Download - Approach to Abnormal LFTs

Approach to Abnormal Approach to Abnormal Liver Function TestsLiver Function Tests

Sobha Sobha Koduru Koduru

Sameer Sameer Gunukula Gunukula

Castro Bali Castro Bali Dr Ellen P Dr Ellen P

RichRich

Relevance of the topicRelevance of the topic

Abnormal LFTs are frequently detected as many Abnormal LFTs are frequently detected as many routine screening test panels include LFTs.routine screening test panels include LFTs.

According to the American GastroenterologicalAccording to the American Gastroenterological Association (AGA), 1- 4 % of the asymptomatic Association (AGA), 1- 4 % of the asymptomatic

population may have elevated serum liver population may have elevated serum liver chemistries.chemistries.

The clinical profile may range from asymptomatic The clinical profile may range from asymptomatic to florid manifestations of liver disease.to florid manifestations of liver disease.

A diagnosis can be established noninvasively in A diagnosis can be established noninvasively in a vast majority of patients. a vast majority of patients.

Source: Source: AGAAGA

ObjectivesObjectives

Familiarize with common liver function Familiarize with common liver function testtest

abnormalitiesabnormalities

Identify the common patterns of liver Identify the common patterns of liver function test abnormalitiesfunction test abnormalities

Discuss differential diagnoses and Discuss differential diagnoses and develop diagnostic approach based on develop diagnostic approach based on the pretestthe pretest

probabilities.probabilities.

CATEGORYCATEGORY TESTTEST

INFLAMMATIONINFLAMMATION AST(10 to 35 IU/LAST(10 to 35 IU/L[[ ) )

ALT(9 to 40 IU/L )ALT(9 to 40 IU/L )

CHOLESTASISCHOLESTASIS ALP(30 to 120 IU/L) ALP(30 to 120 IU/L)

GGT(0 to 42 IU/L )GGT(0 to 42 IU/L )

5’ NT( 2-16 IU/L)5’ NT( 2-16 IU/L)

SYNTHESIS AND SYNTHESIS AND METABOLISMMETABOLISM

BILIRUBIN (0.2–1.2 BILIRUBIN (0.2–1.2 mg/dL )mg/dL )

ALBUMIN (3.5 to 5.3 ALBUMIN (3.5 to 5.3 g/dL )g/dL )

PROTHROMBIN(INR)PROTHROMBIN(INR)

Approach Approach

HistoryHistory:- The most important part in :- The most important part in evaluation of a patient with abnormal evaluation of a patient with abnormal LFTs LFTs

Exposure to any chemicalsExposure to any chemicals Use of any medications Use of any medications The duration of abnormal LFTsThe duration of abnormal LFTs The presence of accompanying The presence of accompanying

symptoms e.g jaundice, arthralgia, Wt symptoms e.g jaundice, arthralgia, Wt loss, fever, pruritusloss, fever, pruritus

ApproachApproach Physical examination:Physical examination:

- ?finding suggestive CLD- ?finding suggestive CLD

Patterns of abnormal LFTsPatterns of abnormal LFTs

Chronic mild elevation of Chronic mild elevation of transaminasestransaminases

Isolated HyperbilirubinemiaIsolated Hyperbilirubinemia

Elevated alkaline phosphataseElevated alkaline phosphatase

Simultaneous elevation of several Simultaneous elevation of several LFTsLFTs

Case 1Case 1A 65-year-old Caucasian woman is seen for a first visit.A 65-year-old Caucasian woman is seen for a first visit.In her record, it is noted that she has had a history ofIn her record, it is noted that she has had a history ofhypertension and a 15-year history of diabetes mellitushypertension and a 15-year history of diabetes mellituswithout end-organ damage. This was initially controlledwithout end-organ damage. This was initially controlledwith oral agents; she is now on insulin. She also received awith oral agents; she is now on insulin. She also received asingle unit of blood in Puerto Rico 25 years ago during ansingle unit of blood in Puerto Rico 25 years ago during anabdominal hysterectomy for a bleeding fibroid uterus. Herabdominal hysterectomy for a bleeding fibroid uterus. Herreview of systems is unremarkable, and her examination isreview of systems is unremarkable, and her examination isnormal. She has a BMI of 32.normal. She has a BMI of 32.Laboratory examination shows normal electrolytes, BUN,Laboratory examination shows normal electrolytes, BUN,and creatinine. Glucose is 123 mg/dl (65-110). ALT (SGPT)and creatinine. Glucose is 123 mg/dl (65-110). ALT (SGPT)is 109 IU/L (9-40) and AST (SGOT) is 83 (10-35). Alkalineis 109 IU/L (9-40) and AST (SGOT) is 83 (10-35). Alkalinephosphatase is 129 IU/L (43-122). Bilirubins are normal.phosphatase is 129 IU/L (43-122). Bilirubins are normal.

