Abnormal liver function tests (LFTs) in asymptomatic patient in primary care

Introduction

Abnormal liver function tests (LFTs) are very common in primary care. They are often found co-incidentally in patients without hepatobiliary symptoms. Such patients should be investigated if
the abnormalities are significant and persistent because most liver disease is silent until advanced. Investigations should determine the aetiology and therefore the treatment to arrest or reverse the disease. Investigations should also stage the disease to detect those with advanced fibrosis or cirrhosis - still often clinically silent - who require further management in secondary care.

Most persistently abnormal LFTs will be due to alcohol, non-alcoholic fatty liver disease (NAFLD) or viral hepatitis. Other causes, although rare, are equally important to diagnose because nearly all are treatable.

Asymptomatic Abnormal ALT, GGT or ALP result

Suggested thresholds for investigation when elevated at least 2 occasions > 4 weeks apart.

• ALT > 70
• ALT 50-70 with an abnormal GGT/ALP (if isolated ALT 50-70 check Hep B&C serology only)
• GGT > 100
• ALP > 200 with an abnormal GGT
• (if ALP raised in isolation investigate for bone disease)

(NE: if ALT/ALP/GGT persistently abnormal but below thresholds for investigation consider repeat LFT’s in 1 year. If still abnormal use clinical judgement and consider patient assessment / liver screen even if remains below thresholds).

Patient Assessment

• History
• Examination
• Liver screen liver ultrasound
• Medication review
• If alcohol suspected, advise abstinence

Refer to GI if any of the referral criteria* are met

If the Referral Criteria have not been met then:

• The abnormal LFT’s are likely to be due to either NAFLD or alcohol and there is nothing to indicate advanced fibrosis/cirrhosis.
• These patients can continue to be safely managed in primary care with appropriate advice e.g. diet, exercise, alcohol abstinence.
• A small number will go on to develop cirrhosis if they do not make the appropriate lifestyle changes.
• At present we are unable to identify which people are most likely to progress but FIB 4 score < 1.45 (or <2 if NAFLD and Age > 65) = Fibrosis excluded.
• Consider yearly check of LFT’s and AST:ALT ratio with reinforcement of lifestyle advice.

History

• Alcohol intake
• Drugs (prescribed, OTC, herbal remedies)
• Hepatitis risk factors (IVDA, sexual history, travel, ethnicity)
• Metabolic syndrome clues (T2DM, obesity, hypertension, hyperlipidaemia)
• Autoimmune disease clues (T1DM, thyroid disease, RA)
• Family history

Examination

• BMI
• Spider naevi, Palmar erythema
• Palpable liver or spleen

Liver Screen

• Abdominal Ultrasound
• FBC
• LRT’s
• AST:ALT ratio
• Albumin
• Immunoglobulin
• Caerulopasmin (if < 55 years)
• α 1 Anti Trypsin
• Glucose
• Cholesterol
• Ferritin (check Transferrin sats if ferritin raised)
• Prothrombin Time (PT)
• Hepatitis serology – HBsAg and anti-HCV Ab
• Immunology – Anti-smooth muscle Ab, anti-nuclear Ab, anti-mitochondrial Ab

Medication Review

Review medications and consider discounting and causative drugs. If in doubt, discuss with GI/Liver.

* GI Referral Criteria

Refer to GI if any of the following apply:

• Diagnostics tests suggest any cause other than alcohol
  or NAFLD
• Evidence of impaired liver function:
•  Bilirubin (not due to Gilbert’s syndrome)
•  PT
•  Albumin
• Evidence of advanced fibrosis/cirrhosis
• AST:ALT ratio > 1.0
• Platelets < 150
• Splenomefaly
• Nodular Liver
• ALT persistently > 200
• Diagnosis or management still uncertain.

FIB 4 score

FIB 4 score is a mathematical method of identifying low risk for fibrosis patients and those with high risk for fibrosis.

• Low fibrosis scores may be appropriate candidates for medical management and may not require liver biopsy if FIB-4 scores continue to stay low.
• Severe fibrosis/cirrhosis scores may need liver biopsy for confirmation of cirrhosis unless there are other clinical or imaging signs of progression to end-stage liver disease.

Hyaluronic acid is a biochemical fibrotic marker available via Lothian.
Where patients have mildly abnormal LFTs, not fulfilling referral guidelines and where the abnormal LFTs are felt to be due to NAFLD or alcohol then a reassuring FIB 4 score and/or hyaluronic acid should guide Primary Care follow up with lifestyle advice and perhaps repeat testing in 2-3 years if appropriate.

One page PDF version of summary

ALT is a sensitive marker of hepatocyte injury.

• However considerable liver injury may be present with normal transaminase levels.
• Serum ALT activity varies with age, sex, race, body mass index, acute illness and exercise.
• There is poor correlation between the level of rise of ALT and biopsy findings. A persistently abnormal ALT should have some investigation performed.
• If ALT remains abnormal after a period of observation and first line investigation reveals no clear cause then a referral (biopsy) threshold of >200 can be used.

GGT is a sensitive marker of liver disease but it is not specific. It is mainly of use for establishing the likely origin of an elevated ALP.

• When raised in isolation it can be suggestive of alcohol excess (especially if raised MCV) or NAFLD.
• Please note that there is no current evidence base with which to guide the investigation and management of an isolated raised GGT. This guideline has therefore been produced by local experts purely to offer guidance to local GPs.

GGT & Alcohol

• GGT is neither a sensitive nor a specific marker of alcohol misuse, although changes in GGT associated with a clear history of alcohol misuse can be used to monitor abstinence, assuming that no liver disease is present.
• If alcohol is suspected to be the reason for an elevated GGT then patients should be asked to abstain from alcohol for at least 4 weeks before a repeat GGT is measured. Please note that in those with hepatic damage (particularly cirrhosis) their GGT may take longer to fall after abstinence or may never return to normal.

