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ASSESEMENT OF ABNORMAL LIVER TESTS
Prof. Eli Zuckerman, M.D.Liver Unit
Haifa and Western Galilee District and Carmel Medical CenterClalit Health Services
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Liver testsLiver tests
ALT (GPT) AST (GOT) LDH ALP (alkaline phosphatase) GGT bilirubin albumin P.T (prothrombin time) globulin CBC
ALTAST, LDH
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CLINICAL ASSESSMENT OF ABNORMAL LIVER CLINICAL ASSESSMENT OF ABNORMAL LIVER TESTSTESTS
Blood tests
• Acute/recent vs. chronic liver disease
• Hepatocellular vs. cholestatic injury
• Etiology of liver disease (ALD, viral…)
• Severity of liver disease (cirrhotic vs. non-cirrhotic)
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Markers of Hepatocellular damageMarkers of Hepatocellular damage(Transaminases)(Transaminases)
AST- liver, heart skeletal muscle, kidneys, brain, RBCs
In liver 20% activity is cytosolic and 80% mitochondrial Clearance performed by sinusoidal cells, half-life
17hrs
ALT – more specific to liver, v.low concentrations in kidney and skeletal muscles.
In liver totally cytosolic. Half-life 47hrs
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Gamma-GT – hepatocytes and biliary epithelial cells, pancreas, renal tubules and intestine
Very sensitive but Non-specific Raised in ANY liver disease 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 LFT’s become abnormal then investigate
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Markers of CholestasisMarkers of Cholestasis
ALP – liver and bone (placenta, kidneys, intestines)
Hepatic ALP present on surface of bile duct epithelia and accumulating bile salts increase its release from cell surface. Takes time for induction of enzyme levels so may not be first enzyme to rise and half-life is 1 week.
ALP isoenzymes, 5-NT or gamma GT may be necessary to evaluate the origin of ALP
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CLINICAL ASSESSMENT OF LIVER DISEASE CLINICAL ASSESSMENT OF LIVER DISEASE SEVERITYSEVERITY
Physical examination (I) Peripheral signs of CLD (“stigmata”):
• spider angiomata
• Dupuytren’s contracture
• palmar erythema
• testicular atrophy
• gynecomastia
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Physical examination (II)Physical examination (II)
Significant liver disease and/or portal HTN
• Enlarged Lt. Lobe
• Firm liver (fibrosis/cirrhosis)
• Abdominal collaterals (portal HTN)
• Splenomegaly (portal HTN)
• Ascites (high SAAG, portal HTN)
• Muscle wasting
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Bilirubin, Albumin and Prothrombin Bilirubin, Albumin and Prothrombin time (INR)time (INR)
Useful indicators of liver synthetic function
In primary care when associated with liver disease abnormalities should raise concern
Thrombocytopenia is a sensitive indicator of liver fibrosis
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Patterns of liver enzyme alterationPatterns of liver enzyme alteration
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)
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CLINICAL ASSESSMENT OF LIVER DISEASE CLINICAL ASSESSMENT OF LIVER DISEASE SEVERITYSEVERITY
Case 1.
ALT (GPT) 1890 AST (GOT) 1750LDH 880ALP 180 GGT 170bilirubin 1.0albumin N P.T 1.4 (60%)globulin 4.3 CBC N
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Admission?
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Differential diagnosis?
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Acute hepatitis (ALT>10xULN)Acute hepatitis (ALT>10xULN)
Viral Ischaemic Toxins Autoimmune Acute Budd-Chiari Early phase of acute obstruction Metastatic liver-diffuse (extremely rare)
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CommentsComments * Extremely high AST & LDH: ischemic, toxic (paracetamol, ecstasy)
* “Hit and run” pattern: (AST 17h, ALT 47h): ischemic, toxic, CBD stone
* Relatively preserved appetite: AIH, drug- induced
* Alcoholic hepatitis: AST/ALT >1 (92%) AST <300 (98%)
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““Hit and Run” pattern of liver enzymesHit and Run” pattern of liver enzymes
AST
ALT
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Diagnostic blood tests?
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Diagnostic tests: acute hepatitis Diagnostic tests: acute hepatitis
* HAV-IgM, HBsAg, HBc-IgM, HCV (± HCV RNA)
* Anti smooth muscle Ab, ANA, anti-LKM-1
* Ultrasound
* CMV-IgM, EBV-IgM
* Additional: toxic screen, Doppler US (hepatic
veins)
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IgG 2430 mg/ml anti-smooth muscle +++ ANA 1:160
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Liver biopsy?
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Interface hepatitisInterface hepatitis
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Lobular HepatitisLobular Hepatitis
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Plasma cell infiltrationPlasma cell infiltration
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Case 2. 28 y/o male, asymptomatic, BMI 27.7,
• ALT (GPT) 132
AST (GOT) 51 LDH 467 ALP 66 GGT 95 bilirubin 0.6 albumin 4.3 P.T 1.1 globulin N CBC N Cholesterol 277 (LDL-C 170) TG 304
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Differential diagnosis?
