Approach to Abnormal Liver Function Tests

Sobha Koduru Sameer Gunukula Castro Bali Dr Ellen P Rich

Relevance of the topic

 

Abnormal LFTs are frequently detected as many routine screening test panels include LFTs. According to the American Gastroenterological Association (AGA), 1- 4 % of the asymptomatic 1population may have elevated serum liver chemistries. The clinical profile may range from asymptomatic to florid manifestations of liver disease. A diagnosis can be established noninvasively in a vast majority of patients. Source: AGA

Objectives


Familiarize with common liver function test abnormalities Identify the common patterns of liver function test abnormalities Discuss differential diagnoses and develop diagnostic approach based on the pretest probabilities.

CATEGORY

TEST AST(10 to 35 IU/L[ ) IU/L[ ALT(9 to 40 IU/L )

INFLAMMATION

CHOLESTASIS

ALP(30 to 120 IU/L) GGT(0 to 42 IU/L ) 5 NT( 2-16 IU/L) 2BILIRUBIN (0.21.2 mg/dL ) (0.2 ALBUMIN (3.5 to 5.3 g/dL ) PROTHROMBIN(INR)

SYNTHESIS AND METABOLISM

Approach
 History:- The most important part in
   

evaluation of a patient with abnormal LFTs Exposure to any chemicals Use of any medications The duration of abnormal LFTs The presence of accompanying symptoms e.g jaundice, arthralgia, Wt loss, fever, pruritus

Approach


Physical examination: - ?finding suggestive CLD

Patterns of abnormal LFTs



Chronic mild elevation of transaminases Isolated Hyperbilirubinemia Elevated alkaline phosphatase Simultaneous elevation of several LFTs

Case 1
A 65-year-old Caucasian woman is seen for a first visit. 65-yearIn her record, it is noted that she has had a history of hypertension and a 15-year history of diabetes mellitus 15without end-organ damage. This was initially controlled endwith oral agents; she is now on insulin. She also received a single unit of blood in Puerto Rico 25 years ago during an abdominal hysterectomy for a bleeding fibroid uterus. Her review of systems is unremarkable, and her examination is normal. She has a BMI of 32. Laboratory examination shows normal electrolytes, BUN, and creatinine. Glucose is 123 mg/dl (65-110). ALT (SGPT) (65is 109 IU/L (9-40) and AST (SGOT) is 83 (10-35). Alkaline (9(10phosphatase is 129 IU/L (43-122). Bilirubins are normal. (43-

Does it merit further testing ?

Patterns of abnormal LFTs

 Chronic

mild elevation of transaminases

Isolated Hyperbilirubinemia Elevated alkaline phosphatase Simultaneous elevation of several LFTs

Chronic mild elevation of transaminases



Defined as less than four times the upper limit of normal of one or both the aminotransferases for six months or greater duration.

Differential diagnoses to consider



         

Medications (Common causes include NSAIDS, antibiotics, statins, antiepileptic drugs, and antituberculous drugs) Alcohol abuse Hepatitis B, C Hereditary hemochromatosis Hepatic steatosis Muscle disorders Thyroid disease Celiac disease Autoimmune hepatitis Wilson disease Alpha 1 antitrypsin deficiency

 

Step 1 Review possible link to medications, herbal therapies or recreational drugs. An asymptomatic elevation of liver function tests does not necessitate the discontinuation of the medication; a risk-benefit assessment must first take place. riskScreen for alcohol abuse (AST/ALT ratio >2:1) Obtain serology for hepatitis B and C (HBsAg, HBsAb, HBcAb, HCV Ab) Evaluate for fatty liver (AST/ALT usually < 1, obtain a RUQ ultrasound) Hemochromatosis screening test being transferrin saturation (fasting serum iron/iron binding capacity over 45%). The frequency of heterozygotes is about 10% in Caucasian populations in the U.S and western Europe.

Diagnostic scheme

 

   

Step 2: Exclude muscle disorders (obtain creatinine kinase or aldolase) Obtain thyroid function tests Consider celiac disease (especially in patients with a h/o diarrhea or unexplained iron deficiency - serum antiendomysial IgA or anti tissue transglutaminase IgA antibodies are reasonable screening tests) Non hepatic causes of AST elevation Myocardial Infarction, severe arrythmias, severe angina, skeletal muscle necrosis and renal necrosis.