Does it merit further Does it merit further testing testing ??


Defined as less than four times the Defined as less than four times the upperupper

limit of normal of one or both the limit of normal of one or both the aminotransferases for six months or aminotransferases for six months or greater duration.greater duration.

Differential diagnoses to Differential diagnoses to considerconsider

Medications (Common causes include NSAIDS, Medications (Common causes include NSAIDS, antibiotics, statins, antiepileptic drugs, and antibiotics, statins, antiepileptic drugs, and antituberculous drugs)antituberculous drugs)

Alcohol abuseAlcohol abuse Hepatitis B, CHepatitis B, C Hereditary hemochromatosisHereditary hemochromatosis Hepatic steatosis Hepatic steatosis Muscle disordersMuscle disorders Thyroid diseaseThyroid disease Celiac diseaseCeliac disease Autoimmune hepatitisAutoimmune hepatitis Wilson diseaseWilson disease Alpha – 1 antitrypsin deficiencyAlpha – 1 antitrypsin deficiency

Diagnostic schemeDiagnostic scheme Step 1 Step 1 Review possible link to medications, herbal therapies Review possible link to medications, herbal therapies

or recreational drugs. An asymptomatic elevation of or recreational drugs. An asymptomatic elevation of liver function tests does not necessitate the liver function tests does not necessitate the discontinuation of the medication; a risk-benefit discontinuation of the medication; a risk-benefit assessment must first take place.assessment must first take place.

Screen for alcohol abuse (AST/ALT ratio >2:1)Screen for alcohol abuse (AST/ALT ratio >2:1) Obtain serology for hepatitis B and C (HBsAg, HBsAb, Obtain serology for hepatitis B and C (HBsAg, HBsAb,

HBcAb, HCV Ab)HBcAb, HCV Ab)

Evaluate for fatty liver (AST/ALT usually < 1, obtain a Evaluate for fatty liver (AST/ALT usually < 1, obtain a RUQ ultrasound)RUQ ultrasound)

Hemochromatosis screening test being transferrin Hemochromatosis screening test being transferrin saturation (fasting serum iron/iron binding capacity saturation (fasting serum iron/iron binding capacity over 45%). The frequency of heterozygotes is about over 45%). The frequency of heterozygotes is about 10% in Caucasian populations in the U.S and western 10% in Caucasian populations in the U.S and western Europe.Europe.

Step 2: -Step 2: - Exclude muscle disorders (obtain Exclude muscle disorders (obtain

creatinine kinase or aldolase) creatinine kinase or aldolase) Obtain thyroid function testsObtain thyroid function tests Consider celiac disease (especially in Consider celiac disease (especially in

patients with a h/o diarrhea or unexplained patients with a h/o diarrhea or unexplained iron deficiency - serum antiendomysial IgA iron deficiency - serum antiendomysial IgA or anti tissue transglutaminase IgA or anti tissue transglutaminase IgA antibodies are reasonable screening tests)antibodies are reasonable screening tests)

Non hepatic causes of AST elevation - Non hepatic causes of AST elevation - Myocardial Infarction, severe arrythmias, Myocardial Infarction, severe arrythmias, severe angina, skeletal muscle necrosis severe angina, skeletal muscle necrosis and renal necrosis.and renal necrosis.

Step 3:-Step 3:- Consider less common causes of liver Consider less common causes of liver disease disease

AAutoimmune hepatitis particularly in women and utoimmune hepatitis particularly in women and those with a history of other autoimmune disorders those with a history of other autoimmune disorders (check serum proteinelectrophoresis, obtain ANA (check serum proteinelectrophoresis, obtain ANA and ASMA) and ASMA)

Consider Wilson's disease in those <40yrs, Consider Wilson's disease in those <40yrs, Neuropsych symptoms, hemolysis (check serum Neuropsych symptoms, hemolysis (check serum ceruloplasmin, evaluate for Kayser Fleischer rings)ceruloplasmin, evaluate for Kayser Fleischer rings)

Consider alpha-1-antitrypsin deficiency especially in Consider alpha-1-antitrypsin deficiency especially in patients with a history of emphysema out of patients with a history of emphysema out of proportion to their age or smoking history (obtain proportion to their age or smoking history (obtain alpha-1-antitrypsin level)alpha-1-antitrypsin level)

Step 4:- Step 4:- Observe if ALT and AST are less than Observe if ALT and AST are less than two-fold elevated two-fold elevated and no chronic liver condition and no chronic liver condition has been identified by the above noninvasive has been identified by the above noninvasive testing. testing.

