Jaundice Or Elevated Bilirubin

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?

Check Hep A/B serology, refer (*)

Elevated alk phos?

Normal ALT and GGT?

BONY!

Alk Phos protocol

ALT > 100

REFER

·  Not ill

·  Normal alk phos

·  ALT < 100

·  Not jaundiced

GP to investigate according to

TRANSAMINASE PROTOCOL

ABNORMAL LFT PROTOCOL (updated 2013)

(*) 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 <70. (Some Gilberts patients go yellower than this but they are probably worth investigating more carefully: REFER or DISCUSS.)

·  Bilirubin will be higher if patient fasting or during intercurrent illness.

·  Ask for conjugated v. unconjugated bilirubin: the hyperbilirubinaemia should be largely unconjugated, but don’t trust the laboratory ranges for conjugated bilirubin, they are too strict, and many Gilberts patients have an elevated conjugated bilirubin.

·  Normal FBC and reticulocyte count (to exclude haemolytic anaemia).

If the patient is well and meets all the above criteria, reassure and explain the diagnosis. Give information leaflet. The patient does not need an ultrasound or referral.

RAISED TRANSAMINASES

Common causes:

·  Alcohol

·  Viral hepatitis

·  Steatosis

·  Medications/toxins e.g. NSAIDs, antibiotics, statins, antiepileptics, antituberculosis drugs

Less Common causes:

·  Autoimmune hepatitis

·  Haemochromatosis

·  Alpha1-antitrypsin deficiency

·  Wilson’s disease

Non-hepatic causes of raised ALT (usually small rises, <120 U/L):

·  Coeliac disease

·  Strenuous exercise

·  Muscle disease

·  Endocrine disease e.g. Hypo- and hyper-thyroidism

TRANSAMINASE PROTOCOL

Most patients with persistently elevated ALT have fatty liver disease due to
alcohol +/- obesity +/- diabetes +/- hyperlipidaemia

STEP 1

·  Careful alcohol history. If intake > 14u/week encourage the patient to abstain completely.

·  Careful drug history. Stop any medications that may be relevant.

·  Think about causes of fatty liver: diabetes, obesity, excess alcohol.

... then recheck the LFTs in 3-4 weeks.

STEP 2: If transaminases > 3x normal proceed to Step 2 & 3 invx and refer

If transaminases < 3x normal then …..

v  Organise the following bloods & GP review:

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

Ø  Check BP

Ø  Fasting chol:HDL & Trigs, Fasting Blood Sugar, FBC and Gamma GT

Ø  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:

Ø  Hep B and Hep C serology

Ø  Autoantibodies including AMA, ASMA, ANF

Ø  Coeliac screen

Ø  Immunoglobulin levels

Ø  Ferritin, Alpha-1-antitrypsin

Ø  Caeruloplasmin if patient aged under 35y

Ø  TFT

Ø  INR

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

FATTY LIVER DISEASE

Only consider the diagnosis if ….

·  HepB, HepC, ferritin, alpha-1-antitrypsin (and caeruloplasmin if age<35) are normal

·  Negative TTG, ANF, antimitochondrial and smooth muscle antibodies

·  Normal platelet count and INR

·  Normal albumin

·  There is a reasonable cause such as obesity, alcohol, diabetes, hyperlipidaemia

·  If ultrasound performed, there should be no splenomegaly and the liver should be either “fatty” (echogenic) or normal

·  Transaminases are below 80 and there is no progressive deterioration.

Address risk factors such as alcohol, obesity. Treat any concurrent conditions such as diabetes and hypertension and hyperlipidaemia. Recheck LFT in 3-4 months. Referral is not usually necessary except if they are obese, age>45 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

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.

Raised alk phos with abnormal ALT and gamma GT

1.  If alk phos rasied check lfts & gamma gt. If abnormal then refer USS, and consider Antimitochondrial antibodies, Smooth Muscle Antibodies and Immunoglobulins.

2.  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'.

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

4.  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.

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

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

Guideline d erived from the 2002 protocol by Dr G Sobala, Consultant Physician, Huddersfield Royal Infirmary. Updated using recent BMJ publications & GP notebook 2013.

Useful references

BMJ 2001;322:33-36 ABC of diseases of liver, pancreas, and biliary system

BMJ2006;333:481-483(2September), doi:10.1136/bmj.333.7566.481 Cases in primary care laboratory medicine Biochemical "liver function tests"
Southern Derbyshire abnormal lfts guideline 2012
BMJ 2013;346:f976 interpretation an isolated raised alkaline phosphatase