Evaluation of Abnormal Liver Function Tests: DR Chris Hovell Consultant Gastroenterologist Dorset County Hospital
Evaluation of Abnormal Liver Function Tests: DR Chris Hovell Consultant Gastroenterologist Dorset County Hospital
Evaluation of Abnormal Liver Function Tests: DR Chris Hovell Consultant Gastroenterologist Dorset County Hospital
LFTs
pancreas, renal tubules and intestine Very sensitive but Non-specific Raised in ANY liver discease hepatocellular or cholestatic Usefulness limited Confirm hepatic source for a raised ALP Alcohol Isolated increase does not require any further evaluation, suggest watch and rpt 3/12 only if other LFTs become abnormal then investigate
Markers of Cholestasis
Useful indicators of liver synthetic function In primary care when associated with liver disease abnormalities should raise concern Thrombocytopaenia is a sensitive indicator of liver fibrosis
Hepatic vs cholestatic
Magnitude of enzyme alteration (ALT >10x vs minor abnormalities) Rate of change Nature of the course of the abnormality (mild fluctuation vs progressive increase)
Viral Hep A, B, C, E, CMV, EBV ALT levels usually peak before jaundice appears. Jaundice occurs in 70% Hep A, 35% acute Hep B, 25% Hep C Check for exposure Check Hep A IgM, Hep B core IgM and HepBsAg, Hep C IgG or Hep C RNA
Ischaemic- sepsis, hypotension ?most common cause in-patients Often extremely high >50x Decrease rapidly LDH raised 80% Rarely jaundiced
Toxins - paracetamol (up to 50% of all cases of Acute Liver Failure) Ecstasy ( 2nd most common cause in the young <35) Any drug herbal remedies Alcohol almost never, AST <7xULN in 98% AST/ALT ratio > 1 in 92%, >2 in 70%
Autoimmune Rarely presents with acute hepatitis Usually jaundiced and progressive liver failure Raised IgG and autoantibodies (anti-SM, -LKM, SLA) Liver biopsy Steroids and azathioprine
Early phase- extrahepatic obstruction/cholangitis Usually have history of pain USS dilated CBD ? ERCP or lap chole
Cholestasis
Isolated ALP 3rd trimester, adolescents Bone exclude by raised GGT, 5-NT or isoenzymes May suggest biliary obstruction, chronic liver disease or hepatic mass/tumour Liver USS/CT most important investigationdilated ducts Ca pancreas, CBD stones, cholangioca or liver mets
Cholestatic jaundice Drugs- Antibiotics, Nsaids, Hormones, ACEI PBC anti- mitochondrial Ab, M2 fraction, IgM PSC associated with IBD 70%, p-ANCA, MRCP and liver biopsy Chronic liver disease Cholangiocarcinoma beware fluctuating levels Primary or Metastatic cancer, lymphoma Infiltrative sarcoid, inflammatory-PMR, IBD Liver biopsy often required
Dear Dr Hepaticus, I have just reviewed our patient data base and have identified 420 patients with persistently abnormal LFTs who are otherwise well and are not known to have liver disease. When can you see them? Yours, Dr G Practice
Transient mild abnormalities which are simply impossible to explain Drugs eg Statins Alcohol excess Hepatitis C Non-Alcoholic Fatty Liver Disease (NAFLD)
PRINCIPLES 2.5% of population have raised LFTs Normal LFTs do not exclude liver disease Interpret LFTs in clinical context Take a careful history for risk factors, drugs (inc OTCs), alcohol, comorbidity, autoimmunity Physical examination for liver disease Chase likely diagnosis rather than follow algorithm unless there are no clues If mild abnormalities and no risk factors or suggestion of serious liver disease , repeat LFTs after an interval (with lifestyle modification)
History and Examination Discontinue hepatotoxic drugs Continue statins but monitor LFTs monthly Lifestyle modification (lose wt, reduce alcohol, diabetic control) Repeat LFTs at 1 month and 6 months
If still abnormal at 6 months: Consider referral to secondary care Hepatitis serology (B, C) Iron studies transferrin saturation + ferritin Autoantibodies & immunoglobulins Consider caeruloplasmin Alpha-1- antitrypsin Coeliac serology TFTs, lipids/glucose Consider liver biopsy esp if ALT > 100)
Hepatits C
Most asymptomatic; acute hepatitis with jaundice is uncommon 80% will have chronic / persistent infection. Of these, 10% will develop cirrhosis of the liver 10 years after infection 20-30% will develop cirrhosis of the liver 30 years after infection 5% will develop hepatocellular carcinoma (liver cancer) 20 years after infection.
