Isolated Abnormal ALT - Adult Leeds

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1.  Background information

Quick info:

This guidance relates to patients with a rise in their transaminase (in Leeds, most commonly measured test is the ALT), no matter how small this rise might be.

The guidance relates to the “well” person in whom the possibility of a chronic liver disease needs investigating. The range of ALT in this situation will typically be >40 to 150 iu/L. It does not relate to the very elevated ALT levels seen in acute liver disease such as acute viral hepatitis, although many of the investigations will be the same and where possible we have tried to highlight this.

There has been a marked rise in deaths from liver disease in England over the last 10 years. Usually, when symptomatic, the disease is at a very late stage in its trajectory with little chance of preventative or curative treatment, yet the majority of chronic liver disease can be prevented or treated with earlier diagnosis or intervention.

The Department of Hepatology at SJUH and the Yorkshire and Humber Liver Network recommend investigation of all abnormalities in LFTs, in order to

(a) seek an explanation and diagnosis

(b) seek a diagnosis for which preventative measures may reduce risk of progression to liver failure and premature death

© seek a diagnosis for which specific treatment can reduce risk of progression to liver failure, liver cancer and premature death.

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2.  Information resources for patients and carers

Quick info:

The British Liver Trust website contains information on a wide range of liver disease and risk factors, and is a resource highly recommended by Leeds hepatologists.

The following are links to various resources. British Liver Trust - Alcohol

British Liver Trust - NAFLD

British Liver Trust - Hepatitis B

British Liver Trust - Hepatitis C

Other recommended resources for patients and carers, produced by organisations certified by The Information Standard:

For details on how these resources are identified, please see Map of Medicine's document on Information Resources for Patients and Carers (URL - http://www.mapofmedicine.com/solution/policy).

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3.  Updates to this care map

Quick info:

Date of publication: March 2015

The content of this pathway has been agreed and approved by the Dept of Hepatology (LTHT) and the Leeds CCGs.

Clinical content has been provided by Dr Rebecca Jones Consultant Hepatologist (LTHT) with Drs Mervyn Davies and Udvitha

Nandasomaand also sourced from Map of Medicine National Pathways.

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4.  Abnormal ALT Well Patient

Quick info:

This guidance is most applicable to chronic liver disease. Patients with acute hepatitis often present unwell/ symptomatically and have very high transaminases (and may occasionally also be jaundiced.) See Red Flag box. They should be referred to Dept. of Hepatology.

Abnormal liver function may be discovered co-incidentally in patients undergoing blood tests for other reasons [1]. Consider screening for abnormal liver function or non-alcoholic fatty liver disease (NAFLD) in patients who suffer from [2]:

  • type 2 diabetes mellitus
  • obesity
  • hypertension
  • hypercholesterolaemia

References:

[1] Contributors representing the Royal College of Physicians (RCP); 2011.

[2] Contributors representing the National Liver Disease Strategy (NLDS) group; 2011.

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5.  History and examination

Quick info:

History: ethnic background, history of blood transfusion or intravenous drug use (at any stage), alcohol intake, preferably with a view on hazardous or harmful drinking, medication history, recreational or performance enhancing drugs and family history.

Plus:

(a) raised body mass index

(b) type 2 diabetes

© hyperlipidaemia

(d) hypertension

Examination: note features of chronic liver disease (e.g. spider naevi, palmar erythema,) and abnormal abdominal findings (e.g. hepatomegaly, splenomegaly or ascites.)