Step 3:- Consider less common causes of liver disease 3:Autoimmune hepatitis particularly in women and those with a history of other autoimmune disorders (check serum proteinelectrophoresis, obtain ANA and ASMA) Consider Wilson's disease in those <40yrs, Neuropsych symptoms, hemolysis (check serum ceruloplasmin, evaluate for Kayser Fleischer rings) Consider alpha-1-antitrypsin deficiency especially in patients alphawith a history of emphysema out of proportion to their age or smoking history (obtain alpha-1-antitrypsin level) alpha-

Step 4:- Observe if ALT and AST are less than two-fold 4:twoidentified by the above noninvasive testing.
elevated and no chronic liver condition has been If transaminases are persistently greater than twofold elevated consider a liver biopsy.

Case Discussion


Her transaminases are 2X the normal range, indicating that they likely represent a significant finding. It is noted that up to 30% of patients with hepatitis B and 10% of patients with hepatitis 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 includes


Given h/o Blood transfusion - viral hepatitis (primarily B and C) nonnon-alcoholic fatty liver disease (her risk factors include obesity and diabetes) Hemochromatosis

In this case, the patients hepatitis C antibody by ELISA is negative. hepatitis B surface antibody is negative. her surface antigen is positive. hepatitis B core antibody (IgG) positive. transferrin saturation is 25%. If this pt was immunocompromised, a PCR RNA should be performed despite a negative ELISA due to an inability to mount an antibody response. Her diagnosis is chronic hepatitis B, probably transmitted by the blood transfusion.

Practice 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: 0.11), ALT, AST, Alk.Phosph., T. protein, albumin are all normal.

Does it merit further testing? testing?

Patterns of abnormal LFTs



Chronic mild elevation of transaminases

 Isolated

Hyperbilirubinemia


Elevated alkaline phosphatase Simultaneous elevation of several LFTs

Isolated Hyperbilirubinemia
Elevation of bilirubin levels Occurs principally in two settings  Overproduction of bilirubin  Impaired uptake, conjugation, or excretion of bilirubin

Case discussion


   


D. bili= 0.1 indicating unconjugated hyperbilirubinemia. LDH, Haptoglobin, PBS was normal Retic count= Normal. Hemolytic disorders ruled out. DIAGNOSIS: Gilberts Syndrome.
up to 3-7% of adult population 3-

Practice Case
An 82-year-old woman is seen because she was 82-yearfound to have an elevated alkaline phosphatase during a physical at another physicians office. She is healthy, takes no medications, herbs, or vitamin supplements. Review of systems is negative. Her physical examination is completely unremarkable. Repeat LFTs show normal transaminases and bilirubins. Her alkaline phosphatase is 314 IU/L(43-122). IU/L(43Her GGT and calcium are normal.

Does it merit further testing ?

Patterns of abnormal LFTs



Chronic mild elevation of transaminases Isolated Hyperbilirubinemia

 Elevated

alkaline phosphatase

Simultaneous elevation of several LFTs

Isolated Alkaline phosphatase elevation



The main sources of alkaline phosphatase are the liver, bone, kidney, intestine, or placenta. First step in evaluation is to confirm the source of ALP whether liver or bone disease & consider physiologic causes.

Differential diagnoses to consider Physiological causes



 

Pregnancy( from placenta especially during third trimester) Normal childhood & teenager growth Physiologic post-prandrial increases postUp to 1.5-2X 1.5Repeat fasting The upper limit of normal may increase by 50% in post-menopausal women

Medications causing Alkaline Phosphatase

     

Hormones- anabolic steroids, estrogen,

methyltestosterone Antimicrobials- augmentin, erythromycin, flucloxacillin, TMP-SMX, Anti retroviral meds. TMPCardiovascular- captopril, diltiazem, quinidine Hyperglycemics- chlorpropamide, tolbutamide

Psychiatric- fluphenazine, imipramine. Others- allopurinol, carbamazepine

Hepatic origin
GGT 5 nucleotidase Alkaline 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

-

ALP

Chronic Cholestasis
Partial bile duct obstruction- RUQ pain obstructionPrimary biliary cirrhosis -Middle aged woman,Check total IgM level and AMA, Look for Xanthomas/ Xanthalasmas. Primary sclerosing cholangitis-70% of cases associated with cholangitisIBD, Male:Female 2:1, PANCA positive, 15% develop cholangiocarcinoma Primary HCC, metastasis - a/w systemic symptoms.


-

Infiltrative liver disease

Sarcoidosis Granulomatous diseases

 Bone

Origin: heat labile fraction (bone

burns) GGT normal Normal heat stable alkaline phosphatase fraction.

