ASSESEMENT OF ABNORMAL LIVER TESTS

Prof. Eli Zuckerman, M.D.

Liver Unit Haifa and Western Galilee District and Carmel Medical Center Clalit Health Services

Liver tests

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

CLINICAL ASSESSMENT OF ABNORMAL LIVER TESTS

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 damage (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 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 SEVERITY

Physical examination (I)

Peripheral signs of CLD (“stigmata”): •

spider angiomata

•

Dupuytren’s contracture

•

palmar erythema

•

testicular atrophy

•

gynecomastia

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 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 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 SEVERITY Case 1.

ALT (GPT) 1890 AST (GOT) 1750 LDH 880 ALP 180 GGT 170 bilirubin 1.0

albumin N P.T 1.4 (60%) globulin 4.3 CBC N

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Admission?



Differential diagnosis?

Acute hepatitis (ALT>10xULN)  Viral  Ischaemic  Toxins  Autoimmune  Acute Budd-Chiari   Early phase of acute obstruction Metastatic liver-diffuse (extremely rare)

Comments

* 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 enzymes

AST ALT



Diagnostic blood tests?

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 hepatitis

Lobular Hepatitis

Plasma 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

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Differential diagnosis?

CLINICAL ASSESSMENT OF ABNORMAL LIVER TESTS

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 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 features

 US sensitivity depends on hepatic fat content >30% fat, sensitivity 80%   10-19% fat, sensitivity 55% Morbid obesity – sensitivity 49%, specificity 75%

MANAGEMENT OF NAFLD • • TO BIOPSY OR NOT TO BIOPSY ?

WHOM TO BIOPSY ?

NASH - RISK FACTORS FOR FIBROSIS AND CIRRHOSIS 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 NAFLD  Weight reduction Diet + exercise * Pharmacological: orlistat,  Bariatric surgery * Insulin sensitizing agents thioglitazones * (pio-, rosi-)  Anti-oxidants metformin * Vit E, betain   Cytoprotective Ursodeoxicholic acid Lipid lowering agents HMG-CoA RI ’s ?

Fibrates ?

Surgery

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

Statins?

  

CBC N Cholesterol 277 (LDL-C 170) TG 304

After 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

FOR THE PHYSICIAN Continued treatment ALAT 3. Fulminant hepatitis 5 ULN 1 ULN 1. Adaptation 2. Chronic liver disease DRUG

CLINICAL

Black, Gastroenterology , 1975;69:289

0.1% Death 1% Jaundice INFRA CLINICAL Unfractionated heparin ALT > 10 ULN Isoniazid 30%

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Transaminases 15%

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Transaminases

Monreal, Eur J Clin Pharmacol 1989;37:415 Huang, Hepatology 2002;35:883-889

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 HBsAg + N Next step ?

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

    

HBsAg + HBeAg HBeAb + HBcAb + HDV -

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HBV DNA (PCR) + HBV DNA 2.8 X 10 4 IU/ml

New approaches to patient management strategy: HBV

HBV TREATMENT

 HBV DNA (viral load)  Elevated ALT  HBeAg status  Severity of liver disease

סיטיטפהB לופיטל םינוירטירק

Iu/mL 2,000 לעמ יפיגנ סמוע  ULN מ > ALT תמר  םייוניש וא סיזורביפל תודע םע היספויב םייתועמשמ םיירוטמלפניא ורקנ 

Liver biopsy Findings in Abnormal 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 LFTs Skelly 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 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 9% 7.6% 2.8% 1.9% 1.4% 1.1% 1.75% 1% 0.3% 0.31%

LIVER 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 ALT < 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 - 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 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

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Drug induced cholestatic liver injury (ACE-I, NSAIDs)

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Fatty liver (GGT-DM).

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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 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 TESTS 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 TESTS 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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CPK 23000

Liver tests