If transaminases are persistently greater than If transaminases are persistently greater than twofold elevated consider a liver biopsy.twofold elevated consider a liver biopsy.

Case DiscussionCase Discussion Her transaminases are 2X the normal range, Her transaminases are 2X the normal range,

indicating that they likely represent a indicating that they likely represent a significant finding.significant finding.

It is noted that up to 30% of patients with It is noted that up to 30% of patients with hepatitis B and 10% of patients with hepatitis hepatitis B and 10% of patients with hepatitis C have no acknowledged risk factor.C have no acknowledged risk factor.

so there should be a low threshold to order serologic testing for these infections (hepatitis B surface antigen, core antibody, surface antibody and hepatitis C ELISA for hep C antibody).

Differential includesDifferential includes

Given h/o Blood transfusion - viral Given h/o Blood transfusion - viral hepatitis (primarily B and C)hepatitis (primarily B and C)

non-alcoholic fatty liver disease (her non-alcoholic fatty liver disease (her risk factors include obesity and risk factors include obesity and diabetes)diabetes)

HemochromatosisHemochromatosis

In this case, the patient’s In this case, the patient’s

hepatitis C antibody by ELISA is negative. hepatitis C antibody by ELISA is negative.

hepatitis B surface antibody is negative.hepatitis B surface antibody is negative.

her surface antigen is positive.her surface antigen is positive.

hepatitis B core antibody (IgG) positive. hepatitis B core antibody (IgG) positive.

transferrin saturation is 25%.transferrin saturation is 25%. If this pt was immunocompromised, a PCR If this pt was immunocompromised, a PCR

RNA should be performed despite a RNA should be performed despite a negative ELISA due to an inability to negative ELISA due to an inability to mount an antibody response.mount an antibody response.

Her diagnosis is chronic hepatitis B, Her diagnosis is chronic hepatitis B, probably transmitted by the blood probably transmitted by the blood transfusion.transfusion.

Practice CasePractice Case 23 y.o caucasian, female, nurse-student, in

usual state of good health found to have mild conjunctival icterus while practicing physical exam skills. Only symptom is anorexia and nausea, that she usually gets during her menstruation.

Denies dark urine, alcohol abuse, drug abuse, h/o hepatitis. Not taking medications other than naproxen for her menstrual cramps. T. bili= 3.2 mg/dl (nl: 0.1-1), ALT, AST, Alk.Phosph., T. protein, albumin are all normal.

Does it merit further Does it merit further testingtesting??

Isolated Isolated HyperbilirubinemiaHyperbilirubinemia

Elevation of bilirubin levelsElevation of bilirubin levels

Occurs principally in two settingsOccurs principally in two settings Overproduction of bilirubinOverproduction of bilirubin Impaired uptake, conjugation, or Impaired uptake, conjugation, or

excretion of bilirubinexcretion of bilirubin

Case discussionCase discussion

D. bili= 0.1 indicating unconjugated hyperbilirubinemia.

LDH, Haptoglobin, PBS was normal Retic count= Normal. Hemolytic disorders ruled out. DIAGNOSIS: Gilbert’s Syndrome. up to 3-7% of adult populationup to 3-7% of adult population

Practice CasePractice Case

An 82-year-old woman is seen because she was An 82-year-old woman is seen because she was

found to have an elevated alkaline phosphatasefound to have an elevated alkaline phosphatase

during a physical at another physician’s office.during a physical at another physician’s office.

She is healthy, takes no medications, herbs, orShe is healthy, takes no medications, herbs, or

vitamin supplements. Review of systems is vitamin supplements. Review of systems is

negative. Her physical examination is negative. Her physical examination is completelycompletely

unremarkable. Repeat LFTs show normal unremarkable. Repeat LFTs show normal

transaminases and bilirubins. transaminases and bilirubins.

Her alkaline phosphatase is 314 IU/L(43-122). Her alkaline phosphatase is 314 IU/L(43-122).

Her GGT and calcium are normal.Her GGT and calcium are normal.




Elevated alkaline Elevated alkaline phosphatasephosphatase

Simultaneous elevation of several LFTsSimultaneous elevation of several LFTs

Isolated Alkaline Isolated Alkaline phosphatasephosphatase

elevationelevation The main sources of alkaline The main sources of alkaline

phosphatase are the liver, bone, phosphatase are the liver, bone, kidney, intestine, or placenta.kidney, intestine, or placenta.