Enquire about:

  • possible parenteral exposures [1]:
    • transfusions
    • intravenous (IV)or intranasal drug use
    • tattoos
    • sexual activity
  • recent travel history [1]
  • exposure to people with jaundice [1]
  • exposure to potentially contaminated foods [1]
  • occupational exposure to hepatotoxins [1]
  • alcohol consumption [1]
  • features of metabolic syndrome [2]:
    • diabetes
    • obesity or weight gain
    • hypertension
    • hypercholesterolaemia
    • hyperuricaemia
  • exposure to any chemical or medication, including [1]:
    • over-the-counter medications
    • herbal preparations
    • Chinese medicines
    • illicit drugs
    • anabolic steroids and other performance enhancing drugs
  • prodromal viral symptoms [1]:
    • jaundice
    • arthralgias
    • myalgias
    • rash
    • anorexia
    • weight loss
  • pain, fever, and rigors [1]
  • pale stools, dark urine [1]
  • skin itching [1]
  • risk factors for non-alcoholic fatty liver disease (NAFLD) [2]:
    • social deprivation
    • age older than 50 years
    • metabolic syndrome [3]

Examine for [1]:

  • jaundice
  • stigmata of chronic liver disease:
    • spider naevi
    • palmar erythema
    • gynaecomastia
    • flapping tremor
  • palpable liver or spleen
  • ascites

References:

[1] Contributors representing the Royal College of Physicians (RCP); 2011.

[2] Contributors representing the National Liver Disease Strategy (NLDS) group; 2011.

[3] American Association for the Study of Liver Diseases (AASLD). The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases et al. Hoboken, NJ: AASLD; 2012.

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8.  Investigations

Quick info:

If there is a risk factor for chronic viral hepatitis B or C, the Department of Hepatology at SJUH recommends testing for both at that stage, and if positive referring to the viral hepatitis clinic (direct booking available through Choose and Book) with the appropriate investigations - see Leeds Viral Hepatitis pathways.

If there is no obvious risk factor, then repeat the ALT at an 8 - 12 week interval and if it remains elevated instigate the investigations below.

During this interval, if there is a history of excess alcohol intake, deliver an intervention to reduce alcohol intake.

The aetiology tests below are indicated once in all patients with a raised ALT. Even patients with a heavy alcohol intake may have additional causes and co-factors are synergistic in increasing the risk of developing cirrhosis, liver cancer and liver failure. Repeat aetiological tests are not required, unless there is a clear indication to do so (e.g. repeated exposure to risk of viral hepatitis)

Please also note that even if risk for viral hepatitis appears low, this must be excluded after a second abnormal ALT.

Measure the patient's BODY MASS INDEX

The following tests can be requested using the ICE Panel.

(a) Ultrasound of liver and upper abdomen

(b) Liver function tests (Bilirubin, ALT, ALP, Albumin)

© Full blood count

(d) Hepatitis B testing (surface antigen - HBsAg)

€ Hepatitis C testing (antibody, and lab will reflex test for viral RNA if positive)

(f) Liver autoantibodies (ANA, AMA, LKM, SMA)

(g) Immunoglobulins (IgA, G, M)

(h) Alpha-1-antitrypsin

(i) Ferritin

(j) Ceruloplasmin (not needed if > 45 yrs)

(k) Thyroid function tests

(l) Coeliac Serology (Tissue transglutaminase antibody -TTG)

(m) HbA1c

The following are useful in further evaluation and for convenience you may choose to do them at the same time:

(a) FBC

(b) Clotting - INR (suggest only done routinely in primary care if patient is jaundiced or has acute hepatitis profile)

© AST (Leeds lab will also provide AST:ALT ratio - this has benefits for alcohol related disease and NAFLD)

Interpretation and guidance for hepatology referral

If all the above tests are normal and a history of excess alcohol, excess weight or metabolic syndrome has been elicited, then these are the most likely causes, and some risk stratification can be done in primary care to assess need for hepatologist review.

Refer if any of the above tests are abnormalexcept

  • Only abnormality being mild elevations of immunoglobulins (polyclonal or IgA alone) as the only abnormal finding in someone with a clear alcohol history.
  • Patients diagnosed with NAFLD who have low risk stratification markers (see NAFLD box for guidance)
  • Positive coeliac serology (see Medication Related or Non-Hepatic Cause Box for guidance)
  • Abnormal thyroid function (see Medication Related or Non-Hepatic Cause Box for guidance)
  • Clear temporal relationship to new medication/other drug (see Medication Related or Non-Hepatic Cause for guidance)

Some tips:

Normal aetiology tests can also be seen in drug induced abnormalities and some rarer forms of liver disease, so if there is no history of excess alcohol, excess weight or metabolic syndrome then a hepatology review is worthwhile, unless the cause is evident. It is reasonable for this to be at discretion of GP who can assess for conditions such as thrombophilic tendency or family history thereof or look at the clinical picture with scan results etc.

