Jaundice or elevated bilirubin - Pennine GP Training



Jaundice or elevated bilirubin?

ALT and Alk phos

Albumin all normal?

Investigate according to GILBERT PROTOCOL

Patient ill or bilirubin > 200?

ADMIT ACUTELY or DISCUSS (*)

Bilirubin 100-200?

Phone or fax consultant gastro for urgent clinic visit (*)

Bilirubin 100

REFER

• Not ill

• Normal alk phos

• ALT < 100

• Not jaundiced

GP to investigate according to

TRANSAMINASE PROTOCOL

ABNORMAL LFT PROTOCOL (updated 2020)

(*) When referring jaundiced patients please provide a detailed drug history (including all prescriptions issued within the preceding three months) and also full results of all investigations performed. On this basis we can decide on urgency required. Most, but not all, jaundiced patients will be allocated to urgent appts.

GAMMA GT

GGT is a sensitive marker for hepatobiliary disease, but its use is limited by poor specificity.

Causes of raised GGT:

• Hepatobiliary disease (often with other liver enzyme abnormalities)

• Pancreatic disease

• Alcoholism

• Chronic obstructive pulmonary disease

• Renal failure

• Diabetes

• Myocardial infarction

• Drugs, e.g. carbamazepine, phenytoin and barbiturates and oral contraceptive pill

The use of GGT is in supporting a hepatobiliary source for other raised liver enzymes, e.g. ALP.

GILBERT PROTOCOL

Isolated hyperbilirubinaemia

This is usually Gilbert’s syndrome.

Check: LFTs, conjugated v unconjugated bilirubin, haemoglobin, reticulocyte count.

Criteria

Bilirubin fluctuates but 3x normal proceed to Step 2 & 3 invx and refer

If transaminases < 3x normal then …..

❖ Organise the following bloods & GP review:

➢ Weigh the patient and calculate BMI. (BMI>25 is abnormal and disease-associated.)

➢ Check BP

➢ Fasting chol:HDL & Trigs, HBa1c, FBC and Gamma GT

➢ GP Review 1 week later

If alcohol or fatty infiltration likely then support lifestyle changes and re-check after 3 months.

If not or if the lfts have not resolved after the 3 months of lifestyle changes then arrange the following investigations and consider referral:

STEP 3:

➢ Hep B and Hep C serology

➢ Autoantibodies including AMA, ASMA, ANF

➢ Coeliac screen

➢ Immunoglobulin levels

➢ Ferritin, Alpha-1-antitrypsin

➢ Caeruloplasmin if patient aged under 35y

➢ TFT

➢ INR

➢ If ALT persistently more than twice normal consider liver ultrasound. Note - not everyone needs an ultrasound!

FATTY LIVER DISEASE - NAFLD

Only consider the diagnosis if ….

HepB, HepC, ferritin, alpha-1-antitrypsin (and caeruloplasmin if age45 with NIDDM (as these patients are at higher risk of NASH and progression to cirrhosis).

Statins are safe to prescribe if the above criteria are satisfied and the patients are low risk for NASH

The majority of patients with abnormal LFTs will have NAFLD( non alcoholic fatty liver disease) or ARLD (Alcohol related liver disease). Most of these patients will need reinforcement of lifestyle advice and ongoing assessment and management in primary care, without referral to a specialist 

NAFLD:

All patients with a clinical diagnosis of NAFLD who have had other causes of liver disease excluded should undertake a non-invasive fibrosis assessment to identify those that have advanced fibrosis. 

NICE recommend the enhanced liver fibrosis (ELF) test is used when people have been diagnosed with NAFLD, hwever, it is not widely available in the UK. The FIB-4 score (online calculator: GIHEP Fibrosis 4 Score), as it is the most accurate score available, and is simpler than the NAFLD fibrosis score to calculate.

To calculate the FIB-4 score you need:

Age

AST

ALT

Platelet

Refer for ELF test of fibroscan if FIB-4 > 1.3 in under 65s or >2.0 over 65 years.

3 yearly screen for hypertension, diabetes, dyslipidaemia and Fib-4 score

Advise weight loss

Aim for a sustained weight loss of least 10% of body weight (they do not need to normalise BMI), as this significantly improves fatty liver and reduces hepatic inflammation

Consider orlistat as per NICE guidance to facilitate weight loss in those who fail with initial dietary changes

Advise exercise at least 30 minutes three times per week (both cardiovascular and resistance exercise are beneficial, even independent of weight loss)

Optimise control of diabetes

Use metformin, a glitazone, or glucagon-like peptide 1 (GLP-1) analogue where possible, as these have been shown to improve fatty liver

Treat hypertension

Use ACEI or ARB first line (these might be anti-fibrotic)

Drink sensibly, within current limits (below 14 units/week for men and women). There is no evidence at present to recommend abstinence

Reduce other risk factors for vascular disease. Statins are safe in patients with NAFLD and should be prescribed as per NICE guidance

Undertake an annual vascular disease risk score. Patients with NAFLD are more likely to die of cardiovascular disease than liver disease

Consider referral for bariatric surgery for individuals with a BMI greater than 35 with other obesity related complications, as per NICE guidelines

Calculate the FIB-4 score every three years, and refer if the FIB-4 score increases above the age related cut-off. Refer if FIB-4 > 1.3 in under 65s or >2.0 over 65 years, as the patient will need a fibroscan or ELF blood test to assess fibrosis risk and ? need for liver biopsy.