First step in evaluation is to confirm First step in evaluation is to confirm the source of ALP whether liver or the source of ALP whether liver or bone disease & consider physiologic bone disease & consider physiologic causes.causes.

Differential diagnoses to Differential diagnoses to consider consider

Physiological causesPhysiological causes Pregnancy( from placenta especially Pregnancy( from placenta especially

during third trimester)during third trimester) Normal childhood & teenager growthNormal childhood & teenager growth Physiologic post-prandrial increasesPhysiologic post-prandrial increases

– –Up to 1.5-2XUp to 1.5-2X

– –Repeat fastingRepeat fasting The upper limit of normal may increase

by 50% in post-menopausal women

MedicationsMedications causing causing ↑Alkaline Phosphatase↑Alkaline Phosphatase

HormonesHormones- anabolic steroids, estrogen, - anabolic steroids, estrogen, methyltestosteronemethyltestosterone

AntimicrobialsAntimicrobials- augmentin, erythromycin, - augmentin, erythromycin, flucloxacillin, TMP-SMX, Anti retroviral meds.flucloxacillin, TMP-SMX, Anti retroviral meds.

CardiovascularCardiovascular- captopril, diltiazem, - captopril, diltiazem, quinidinequinidine

HyperglycemicsHyperglycemics- chlorpropamide, - chlorpropamide, tolbutamidetolbutamide

PsychiatricPsychiatric- fluphenazine, imipramine.- fluphenazine, imipramine. OthersOthers- allopurinol, carbamazepine- allopurinol, carbamazepine

Hepatic originHepatic origin

– ↑– ↑GGTGGT

– ↑– ↑5’ nucleotidase5’ nucleotidase

– ↑– ↑Alkaline phophatase heat stable isoenzymeAlkaline phophatase heat stable isoenzyme

Gel electrophoresis (isoenzyme determination) and heat separation methods are available for this purpose. However, simple measurement of a GGTP or 5-nucleotidase is quicker and less

expensive and parallel the rise in liver ALP.

Hepatic causes of ↑ ALPHepatic causes of ↑ ALP Chronic CholestasisChronic Cholestasis- Partial bile duct obstruction- RUQ painPartial bile duct obstruction- RUQ pain- Primary biliary cirrhosis -Middle aged Primary biliary cirrhosis -Middle aged

woman,Check total IgM level and AMA, Look for woman,Check total IgM level and AMA, Look for Xanthomas/ Xanthalasmas.Xanthomas/ Xanthalasmas.

- Primary sclerosing cholangitis-70% of cases Primary sclerosing cholangitis-70% of cases associated with IBD, Male:Female 2:1, PANCA associated with IBD, Male:Female 2:1, PANCA positive, 15% develop cholangiocarcinomapositive, 15% develop cholangiocarcinoma

- Primary HCC, metastasis - a/w systemic Primary HCC, metastasis - a/w systemic symptoms.symptoms.

Infiltrative liver diseaseInfiltrative liver disease- SarcoidosisSarcoidosis- Granulomatous diseasesGranulomatous diseases

Bone OriginBone Origin: heat labile fraction : heat labile fraction (bone burns)(bone burns)

– –GGT normalGGT normal

– –Normal heat stable alkaline Normal heat stable alkaline phosphatase fraction.phosphatase fraction.

HyperparathyroidismHyperparathyroidism Paget’s diseasePaget’s disease Metastatic bone tumorMetastatic bone tumor Osteogenic sarcomaOsteogenic sarcoma OsteomalaciaOsteomalacia

Our caseOur case

Normal GGT indicates that this patient’s Normal GGT indicates that this patient’s ALP does not come from liver.ALP does not come from liver.

Intact parathyroid hormone was normal. Intact parathyroid hormone was normal.

Bone scan was performed which showed Bone scan was performed which showed uptake on the iliac side of the right uptake on the iliac side of the right sacroiliac joint. sacroiliac joint.

Plain films of the pelvis showed changes Plain films of the pelvis showed changes consistent with Paget’s disease of bone.consistent with Paget’s disease of bone.

Isolated or Predominant GGT Elevation

Causes include alcohol use, anticonvulsant medications, and

warfarin. Age, gender, BMI, and smoking status can also influence GGT levels.

However, an isolated GGTP elevation should distinctly raise the suspicion of alcoholic liver disease.

Alcohol avoidance for 2 to 3 months and follow-up GGTP testing is a reasonable approach in the absence of other evidence of liver disease.





