1. Michele Ritter Argy Resident – February, 2007
Abnormal LFTs
Michele Ritter
Argy Resident – February, 2007

2. Liver Function Test Albumin Bilirubin: Serum aminotransferases
Total Bilirubin
Direct Bilirubin (conjugated bilirubin)
Serum aminotransferases
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Alkaline Phosphatase
Prothrombin time

3. Albumin Synthesized in the liver
Production is controlled by multiple factors including nutritional status, serum oncotic pressure, cytokines, and hormones
A serum albumin may be reflection of the synthetic function of the liver.

4. Bilirubin

5. Bilirubin
Used to determine liver’s ability to clear endogenous/exogenous substances from the circulation
Indirect (unconjugated) bilirubin
Elevated with hemolysis, hepatic disease
Direct (conjugated) bilirubin
Elevated with biliary obstruction and hepatocellular disease.
Jaundice usually develops with a bilirubin ≥ 3 mg/dL

6. Biliary Tract

7. Aminotransferases
Hepatic enzymes that are usually intracellular, but are released from hepatocytes with hepatocellular injury.
Includes aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
AST/ALT ratio
Normal is 0.8
In alcoholic hepatitis, is usually > 2

8. Alkaline Phosphatase
A group of enzymes that catalyze the hydrolysis of a large number of organic phosphate esters.
In liver, believed to play an active role in down-regulating the secretory activities of the intrahepatic biliary epithelium
Found in:
Liver
Bone
intestine
First trimester placenta
Kidney
Gamma-glutamyl transpeptidase (GGT):
Liver origin: Elevated GGT
Bone origin: Normal GGT

9. Prothrombin Time (PT)
Liver is in charge of the synthesis of many clotting factors :
Factor I (fibrinogen)
Factor II (prothrombin)
Factor V
Factor VII
Factor IX
Factor X
Factors XII and XIII
Elevated PT may be reflection of decreased synthetic activity of liver.

11. Assessing the patient with abnormal Liver Function Tests
Most of the time, the cause of elevated LFTs can be illicited without invasive testing (biopsy)
If no cause of abnormality is found, most frequently the cause is alcohol liver disease, steatosis, or steatohepatitis
Certain patterns exist with LFTs
Hepatocellular Injury: Very high AST, ALT with mild/moderately elevated alkaline phosphatase.
Cholestatis: mild/moderately elevated AST/ALT with very high alkaline phosphatase
Bilirubin can be elevated with both combinations.

12. Hepatocellular Injury
Medications:
History: Need to assess temporal relationship with drug, see if patient improves once medication removed
NSAIDs, antibiotics, statins, anti-tuberculosis medications, anti-epileptic drugs, acetaminophen
Frequently cause isolated elevated aminotransferases
Acetaminophen overdose
Toxicity is likely to occur with single ingestions greater than 250 mg/kg or those greater than 12 g over a 24-hour period
AST/ALT elevations is first sign of liver damage (usually 24-hours after ingestion)
Alcohol Use:
Frequently have AST:ALT ratio ≥ 2:1
History: Need accurate assessment of alcohol intake, including CAGE questions.

13. Hepatocellular Injury
Hepatitis A:
Acute infection
History: travel, recent outbreak, MSM; nausea, vomiting, jaundice
Labs: Hepatitis A IgM, frequent elevated bilirubin
Hepatitis B:
Can be acute or chronic
History: See if patient from Asia, Subsaharan Africa; Sexual history, Drug use
Labs: Hepatitis B surface antigen, surface antibody, core antibody
Hepatitis C:
History: IV drug abuse, blood transfusion prior to 1992, Sexual history, Tattoos
Labs: Hepatitis C antibody (Hepatitis C viral load if HIV positive or immunocompromised)
HIV:
Often causes isolated elevated aminotransferases
History: Sexual History, IV drug use
Labs: HIV Antibody test (ELISA with reflex Western Blot)

14. Hepatocellular Injury
Hereditary Hemochromatosis
History: Family history of liver disease? Diabetes? Heart Failure? Bronze skin?
Labs:
Serum iron, TIBC
Calculate iron saturation = serum iron/TIBC
If iron saturation > 45%, check ferritin
Ferritin
If > 400 ng/mL in men, or > 300 ng/mL in women, then need to check liver biopsy or genetic testing
Liver biopsy
Homozygous hereditary hemochromatosis if iron index > 1.9
If under age 40, and positive genetic testing, no biopsy needed.
Genetic Testing

15. Hepatocellular Injury
Hepatic steatosis/Non-alcoholic steatohepatitis (NASH)
Increase in AST/ALT are usually less than 4-fold.
Ratio of AST/ALT is usually < 1
History: Female, obesity, diabetes
Labs:
Labs to rule out other causes of hepatitis
Abdominal Ultrasound: look for fatty infiltration of liver

16. Hepatocellular Injury
Autoimmune Hepatitis
History: Young to middle-aged female
Labs:
Serum protein electrophoresis (SPEP) – if polyclonal increase in gamma globulin
Anti-nucleur antibody: Positive
Anti-smooth-muscle antibody (SMA)
Liver biopsy: should be performed if the above are negative, but autoimmune hepatitis still suspected.

