• Suspected malignancy – weight loss, jaundice, marked cholestasis – organise urgent ultrasound and refer urgently (2-Week Wait)
• Signs of liver decompensation – ascites, encephalopathy, bleeding – for urgent admission via Acute Medical Unit (AMU) or refer for urgent outpatient liver appointment
• Synthetic failure – jaundice, low albumin, prolonged INR – urgent referral
• ALT greater than 10x upper limit of normal – phone on-call Gastroenterologist for advice

Management Step 1: Clinical Pattern Recognition

Isolated raised bilirubin - see Figure 1

• Most commonly due to Gilbert's syndrome – a benign condition which does not need a referral. It occurs in about 5-8% of the population
• Repeat LFTs on a fasting sample with a full blood count (FBC), conjugated bilirubin [and unconjugated bilirubin^# if available]
• The total bilirubin should rise further (owing to the unconjugated component) and there should be unconjugated hyperbilirubinaemia and no evidence of anaemia » Gilbert's syndrome confirmed, provide patient information leaflet
• If the patient is anaemic, haemolysis needs to be excluded by requesting reticulocyte count, haptaglobin and lactate dehydrogenase (LDH). Consider referral to Haematology

# If not available use Formula: Unconjugated Bilirubin = Total bilirubin minus (-) conjugated bilirubin level

Isolated cholestatic liver enzymes - see Figure 2

• Raised Alkaline phosphatase (ALP)
• Repeat LFTs with gamma-GT (GGT) to help determine if ALP is liver in origin
• If ALP raised in isolation, consider bone origin - vitamin D deficiency, Paget's disease or physiological elevation - pregnancy (usually third-trimester), during periods of rapid growth in childhood or bone growth in adolescents
• Common causes: Primary Biliary Cholangitis (PBC), Primary Sclerosing cholangitis (PSC), biliary obstruction (stones, strictures, neoplasia, etc), hepatic congestion secondary to right-sided heart failure and drug-induced cholestasis

Hepatitic pattern - see Figure 3

• Predominantly raised Alanine transferase (ALT) and Aspartate transferase (AST) (indicating hepatocellular injury / hepatitis)
• This can be transient due to intercurrent illness, normalising a few weeks later
• Common causes – viral hepatitis, non-alcohol fatty liver disease (NAFLD), alcohol-related liver disease, autoimmune hepatitis, drug-induced liver injury, etc
• See Management Step 2: First Assessment onwards

Management Step 2: First Assessment

1. Obtain a thorough clinical history

• Age, ethnicity, country of birth (to explore possible risk of hepatitis B or C)
• Any liver related symptoms (abdominal pain, jaundice, pruritus, weight loss, etc)
• Presence of co-morbidities (e.g. heart failure, autoimmune conditions, inflammatory bowel disease, malignant disease) and features of metabolic syndrome (central obesity, hypertension, diabetes/insulin resistance and dyslipidaemia)
• Drug history: Use of any prescribed, over-the-counter, herbal, illicit or injected drugs
• Alcohol history – Use AUDIT-C^a or FAST^b questionnaire to detect harmful or hazardous drinking
• Recent Travel
• Occupation
• Tick bites
• Muscle injury
• Family history

NOTE: The majority of adults with abnormal LFTs will be identified to have non-alcohol fatty liver disease (NAFLD) or alcohol-related liver disease (ARLD). Most will not need a referral to hepatology services but will require reinforcement of lifestyle advice and ongoing assessment in primary care

2.Provide general advice as appropriate

• Reduction in alcohol intake, encourage abstinence
• If BMI greater than 25 – encourage weight reduction by diet and exercise

3. Review medications – Recent statins*, antibiotics, NSAIDs; STOP any drugs known to be associated with drug-induced liver injury. If there is a temporal relationship between a new medication and LFT changes, consider drug-induced liver injury and consider stopping the drug. Repeat LFTs after 1-3 months.

* Whilst statins can cause an acute change in liver enzymes, they are safe in patients with known chronic liver disease.