Simultaneous elevation of Simultaneous elevation of several LFTsseveral LFTs

Simultaneous elevation of Simultaneous elevation of several LFTsseveral LFTs

Differential diagnoses to considerDifferential diagnoses to consider

Step 1Step 1: Identify if there is : Identify if there is predominantlypredominantly

hepatocellular process or hepatocellular process or predominantlypredominantly

cholestatic process.cholestatic process.

Hepatocellular Hepatocellular Predominant PatternPredominant Pattern

↑↑ ↑↑ AST & ALT elevations predominateAST & ALT elevations predominate Alkaline Phosphatase & GGT nl to ↑Alkaline Phosphatase & GGT nl to ↑ Bilirubin normal in mild injury Bilirubin normal in mild injury Bilirubin high in severe injuryBilirubin high in severe injury

- Viral hepatitis, Alcoholic or drug induced - Viral hepatitis, Alcoholic or drug induced hepatitis, cirrhosis from any cause, auto- hepatitis, cirrhosis from any cause, autoimmune hepatitis, wilson disease.immune hepatitis, wilson disease.

VIRAL HEPATITISVIRAL HEPATITIS Patients with acute viral hepatitis and toxin Patients with acute viral hepatitis and toxin

related injury severe enough to produce jaundice related injury severe enough to produce jaundice typically have aminotransferasestypically have aminotransferasesgreater than 500 U/L with the ALT greater than or greater than 500 U/L with the ALT greater than or equal to the AST. equal to the AST.

Appropriate testing for suspected acute viral Appropriate testing for suspected acute viral hepatitishepatitisincludes a:includes a:

Hepatitis A IgM antibodyHepatitis A IgM antibodyHepatitis B surface antigenHepatitis B surface antigenHepatitis B core IgM antibodyHepatitis B core IgM antibodyHepatitis C viral RNA (hepatitis C antibody may Hepatitis C viral RNA (hepatitis C antibody may take weeks totake weeks tomonths to become detectable. )months to become detectable. )

VIRAL HEPATITISVIRAL HEPATITISChronic Active Hepatitis BChronic Active Hepatitis B

Persistent HBsAntigen > 6 monthsPersistent HBsAntigen > 6 months

Liver enzymes >2x ULNLiver enzymes >2x ULN

Liver biopsy confirms active disease.Liver biopsy confirms active disease.

HBSAg + ve, HBV DNA and HBeAg -ve HBSAg + ve, HBV DNA and HBeAg -ve suggests carrier state of hepatitis B which is a suggests carrier state of hepatitis B which is a non-replicative state. non-replicative state.

The presence of a carrier state does not explain The presence of a carrier state does not explain elevated aminotransferases, and another cause elevated aminotransferases, and another cause needs to be sought. needs to be sought.

Chronic Hepatitis CChronic Hepatitis C HCV antibody +, With detectable HCV RNAHCV antibody +, With detectable HCV RNA

Liver enzymes often normal to < 2X ULNLiver enzymes often normal to < 2X ULN

30% have persistently normal ALT and rarely 30% have persistently normal ALT and rarely progress.progress.

Genotype important in treatment and prognosisGenotype important in treatment and prognosis

About 16% of patients with hepatitis C may have normal liver tests despite having histological damage. So a liver biopsy would be accurate to demonstrate underlying histological abnormalities than liver tests.

Laboratory Clues to Laboratory Clues to Alcoholic Alcoholic

Liver Disease (ALD)Liver Disease (ALD) ↑↑↑↑AST more than twice ↑ALTAST more than twice ↑ALT >90% predictive when AST 2X >ALT>90% predictive when AST 2X >ALT The AST rarely exceeds 300 U/L The AST rarely exceeds 300 U/L GGT ↑↑ >2X highly predictive of alcoholic liver GGT ↑↑ >2X highly predictive of alcoholic liver disease disease

Poor prognosis factors for ALDPoor prognosis factors for ALD ↑↑↑↑Total and direct BilirubinTotal and direct Bilirubin ↓↓ ↓↓ Albumin Albumin ↑↑ ↑↑ PT PT Child’s Pugh grade C, MELD score >10Child’s Pugh grade C, MELD score >10

Non-alcoholic Fatty Liver Disease Non-alcoholic Fatty Liver Disease (NAFLD) & (NAFLD) &

Non-alcoholic Steatohepatitis Non-alcoholic Steatohepatitis (NASH)(NASH)

↑↑ ↑↑ Incidence with several known risk Incidence with several known risk factorsfactors

