirmed by a significant titre of antimitochondrial antibodies.10,11

Haemochromatosis

Haemochromatosis is a common genetic disorder among Northern Europeans, affecting 1 in 300 people. It can lead to liver damage through increased absorption and deposition of iron in the body, with investigations revealing high levels of serum iron and ferritin, with decreased total iron binding capacity.12

Drug-induced toxicity

There are many medications that can cause liver damage, including paracetamol, sulphasalazine, amiodarone, and flucloxacillin. A raised ALT level should alert the practitioner to assess drug intake, both on and off prescription, and both medical and recreational.

NAFLD and metabolic syndrome

The growing prevalence of metabolic syndrome has serious implications for patient morbidity and mortality. The most obvious concern is the increased risk of cardiovascular disease, increased incidence of type 2 diabetes, and subsequent complications.7 More recently it has been suggested that the characteristics of metabolic syndrome greatly increase the risk of developing NAFLD.

There is evidence of insulin resistance in those with NAFLD, but which is the primary event is not clear as yet. Peripheral insulin resistance is thought to provide increased free fatty acids (FFAs) by reducing suppression of adipocyte lipolysis. The liver therefore receives more FFAs. Increased fat in the liver promotes inflammation and fibrosis in the organ and progression to NASH.2 Therefore, NAFLD can be regarded as one of the manifestations of metabolic syndrome.

The adult treatment panel III of the US National Cholesterol Education Program has proposed the presence of three or more of the following criteria as being diagnostic for metabolic syndrome:13

• blood pressure >130/85 mmHg
• serum high density lipoprotein cholesterol concentration <1.04 mmol/l in men and <1.29 mmol/l in women
• serum triglyceride concentration >1.69 mmol/l
• fasting plasma glucose >6.1 mmol/l
• abdominal obesity (waist circumference >102 cm in men and >88 cm in women).

When to consider liver biopsy

The following clinical features are good predictors of NASH.5 A patient with many or all of these features should be referred for a liver biopsy to differentiate between NAFLD and NASH:

• age >45 years
• body mass index >30 kg/m2
• type 2 diabetes mellitus or elevated fasting glucose
• AST>ALT.

In addition to these factors, the clinician should consider whether the investigation will subsequently impact on treatment. The presence of fibrosis may encourage the initiation of more aggressive management, including pharmacological treatments and, possibly, bariatric surgery to achieve weight loss. Finally, it is important that the patient is made aware of the reason for a liver biopsy, as well as the potential consequences if one is not performed. General practitioners should inform patients of the risks and benefits of liver biopsy in diagnosing NASH.

Management of NAFLD

Studies have shown that patients with NAFLD have a significantly higher risk of premature mortality compared with the general population, and a high percentage of these patients have features of metabolic syndrome. It is essential to address the risks this imposes for people developing cardiovascular disease. Dyslipidaemia in patients with NAFLD can be effectively treated with statins, accompanied by monitoring of liver function tests.

Insulin resistance plays a key role in the pathogenesis of NAFLD and many patients will eventually develop impaired glucose tolerance or overt type 2 diabetes. Up to 50% of people in the USA with diabetes have NAFLD.14 Accordingly, pharmacotherapy should aim to improve insulin sensitivity.

Pharmacology

Peroxisome proliferator-activated receptor (PPAR-γ) agonists such as pioglitazone and rosiglitazone and metformin are thought to show the greatest efficacy in clinical practice.3,15 Studies have shown that PPAR-γ agonists can reduce liver enzymes to within their normal range, in addition to reducing steatosis and inflammation on histology.3 Metformin is effective in NAFLD as it reduces the risk of developing diabetes and improves liver biochemistry. Neither class of drug is currently licensed for use in NAFLD in the absence of diabetes, and both have potential side-effects and contra-indications. Studies into the long-term effects of both classes of agent on fibrosis are still ongoing.16

Conversely, specific anti-obesity drugs, orlistat, sibutramine, and rimonabant are licensed for obese patients, and certain overweight patients with co-morbidities, a group that covers the majority of NAFLD sufferers. The two former drugs have been approved by NICE,17 and the institute is in the process of assessing the third. These drugs address insulin resistance, and have cardiometabolic benefits over and above that which would be anticipated by weight loss alone.18,19 Some improvement in NASH and NAFLD has been seen after use of orlistat compared with placebo,20 and with sibutramine.21

Excess intra-abdominal fat can lead to steatohepatitis and, therefore, maintaining an increased waist circumference will exacerbate the histological changes within the liver.22 A weight loss of greater than 5% of body mass by dietary restriction and increased physical activity can normalise liver biochemistry.23 It has been postulated that if this weight loss is maintained, patients can expect a complete reduction in hepatic steatohepatitis.

Management of NAFLD should, therefore be aimed at treatment of obesity to prevent the condition progressing to end-stage liver failure. However, long-term weight loss can be difficult to achieve and should, therefore, be approached as a lifestyle change in accordance with NICE guidance.17

Summary

It is hoped that the management of raised ALT levels in general practice is improved by the use of a clear guideline. Using this will increase the diagnosis of NAFLD and NASH within the practice. The prevention, detection, and management of NAFLD requires the skills of the primary care team, both in clinical management and in patient-centred consultation. The association of NAFLD and the metabolic syndrome means that active management, especially weight loss and the management of other risk factors associated with metabolic syndrome, will help to reduce the patient’s future incidence of cardiovascular disease, diabetes mellitus, NASH, and progressive liver complications.

Key points

The liver has excellent regeneration abilities and early detection of NAFLD and treatment has been shown to improve liver biochemistry and histology On clinical diagnosis: patients may have raised levels of ALT and AST; other aetiology of liver disease can be ruled out; ultrasound may reveal fat accumulation in the liver; patients may exhibit other features suggestive of metabolic syndrome and a raised BMI Differential diagnosis should rule out alcoholic liver disease, viral hepatitis, autoimmune liver disease, and drug-induced hepatotoxicity The characteristics of metabolic syndrome may predispose patients to developing NAFLD Liver biopsy can differentiate NAFLD from NASH Excess intra-abdominal fat can lead to steatosis—raised BMI further exacerbates the changes within the liver, and long-term weight loss should be encouraged

NAFLD=non-alcoholic fatty liver disease; ALT=alanine transaminase; AST=aspartate transaminase; BMI=body mass index; NASH=non-alcoholic steatohepatitis

Practice-based commissioning take home messages

written by Dr David Jenner, NHS Alliance PBC Lead NAFLD is a very common condition characterised by raised ALT levels and linked to the metabolic syndrome Key elements of management in primary care are weight loss, diet, and exercise PBC collectives should agree local referral pathways for NASH/NAFLD to ensure appropriate and cost-effective investigation Using these local pathways for care management can avoid the need for referral Liver biopsy to exclude NASH is expensive and potentially harmful Tariff prices:a hepatology outpatient = £308 new, £107 follow up liver biopsy day case (G08) = £9081

PBC=practice-based commissioning; NAFLD=non-alcoholic fatty liver disease; ALT=alanine transaminase; NASH=non-alcoholic steatohepatitis a

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Teruni Muthuveloe, Manchester University Medical Student
Dr Jane Wilcock, GP
Swinton, Salford