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CLINICAL ASSESSMENT OF ABNORMAL LIVER CLINICAL ASSESSMENT OF ABNORMAL LIVER TESTSTESTS
Case 2.• D.D
Fatty liver or NASH (non alcoholic steatohepatitis) (DM II, HLP, obesity, insulin resistance) Chronic viral hepatitis (HBV, HCV) Alcoholic liver disease (AST>ALT, MCV , GGT ) Autoimmune hepatitis (ANA, aSMA, LKM-1) Wison’s disease (age < 55) (hemochromatosis, A1AT) Drug induced liver injury Celiac disease, Addison.
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Diagnostic blood tests?
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Diagnostic tests case 2: asymptomatic Diagnostic tests case 2: asymptomatic abnormal LT (X2-5)abnormal LT (X2-5)
* Viral serology: HBsAg, HCV (± HCV RNA)
* Autoimmune screen: anti-smooth muscle Ab,
ANA, anti-LKM-1, (anti mitochondrial)
* Metabolic (age < 50): ceruloplasmin, ferritin,
transferin, iron, α1 anti-trypsin
* NAFLD: lipids, HbA1c, insulin resistance, glucose
* US
* Additional: celiac (anti-transglutaminase, endomysial)
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All diagnostic blood tests negative
except anti-smooth muscle Ab ±
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Imaging featuresImaging features
US sensitivity depends US sensitivity depends on hepatic fat content- on hepatic fat content- >30% fat, sensitivity >30% fat, sensitivity 80%80%
10-19% fat, sensitivity 10-19% fat, sensitivity 55%55%
Morbid obesity – Morbid obesity – sensitivity 49%, sensitivity 49%, specificity 75%specificity 75%
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MANAGEMENT OF NAFLDMANAGEMENT OF NAFLD
•• TO BIOPSY OR NOT TO BIOPSYTO BIOPSY OR NOT TO BIOPSY ? ?
•• WHOM TO BIOPSY ? WHOM TO BIOPSY ?
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NASH - RISK FACTORS FOR FIBROSIS AND NASH - RISK FACTORS FOR FIBROSIS AND
CIRRHOSISCIRRHOSIS
Independent risk factors in several studies: Age >45 ALT > 2x normal AST/ALT ratio > 1 Obesity, particularly truncal , BMI > 27 Type 2 diabetes Insulin Resistance Hyperlipdemia (trigycerides > X1.7)
NB: Studies are in selected groups; may not apply to all patients
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Case 3. 48 y/o male, asymptomatic, BMI 36
• ALT (GPT) 100
AST (GOT) 125 LDH 467 ALP 66 GGT 95 bilirubin 0.6 albumin 3.7 P.T 1.1 globulin 4.0 PLT 138000 Cholesterol 277 (LDL-C 170) TG 304
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HIT # 1
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NAFLD-”simple” steatosis
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NASH Fibrosis
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NASH cirrhosis
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Management?
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Treatment of NAFLDTreatment of NAFLD
Weight reduction Weight reduction Diet + exerciseDiet + exercise**
Pharmacological: orlistat, Pharmacological: orlistat,
Bariatric surgery Bariatric surgery ** Insulin sensitizing agentsInsulin sensitizing agents thioglitazones thioglitazones ** (pio-, rosi-) (pio-, rosi-)
metformin metformin ** Anti-oxidantsAnti-oxidants Vit E, betain Vit E, betain Cytoprotective Cytoprotective Ursodeoxicholic acidUrsodeoxicholic acid Lipid lowering agents Lipid lowering agents HMG-CoA RI’s ?HMG-CoA RI’s ?
Fibrates ?Fibrates ?
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SurgerySurgery
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Case 4. 61 y/o male, asymptomatic, BMI 27.7,
IHD (PTCA + stent RCA), HTN, US: “fatty liver”
• ALT (GPT) 87
AST (GOT) 51 ALP 66 GGT 95 bilirubin 0.6 albumin 4.3 P.T 1.1 globulin N CBC N Cholesterol 277 (LDL-C 170) TG 304
Statins?
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After 12 weeks of Rx with statinsAfter 12 weeks of Rx with statins • ALT (GPT) 220
AST (GOT) 110 ALP 100 GGT 95 bilirubin 1.0 albumin 4.3 Cholesterol 210 (LDL-C 123) TG 220
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Continued treatment
ALAT
1 ULN
5 ULN
DRUG
3. Fulminant hepatitis
1. Adaptation
2. Chronic liver
disease
FOR THE PHYSICIAN
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CLINICAL
INFRA-CLINICAL
15% Transaminases
1% Jaundice0.1% Death
30% Transaminases
Monreal, Eur J Clin Pharmacol1989;37:415
Unfractionatedheparin Isoniazid
Black, Gastroenterology , 1975;69:289
Huang, Hepatology2002;35:883-889
ALT > 10 ULN
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Case 5. 28 y/o male, asymptomatic, BMI 27,
• ALT (GPT) 132
AST (GOT) 51 LDH 467 ALP 66 GGT 95 bilirubin 0.6 albumin 4.3 P.T 1.1 globulin N CBC N Cholesterol 177 (LDL-C 108), TG 120 HCV +
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Case 6. 28 y/o male, asymptomatic, BMI 27,
• ALT (GPT) 98 AST (GOT) 51 LDH 467 ALP 66 GGT 95 bilirubin 0.6 albumin 4.3 P.T 1.1 globulin N CBC N HBsAg +
Next step ?