– – NASH more common in womenNASH more common in women – – ObesityObesity – – HyperlipidemiaHyperlipidemia – – Type 2 diabetesType 2 diabetes Most common cause of ↑AST & ALT <2x Most common cause of ↑AST & ALT <2x – – Elevation of AST & ALT usually <4xElevation of AST & ALT usually <4x – – AST:ALT ratio usually <AST:ALT ratio usually <1

Autoimmune HepatitisAutoimmune Hepatitis PresentationPresentation

Middle aged woman with autoimmune Middle aged woman with autoimmune diseasesdiseases

Female:Male 4:1Female:Male 4:1 DiagnosisDiagnosis

Check ANA (28%), ASMA (40%), anti-LKM Check ANA (28%), ASMA (40%), anti-LKM (Rare)(Rare)Sensitivities aboveSensitivities above

80% will have hypergammaglobulinemia80% will have hypergammaglobulinemia Prevalence is 1:6000-1:7000Prevalence is 1:6000-1:7000 Rapid response to corticosteroidsRapid response to corticosteroids

Relapse and remission is commonRelapse and remission is common NEJM

Wilson’s DiseaseWilson’s Disease• • Usually <40 years of ageUsually <40 years of age• • Neuropsychiatric historyNeuropsychiatric history• • HemolysisHemolysis• • Dx: low serum ceruloplasmin, high Dx: low serum ceruloplasmin, high

urinary copper urinary copper • • Kayser Fleischer rings (requires Slit Kayser Fleischer rings (requires Slit

lamp eye exam) lamp eye exam) • • Treatment: Chelation of excess copper Treatment: Chelation of excess copper • • Acute hepatic failure: Liver transplantAcute hepatic failure: Liver transplant• • Rare cause of acute fulminant hepatic Rare cause of acute fulminant hepatic

failure failure

Cholestatic Predominant Cholestatic Predominant PatternPattern

↑↑ ↑↑ Alkaline PhosphataseAlkaline Phosphatase ↑↑ ↑↑ GGT GGT Normal to minimal ↑ AST & ALTNormal to minimal ↑ AST & ALT Bilirubin usually ↑ to ↑↑ ElevateBilirubin usually ↑ to ↑↑ Elevate

Intrahepatic causes vs. extrahepatic Intrahepatic causes vs. extrahepatic causescauses

Check Right upper quadrant Check Right upper quadrant ultrasoundultrasound

Ultrasound has Sens:85% Spec:90% Ultrasound has Sens:85% Spec:90% for obstruction. Better than CT at for obstruction. Better than CT at identifying stones.identifying stones.

ERCP:- Gold standard for biliary ERCP:- Gold standard for biliary imagingimaging Invasive/ExpensiveInvasive/Expensive

Sens: 95% Spec:99% for obstructionSens: 95% Spec:99% for obstruction

Practice CasePractice CaseA 40-year-old man is seen because of bloody diarrhea. HeA 40-year-old man is seen because of bloody diarrhea. Hedenies a history of hepatitis, alcohol intake, intravenousdenies a history of hepatitis, alcohol intake, intravenousdrug use, multiple sexual partners, or blood transfusion.drug use, multiple sexual partners, or blood transfusion.His only medication at home is over-the-counterHis only medication at home is over-the-counteribuprofen. On examination, he is anicteric. His abdomen isibuprofen. On examination, he is anicteric. His abdomen isslightly distended with clinical evidence of ascites. His slightly distended with clinical evidence of ascites. His

liverliveris not enlarged, and he has trace edema. Skin examinationis not enlarged, and he has trace edema. Skin examinationis significant for spider angiomata. Electrolytes, BUN, andis significant for spider angiomata. Electrolytes, BUN, andcreatinine are normal. Total bilirubin is 2.3 mg/dl withcreatinine are normal. Total bilirubin is 2.3 mg/dl withconjugated bilirubin of 1.5. Albumin is 3.1 grams/dl (3.2-conjugated bilirubin of 1.5. Albumin is 3.1 grams/dl (3.2-5.1). Alkaline phosphatase is 393 IU/L (43-122) with a GGT5.1). Alkaline phosphatase is 393 IU/L (43-122) with a GGTof 182 U/l (8-78). Transaminases are normal. WBC is 9,700.of 182 U/l (8-78). Transaminases are normal. WBC is 9,700.hgb 8.2 grams/dl, MCV 74 fl (80-100) and platelethgb 8.2 grams/dl, MCV 74 fl (80-100) and plateletcount 148Kcount 148K

Case DiscussionCase Discussion This patient has bloody diarrhea with elevated This patient has bloody diarrhea with elevated

LFTs which raises the possibility of chronic LFTs which raises the possibility of chronic liver disease associated with chronic bowel liver disease associated with chronic bowel disease.disease.