    

Hyperparathyroidism Pagets disease Metastatic bone tumor Osteogenic sarcoma Osteomalacia

Our case


Normal GGT indicates that this patients ALP does not come from liver. Intact parathyroid hormone was normal. Bone scan was performed which showed uptake on the iliac side of the right sacroiliac joint. Plain films of the pelvis showed changes consistent with Pagets 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.

Patterns of abnormal LFTs



Chronic mild elevation of transaminases Isolated Hyperbilirubinemia Elevated alkaline phosphatase

 Simultaneous

elevation of several LFTs

Simultaneous elevation of several LFTs

Differential diagnoses to consider Step 1: Identify if there is predominantly 1: hepatocellular process or predominantly cholestatic process.


Hepatocellular Predominant Pattern

AST & ALT elevations predominate  Alkaline Phosphatase & GGT nl to  Bilirubin normal in mild injury  Bilirubin high in severe injury - Viral hepatitis, Alcoholic or drug induced hepatitis, cirrhosis from any cause, autoautoimmune hepatitis, wilson disease.


VIRAL HEPATITIS


Patients with acute viral hepatitis and toxin related injury severe enough to produce jaundice typically have aminotransferases greater than 500 U/L with the ALT greater than or equal to the AST. Appropriate testing for suspected acute viral hepatitis includes a: Hepatitis A IgM antibody Hepatitis B surface antigen Hepatitis B core IgM antibody Hepatitis C viral RNA (hepatitis C antibody may take weeks to months to become detectable. )

VIRAL HEPATITIS
Chronic Active Hepatitis B
   

Persistent HBsAntigen > 6 months Liver enzymes >2x ULN Liver biopsy confirms active disease. HBSAg + ve, HBV DNA and HBeAg -ve suggests carrier state of hepatitis B which is a non-replicative state. nonThe presence of a carrier state does not explain elevated aminotransferases, and another cause needs to be sought.

Chronic Hepatitis C
    

HCV antibody +, With detectable HCV RNA Liver enzymes often normal to < 2X ULN 30% have persistently normal ALT and rarely progress. Genotype 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 Alcoholic Liver Disease (ALD)

 

AST more than twice ALT >90% predictive when AST 2X >ALT




The AST rarely exceeds 300 U/L

GGT disease >2X highly predictive of alcoholic liver

Poor prognosis factors for ALD

   

Total and direct Bilirubin Albumin PT Childs Pugh grade C, MELD score >10

NonNon-alcoholic Fatty Liver Disease (NAFLD) & NonNon-alcoholic Steatohepatitis (NASH)



Incidence with several known risk factors NASH more common in women Obesity Hyperlipidemia Type 2 diabetes Most common cause of AST & ALT <2x Elevation of AST & ALT usually <4x AST:ALT ratio usually < <1

Autoimmune Hepatitis


 

Presentation  Middle aged woman with autoimmune diseases  Female:Male 4:1 Diagnosis  Check ANA (28%), ASMA (40%), anti-LKM (Rare) anti Sensitivities above  80% will have hypergammaglobulinemia Prevalence is 1:6000-1:7000 1:6000Rapid response to corticosteroids NEJM  Relapse and remission is common

Wilsons Disease
Usually <40 years of age Neuropsychiatric history Hemolysis Dx: low serum ceruloplasmin, high urinary copper Kayser Fleischer rings (requires Slit lamp eye exam) Treatment: Chelation of excess copper Acute hepatic failure: Liver transplant Rare cause of acute fulminant hepatic failure

Cholestatic Predominant Pattern

   

Alkaline Phosphatase GGT Normal to minimal AST & ALT Bilirubin usually to Elevate

Intrahepatic causes vs. extrahepatic causes Check Right upper quadrant ultrasound  Ultrasound has Sens:85% Spec:90% for obstruction. Better than CT at identifying stones.  ERCP:- Gold standard for biliary imaging ERCP:


Invasive/Expensive

Sens: 95% Spec:99% for obstruction

Practice Case
A 40-year-old man is seen because of bloody diarrhea. He 40-yeardenies a history of hepatitis, alcohol intake, intravenous drug use, multiple sexual partners, or blood transfusion. His only medication at home is over-the-counter over-theibuprofen. On examination, he is anicteric. His abdomen is slightly distended with clinical evidence of ascites. His liver is not enlarged, and he has trace edema. Skin examination is significant for spider angiomata. Electrolytes, BUN, and creatinine are normal. Total bilirubin is 2.3 mg/dl with conjugated bilirubin of 1.5. Albumin is 3.1 grams/dl (3.2(3.25.1). Alkaline phosphatase is 393 IU/L (43-122) with a GGT (43of 182 U/l (8-78). Transaminases are normal. WBC is 9,700. (8hgb 8.2 grams/dl, MCV 74 fl (80-100) and platelet (80count 148K

Does it merit further testing ?

