An Approach to Abnormal LFTs

Robert C. Lowe, M.D.Boston Medical Center

July 17, 2013

AST

ALT

ALP

T. BIL

ALB

INR

GGT

Chessboard

ALTASTT. BILALPALBGGT

Case 1

30 year old woman4 days of malaise, fevers to 101, nausea1 day of RUQ pain and jaundice

Exam - T 100.5Icteric sclerae and jaundiceTender hepatomegaly, no spleen tip

Case 1

AST 1535 WBC 8.1ALT 1602 HCT 41ALP 128 PLT 353T. Bil 7.3Albumin 3.9

Transaminases

AST - aspartate aminotransferase

ALT - alanine aminotransferase

Released when hepatocytes are injured - a sign of necrosis.

AST - less specific for liver disease Muscle (skeletal and cardiac) Kidney Erythrocytes

ALT - very little outside of liver. A better marker of liver disease.

Differential Diagnosis

Sky high transaminases > 15x normal

Differential Diagnosis

Sky high transaminases > 15x normal

Virus

Drug

Ischemia

} >80% of cases

AST/ALT>1000

Virus

Toxin

Ischemia

History and Exam Points

AST/ALT>1000

Virus

Toxin

Ischemia

History and Exam Points

IVDU ArthralgiasSexual partners UrticariaTravel Herpetic lesionsFood exposures Stigmata of liver dz

AST/ALT>1000

Virus

Toxin

Ischemia

History and Exam Points

IVDU ArthralgiasSexual partners UrticariaTravel Herpetic lesionsFood exposures Stigmata of liver dz

AST/ALT>1000

Virus

Toxin

Ischemia

History and Exam Points

IVDU ArthralgiasSexual partners UrticariaTravel Herpetic lesionsFood exposures Stigmata of liver dz

MedsOTC medsHerbs and supplements

AST/ALT>1000

Virus

Toxin

Ischemia

History and Exam Points

IVDU ArthralgiasSexual partners UrticariaTravel Herpetic lesionsFood exposures Stigmata of liver dz

MedsOTC medsHerbs and supplements

Recent surgeryHypotensionCardiac arrestCMP

AST/ALT>1000

AST/ALT>1000

Autoimmune

Wilson Disease

Bile DuctObstruction

Budd-Chiari

AST/ALT>1000

Autoimmune

Wilson Disease

Bile DuctObstruction

Budd-Chiari

Clinical Clues

Female gender

Personal or Family Hx of autoimmune dz

AST/ALT>1000

Autoimmune

Wilson’s Disease

Bile DuctObstruction

Budd-Chiari

Clinical Clues

Female gender

Personal or Family Hx of autoimmune dz

ANAASMAIg levels

AST/ALT>1000

Autoimmune

Wilson’s Disease

Bile DuctObstruction

Budd-Chiari

AST/ALT>1000

Autoimmune

Wilson’s Disease

Bile DuctObstruction

Budd-Chiari

Clinical Clues

Male gender

< age 40

Neuropsychiatric syndromePsychosisMovement disorder

AST/ALT>1000

Autoimmune

Wilson’s Disease

Bile DuctObstruction

Budd-Chiari

Clinical Clues

Male gender

< age 40

Neuropsychiatric syndromePsychosisMovement disorder

Low ALPHemolysisCeruloplasmin less useful in acute disease

KF Rings

Head CT

AST/ALT>1000

Autoimmune

Wilson Disease

Bile DuctObstruction

Budd-Chiari

AST/ALT>1000

Autoimmune

Wilson Disease

Bile DuctObstruction

Budd-Chiari

Clinical Clues

H/O biliary colic or GS diseaseFH of gallstones

RUQ painN/V

Transaminases fall rapidly - over 1-3 days

U/S often diagnostic, but may need further imaging with MRCP/ERCP

AST/ALT>1000

Autoimmune

Wilson Disease

Bile DuctObstruction

Budd-Chiari

AST/ALT>1000

Autoimmune

Wilson Disease

Bile DuctObstruction

Budd-Chiari

Clinical Clues

OCP usePrior venous thrombosisMyeloproliferative disorderMalignancy

Abdominal PainAscites

Laboratory Testing

• Hepatitis A - IgM and IgG• Hepatitis B - sAg, cAb, eAg, HBV DNA• Hepatitis C - RNA level• ANA, ASMA, Ig levels• RUQ U/S with Doppler Study

• Consider other viral serologies, ceruloplasmin, MRCP

Prognostic Features

Prognostic Features

• Coagulopathy– INR elevation

• Encephalopathy– Mental Status– Asterixis– Apraxia

Case 2

• Asymptomatic 45 year-old woman• Cholesterol 245, Trig 266• No significant FH• No meds• Works as an accountant

Case 2

AST 84 WBC 6.6ALT 46 HCT 37ALP 121 PLT 165T. Bil 0.8ALB 3.7

Alcoholic LFT Pattern

• AST/ALT > 2:1

• Absolute AST and ALT < 300

• GGT elevation is helpful, but nonspecific.