Autoantibodies can be negative in autoimmune hepatitis, so look at the immunoglobulins - if the IgG is up please refer. High Alpha -1-antitrypsin (A1AT) and high caeruloplasmin levels are not worrying for A1AT deficiency or Wilson’s disease respectively and can be ignored in this context. Low levels need investigating and referral to hepatology is needed.

Positive immunological markers/ high immunoglobulins can indicate immune mediated liver damage or possibly be surrogate markers of disease severity. Referral to hepatology is needed. The exception here is the finding of mild elevations of immunoglobulins (polyclonal or IgA alone) as the only abnormal finding in someone with a clear alcohol history.

Ferritin can be difficult to interpret because it is a non-specific screening test for haemochromatosis. If elevated, then testing formal iron studies is advisable. If the iron binding saturation (LTHT test for this instead of transferrin saturation) is >45% then this is more suggestive of possible iron overload and in the context of abnormal liver function tests, no matter how mild, hepatology should assess ahead of haematology. If <45% and there is an alcohol history, then work on abstinence.

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9.  Red Flags

Quick info:

This pathway does not cover acute hepatological conditions - however we recognise some GPs may access it for guidance. Patients with acute hepatitis often present unwell/ symptomatically and/or have very high transaminases, ALT > 500+ (and may occasionally be jaundiced).

Most usually this is viral infection, drug induced or immunological in nature.

The mental alertness of the patient and INR/prothrombin time must be checked.

Requiring emergency admission:

If the patient or family report symptoms of confusion or the INR/PT is prolonged, urgent admission is required as this signifies a liver at risk of acute liver failure. Most usually the patient will also be jaundiced in this situation. Admit through the usual medical admissions process.

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10. Investigations

Quick info:

The Department of Hepatology at St James's Hospital will accept referrals for all patients with an ALT greater than 150iu, even if they are well and have risk factors for NAFLD (Obesity and metabolic syndrome components) or alcohol. This is because the majority of patients (>80%) with these conditions. They will be assessed regarding need for diagnostic liver biopsy.

The aetiology tests below are indicated once in all patients with a raised ALT. Even patients with a heavy alcohol intake may have additional causes and co-factors are synergistic in increasing the risk of developing cirrhosis, liver cancer and liver failure. Repeat aetiological tests are not required, unless there is a clear indication to do so (e.g. repeated exposure to risk of viral hepatitis)

Please also note that even if risk for viral hepatitis appears low, this must be excluded after a second abnormal ALT.

Measure the patient's BODY MASS INDEX

The following tests can be requested using the ICE Panel.

(a) Ultrasound of liver and upper abdomen

(b) Liver function tests (Bilirubin, ALT, ALP, Albumin)

© Full blood count

(d) Hepatitis B testing (surface antigen - HBsAg)

€ Hepatitis C testing (antibody, and lab will reflex test for viral RNA if positive)

(f) Liver autoantibodies (ANA, AMA, LKM, SMA)

(g) Immunoglobulins (IgA, G, M)

(h) Alpha-1-antitrypsin

(i) Ferritin

(j) Ceruloplasmin (not needed if > 45 yrs)

(k) Thyroid function tests

(l) Coeliac Serology (Tissue transglutaminase antibody -TTG) (m) HbA1c

Although this pathway is not written for the acute hepatitis presentation the following may be useful:

  • If the patient is acutely unwell, and has viral-like symptoms etc please also request an acute viral hepatitis screen including serology for acute hepatitis, Epstein Barr virus and Cytomegalovirus. Indicate clearly on the request that acute hepatitis is suspected.
  • If there is a history of LFTs being entirely normal prior to the onset of these acute symptoms the tests for the more chronic conditions are not necessary - these include alpha-1-antitrypsin and ferritin. These can wait until the acute episode has passed and can be done only if the LFTs remain abnormal afterwards.
  • However, liver antibodies and immunoglobulins are an essential part of an acute hepatitis screen as autoimmune disease can present in this way, not infrequently.