Case Discussion


This patient has bloody diarrhea with elevated LFTs which raises the possibility of chronic liver disease associated with chronic bowel disease. Elevated ALP and GGT is suggestive of an intrahepatic or extrahepatic cholestatic process. RUQ US was performed which was however normal. Serologies for hepatitis B and C showed no evidence of past or current infection. On occasion, extrahepatic causes of cholestasis may be missed by ultrasound. In cases where the suspicion for extrahepatic disease exists despite a normal ultrasound, additional studies (such as MR cholangiogram or ERCP) of the extrahepatic bile ducts are required.

Because of the clinical suspicion and negative ultrasound, further testing was pursued. ERCP showed sclerosing cholangitis without cholangiocarcinoma. Colonoscopy with biopsy revealed a pan-colitis panconsistent with severe ulcerative colitis. The final diagnosis, then, is sclerosing cholangitis associated with ulcerative colitis.

ALBUMIN
Not a reliable indicator of acute liver disease T1/2 = 19-21 days. 19 decrease : poor nutrition status, severe illness with protein catabolism, nephrosis, malabsorption, PLE, burns, heavy alcohol intake.


Correlates with prognosis in CLD

PROTHROMBIN TIME
Prolonged :  vitamin K deficiency (malnutrition, malabsorption, antibiotics)  massive transfusion  congenital disease  liver disease  warfarin  DIC
 

in vit K deficiency, vit K 10 mg SC decreases prolonged PT >30% within 24 hrs. The failure to correct with parenteral administration of vitamin K indicates severe hepatocellular injury.

When to consider Liver Biopsy

 

 

Definitive determination of nature/extent hepatic damage If elevated LFTs cannot be explained by other means proceed with Bx  Unexpected dx is seen in 10%  Biopsy changes management in 12% Can help with prognosis in known disease If elevation less than 2x ULN can observe alone.

Practice Cases

In 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.

References


American Gastroenterological Association. American Gastroenterological Association medical position statement: evaluation of liver chemistry tests. Gastroenterology 2002; 123:1364. Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in liverasymptomatic patients. N Engl J Med 2000; 342:1266. Ioannou GN, Boyko EJ, Lee SP. The prevalence and predictors of elevated serum aminotransferase activity in the United States in 1999-2002. Am J 1999Gastroenterol 2006; 101:76. Prati D, Taioli E, Zanella A, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med 2002; 137:1. Piton A, Poynard T, Imbert-Bismut F, et al. Factors associated with serum Imbertalanine transaminase activity in healthy subjects: consequences for the definition of normal values, for selection of blood donors, and for patients with chronic hepatitis C. MULTIVIRC Group. Hepatology 1998; 27:1213.

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

Differential includes Hepatitis A, B, & C serology Iron Studies (Fe, Ferritin, Iron saturation) Autoimmune/ANA Panel Celiac Sprue Panel Thyroid Functions Fasting Lipid Panel

Transaminases 5-10x ULN 5

n

Screen for alcohol use/abuse

NAFLD, Hemochromatosis, Infiltrative dz, ETOH, Chronic hepatitis, autoimmune disease

Transaminases >10x ULN

    

Viral hepatitis Drugs/Toxins/Ischemia (usually even higher) Budd Chiari Autoimmune hepatitis Wilsons Disease

MELD SCORE


    

serum bilirubin, serum creatinine, and bilirubin, creatinine, the international normalized ratio for prothrombin time (INR) to predict 3month survival. 40 or more 71.3% mortality 3039 52.6% mortality 30 2029 19.6% mortality 20 1019 6.0% mortality 10 <9 1.9% mortality

Course of Chronic Hepatitis C

Chronic indolent 10-30 year course 10 Overall low risk (20-30%) progression to endstage liver (20disease Morbidity & mortality related to cirrhosis 20-30% have progressive liver disease over 2010-20 years 10 2-4%/year risk of Hepatocellular Carcinoma (HCC) Risk increased by alcohol intake >50g/day

Patients Who Should be Considered for Chronic Hepatitis C treatment?

Viral Genotypes 2 & 3( less common 10%) statistically good response Genotype 1(more common 70-90%) with -risk factors 70 Need to reduce potential of transmission e.g. health care workers doing invasive procedures Those with increase risk of cirrhosis History long duration History of alcohol abuse Presence of fibrosis on liver biopsy Extra-hepatic manifestations/complications Extra Anticipated long life span.