Predominant rise in ALP is suggestive of biliary or infiltrative disease.

• ALP has two main sources in the non-pregnant adult: liver and bone. Higher ALP activities are also seen as a normal variant and are associated with a range of medical conditions (congestive heart failure, hyperthyroidism, pregnancy and intrahepatic cholestasis during sepsis) and certain drugs (ibuprofen, paracetamol, cefotaxime).
• Liver and bone profiles should be checked if not already carried out, to exclude other raised indices.
• Isolated raised values up to approximately 145 IU/l are more likely to reflect a statistical rather than clinical finding.
• Although the reference range for women rises with age, the prevalence of primary biliary cirrhosis also rises. Measurement of anti-mitochondrial antibodies in cases of persistently increased ALP >200 of liver origin would therefore seem appropriate.
• Raised ALP without a concomitant rise in GGT in a non-pregnant adult is likely to be of bone origin. If doubt still exists ALP isoenzyme analysis is useful e.g. if co-incidentally on enzyme inducing drugs which elevate GGT.

Gilbert‘s syndrome

Gilbert’s syndrome is a benign congenital defect of glucuronide conjugation present in up to 5% of the population. It results in an unconjugated hyperbilirubinaemia which is indicated by the presence of a high serum bilirubin in the absence of urinary bilirubin (as only conjugated bilirubin passes into the urine). In Gilbert’s syndrome the bilirubin level typically increases after fasting and during intercurrent illness, usually, to a level not exceeding 70 umol/l.

Please note that bilirubin should be >30umol/L for measurement of conjugated bilirubin to be valid. Therefore please do not request conjugated bilirubin testing in patients whose total bilirubin
is below this level.

If diagnostic uncertainty remains then genetic analysis for Gilberts is available. However it is expensive and usually unnecessary. If it is required, send a single EDTA tube (red/FBC tube) with a haematology/biochemistry form requesting “Gilbert’s analysis”.

Haemolysis

Haemolysis is conventionally diagnosed by the laboratory appearances on a blood film, combined with reduced haptoglobin, reticulocytosis and raised lactate dehydrogenase. There is no clear evidence as to whether one or all of these tests are required. If evidence of haemolysis is
found, further investigation will be determined by the clinical context, usually in conjunction with secondary care advice

Patients with normal LFTs prior to starting statins:

• LFT derangement typically occurs within the first three months of therapy and is usually dose dependent.
• LFTs should be checked 6 to 8 weeks after commencing treatment or any dosage increase. 
• A yearly check of LFTs is not required for patients who are stable on long-term treatment. 
• If ALT <150: continue statin but recheck LFTs within 4 weeks to exclude further increase in ALT. No extra monitoring required if ALT remains stable.
• If ALT >150: stop statin and recheck LFTs within 4 weeks to ensure values settle. If they return to normal consider re introducing a different statin at a later date with repeat LFTs at 2, 6 and 12 weeks. If the LFTs do not improve after stopping statin treatment perform initial liver screen and continue as per abnormal ALT pathway.

Patients with abnormal LFTs prior to starting statins:

• Patients with abnormal LFTs should not be routinely excluded from statin treatment. There is evidence that statins are safe and have beneficial effects for patients with NAFLD.
• If ALT <100 - start statin treatment with repeat LFTs as usual in 6 weeks to check ALT remains stable. If ALT has risen at the 6 weeks a rise of up to 150 is allowable but further repeat LFTs should be arranged every 4 weeks until the ALT level is stable. The patient should also be investigated and managed as per the rise in ALT pathway (if this has not already been done) and, if felt appropriate, this could be done alongside starting statin treatment.
• If ALT 100 – 150 - ideally the abnormal LFTs should be investigated prior to starting statin treatment. Once investigated statins can be started with repeat LFTs at 2, 6 and 12 weeks.
• If ALT >150 – patients with an ALT persistently >150 should undergo GI review and statins should only be initiated following specialist advice.

Patients on long term statin treatment with abnormal LFTs:

• If you are unsure whether the abnormal LFTs are related to statin treatment then the dose of the statin should be reduced and the LFTs repeated in 6 weeks. If there is no improvement following dose modification perform an initial liver screen, and continue to manage the patient as per the abnormal ALT pathway.

This list is not exhaustive and there may be a mixed pattern of abnormal LFTs. Please see the BNF for further information.

Cholestatic pattern (ALP/GGT) 

Co-amoxiclav 
Anabolic steroids 
Chlorambucil 
Chlorpromazine 
Chlorpropamide 
Clopridogrel 
Colchicine 
Erythromycin 
Estrogen (oral contraceptives)
Flucloxacillin 
Mirtazapine 
Phenobarbital 
Terbinafine 
6-Mercaptopurine 
Nitrofurantoin 
Omeprazole
Paracetamol
Paroxetine
Phenytoin
Propylthiouracil
Rifampin
Risperidone
“Statins”
Sertraline
Sulfonamides
Tetracyclines
Tricyclics
Trimethoprim
Trazodone
Valproate

Cytotoxic pattern ( ALT)

Allopurinol
Amiodarone
Aspirin
Azathioprine/6-Mercaptopurine
Carbamazepine
Etretinate
HAART drugs
Hydralazine
Isoniazid
NSAIDs
Ketoconazole/Fluconazole
Lisinopril
Methotrexate
Methyldopa
Nicotinic acid (especially S/R)

(Taken from: Liver function tests (normal, low and high levels and results: http://www.medicinenet.com/liver_blood_tests/page4.htm#6whatmedications)

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