Section 1

Cassie, a 49-year-old with a 2-year history of type 2 diabetes, is being considered for statin therapy. She attended the practice diabetes clinic with the following test results: HbA_1c 55 mmol/mol; cholesterol 5.8 mmol/L, triglycerides 3.4 mmol/L, HDL-cholesterol 0.9 mmol/L, non-HDL cholesterol 4.9 mmol/L; ALT 87 U/L (normal range 0–65 U/L), gamma GT 85 U/L (0–75 U/L), alk phos 98 U/L (40–120 U/L), bilirubin 18 µmol/L (0–21 µmol/L), albumin 42 g/L; eGFR 85 mL/min/1.73 m²; BP 148/92 mmHg; BMI 32.1 kg/m²; waist circumference 89 cm.

Cassie’s regular medications are metformin 1 g twice daily and lisinopril 10 mg once daily. She is a non-smoker and drinks alcohol occasionally, not more than 8 units a week.

What is the most likely cause of Cassie’s elevated liver function tests and why?

Section 2

Given Cassie’s type 2 diabetes, obesity and low alcohol consumption, non-alcoholic fatty liver disease (NAFLD) is the most likely cause of her abnormal liver function tests (LFTs) (1). It has been estimated that up to 75% of individuals with type 2 diabetes have NAFLD (2).

Cassie displays a range of features consistent with metabolic syndrome (3,4) (see below) and indeed NAFLD may be regarded as the hepatic manifestation of metabolic syndrome. NAFLD is not associated with type 1 diabetes.

Features of metabolic syndrome (4)

• Central obesity (waist circumference >102 cm [men]; >88 cm [women])
• Hypertension (BP >135/85 mmHg)
• Dyslipidaemia (TG >1.7 mmol/L; HDL <1.04 mmol/L [men], <1.30 mmol/L [women])
• Insulin resistance (fasting glucose >6.1 mmol/L)

What is the characteristic feature of NAFLD?

Section 3

NAFLD is characterised by the accumulation of excess fat in the liver (steatosis) that is not the consequence of excessive alcohol consumption or manifestation of another cause of liver disease (5). It is defined by the presence of steatosis in >5% of hepatocytes (from histology) or if fat accounts for >5% of the weight of the liver (from imaging) (6).

Because the diagnosis of NAFLD depends on exclusion of other chronic liver diseases and consumption of excess alcohol, the term MAFLD (metabolic dysfunction associated with fatty liver disease) has been proposed with positive criteria (based on histology, imaging or blood biomarkers along with either overweight/obesity, type 2 diabetes or evidence of metabolic dysfunction) (7).

It is important to recognise that in many cases the cause of fatty liver will be multifactorial.

What pattern of LFT disturbance might you expect if Cassie had NAFLD? Can NAFLD be present in the absence of raised LFTs?

Section 4

The rise in Cassie’s ALT (alanine transaminase) is consistent with NAFLD. NAFLD may be suspected in type 2 diabetes when LFTs show a mild-to-moderate rise in serum aminotransferases. Typically, ALT is elevated more than aspartate aminotransferase (AST). However, as NAFLD progresses, the ratio of AST to ALT tends to rise (8).

Smaller rises in other liver enzymes, notably gamma GT (as seen with Cassie), may also be seen in NAFLD, although large rises in gamma GT are characteristically seen in alcoholic liver disease. Increases in alkaline phosphatase, gamma GT and bilirubin are consistent with intrahepatic cholestasis. Rising bilirubin levels and falling albumin levels may identify failing liver metabolic and synthetic function, respectively.

In fact, only around half of people with NAFLD will have elevated LFTs, so looking for a rise in LFTs is not a sensitive method for picking up NAFLD (there would be many false negatives) (8). Furthermore, the degree of liver damage and extent of fibrosis is not accurately reflected in LFT changes.

Would you expect Cassie to have any symptoms or signs of liver disease?

Section 5

The majority of people with NAFLD will be asymptomatic. Symptoms and signs of chronic liver disease are more likely to appear in more advanced disease.