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11. Medication Related or Non-Hepatic Cause

Quick info:

Medication Related

Prescribed Medication Related:

Almost any medication can cause an elevation of liver enzymes, particularly:

  • NSAIDs
  • Antibiotics
  • Statins -many patients have a very strong indication for statins. A mild rise in ALT is common after starting a statin. If the pre- treatment ALT was abnormal seek a cause. If it was normal and rise is under x3ULN, continue and repeat. See prescribing guidance from Yorks+Humber liver network www.yhln.org.uk
  • Anti-epileptic drugs (AEDs)
  • Anti-tuberculous medications (discuss with supervising respiratory consultant/infectious disease consultant)

If there is a clear temporal relationship with other drugs (e.g. antibiotics) stop the drug and monitor for improvement. If ALT>3ULN or patient jaundiced refer hepatology (urgently if jaundice present - Please fax through urgent referrals to 0113 2066462)

Non-prescribed Medication Related:

  • Herbal preparations
  • Chinese medicines
  • Illicit drugs
  • Anabolic steroids and other performance enhancing drugs e.g. gym supplements

Non-hepatic causes

  • Thyroid disease
  • Muscle damage
    • Polymyositis
    • Heavy exercise (e.g. long distance running)
    • Increased aminotransferases associated with increased Creatine Kinase (CK) and aldolase
  • Coeliac disease (undiagnosed)
    • Serum AST range from 29-80 IU/L, and serum ALT range from 60-130 IU/L with the ALT usually slightly greater than AST
    • AST/ ALT return to normal following a gluten-free diet
    • Referral for endoscopy and duodenal biopsies is needed to make the diagnosis

For all non-hepatic causes an immediate referral to hepatology is not needed. Instead, treat the underlying problem and repeat the LFTs at 3 months. Refer if remain abnormal or not improving at that point.

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12. Hepatitis B

Quick info:

The screening test in the pathway is HBsAg (hepatitis B surface antigen) .

If positive refer hepatology to the viral hepatitis clinic on Choose and Book

SJUH clinic on Choose and Book is Viral Hepatology (this is a joint hepatology/ID clinic)

See HBV referral guidance.

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13. Hepatitis C

Quick info:

The screening test in the pathway is HCV antibody.

This indicated exposure only, but if positive the Leeds laboratory will automatically screen for viral RNA - this is the HCV-PCR result.

If positive refer hepatology.

See HCV referral guidance.

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14. Auto-Immune Hepatitis / Globulinaemia

Quick info:

Refer all:

SJUH clinic on Choose and Book currently is General Hepatology Wednesday afternoons. Some referrals may be redirected.

For info:

Auto-immune hepatitis [1]:

  • type 1 (formerly called lupoid):
    • mainly found in young to middle-aged women
    • majority, associated with high titres of anti-nuclear antibodies (ANA) and anti-smooth muscle antibodies (SMA)
    • polyclonal hypergammaglobulinemia is common
    • type 1 autoimmune hepatitis is suggested by positive ANA, ASMA, and raised IgG
  • type 2:
    • mainly found in children
    • more common in Northern Europe
    • associated with auto-antibodies against liver kidney microsomes (LKM1)
  • type 3:
    • mainly found in young women
    • associated with antibodies to soluble liver antigen and to liver and pancreas antigen (may have ANA)
  • a diagnosis of autoimmune chronic hepatitis is suggested by the absence of viral hepatitis with chronic hepatic injury and elevated immunoglobulins
  • this condition usually responds to immunosuppressive treatment

Reference:

[1] Dufour DR. Laboratory guidelines for screening, diagnosis, and monitoring of hepatic injury. Clin Chem 2000; 46: 2027-49.