ALKALINE PHOSPHATASE PROTOCOL

Reference intervals contain 95% of the population, therefore 2.5% of the normal population have values above the upper reference limit. The combined analytical and biological variation for serum ALP is around 8%. For example, an ALP result of 125 U/L could be between 108 U/L and 143 U/L, spanning the upper reference limit. Minor increases in serum ALP levels are therefore more likely to be analytical, physiological, or statistical anomalies rather than indicating disease.

Elevations may be physiological or pathological

Common causes for raised ALP:

Physiological

• Third trimester of pregnancy

• Adolescents, due to bone growth

• Benign, familial

Pathological

• Bile duct obstruction

• Primary biliary cirrhosis

• Primary sclerosing cholangitis

• Drug induced cholestasis, e.g. anabolic steroids

• Metastatic liver disease

• Bone disease e.g Pagets

• Heart failure

Isolated raised alk phos with normal ALT and gamma GT

This suggests alk phos of bony origin. A careful medical and drug history and physical examination. Key features include abdominal pain or swelling, unintentional weight loss, back pain, bone pain, clinical indicators of liver disease, congestive cardiac failure, and end stage chronic kidney disease.

If patients are asymptomatic but have raised ALP levels of unknown cause, then the test for ALP should be repeated with Gamma GT, ALT, adj calcium, (PTH?) and Vit D levels, TFTs, Cr&Es, and FBC checked within four weeks if not part of the original profile. Don’t forget PSA in men, CXR in smoker, plasmaphoresis and ESR and breast exam if malignancy suspected. Also Paget’s Disease in the elderly.

Assuming bloods above are normal

1. If alk phos < 1.5 Upper Limit of Normal (ULN) re-check in 1 month. Values up to 20% over ULN are likely to be statistical rather than clinical 'abnormals'.

2. If < 1.2 x ULN recheck at 3 months and annually if stable

3. If on repeat > 1.2 x ULN then arrange alk phos isoenzymes (and if of bony origin consider PSA in men, CXR in smokers, breast exam in women, FBC & ESR +/- myeloma screen etc) but if not of bony origin consider transaminase bloods and discuss/refer.

4. If alkaline phosphatase >2 ULN (on a single measurement) then further investigation & probable referral is indicated.

Raised Alk Phos & ALT & Gamma GT

You should take a detailed history of your patient’s alcohol consumption, review their current and previous medications (prescribed and unprescribed), ask about any herbal/alternative remedies they might be taking, and identify any risk factors they may have for viral hepatitis. Red flag screening for possible malignancy. BP, P, BMI and abdominal examination (prostate and breast if appropriate)

Primarily a hepatitis picture

Gamma GT and AST if not already done

FBC

Ferritin/iron studies

Hepatitis B, C

Coeliac screen

Autoimmune screen and Immunoglobulins

Hba1c & Lipids

• ALT > 100 = refer

• ALT < 100 = lifestyle changes and repeat at 1 month

• USS if ALT remains x2 ULN but < 100 at 1 month

• 2ww if malignancy suspected

Primarily an obstructive picture

Gamma GT and AST if not already done

FBC

INR

Ferritin/iron studies

Alpha 1 antitrypsisn

Ceruloplasmin if under 35

Auto-antibody screen and Immunoglobulins

• Routine USS if INR normal and not jaundiced or malignancy not suspected

• Urgent USS/referral if INR prolonged, low albumin or patient jaundiced

• 2ww if malignancy suspected

Appendix

Drugs which causes abnormal LFTs

Common drug causes of raised alkaline phosphatase levels6 17

|Drugs |Mechanism |

|Antibiotics: | |

|Penicillin derivatives  |Intrahepatic cholestasis |

|Erythromycin  |Intrahepatic cholestasis |

|Aminoglycosides  |Enzyme induction |

|Antiepileptic drugs: | |

|Carbamazepine  |Intrahepatic cholestasis |

|Phenobarbital  |Enzyme induction |

|Phenytoin  |Enzyme induction |

|Antihistamines: | |

|Cetirizine  |Intrahepatic cholestasis |

|Cardiovascular drugs: | |

|Captopril  |Intrahepatic cholestasis |

|Diltiazem  |Enzyme induction |

|Felodipine  |Enzyme induction |

|Disease modifying agents: | |

|Penicillamine  |Intrahepatic cholestasis |

|Oral contraceptive pill (oestrogen)  |Enzyme induction |

|Steroids  |Enzyme induction |

|Psychotropic drugs: | |

|Monoamine oxidase inhibitors  |Intrahepatic cholestasis |

|Chlorpromazine  |Intrahepatic cholestasis |

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