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Case 6. 28 y/o male, asymptomatic,,
HBsAg + HBeAg - HBeAb + HBcAb + HDV - HBV DNA (PCR) + HBV DNA 2.8 X 104 IU/ml
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New approaches to patient New approaches to patient management strategy: HBVmanagement strategy: HBV
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HBV TREATMENTHBV TREATMENT
HBV DNA (viral load)
Elevated ALT
HBeAg status
Severity of liver disease
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BB הפטיטיסהפטיטיסלטיפול לטיפול קריטריונים קריטריונים
2,000עומס נגיפי מעל Iu/mL
רמתALT -מ < ULNאו ביופסיה עם עדות לפיברוזיס
שינויים נקרו-אינפלמטוריים משמעותיים
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Liver biopsy Findings in Liver biopsy Findings in Abnormal LFTsAbnormal LFTs
Skelly et al: 354 Asymptomatic patients Transaminases persistently 2X normal No risk factors for liver disease Alcohol intake < 21 units/week Viral and autoimmune markers negative Iron studies normal
Skelly et al. J Hepatol 2001; 35: 195-294
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Liver biopsy Findings in Abnormal Liver biopsy Findings in Abnormal LFTs LFTs Skelly et al. J Hepatol 2001Skelly et al. J Hepatol 2001
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
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Other Liver biopsy Findings in Other Liver biopsy Findings in Abnormal LFTs Abnormal LFTs Skelly et al. J Hepatol 2001Skelly et al. J Hepatol 2001
Cryptogenic hepatitis 9% Drug induced 7.6% Alcoholic liver disease 2.8% Autoimmune hepatitis 1.9% PBC 1.4% PSC 1.1% Granulomatous disease 1.75% Haemochromatosis 1% Amyloid 0.3% Glycogen storage disease 0.31%
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LIVER BIOPSY FOR SERONEGATIVE ALT < 2X NORMALLIVER BIOPSY FOR SERONEGATIVE ALT < 2X NORMAL
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%, metabolic 2.1%, biliary 1.8%
Ryder et al BASL 2003
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LIVER BIOPSY FOR SERONEGATIVE LIVER BIOPSY FOR SERONEGATIVE ALT < 2X NORMALALT < 2X NORMAL
Of those with NAFLD: 56% had simple steatosis 44% inflammation and/or fibrosis
Risk of Severe Fibrotic Disease associated with:
BMI >27 Gamma GT > 2x normal
Ryder et al BASL 2003
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Abnormal LFTs - ConclusionsAbnormal LFTs - Conclusions
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
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CLINICAL ASSESSMENT OF ABNORMAL LIVER TESTSCLINICAL ASSESSMENT OF ABNORMAL LIVER TESTS
Case 7.
• ALT (GPT) 48 AST (GOT) 52 LDH 214 ALP 348 GGT 488 bilirubin 1.0 albumin N globulin 3.2 P.T 0.8 CBC N
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Case 7
• D.D ULTRASOUND (± CT): dilated vs. non- dilated ducts
PBC (anti-mitochondrial Ab, IgM) PSC (IBD-UC, ANCA, ERCP, MRCP) Infiltrative disease (neoplastic, amyloidosis ) Granulomatous disease (sarcoidosis, TB, Q fever) Granulomatous hepatitis Drug induced cholestatic liver injury (ACE-I, NSAIDs) Fatty liver (GGT-DM). Extra-hepatic obstruction (stones, neoplasm, stricture)
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Case 6
• anti-mitochondrial Ab +,
IgM 330, IgG 1400 ANA +, anti-smooth muscle Ab -
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CLINICAL ASSESSMENT OF ABNORMAL LIVER TESTSCLINICAL ASSESSMENT OF ABNORMAL LIVER TESTS
Case 8
• ALT (GPT) 24 AST (GOT) 37 LDH 214 ALP 100 GGT 112 bilirubin 1.0 albumin N globulin 3.2 P.T 0.8 CBC N
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CLINICAL ASSESSMENT OF ABNORMAL LIVER CLINICAL ASSESSMENT OF ABNORMAL LIVER TESTSTESTS
Case 8. (ICU) (IDU, susp ABE, sepsis, renal failure)
AST (GOT) 7800 ALT (GOT) 2500 LDH 8900 ALP 125 GGT 69 bilirubin 5.2 albumin 3.4 P.T 1.7 (40%) globulin N CBC 18,000
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CLINICAL ASSESSMENT OF ABNORMAL LIVER CLINICAL ASSESSMENT OF ABNORMAL LIVER TESTSTESTS
Case 8. (ICU) (IDU, susp ABE, sepsis, renal failure)
AST (GOT) 7800 ALT (GOT) 2500 LDH 8900 ALP 125 GGT 69 bilirubin 5.2 albumin 3.4 P.T 1.7 (40%) globulin N CBC 18,000
CPK 23000
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Liver tests