4. Refer to liver clinic for advice if certain drugs are more difficult to stop (e.g. neuroleptics, anti-epileptics)

5.Repeat the LFTS– requesting AST (+/- GGT) with a FBC

^aAUDIT-C: Alcohol use disorders Identification test consumption: Online link:

^bFAST: Fast alcohol screening test: Online link:

When to repeat the LFTs and further action:

Management Step 3: Second Assessment (Persistently abnormal LFTs)

If the abnormalities have persisted for 1-3 months despite the above measures, then a non-invasive liver screen (NILS) should be done:

• Ultrasound (USS) of liver, biliary tree and pancreas
• Viral screen (hepatitis B surface antigen [HBsAg] and hepatitis C antibody [HCV Ab])
• Autoimmune Liver screen ([ANA, AMA, SMA, LKM-Ab] and Immunoglobulins [Ig])
• Coeliac screen (Tissue transglutaminase [anti-TTG])
• Ferritin and Iron studies [transferrin saturation]
• Fasting blood glucose, glycated haemoglobin [HbA1c], fasting lipids, thyroid stimulating hormone [TSH]
• Alpha-1-antitrypsin
• Caeruloplasmin (if aged below 55 years)

Management Step 4: Decide who to refer

Based on the history and results, the following pathologies will need referral for further assessment and management:

Patients who do not require referral to liver clinic:

• Alcohol related fatty liver disease without fibrosis – from the history, raised MCV and GGT, raised Immunoglobulin A (IgA), fatty liver on USS and AST: ALT greater than 2:1 » See APPENDIX Figure 1 (BSG, 2017)
• Refer to liver clinic if there are signs of advanced alcohol-related liver disease – indicated by splenomegaly, other signs of portal hypertension on USS, low platelets, low albumin or raised bilirubin
• The hazardous/harmful drinker without evidence of advanced liver disease requires advice, regular counselling and where appropriate, referral to alcohol services and secondary alcohol addiction specialists
• We currently do not have the capacity to offer Fibroscan for all patients who drink harmfully (greater than 35 units/ week for women; greater than 50 units / week for men), as recommended by the BSG guidelines (2017). Current advice: Please write to the Hepatologists for advice if your patient falls in this category AND is currently actively engaging with alcohol services.

Non-alcohol fatty liver disease (NAFLD) without fibrosis [see Management Step 5 of this guidance] – USS showing fatty liver only, negative liver screen, absence of excessive alcohol consumption, raised BMI or waist circumference, hypertension, impaired fasting glucose or diabetes mellitus type 2, raised triglyceride and low HDL cholesterol. LFT shows mainly isolated raised ALT.

Management Step 5: Risk Stratification of patients with NAFLD

NAFLD is closely associated with the metabolic syndrome and encompasses simple steatosis (fat but no inflammation or hepatocellular injury) through to non-alcoholic steatohepatitis (NASH = fat + inflammation + hepatocellular injury) and fibrosis to cirrhosis. Up to a third of the population has been estimated to have NAFLD and 40% of patients with NAFLD develop progressive fibrosis which can progress to cirrhosis in 10-20%. Patients with cirrhosis are at risk of serious life-threatening complications such as hepatocellular carcinoma, portal hypertension and liver failure.

The most important predictor of mortality in individuals with NAFLD is the stage of liver fibrosis. Patients with moderate or severe liver fibrosis are at an increased risk of mortality and liver related complications in the future. There are several non-invasive scoring systems for fibrosis that have been assessed and validated in NAFLD. These utilise simple blood tests and clinical parameters that can accurately exclude advanced fibrosis. These can be used to risk-stratify patients to decide who requires referral to secondary care for further investigation and management.

The Fibrosis-4 (FIB-4) and NAFLD fibrosis score (NFS) are well-validated for this purpose. We would recommend the FIB-4 score as it performed slightly better than the NFS in most studies and requires fewer variables to calculate.

For all patients with a clinical diagnosis of NAFLD who have had other causes of liver disease excluded, the FIB-4 score should be calculated.

To calculate the FIB-4 score, you need:

• Age
• AST
• ALT
• Platelets

Please use the available online calculator:

see figure 3

• For patients below 65 years of age, a FIB-4 score lower than 1.3 reliably excludes advanced fibrosis and can be managed in primary care.
• For patients over 65 years old, a FIB-4 score lower than 2.0 reliably excludes advanced fibrosis and can be managed in primary care.
• If FIB-4 score is greater than 1.3 (below 65 years old) or greater than 2.0 for over 65 year olds » patients have a significant risk of having advanced fibrosis » Refer to liver clinic.