17. Hepatocellular Injury
Alpha-1-antitrypsin deficiency
History: Family history, emphysema, young age
Labs:
Alpha-1-antitrypsin level/phenotype
Treatment:
Intravenous alpha-1 antiprotease helps with lung disease, but liver transplant is ultimately only treatment for liver disease.

18. Hepatocellular Injury
Wilson’s Disease
A genetic disorder of biliary copper excretion
History: Age (usually age 5 – 25, but up to age 40), family history of liver disease; neuropsychiatric disease
Evaluation:
Serum ceruloplasmin: Low
Opthalmologist: Exam for Kayser-Fleisher rings
24-hour urine copper
Liver biopsy: Evaluate liver copper levels
Treatment:
Copper chelating agents
Zinc
In some cases, ultimately liver transplant

19. Wilson’s Disease – Kayser-Fleisher Rings

20. Hepatocellular Injury
Shock Liver (ischemic hepatitis)
Etiology: Shock, severe hypotension
Severely elevated AST/ALT (50 times normal)
Treatment: Re-establish good blood pressure/perfusion.
Prognosis: Usually patients recover, but can progress to fulminant liver failure requiring transplant.

21. Hepatocellular Injury
Non-Hepatic Causes
Usually only mild increase in AST/ALT
Muscle disorders
Hypothyroidism/Hyperthyroidism
Celiac Disease
Adrenal Insufficiency
Anorexia nervosa

22. Hepatocellular Injury
What if work-up is negative and AST/ALT remain elevated?
Observe:
Patients with two-fold or less increase in AST/ALT and no hyperbilirubinemia
Liver Biopsy
Patients with > two-fold increase in AST/ALT, or abnormalities of other liver function tests.

23. Cholestatic Pattern Predominantly elevated alkaline phosphatase
Need to check GGT to see if bone or liver in origin
Blood types O and B: can have elevated serum alkaline phosphatase after eating a fatty meal due to an influx of intestinal alkaline phosphatase
Need to determine if the cholestasis is intrahepatic or extrahepatic in origin.

24. Cholestatic Pattern - Intrahepatic
Drugs:
Anabolic steroids, contraceptives, antibiotics
Total parenteral nutrition (TPN)
Cirrhosis:
Viral hepatitis (Hepatitis B, C)
Alcohol hepatitis

25. Cholestatic Pattern - Intrahepatic
Primary Biliary Cirrhosis
Autoimmune disease
Predominately in women, usually ages 35-65
May have history of other autoimmune disease
Symptoms: Prurutis, fatigue, hyperpigmentation, musculoskeletal complaints
Labs:
RUQ Ultrasound
Anti-mitochondrial antibody
Liver biopsy to verify diagnosis

26. Cholestatic Pattern – Both Intrahepatic and Extrahepatic
Primary Sclerosing Cholangitis
chronic progressive disorder of unknown etiology that is characterized by inflammation, fibrosis, and stricturing of medium size and large ducts in the intrahepatic and extrahepatic biliary tree
~ 90% have inflammatory bowel disease, especially ulcerative colitis
Symptoms: Pruritus, fatigue, RUQ pain
Diagnosis:
Ultrasound
Cholangiogram: multifocal stricturing and dilation of intrahepatic and/or extrahepatic bile ducts
Prognosis:
Poor; average life expectancy after diagnosis is ~12 years
10-15% risk of developing cholangiocarcinoma
Liver transplant is ultimate only treatment

27. Cholangiogram of Primary Sclerosing Cholangitis

28. Cholestatic Pattern - Extrahepatic
Choledocholithiasis (gall stones!)
History:
The 3 F’s
RUQ colicky abdominal pain
Diagnosis/Treatment: Ultrasound, ERCP (to remove stones)
Malignancy
Cholangiocarcinoma
Pancreatic
Metastatic cancer
Diagnosis: Ultrasound, MRCP
Treatment: ERCP, biliary stent

29. Cholestatic Pattern - Extrahepatic
Chronic Pancreatitis
History: Recurrent pancreatitis
Symptoms: Abdominal pain, frequently referred to back
HIV Cholangiopathy
Usually seen in AIDS patients with CD4 count well below 100/mm3
Usually caused by: Cryptosporidium. Microsporidium, CMV
Symptoms: RUQ pain, Diarrhea, Occassional fever, Occassional jaundice
Diagnosis:
ERCP
Cholangiography – shows multifocal strictures of extrahepatic biliary tree