Elevated ALP and GGT is suggestive of an Elevated ALP and GGT is suggestive of an intrahepatic or extrahepatic cholestatic intrahepatic or extrahepatic cholestatic process. RUQ US was performed which was process. RUQ US was performed which was however normal. Serologies for hepatitis B and however normal. Serologies for hepatitis B and C showed no evidence of past or current C showed no evidence of past or current infection. infection.

On occasion, extrahepatic causes of cholestasis On occasion, extrahepatic causes of cholestasis may be missed by ultrasound. In cases where may be missed by ultrasound. In cases where the suspicion for extrahepatic disease exists the suspicion for extrahepatic disease exists despite a normal ultrasound, additional studies despite a normal ultrasound, additional studies (such as MR cholangiogram or ERCP) of the (such as MR cholangiogram or ERCP) of the extrahepatic bile ducts are required.extrahepatic bile ducts are required.

Because of the clinical suspicion and Because of the clinical suspicion and negative ultrasound, further testing was negative ultrasound, further testing was pursued. pursued.

ERCP showed sclerosing cholangitis ERCP showed sclerosing cholangitis without cholangiocarcinoma. without cholangiocarcinoma.

Colonoscopy with biopsy revealed a pan-Colonoscopy with biopsy revealed a pan-colitis consistent with severe ulcerative colitis consistent with severe ulcerative colitis. colitis.

The final diagnosis, then, is The final diagnosis, then, is sclerosing sclerosing cholangitis associated with ulcerative cholangitis associated with ulcerative colitis. colitis.

ALBUMINALBUMIN

• Not a reliable indicator of acute liver Not a reliable indicator of acute liver disease T1/2 = 19-21 days.disease T1/2 = 19-21 days.

decrease : poor nutrition status, decrease : poor nutrition status, severe illness with protein severe illness with protein catabolism, nephrosis, catabolism, nephrosis, malabsorption, PLE, burns, heavy malabsorption, PLE, burns, heavy alcohol intake.alcohol intake.

Correlates with prognosis in CLDCorrelates with prognosis in CLD

PROTHROMBIN TIMEPROTHROMBIN TIME Prolonged : Prolonged :

vitamin K deficiency (malnutrition, malabsorption, vitamin K deficiency (malnutrition, malabsorption, antibiotics)antibiotics)

massive transfusion massive transfusion congenital disease congenital disease liver diseaseliver disease warfarin warfarin DICDIC

in vit K deficiency, vit K 10 mg SC decreases in vit K deficiency, vit K 10 mg SC decreases prolonged PT >30% within 24 hrs. prolonged PT >30% within 24 hrs.

The failure to correct with parenteral administration The failure to correct with parenteral administration of vitamin K indicates severe hepatocellular injury.of vitamin K indicates severe hepatocellular injury.

When to consider Liver When to consider Liver BiopsyBiopsy

Definitive determination of Definitive determination of nature/extent hepatic damagenature/extent hepatic damage

If elevated LFTs cannot be explained by If elevated LFTs cannot be explained by other means proceed with Bxother means proceed with Bx Unexpected dx is seen in 10%Unexpected dx is seen in 10% Biopsy changes management in 12%Biopsy changes management in 12%

Can help with prognosis in known Can help with prognosis in known diseasedisease

If elevation less than 2x ULN can If elevation less than 2x ULN can observe alone.observe alone.

Practice CasesPractice Cases

In conclusionIn conclusion

Based on diagnostic clues obtained during clinical evaluation (detailed history, physical examination, a review of all abnormally elevated LFTs, and other diagnostic data), an individualized diagnostic approach should be formulated.

It is important to focus on the duration, fluctuation, ratio, severity, and peak in LFT abnormalities and its relationship to exposure to potential hepatotoxic agents.

A selective diagnostic approach is cost effective and prudent in asymptomatic outpatients with abnormal LFTs.

ReferencesReferences American Gastroenterological Association. American GastroenteroloAmerican Gastroenterological Association. American Gastroenterolo

gical Association medical position statement: evaluation of liver chegical Association medical position statement: evaluation of liver chemistry tests. Gastroenterology 2002; 123:1364.mistry tests. Gastroenterology 2002; 123:1364.

Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results iPratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N n asymptomatic patients. N EnglEngl J Med 2000; 342:1266. J Med 2000; 342:1266.

IoannouIoannou GN, GN, BoykoBoyko EJ, Lee SP. The prevalence and predictors of elevated serum EJ, Lee SP. The prevalence and predictors of elevated serum aminotransferaseaminotransferase activity in the United States in 1999-2002. Am J activity in the United States in 1999-2002. Am J GastroenterolGastroenterol 2006; 101:76. 2006; 101:76.

