ASSESEMENT OF ABNORMAL LIVER TESTS

Prof. Eli Zuckerman, M.D.Liver Unit

Haifa and Western Galilee District and Carmel Medical CenterClalit Health Services

Liver testsLiver tests

ALT (GPT) AST (GOT) LDH ALP (alkaline phosphatase) GGT bilirubin albumin P.T (prothrombin time) globulin CBC

ALTAST, LDH

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)

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

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

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

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

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

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

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)

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

Admission?

Differential diagnosis?

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)

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%)

““Hit and Run” pattern of liver enzymesHit and Run” pattern of liver enzymes

AST

ALT

Diagnostic blood tests?

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)

IgG 2430 mg/ml anti-smooth muscle +++ ANA 1:160

Liver biopsy?

Interface hepatitisInterface hepatitis

Lobular HepatitisLobular Hepatitis

Plasma cell infiltrationPlasma cell infiltration

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

Differential diagnosis?

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.

Diagnostic blood tests?

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)

All diagnostic blood tests negative

except anti-smooth muscle Ab ±

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%

MANAGEMENT OF NAFLDMANAGEMENT OF NAFLD

•• TO BIOPSY OR NOT TO BIOPSYTO BIOPSY OR NOT TO BIOPSY ? ?

•• WHOM TO BIOPSY ? WHOM TO BIOPSY ?

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

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

HIT # 1

NAFLD-”simple” steatosis

NASH Fibrosis

NASH cirrhosis

Management?

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 ?

SurgerySurgery

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?

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

Continued treatment

ALAT

1 ULN

5 ULN

DRUG

3. Fulminant hepatitis

1. Adaptation

2. Chronic liver

disease

FOR THE PHYSICIAN

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

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 +

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 ?

Case 6. 28 y/o male, asymptomatic,,

HBsAg + HBeAg - HBeAb + HBcAb + HDV - HBV DNA (PCR) + HBV DNA 2.8 X 104 IU/ml

New approaches to patient New approaches to patient management strategy: HBVmanagement strategy: HBV

HBV TREATMENTHBV TREATMENT

HBV DNA (viral load)

Elevated ALT

HBeAg status

Severity of liver disease

BB הפטיטיסהפטיטיסלטיפול לטיפול קריטריונים קריטריונים

2,000עומס נגיפי מעל Iu/mL

רמתALT -מ < ULNאו ביופסיה עם עדות לפיברוזיס

שינויים נקרו-אינפלמטוריים משמעותיים

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

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

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%

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

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

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

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

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)

Case 6

• anti-mitochondrial Ab +,

IgM 330, IgG 1400 ANA +, anti-smooth muscle Ab -

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

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

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

Liver tests