30. Isolated Hyperbilirubinemia
Unconjugated (indirect) hyperbilirubinemia
Overproduction of bilirubin
Hemolysis
Dubin-Johnson Syndrome and Rotor Syndrome
Decrease in uptake, conjugation, or excretion of bilirubin
Increased unconjugated (indirect) bilirubin
Liver Disease

31. Isolated Unconjugated Hyperbilirubinemia
Drugs
Probenecid, Rifampicin
Gilbert’s Disease
Autosomal recessive disorder
3 to 7 % of population
Most common in white males
Jaundice, increased unconjugated bilirubin (always < 6)
Occurs when patient under stress/infection
Crigler-Najjar type II
Caused by gene mutation
Reduced activity of Bilirubin UDP glucuronosyl

32. SUMMARY Hepatocellular Injury – mostly  AST/ALT Drugs
Alcohol hepatitis
Hepatitis A
Hepatitis B
Hepatitis C
Steatohepatitis (NASH)
Autoimmune hepatitis
Wilson’s Disease
Hereditary Hemochromatosis
Alpha-1 antitrypsin deficiency

33. SUMMARY Cholestatic Pattern EXTRAHEPATIC INTRAHEPATIC Gall stones
Primary Sclerosing Cholangitis
Malignancy
Chronic pancreatitis
HIV cholangiopathy
Cholestatic Pattern
INTRAHEPATIC
Drugs
Hepatitis A, B, C
Alcoholic hepatitis
TPN
Primary Sclerosing Cholangitis
Primary Biliary Cirrhosis

34. SUMMARY Isolated elevated indirect (unconjugated) bilirubin Hemolysis
Drugs
Gilbert’s Disease
Crigler-Najjar type II

35. Scenario # 1
A 43-year old woman who has consumed a pint of 80-proof whiskey daily for 18 years presents with right upper quadrant pain. The pain began approximately a week ago and has been transiently relieved by her taking two extra-strength acetaminophen tablets every 4 hours for the past 4 days. She has had some nausea and vomiting but no fever. There is no history of jaundice or cholelithiasis. The patient used intravenous drugs and shared needles during her late teen years.

36. Scenario # 1 Physical Exam Labs: Bilirubin: 2 mg/dL AST: 3800
Enlarged tender liver that percusses to 17 cm in the right midclavicular line and a tattoo on the right buttock
Labs:
Bilirubin: 2 mg/dL AST: 3800
Alk. Phos: 198
PT: normal

37. Scenario #1 The most likely diagnosis is: (A) Alcoholic hepatitis
(B) Acute cholecystitis
(C) Acetaminophen hepatotoxicity
(D) Acute viral hepatitis B
(E) Acute viral hepatitis C

38. Scenario # 2
A 54-year old asymptomatic man volunteers to donate blood and is found to have elevated aminotransferase levels. He has no known medical problems and no history of hepatitis. He drinks no alcohol, takes no medications, and has not seen a physician in more than 10 years. He is active, works as a truck driver, and has noted no change in his physical condition. He has no family history of liver disease.

39. Scenario # 2 Physical Exam: Labs: Liver biopsy:
Obesity – Ht: 5’ 10”, 115 kg
Labs:
AST: 45 ALT: 85 Alk. Phos: 90
Hepatitis serologies (A, B, C): negative
ESR: normal ANA: negative
Smooth muscle antibody: negatie
Total chol: 260 LDL; 225 Triglycerides: 830
Liver biopsy:
Large-droplet steatosis without significant inflammatory reaction and no fibrosis. Ultrasonography shows a mildly enlarged fatty liver.

40. Scenario # 2 The appropriate management of this patient would be:
Interferon therapy for presumed chronic non-B, non-C hepatitis
Alcohol rehabilitation and counseling
Weight loss and therapy for hyperlipidemia
Endoscopic retrograde cholangiopancreatography (ERCP) to evaluate the biliary tree
Corticosteroid therapy

41. Scenario # 3
A 43-year old woman complains of itching that keeps her awake at night. Physical examination is normal except for the liver, which is felt 7 cm below the right costal margin.
CBC is normal
Creatinine: 0.8 mg/dL, Bilirubin: 0.6 mg/dL
ALT: 78 U/L, Albumin: 4.2 g/dL
Alkaline Phosphatase: 450 U/L
Cholangiogram: normal

42. Scenario # 3
Which test would be most accurate in diagnosing her underlying disorder?
(A) Serum protein electrophoresis
(B) Anti-Smooth Muscle Antibody
(C) Antimitochondrial antibody
(D) Technetium-99m liver-spleen scan
(E) Endoscopic retrograde cholangiopancreatography (ERCP)