Alcoholic LFT Pattern

WHY?

ALT synthesis is decreased in EtOH hepatitis.

Partially due to pyridoxine deficiency - may correct with B6 therapy.

Case 2

AST 84 WBC 6.6ALT 46 HCT 37ALP 121 PLT 165T. Bil 0.8ALB 3.7

Case 2

AST 84 WBC 6.6ALT 89 HCT 37ALP 121 PLT 165T. Bil 0.8ALB 3.7

Mildly Elevated Transaminases

ABCDE

FGH

Mildly Elevated Transaminases

Alcohol / AutoimmuneB HepatitisC HepatitisDrugExotic

Wilson DiseaseAlpha-1-antitrypsin deficiency

Fatty liverGluten sensitive enteropathyHemochromatosis

Mildly Elevated Transaminases

Alcohol / AutoimmuneB Hepatitis C HepatitisDrugExotic

Wilson DiseaseAlpha-1-antitrypsin deficiency

Fatty liverGluten sensitive enteropathyHemochromatosis

Thyroid disease, myopathies

Mildly Elevated Transaminases

Alcohol / Autoimmune Alcohol HxB Hepatitis HBsAg, HBcAb, HBsAbC Hepatitis HCV AbDrug Drug HxExotic

Wilson DiseaseAlpha-1-antitrypsin deficiency

Fatty liver RUQ U/S, TGGluten sensitive enteropathyHemochromatosis

Thyroid disease, myopathies

Mildly Elevated Transaminases

Alcohol / Autoimmune ANA, ASMA, Ig levelsB Hepatitis HBsAg, HBcAb, HBsAbC Hepatitis HCV AbDrug Drug HxExotic

Wilson DiseaseAlpha-1-antitrypsin deficiency

Fatty liver RUQ U/S, TGGluten sensitive enteropathyHemochromatosis Fe, TIBC, Ferritin

Thyroid disease, myopathies

Mildly Elevated Transaminases

Alcohol / Autoimmune ANA, ASMA, Ig levelsB Hepatitis HBsAg, HBcAb, HBsAbC Hepatitis HCV AbDrug Drug HxExotic

Wilson Disease CeruloplasminAlpha-1-antitrypsin deficiency A-1-AT level

Fatty liver RUQ U/S, TGGluten sensitive enteropathyHemochromatosis Fe, TIBC, Ferritin

Thyroid disease, myopathies

Mildly Elevated Transaminases

Alcohol / Autoimmune ANA, ASMA, Ig levelsB Hepatitis HBsAg, HBcAb, HBsAbC Hepatitis HCV AbDrug Drug HxExotic

Wilson Disease CeruloplasminAlpha-1-antitrypsin deficiency A-1-AT level

Fatty liver RUQ U/S, TGGluten sensitive enteropathy Anti-TTGHemochromatosis Fe, TIBC, Ferritin

Thyroid disease, myopathies TSH, CK, Aldolase

Liver Biopsy

1124 pts referred for elevated ALT ---81 cases with negative serologic workup

Liver Biopsy

1124 pts referred for elevated ALT ---81 cases with negative serologic workup

Biopsies -- 41 pts with steatosis 26 pts with NASH

8% normal biopsies

Daniel, et al. Am J Gastro, 1999

Liver Biopsy

354 patients with elevated ALT and negative workup

Biopsies -- 32% with steatosis 34% with NASH 9% cryptogenic 7.6% Drug-induced 5.9% normal histology 2.8% ETOH

Granulomatous dz, PBC, PSC, hemochromatosis,amyloidosis, glycogen storage disease = 6.3%

In 18%, management was changed based on the pathology.

Skelly, et al. J Hepatol, 2001

66% with NAFLD

PAS with Diastase digestion

An Approach to Abnormal LFTs

Robert C. Lowe, M.D.Boston Medical Center

July 17, 2013

An Approach to Abnormal LFTsPart 2

Robert C. Lowe, M.D.Boston Medical Center

July 25, 2013

AST/ALT>1000

Virus

Toxin

Ischemia

AST/ALT>1000

Virus

Toxin

Ischemia

Autoimmune

Wilson’s Disease

Bile DuctObstruction

Budd-Chiari

Alcohol / AutoimmuneB Hepatitis C HepatitisDrugExotic

Wilson’s DiseaseAlpha-1-antitrypsin deficiency

Fatty liverGluten sensitive enteropathyHemochromatosis

Thyroid disease, myopathies

Case 3

35 year old womanMild fatigueNo significant PMHNo meds

Exam - cervical LAN 0.5 cm, nontender Liver 3 cm below RCM

Case 3

AST 42ALT 34ALP 442T. BIL 0.7Albumin 3.9INR 1.0

Case 3

AST 42ALT 34ALP 442T. BIL 0.7Albumin 3.9INR 1.0

GGT = 650

Alkaline Phosphatase

Produced in liver, bone, placenta, intestine.

