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

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

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.

Bilirubin

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

Biliary Tract

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

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

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.

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.

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.

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)

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

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

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.

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.

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

Wilson’s Disease – Kayser-Fleisher Rings

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.

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

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.

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.

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

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

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

Cholangiogram of Primary Sclerosing Cholangitis

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

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

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

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

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

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

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

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.

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

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

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.

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.

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

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

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)