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15. Alcohol Related

Quick info:

Currently the Department of Hepatology at SJUH is happy to accept referrals for evaluation regarding stage of disease or further management.

An alcohol related liver disease pathway will be developed asap.

Please complete investigations (see Investigations Box) ahead of referral.

The Department of Hepatology at SJUH and the Yorkshire and Humber Liver Network recommend the British Liver Trust http://www.britishlivertrust.org.uk/ as an excellent source of patient information

Alcohol misuse [1]:

  • can be difficult to diagnose
  • diagnosis is supported by an aspartate aminotransferase (AST):alanine aminotransferase (ALT) ratio of 2:1 or greater
  • AST:ALT ratio may occasionally be elevated in non-alcoholic steatohepatitis and frequently in cirrhotic hepatitis C
  • it is rare for the AST to be raised by more than 8 times, and even less common for the ALT to be elevated more than 5 times

Reference:

[1] Contributors representing the Royal College of Physicians (RCP); 2011.

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16. Non-Alcoholic Fatty Liver Disease (NAFLD)

Quick info:

Features allowing confident diagnosis of NAFLD in Primary Care

GP Diagnosis: Confident parameters for potential primary care management

  • ALT Normal-x3ULN
  • BMI >28
  • BMI<28 plus any metabolic syndrome history
  • Negative aetiology screen
  • Fatty liver on USS
  • Asymptomatic / Otherwise well patient

GP Diagnosis: Parameters where further assessment in secondary care is advised

  • ALT >x3ULN
  • BMI <28, no other metabolic syndrome history
  • Normal USS
  • ALP rise only abnormality, even with features
  • Any positivity on aetiology screen
  • Symptomatic patient
  • Hepatomegaly
  • Thrombocytopaenia, low albumin, raised bilirubin, splenomegaly on USS

If a diagnosis of NAFLD cannot be made confidently in primary care along the above guidelines, please refer to Hepatology. Where is can be made confidently please proceed to fibrosis risk stratification.

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17. Urgent Hepatology Referral

Quick info:

The Dept. of Hepatology will see anyone with an ALT > 500iu/ml (not meeting criteria for emergency admission) urgently as an outpatient.

Please fax through urgent referrals to 0113 2066462. The hepatology registrar is also available for advice via SJUH switchboard.

In addition to the tests outlined in the 'Investigations' box, urgent viral serology is needed, including Hepatitis A, (B and C included in the investigations box), CMV and EBV (and HSV if any history or signs of coldsores etc), stating on request that acute hepatitis is suspected.

If there is any history of intravenous drug use in the previous 12 weeks acute hepatitis C is a possibility and hepatitis C - PCR

should be specifically requested (as the antibody may be negative and misleading).

All patients with ALT > 150 iu/ml (x3 upper limit normal) will be assessed by Hepatology on this pathway. Please comment on specific concerns in the referral information if an urgent review is requested outside the above examples. Referrals for patients with ALT between 150 and 500 are triaged within the department.

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18. Treat Underlying Cause

Quick info:

Thyroid disease

Abnormal LFTs (ALT and ALP) are commonly seen at varying levels in active thyroid disease, both hypo and hyper-thyroidism. If either are found the Department of Hepatology recommends treating the thyroid disease appropriately first, with ALT monitoring. It should settle within 3 months of normalising the thyroid function. If it does not, then please refer at that stage.

Patients to consider referring earlier are patients with an ALT>150 and positive anti-smooth muscle or LKM antibodies or anti- mitochondrial antibodies, as these may be indicators of co-existent autoimmune liver disease.

Muscle Disease

High ALTs are sometimes seen in long distance runners, or patients with symptoms of myositis. In this setting the creatine kinase

(CK) is usually elevated. It would be appropriate, depending on the clinical picture to consider referral first to rheumatology services.