Blood group O and B may release intestinal ALP after a fatty meal.

Elevations up to 2x normal are very nonspecific. Up to 1/3 have no disease.

Elevated ALP

Bone disease -- Paget’s Metastases

Myeloma

Use GGT or 5’NT to distinguish bone from liver.

GGT and 5’ NT

GGT - not found in bone, present in biliary epithelium.

Problems - induced by EtOH, anticonvulsants, warfarin, so specificity is a problem.

GGT/ALP > 2.5 suggests EtOH, but only 33% sensitive!

5’ Nucleotidase

More specific than GGT

Rises over several days after bile duct obstruction, slower than GGT.

Elevated ALP

Elevated ALP

Biliary obstruction Tumor masses - primary or metastaticDrug Effect

Elevated ALP

Special circumstances -

Malignancy without liver involvement -- tumors produce Regan isoenzyme of ALP (gonadal and urologic)

Hodgkin’s Disease and RCC - can cause nonspecific hepatitis with elevated ALP

Workup of ALP Elevation

1) Confirm liver origin with 5’-NT or GGT

Workup of ALP Elevation

1) Confirm liver origin with 5’-NT or GGT

2) U/S or CT to R/O mass and dilated ducts

Mass -- biopsyDilated ducts -- MRCP/ERCP

AST 42ALT 34ALP 442T. BIL 0.7Albumin 3.9INR 1.0

AST 42ALT 34ALP 442T. BIL 0.7Albumin 3.9INR 1.0

Pruritus for 4 months with no rash

AST 42ALT 34ALP 442T. BIL 0.7Albumin 3.9INR 1.0

Pruritus for 4 months with no rash

AMA = 1:2500

Primary Biliary Cirrhosis

• F:M = 8-9:1• Classic = fatigue, itching, elevated ALP• Common = asyx elevated ALP• NO jaundice until end-stage• AMA is diagnostic (95% positive)• Treat with ursodiol

AST 42ALT 34ALP 442T. BIL 0.7Albumin 3.9INR 1.0

AST 42ALT 34ALP 442T. BIL 0.7Albumin 3.9INR 1.0

AST 42ALT 34ALP 442T. BIL 0.7Albumin 3.9INR 1.0

Patient reveals a 12 year history of ulcerative colitis

Primary Sclerosing Cholangitis

• IBD in > 70% (typically UC)• MRCP makes diagnosis• pANCA (+) in the majority• Progression to cirrhosis – median

survival 10-12 yrs after Dx• Risk of cholangiocarcioma is 10-15%

AST 42ALT 34ALP 442T. BIL 0.7Albumin 3.9INR 1.0

AST 42ALT 34ALP 442T. BIL 0.7Albumin 3.9INR 1.0

Patient with Cr. 2.0 and significant proteinuria

Liver biopsyLiver biopsy

Liver biopsyLiver biopsy

AST 42ALT 34ALP 442T. BIL 0.7Albumin 3.9INR 1.0

AST 42ALT 34ALP 442T. BIL 0.7Albumin 3.9INR 1.0

41 M with advanced HIV – CD4 27

HIV Cholangiopathy

• Seen in advanced AIDS – CD4 <50• High ALP, mildly elevated bilirubin• Significant RUQ pain• Survival is 6-9 months – due to other

infections, wasting…

Case 3

35 year old womanMild fatigueNo significant PMHNo meds

Exam - cervical LAN 0.5 cm, nontender Liver 3 cm below RCM

Elevated ALP

Biliary obstruction Tumor masses - primary or metastaticDrug Effect

Elevated ALP

Biliary obstruction Tumor masses - primary or metastaticDrug Effect

PBC, PSCInfiltrative disease - amyloidGranulomatous diseases – sarcoid, TB, fungiAutoimmune variants

Workup of ALP Elevation1) Confirm liver origin with 5’-NT or GGT

2) Take a thorough drug history

3) U/S or CT to R/O mass and dilated ductsMass -- biopsyDilated ducts -- MRCP/ERCP

4) Neither -- check AMA, then biopsy liver.

Final Case

AST 175ALT 112ALP 163T. Bili 12.3INR 1.9ALB 3.0

An Approach to Abnormal LFTsPart 2

Robert C. Lowe, M.D.Boston Medical Center

July 25, 2013