You should ask Cassie if she has experienced any right upper quadrant pain or any episodes of jaundice. Fatigue is a non-specific symptom of liver disease. Signs of chronic liver disease are more likely to appear in progressive conditions such as cirrhosis (see below).

• Palmar erythema
• Spider naevi
• Gynaecomastia
• Testicular atrophy
• Jaundice
• Ascites
• Oedema
• Variceal bleeding (e.g. haematemesis from oesophageal varices)
• Caput medusa (dilated veins radiating from the umbilicus)
• Hepatomegaly (or small liver)
• Splenomegaly
• Encephalopathy

What might be your next investigation for Cassie to follow up her abnormal LFTs?

Section 6

A useful non-invasive investigation for Cassie would be an ultrasound scan of the liver. Increased hepatic echogenicity is consistent with the diagnosis of fatty liver, although a normal scan does not exclude the diagnosis (7).

Compared to histology (the gold standard from liver biopsy), ultrasound has a sensitivity of 85% and specificity of 91% for detecting moderate steatosis (1). Thus, ultrasound is a good first-line imaging technique that also can be useful in excluding other pathology (e.g. gallstones). It does not, however, accurately identify mild degrees of steatosis, assess fibrosis or predict the likelihood of disease progression. 

What range of liver pathology can occur with fatty liver disease?

Section 7

NAFLD comprises a range of hepatic pathology. The first stage of NAFLD is hepatic steatosis (non-alcoholic fatty liver  [NAFL]), which is an accumulation of fat in the liver without inflammation or fibrosis. Beyond this, a proportion of patients with NAFL (around 20%) can progress to non-alcoholic steatohepatitis (NASH), a condition characterised by hepatocyte inflammation and subsequent fibrosis, that is a harbinger of more serious liver disease. Around 20% of those with NASH will develop cirrhosis (destructive fibrosis) over a 10-year period, which heralds hepatic failure, and there is an associated risk of hepatocellular carcinoma (2,9).

It is the accumulation of visceral fat that drives NAFLD, rather than raised BMI. Visceral fat has relatively high metabolic activity generating inflammatory cytokines that accelerate progression to NASH (2).

Why is it important to establish whether or not Cassie has NAFLD?

Section 8

Individuals with NAFLD who have type 2 diabetes are more likely to progress to NASH and beyond (9). As alluded to in Section 7, NAFLD can progress to cirrhosis with increased risk of hepatocellular carcinoma, and these conditions are increasingly an indication for liver transplantation (10).

NAFLD is associated with increased cardiovascular (CV) risk (11). It is a risk factor for atrial fibrillation, myocardial infarction, ischaemic stroke and CV death. For individuals with NAFLD who have not progressed to cirrhosis, CV-related deaths are more common than liver-related deaths (12). It is essential, therefore, to consider intensive CV risk-factor management for Cassie (5).

People with type 2 diabetes and NAFLD are also at increased risk of extra-hepatic cancers (e.g. carcinoma of stomach, colon and pancreas) (13).

Clearly, Cassie needs to be aware of any steps that can attenuate NAFLD progression.

What impact might you expect NAFLD to have on Cassie’s glycaemic control?

Section 9

Accumulation of fat in the liver is responsible for increased hepatic insulin resistance so that glucose release from the liver is less well controlled in the presence of NAFLD. We might expect Cassie’s glycaemic control to be more challenging (2).

NAFLD is associated with the onset of type 2 diabetes, and the finding of NAFLD in an individual not diagnosed with type 2 diabetes should prompt a test for diabetes (1).

Cassie has a repeat set of LFTs that show very similar results. Her ultrasound reveals increased echogenicity consistent with fatty infiltration of the liver.

What other causes of abnormal LFTs might you consider?

Section 10

It is important to consider causes of disturbed LFTs other than NAFLD. Sensitively, establish levels of alcohol consumption. If consumption is > (alternatively <30 g [3.75 units]/day men; <20 g [2.5 units]/day women). Is there risk of hepatitis virus transmission (IV drug use, blood transfusion, sexual transmission, country of origin with high prevalence of hepatitis)? Has there been upper abdominal pain or jaundice? Check medications, including OTC remedies for potential hepatotoxic drugs eg methotrexate, amiodarone.