Management Step 6: Manage Patients with Lower Risk NAFLD

Presently, the mainstay of treatment for patients with NAFLD without advanced fibrosis is lifestyle modification (weight loss, diet, exercise) and optimisation of diabetes and cardiovascular risk factors.

1. Lose weight if BMI greater than 25 or raised waist circumference

• Aim for at least loss of 10% of body weight
• Consider orlistat - Refer to formulary guidance on drugs used in the treatment of obesity..
• Advise: Exercise at least 30 minutes, 3 times per week (both cardiovascular and resistance exercise are beneficial even independent of weight loss); explain to patients there is some evidence that exercise reduces liver fat content

2. Optimise control of diabetes

• Refer to formulary guidance on the management of type 2 diabetes.

3. Treat hypertension

• Refer to formulary guidance on the management of hypertension.

4. Advise patients to drink alcohol within national recommended limits. There is no evidence at present to recommend abstinence

5. Assess cardiovascular risk annually – QRISK3 ,consider statin

• Statins are safe in patients with NAFLD
• Only stop statins if liver enzyme levels double within 3 months of starting statins, including in people with abnormal baseline liver blood results.

6. Calculate FIB-4 score every 3 years and refer if FIB-4 score increases above the age-related cut-off

Refer to Hepatology: See the management: Step 4 & 5 in this guideline and Red Flags section of this guidance

Refer to gastroenterology if:

• Coeliac screen +ve

Consider Referral to haematology if:

• Anaemic/abnormal FBC (see Figure 1)

Referral Instructions

Referral to Hepatology

• Referral using e-Referrals Service
• Service: GI and Liver (Medicine and Surgery)
• Clinic type: Hepatology
• Service: DRSS- Eastern-GI & Liver (Medicine & Surgery)-Devon ICB-15N

Referral to Gastroenterology

• Referral using e-Referrals Service
• Service: GI and Liver (Medicine and Surgery)
• Clinic type: Lower GI
• Service: DRSS- Eastern-GI & Liver (Medicine & Surgery)-Devon ICB-15N

Referral to Haematology

• Referral using e-Referrals Service
• Service: Haematology
• Clinic type: Not Otherwise Specified
• Service: DRSS- Eastern- Haematology-Devon ICB-15N

Any queries call Dr John Christie 01392 402791, Dr Lin Lee Wong 01392 404615, Dr Ben Hudson 01392 408 808 or Gastro Registrar via switch board 01392 411611

Referral form

DRSS Referral Form

References

1. Williams R et al; The Lancet Commission: Addressing liver disease in the UK: a blueprint for attaining excellence in health care and reducing premature mortality from lifestyle issues of excess consumption of alcohol, obesity, and viral hepatitis; Lancet 2014; 384: 1953- 1997

2. Sheridan D; Assessment of Abnormal Liver Function Tests; South and West Devon Formulary and Referral 2016 Online access

3. Hudson M, McPherson S et al; Guidelines for the Management of Adults with Asymptomatic Liver Function Abnormalities; Northern England Strategic Clinical Networks; 2016 (version 2)

4. Newsome P et al; Guidelines on the management of abnormal liver blood tests; Gut 2017; 0: 1-14

5. Kwo P et al; American College of Gastroenterology Clinical Guideline: Evaluation of Abnormal Liver

Chemistries; AJG 2017; 122: 18-35

6. Rashid L et al; Southern Derbyshire Shared Care Pathology Guidelines: Abnormal Liver Function Tests (LFTs) in Adults; 2016 Online access:

7. Miller M et al; Development and validation of diagnostic triage criteria for liver disease from a minimum data set enabling the 'intelligent LFT' pathway for the automated assessment of deranged liver enzymes; Frontline Gastroenterology 2018; 9: 175-182

8. EASL-EASD-EASO Clinical Practice Guidelines for the Management of Non-Alcohol Fatty Liver Disease; Journal of Hepatology 2016; 64: 1388-402

9. Gallacher J and Mcpherson S; Practical Diagnosis and Staging of Nonalcoholic Fatty Liver Disease: A Narrative Review; European Medical Journal 2018; 3: 108-118

10. NICE guidance 49: Non-alcohol fatty liver disease (NAFLD): Assessment and management; NICE 2016 Online access

Pathway Group

This guideline has been signed off on behalf of NHS Devon.

Publication date: November 2019