Treatment of Hepatitis C
Hep C RNA by PCR Liver biopsy for genotype I, treatment is recommended for patients with moderate to severe hepatitis Peg-interferon given by sc injection 1/ week, Ribavirin bd dose Patients with genotypes II and III are treated with for 6 months. Response rate 70% Patients with genotypes I, IV, V, and VI are treated with interferon and ribavirin for 12 months, if responsive on viral load at 3/12. Response rate 30%-40%.
Genetics of Haemochromatosis
Autosomal recessive Mutations in HFE gene (C282Y and H63D) Cause increased intestinal absorption of Fe
C282Y/C282Y and C282Y/H63D are responsible for 95% of genetic haemochromatosis
Skin pigmentation Liver disease Diabetes mellitus Arthropathy Impotence Fatigue Cardiomegaly
6% Normal 26% Fibrosis 6% Cirrhosis 34% NASH (11% of which had bridging fibrosis and 8% cirrhosis) 32% Simple Fatty Liver 18% Alteration in Management 3 Families entered into screening programmes
Other Liver biopsy Findings in Abnormal LFTs Skelly et al. J Hepatol 2001
Cryptogenic hepatitis Drug induced Alcoholic liver disease Autoimmune hepatitis PBC PSC Granulomatous disease Haemochromatosis Amyloid Glycogen storage disease
The most accurate way to grade the severity of liver disease Aminotransferase levels correlate poorly with histological activity Narrows the diagnostic options, if not diagnostic
N = 249, mean age 58, etoh < 25 units per week, 9% diabetes, 24% BMI > 27 ALT 51-99 (over 6 m)
72% NAFLD 10% Normal histologically
Others: Granulomatous liver disease 4%, Autoimmune 2.7%, cryptogenic hepatitis 2.5%, ALD 1.4%, metobolic 2.1%, biliary 1.8%
Detects Fatty Liver Increased echogenicity may not be specific for fat Unable to detect Inflammation or cirrhosis (unless advanced)
Therefore unable to discriminate between
NASH and simple fatty liver or identify other types of liver disease (which may include fatty change)
Liver biopsy is the only way to make an accurate diagnosis It may be worth treating fatty liver for 6 months before considering referral for biopsy
Type 2
Type 3 Type 4 bodies
Fat + inflammation
Fat + ballooning degeneration Fat + fibrosis and/or Mallory
Only types 3 and 4 have been definitively shown to progress to advanced liver disease and can be classified as NASH
PRIMARY Increased insulin resistance syndrome Diabetes mellitus (type II) Obesity
Hyperlipidemia
Surgical Procedures
Gastroplexy Jejunoileal bypass Extensive small bowel resection Biliopancreatic diversion
Miscellaneous
Hepatitis C Abetalipoproteinaemia Weber-Christian disease TPN with glucose Environmental toxins S.bowel diverticulosis Wilsons disease Malnutrition
IBD
HIV infection
Car Crash post mortem study - 24% NAFL, 2.4% NASH - Hilden et al 1977 (n=503) USS - 16.4- 23% NAFL (Italy, and Japan)
Severely obese subjects - 25% incidence of NASH at laparoscopy Type 2 diabetes - 28-55% NAFL Hyperlipidaemia - 20-90% NAFL Approx 60% of NAFL occurs in females Many patients are neither obese nor diabetic
(Bacon et al 1994, George et al 1998)
Prevalence increases with weight Up to 80% of obese individuals Up to 10-15% of normal subjects
Correspondingly, 15-20% of morbidly obese subjects and 3% of non-obese subjects have NASH Increasing prevalence in children
Mostly an incidental finding in asymptomatic individuals ALT 2-5x normal AST:ALT < 1 except in severe injury ALP, GGT 2-3x normal <50% Bilirubin rarely raised RUQ discomfort, fatigue and malaise in some patients
15-50% of NASH patients have fibrosis or cirrhosis at index biopsy James and Day 1998 In Aetiological studies NASH is now the most common cause of cryptogenic cirrhosis Caldwell
et al 1999, Poonwala et al 2000
In a 19 year follow up study, steatosis (alone) did not progess histologically Teli et al 1995
30 25 20
%
28 21
% Developing Cirrhosis
Matteoni et al 1999
NASH-natural history