Alcoholic liver disease is common and is associated with high levels of gamma GT and triglycerides along with a macrocytosis. Raised levels of alkaline phosphatase, gamma GT and bilirubin are consistent with intrahepatic cholestasis. Low albumin concentrations and raised INR levels (low levels of coagulation factors) reflect reduced synthetic function of the liver and platelet count falls in advanced liver disease.

Depending on clinical features, consider other diagnoses (and accordingly investigations) as listed below.

Common

• NAFLD
• Alcoholic liver disease
• Viral hepatitis (hepatitis B and C serology)
• Hepatobiliary obstruction, gallstones (ultrasound)
• Metastatic disease of the liver or primary hepatic tumour (ultrasound/CT/MRI scan)
• Medication (including OTC medication, complementary and alternative remedies)

Less common

• Primary biliary cirrhosis (antimitochondrial antibodies)
• Autoimmune hepatitis (autoantibody screen)
• Haemochromatosis (raised Hb and ferritin levels)*
• Alpha-1 antitrypsin deficiency (reduced enzyme levels)
• Wilson’s disease (low serum caeruloplasmin level)

*Haemochromatosis in itself carries a higher risk of diabetes.

What advice would you offer Cassie to manage her fatty liver disease?

Section 11

The focus should be on lifestyle management. Encourage Cassie to lose weight as this leads to a reduction in liver fat, can improve liver enzyme profiles and may improve histopathology (14,15). Losing weight will reduce insulin resistance, benefiting glycaemic control and decreasing CV risk. Thus, a 5% weight loss can lead to an improvement in steatosis and a ≥10% weight loss can induce regression of fibrosis (16). A 5–10% weight loss achieved by a combination of dietary restriction and physical exercise appears to be the most effective means of improving NAFLD, but is likely to need intensive support to succeed (17). Setting a target weight reduction may be helpful but, if this is not achieved, it should be viewed not as failure but an opportunity to learn and move on.

Offer Cassie advice on diet () and exercise (150 min/week spread over several days) (5,18). The Mediterranean diet has been demonstrated to lower liver fat (even in the absence of weight loss) as well as reducing CV disease and benefiting glycaemic control (19). Pragmatically, Cassie should choose a diet that is acceptable to her and an exercise pattern that is achievable and sustainable.

Signposting to local exercise referral schemes may be helpful. The NHS Digital Weight Management Programme offering behavioural and lifestyle advice has commenced for individuals with diabetes (and/or hypertension) (20).

It is important that Cassie avoids excessive alcohol intake, as this can act synergistically to increase the accumulation of fat in the liver and accelerate disease progression (21). Whether or not complete abstinence from alcohol should be recommended in NAFLD remains uncertain given the finding of reduced CV mortality at low levels of alcohol consumption (2).

To successfully achieve this requires the person to be on board and motivated. Whilst the healthcare professional needs to inform individuals about the need to tackle lifestyle factors, this should not take the form of personal criticism or inducing fear, as this may lead to demotivation and disengagement. Remember that the psychosocial aspects driving eating (comfort eating rather than eating to satisfy hunger) may need attention (22).

If possible, other drugs (including OTC medication, complementary and alternative remedies) with the potential to be hepatotoxic should be avoided.

In addition to lifestyle advice what else could you offer Cassie to reduce cardiovascular risk?

Section 12

Offer Cassie statin therapy to provide CV protection and to benefit her NAFLD (may improve aminotransferase levels) (23). The caveat to this advice is that the safety of statins in patients with transaminase levels >3 times the upper normal limit is uncertain and specialist advice should be sought before proceeding (8). In all cases, it is appropriate to check LFTs along with lipid profile within 3 months of initiation; NICE advise considering stopping statin therapy only if liver enzyme levels have doubled, including people with abnormal baseline LFTs (5).

Smoking cessation and control of hypertension (40–70% of those with NAFLD have hypertension) and hyperglycaemia are also central to reducing CV risk.