Coeliac Disease

Patients with positive coeliac serology should be referred for endoscopy and duodenal biopsies as suspected to have coeliac disease. These patients do not need referring to Department of Hepatology until this disease is excluded.

If coeliac disease is confirmed, a gluten free diet will usually result in normalisation of the ALT. If the ALT remains persistently elevated 3-6 months after commencing a gluten free diet, please refer to Department of Hepatology for further evaluation.

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19. Wilson's Disease

Quick info:

It is not necessary to routinely look for this in patients with a raised ALT who are over the age of 45 yrs.

We recommend testing ceruloplasmin levels as the screening test. Testing is only needed once in primary care. Please refer all patients with a low ceruloplasmin to the Department of Hepatology at SJUH for further evaluation. SJUH clinic on Choose and Book is General Hepatology Wednesday afternoons.

Wilson's disease is an autosomal recessive disease, characterised by low caeruloplasmin [1].

Reference:

[1] Dufour DR. Laboratory guidelines for screening, diagnosis, and monitoring of hepatic injury. Clin Chem 2000; 46: 2027-49.

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20. Re-Test

Quick info:

This part of the pathway covers a number of causes of raised ALT so one strategy does not fit all. Symptoms of polymyalgia/myosis etc without risk factors for liver disease need urgent referral to rheumatology.

Tests suggestive of coeliac disease need investigating further, and then coeliac disease treating if confirmed. LFTs may take 3-6 months to settle down, and could reasonably be observed during that period. In a well patient repeat at 3 and 6 months. If unwell or other symptoms, positive liver immunology etc refer if not settling as auto-immune diseases can co-exist. Similarly for thyroid disease associated with abnormal ALT.

If drug induced liver enzyme rise is suspected and the drug stopped, then more frequent monitoring to establish normalisation rather than deterioration is needed. If deteriorating it is worth asking for advice / referring.

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21. Alpha-1 Antitrypsin Deficiency

Quick info:

Request alpha-1 antitrypsin phenotyping in patients with levels below normal and refer all patients with low levels in the above to the

Department of Hepatology at SJUH for further evaluation.

SJUH clinic on Choose and Book is General Hepatology Wednesday afternoons.

Patients with alpha-1 antitrypsin deficiency (the PiZZ phenotype) may develop liver disease, but the spectrum stretches from liver failure requiring transplantation in childhood to chronic liver disease in adults [1]:

  • incidence at age 50 years is 15% (men more than women)
  • alpha-1 antitrypsin deficiency testing should be considered in:
    • those with no other apparent cause for their chronic hepatic injury
    • neonates with evidence of hepatic injury

Reference:

[1] Dufour DR. Laboratory guidelines for screening, diagnosis, and monitoring of hepatic injury. Clin Chem 2000; 46: 2027-49.

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22. Haemochromatosis

Quick info:

The screening test for this condition is ferritin. It is a non-specific marker, frequently elevated in other conditions also.

Formal iron studies are needed. These are best done fasting. Iron binding saturations (similar to transferring saturations) >45 can indicate the possibility of iron overload causing the raised ALT. Genetic testing for haemochromatosis is needed.

Refer patients with this suspected diagnosis and a raised ALT, with the above tests, to the Department of Hepatology for evaluation and consideration of a liver biopsy.

NB: Testing for haemochromatosis is sometimes done in patients with normal ALT for other reasons. Follow the above advice. If iron overload is confirmed, and the ferritin >1000, even in the setting of normal ALT, please refer to Department of Hepatology.

SJUH clinic on Choose and Book is General Hepatology Wednesday afternoons.

Patients with iron overload and normal ALT with ferritin <1000, can be referred to department of Haematology first.

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23. Abnormal - Manage Accordingly

Quick info:

Manage as per advice in 're-test' box above.

Key Dates

Published: 19-Mar-2015, by Leeds

Valid until: 01-Mar-2017

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