PratiPrati D, D, TaioliTaioli E, E, ZanellaZanella A, et al. Updated definitions of healthy ranges for serum A, et al. Updated definitions of healthy ranges for serum alaninealanine aminotransferaseaminotransferase levels. Ann Intern Med 2002; 137:1. levels. Ann Intern Med 2002; 137:1.

Piton A, Piton A, PoynardPoynard T, T, Imbert-BismutImbert-Bismut F, et al. Factors associated with serum F, et al. Factors associated with serum alaninealanine transaminasetransaminase activity in healthy subjects: consequences for the definition of norm activity in healthy subjects: consequences for the definition of normal values, for selection of blood donors, and for patients with chronical values, for selection of blood donors, and for patients with chronic hepatitis C. MULTIVIRC Group. hepatitis C. MULTIVIRC Group. HepatologyHepatology 1998; 27:1213. 1998; 27:1213.

Elevated AST & ALT <2-5x Elevated AST & ALT <2-5x NormalNormal

Differential includesDifferential includes • • Hepatitis A, B, & C serologyHepatitis A, B, & C serology • • Iron Studies (Fe, Ferritin, Iron Iron Studies (Fe, Ferritin, Iron

saturation)saturation) • • Autoimmune/ANA PanelAutoimmune/ANA Panel • • Celiac Sprue PanelCeliac Sprue Panel • • Thyroid FunctionsThyroid Functions • • Fasting Lipid PanelFasting Lipid Panel

Transaminases 5-10x ULNTransaminases 5-10x ULN

• • Screen for alcohol use/abuseScreen for alcohol use/abusen NAFLD, Hemochromatosis, Infiltrative dz, ETOH, NAFLD, Hemochromatosis, Infiltrative dz, ETOH,

Chronic hepatitis, autoimmune diseaseChronic hepatitis, autoimmune disease

Transaminases >10x ULNTransaminases >10x ULN

Viral hepatitisViral hepatitis Drugs/Toxins/Ischemia (usually even higher)Drugs/Toxins/Ischemia (usually even higher) Budd ChiariBudd Chiari Autoimmune hepatitisAutoimmune hepatitis Wilson’s DiseaseWilson’s Disease

MELD SCORE MELD SCORE

serum serum bilirubinbilirubin, serum , serum creatininecreatinine, and , and the the international normalized ratio for international normalized ratio for prothrombinprothrombin time (INR) time (INR) to predict to predict 3month survival. 3month survival.

40 or more — 71.3% mortality40 or more — 71.3% mortality 30–39 — 52.6% mortality30–39 — 52.6% mortality 20–29 — 19.6% mortality20–29 — 19.6% mortality 10–19 — 6.0% mortality10–19 — 6.0% mortality <9 — 1.9% mortality<9 — 1.9% mortality

Course of Chronic Hepatitis Course of Chronic Hepatitis CC

• • Chronic indolent 10-30 year course Chronic indolent 10-30 year course • • Overall low risk (20-30%) progression to Overall low risk (20-30%) progression to

endstage liver diseaseendstage liver disease• • Morbidity & mortality related to cirrhosisMorbidity & mortality related to cirrhosis– – 20-30% have progressive liver disease 20-30% have progressive liver disease

over over 10-20 years10-20 years– – 2-4%/year risk of Hepatocellular 2-4%/year risk of Hepatocellular

Carcinoma Carcinoma (HCC)(HCC)– – Risk increased by alcohol intake >50g/dayRisk increased by alcohol intake >50g/day

Patients Who Should be Patients Who Should be Considered Considered

for Chronic Hepatitis C for Chronic Hepatitis C treatment?treatment?

• • Viral Genotypes 2 & 3( less common 10%) Viral Genotypes 2 & 3( less common 10%) statistically good responsestatistically good response

• • Genotype 1(more common 70-90%) with -risk Genotype 1(more common 70-90%) with -risk factorsfactors

• • Need to reduce potential of transmissionNeed to reduce potential of transmission– – e.g. health care workers doing invasive e.g. health care workers doing invasive

proceduresprocedures• • Those with increase risk of cirrhosisThose with increase risk of cirrhosis– – History long durationHistory long duration– – History of alcohol abuseHistory of alcohol abuse– – Presence of fibrosis on liver biopsyPresence of fibrosis on liver biopsy• • Extra-hepatic manifestations/complicationsExtra-hepatic manifestations/complications• • Anticipated long life span.Anticipated long life span.