Strong evidence of specific drugs benefiting NAFLD is lacking, but some advice on using glucose-lowering agents in NAFLD is included at the end of this case study.

The likely diagnosis of NAFLD was explained to Cassie, along with the need to manage this to avoid serious liver complications and to address CV risk. The importance of diet, exercise and weight loss was emphasised. Atorvastatin 20 mg once daily was commenced to reduce CV risk. BP remained elevated at 152/93 mmHg and the dose of lisinopril was increased to 20 mg once daily (target 140/90 mmHg).

What follow-up arrangements would you make for Cassie?

Section 13

A follow-up appointment in a few months’ time would be appropriate following a repeat set of blood tests (LFTs, lipid profile) to further support Cassie and review the effectiveness of the management plan.

At review 4 months later, Cassie had managed to lose 4 kg in weight (after enrolling in a weight-loss programme), BMI 30.3 kg/m². ALT had fallen to 71 U/L and gamma GT levels were back within normal range. Lipid profile was significantly improved on atorvastatin, and HbA_1c had fallen to 51 mmol/mol. Cassie was congratulated and encouraged to continue with her lifestyle changes and medication.

Given the insensitivity of LFTs and ultrasound in identifying more advanced liver disease (beyond simple steatosis), do you know of any other tools that can be used to help identify this.

Section 14

Once a diagnosis of NAFLD has been made, a key question is whether or not there has been progression to fibrosis, with its associated risk of complications. In individuals with NAFLD, hepatic fibrosis is strongly predictive of morbidity and mortality (24).

An assessment of liver fibrosis can be made non-invasively (including from primary care) using a validated fibrosis score calculator that can help direct who needs referral to secondary care for further investigation (25–28). Thus, for example, the NAFLD fibrosis score online calculator factors in age, BMI, diabetes status, and levels of AST, ALT, platelets and albumin. A low score is reassuring, but a high score would direct to further investigation. This may take the form of a FibroScan (transient elastography – a measure of liver stiffness) or, as recommended by NICE, an ELF (enhanced liver fibrosis) test (5). The latter test, which measures three serum biomarkers, could potentially be undertaken in primary care. The availability of these tests will depend on local arrangements.

If the initial assessment of liver fibrosis is negative, it should be repeated on a 3-yearly basis.

Who should be referred to hepatology?

Section 15

Triggers for referral to a hepatologist are suggested below (5). Ultimately, a liver biopsy may be necessary, including where there is diagnostic uncertainty.

• Marked elevation of LFTs
• Sudden deterioration of LFTs
• Clinical signs of advanced liver disease
• High score from fibrosis calculator
• High ELF score (≥10.51)
• Uncertain diagnosis of liver disease

Individuals with NAFLD with suspected advanced fibrosis should be seen by hepatology for assessment and management of portal hypertension complications, and where surveillance for hepatocellular carcinoma can be undertaken.

Section 16: Using antidiabetes agents in NAFLD

There are no licensed treatments for NAFLD, but pioglitazone has been shown to improve NASH in type 2 diabetes (29), although whether this translates into better long-term outcomes is uncertain. GLP-1 receptor agonists (with their potential for weight loss) may be used in NAFLD and liraglutide has been demonstrated to benefit those with type 2 diabetes having NASH (30). In a randomised controlled trial, sitagliptin did not appear to help hepatic steatosis or fibrosis (31).

Metformin does not appear to provide histological benefit in NAFLD (32) and should be avoided in advanced liver disease where there is an increased risk of lactic acidosis. Sulfonylureas are metabolised in the liver and thus a dose reduction (to reduce the risk of hypoglycaemia) may be necessary in cirrhosis. Insulin does not carry a risk of hepatotoxicity and can, therefore, be used in advanced liver disease, although the risk of hypoglycaemia is raised and there is likely to be weight gain. Neither sulfonylureas nor insulin offer benefit in NAFLD (33). There is limited evidence that SGLT2 inhibitors can improve levels of liver enzymes and reduce steatosis and fibrosis (34).

Bariatric surgery is a further modality of treatment that can help improve histological and biochemical markers of NAFLD (35).