Steatosis only can progress to cirrhosis 1-2 % over 5-17yrs (Danish and Italian studies) NASH + fibrosis cirrhosis 0% at 5yrs 12% at 8ys Prognosis in cirrhotics poor-30% developing liverrelated morbidity or mortality (liver failure + HCC) over short period
Age >45 ALT > 2x normal AST/ALT ratio > 1 Obesity, particularly truncal Type 2 diabetes Insulin Resistance Hyperlipdaemia (trigycerides > 1.7) Hypertension Iron overload
NB: Studies are in selected groups; may not apply to all patien
ALT > 2x normal AST > ALT At least moderate central obesity NIDDM or Impaired glucose tolerance Hypertension Hypertriglyceridaemia
Day, Gut 2002;50:5585-588
NASH should be viewed as part of a multifactorial disease Commonly associated with syndrome X 85% in a retrospective study (Wilner et al 2001) Treatment strategies may be directed at Insulin Resistance
NASH - TREATMENT
Steady Weight Loss - logical treatment Reduces fatty infiltration Improves LFTs CAUTION - In some patients, inflammation and fibrosis increase especially with rapid wt loss (cf gastric and intestinal bypass) Improved diabetic control - little histological
data Exercise - patients with NAFLD have very poor respiratory quotients. LFTs and RQ improve with exercise Elias 2001
Laurin et al 1996
Gemfobrozil
One randomized study, improved LFTs after 4
Ursodeoxycholic Acid
3 open label studies (n = 24, 24, 31) One randomised (vs diet alone)
Improvement in aminotransferases
12 month study demonstrated improvement in
steatosis but not other histological features RCT trial now underway * Laurin et al 1996, Guma et al 1997, Ceriani et al 1998
Betaine (methionine)
Improved LFTs, steatosis and inflammation n = 8, 12 months therapy, Abdelmalek et al 2000
N-Acetylcysteine
Improved LFTs n = 11, Gulbahar et al 2000
Vitamin E - Tocopherol
Improved LFTs over 4-10 months n = 11, Lavine et al 2000
with NASH compared with diet alone over 4m Reduced liver volume n = 20, Marchesini et al 2001 RCT planned by BASL
Troglitazone
Improved LFTs but no histological change n = 6, 4 months, Caldwell et al 2001
Management of NAFLD
NAFLD CONCLUSIONS
NAFLD is common A small proportion progress to cirrhosis NASH is the commonest cause of cryptogenic cirrhosis More information needed on prevalence, pathogenesis and natural history RCTs urgently needed - Metfomin, antioxidants and UDCA
Many abnormal LFTs will return to normal spontaneously An important minority of patients with abnormal LFTs will have important diagnoses, including communicable and potentially life threatening diseases Investigation requires clinical assessment and should be timely and pragmatic
GUIDELINES TO IX AND BX OF PATIENTS WITH ABNORMAL LFTs AND NO CLEAR DIAGNOSIS AFTER ROUTINE TESTS: WITH EMPHASIS ON FATTY LIVER AND NASH AS UNDERLYING DIAGNOSIS
SCREEN FOR XS ALCOHOL CONSUMPTION INTERVENE AND REVIEW
LFTs IMPROVED RE-EVALUATE CLINICAL RISK FACTORS CONSIDER BIOPSY AND FURTHER IMAGING SEE GUIDANCE NOTES
MONITOR
GUIDANCE NOTES
PREDICTIVE OF PATHOLOGY VS NORMAL: ALT > 2 x Normal AST: ALT >1 Age > 50 Low Platelet Count PREDICTORS OF NASH AND FIBROSIS IN PRESENCE OF NASH ALT > 2 x Normal AST > ALT Moderate Central Obesity BM1 > 28 NIDDM/Impaired GTT BP TGs. OTHER GROUPS WITH HIGH RISK PATHOLOGY: Raised Conjugated Bili with: ALT ALK P Consider: BX; MRCP; ERCP Any abnormality of ALK P in addition to abnormality ALT/AST Consider BX
SUGGESTED ROUTINE SEROLOGICAL INVESTIGATIONS: Alpha 1 AT; HAV; HBV; HCV; AIP and Igs; Fe Studies and HFE genotype; Caeruloplasmin; USS Fatty Change or Normal echo only; Bilirubin and haemolysis studies if appropriate - ANY ABNORMALITIES IN THESE PARAMETERS, RE-EVALUATE POTENTIAL DIAGNOSIS AND CONSIDER BIOPSY
N.B. THESE NOTES/ALGORITHMS ARE FOR GUIDANCE ONLY. THIS IS A MOVING FIELD AND DESPITE IMPROVEMENTS IN SEROLOGICAL AND RADIOLOGICAL TECHNIQUES, THERE REMAIN SMALL NUMBERS OF PATIENTS WHO HAVE SIGNIFICANT LIVER DISEASE WITH ONLY MILDLY ABNORMAL LFTs. THE ALGORITHM IS NO SUBSTITUTE FOR CAREFUL AND REPEATED CLINICAL EVALUATION AND CLINICAL VIGILANCE.